EP1907372A1 - Substituted cyclohexyl derivatives as nk-3 receptor antagonists - Google Patents

Substituted cyclohexyl derivatives as nk-3 receptor antagonists

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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Withdrawn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
German (de)
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/en
Withdrawn legal-status Critical Current

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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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Abstract

The present invention relates to the compounds of formula (I): wherein A,B, n, X, Y, Z, R1, R2, R3, R4, R5, R6, R7 and R8 are defined herein, and pharmaceutically acceptable salts thereof, 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.

Description

Substituted cvclohexyl derivatives as NK-3 receptor antagonists
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.
Background information on 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).
Substituted cyclohexyl derivatives are known in the art. For instance, 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. However, neither document discloses that 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):
wherein: rings A and B are independently aryl or heteroaryl; n is 0, 1 or 2;
X and Y are independently selected from a bond, -CH2-, and -N(Ci-4alkyl)-; Z is a bond, -CH2- or R1 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, hydroxy, Ci-6alkoxy, halogen,
CN, CO2(Ci-6alkyl) or C(CH3)2OH, optionally substituted by 1 to 8 halogen atoms;
R2 is hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or halogen; R3 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, hydroxy, Ci-6alkoxy, halogen or CN, optionally substituted by 1 to 8 halogen atoms; R4 is hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or halogen;
R5 and R6 are independently selected from hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3- scycloalkyl, hydroxy, Ci-6alkoxy or halogen; R7 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (CH2)0-2aryl, (CH2)0- 2heteroaryl 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
R8 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl or C3-8cycloalkyl; or R7 and R8, 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_6alkyl, C2- 6alkenyl, C2-6alkynyl or C3-8CyClOaIlCyI, hydroxy, oxo, (CH2)0-3Ci-6alkoxy, (CH2)o_3Oaryl, (CH2)o_3aryl, (CH2)o_3heteroaryl, (CH2)0-3Het, or (CH2)0-3NRaRb , wherein said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from Ci-6alkyl, hydroxy, oxo, Ci-6alkoxy or halogen, which Ci-6alkyl being optionally substituted by hydroxy or 1 to 5 halogen atoms, and where said aryl, heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains 1, 2 or 3 heteroatoms selected from N, O or S and which ring is optionally substituted by hydroxy, oxo, or halogen, and which heterocycle may optionally be fused to heteroaryl, which heteroaryl is optionally substituted by Ci-6alkyl or trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5- or 10-membered mono- or bi-cyclic ring system optionally containing 1, 2 or 3 heteroatoms selected from N, O and S, and further optionally containing 1, 2 or 3 double bonds and also optionally substituted by 1 to 3 groups independently selected from Ci-6alkyl, hydroxy, oxo, phenyl and SO2Ci-6alkyl;
Ra is hydrogen, Ci-6alkyl, C(O)Ci-6alkyl, C(O)OCi-6alkyl, C(O)NH(Ci-6alkyl), (CH2)0-3aryl, (CH2)o-3heteroaryl or SO2Ci-6alkyl, optionally substituted by Ci-6alkyl;
Rb is hydrogen, Ci-6alkyl or aryl; and pharmaceutically acceptable salts thereof.
In one embodiment, ring A is phenyl, pyridyl or pyrimidyl. Preferably, ring A is phenyl or pyridyl.
In another embodiment, ring B is aryl or pyridyl. Preferably, ring B is phenyl.
In another embodiment, n is 1 or 2. Preferably, n is 2. In another embodiment, X is a bond, -CH2- or Preferably, X is a bond or -
CH2-. More preferably, X is a bond.
In another embodiment, Y is a bond, -CH2- or Preferably, Y is a bond or - CH2-. More preferably, Y is a bond.
In another embodiment, Z is a bond or -CH2-. Preferably, Z is a bond. In another embodiment, R1 is hydrogen, Ci-6alkyl; hydroxy, Ci-6alkoxy, halogen, CN, CO2(Ci-
4alkyl) or C(CH3)2OH, optionally substituted by 1 to 5 halogen atoms. Preferably, R1 is hydrogen, Ci- 4alkyl, Ci-4alkoxy, halogen, CN, CO2CH3 or C(CH3)2OH, optionally substituted by 1 to 3 halogen atoms. More preferably, R1 is hydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy, CN, CO2CH3 or C(CH3)2OH.
In another embodiment, R2 is hydrogen or Ci-6alkyl. Preferably, R2 is hydrogen or methyl. More preferably, R2 is hydrogen. In another embodiment, R3 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. Preferably, R3 is hydrogen, Ci-4alkyl, Ci-4alkoxy, halogen or CN, optionally substituted by 1 to 3 halogen atoms. More preferably, R3 is hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN.
In another embodiment, R4 is hydrogen or halogen. Preferably, R4 is hydrogen, fluorine or chlorine.
In another embodiment, R5 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, or halogen. Preferably, R5 is hydrogen, methyl, hydroxy, methoxy or fluorine. More preferably, R5 is hydrogen, hydroxy or fluorine. Most preferably, R5 is hydrogen.
In another embodiment, R6 is hydrogen or Ci-6alkyl. Preferably, R6 is hydrogen or methyl. More preferably, R6 is hydrogen.
In another embodiment, R7 is hydrogen, Ci-6alkyl, (CH2)o-2aryl, or Het, optionally substituted by or heteroaryl, which heteroaryl is optionally substituted by 1 or 2 methyl or ethyl groups. Preferably, R7 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, R7 is hydrogen, A- methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl.
In another embodiment, R8 is hydrogen or Ci-6alkyl. Preferably, R8 is hydrogen or methyl. More preferably, R8 is hydrogen.
In another embodiment, R7 and R8, 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, CH2-O-phenyl, phenyl, heteroaryl, CH2heteroaryl, Het, NH2, (CH2)0-iNHRa or CH2N(phenyl)SO2CH3, where said aryl, heteroaryl, and Het are optionally substituted by 1, 2 or 3 groups selected from oxo or halogen, which Ci-4alkyl 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-4alkoxy, and which heterocycle may optionally be fused to pyridyl or triazolyl, optionally substituted by trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5-membered monocyclic or a 8- or 9-membered bicyclic ring system, optionally containing 1 or 2 N atoms, further optionally containing 2 or 3 double bonds and also optionally substituted by oxo, phenyl, or and Ra is as hereinbefore defined. Preferably, R7 and R8, 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, NH2,
and which ring is optionally fused to 3-trifluoromethylpyridyl or 1,2,4-triazolyl, and which ring is further optionally spiro-fused to
where • indicates the spiro-centre.
In one embodiment of the present invention, there is provided the compound of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein ring A, n, X, Y, R1, R3, R4, R7 and R8 are as defined in relation to formula (I).
Preferably, ring A is phenyl or pyridyl.
Preferably, n is 1 or 2. More preferably, n is 2.
Preferably, X is a bond or -CH2-. More preferably, X is a bond. Preferably, Y is a bond or -CH2-. More preferably, Y is a bond.
Preferably, R1 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, halogen, CN, or C(CH3)2OH, optionally substituted by 1 to 5 halogen atoms. More preferably, R1 is hydrogen, Ci-4alkyl, halogen, CN, CO2CH3 or C(CH3)2OH, optionally substituted by 1 to 3 halogen atoms. Most preferably, R1 is hydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy, CN, CO2CH3 or C(CH3)2OH.
Preferably, R3 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. More preferably, R3 is hydrogen, Ci-4alkyl, halogen or CN, optionally substituted by 1 to 3 halogen atoms. Most preferably, R3 is hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN. Preferably, R4 is hydrogen or halogen. More preferably, R4 is hydrogen, fluorine or chlorine. Preferably, R7 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, R7 is hydrogen, 4-methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl. Preferably, R8 is hydrogen.
In an alternative preference, R7 and R8, 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, CH2heteroaryl, Het, NH2, (CH2)0-iNHRa or CH2N(phenyl)SO2CH3, where said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3 groups selected from Ci-4alkyl, oxo, halogen, which Ci-4alkyl 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-4alkoxy, and which heterocycle may optionally be fused to pyridyl or triazolyl, optionally substituted by trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5- membered monocyclic or a 8- or 9- membered bicyclic ring system, optionally containing 1 or 2 N atoms, further optionally containing 2 or 3 double bonds and also optionally substituted by Ci-4alkyl, oxo, phenyl or SO2Ci-4alkyl; and where Ra is as defined in relation to formula (I).
More preferably, R7 and R8, 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, CH2 -O-phenyl, NH2,
N /
and further optionally fused to 3-trifluoromethylpyridyl or 1,2,4— triazolyl, and further optionally spiro-fused to
where • indicates the spiro-centre.
In one preferred embodiment of the present invention, there is provided the compound of formula (Iaa):
or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are as defined in relation to formula (I), and R9 is (CH2)o-3NRaRb, where Ra and Rb are as defined in relation to formula (I), or (CH2)o-3heteroaryl or (CH2)o-3Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from Ci-6alkyl, hydroxy, oxo, Ci-6alkoxy or halogen, which Ci-6alkyl 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-4alkyl, hydroxy or
Preferably, R1 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, halogen, CN, or C(CH3)2OH, optionally substituted by 1 to 5 halogen atoms. More preferably, R1 is hydrogen, methyl, trifluoromethyl, trifluoromethoxy, chlorine, CN, CO2CH3 or C(CH3)2OH.
Preferably, R3 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms. More preferably, R3 is methyl, trifluoromethyl, trifluoromethoxy, CN, fluorine, chlorine or bromine.
Preferably, R9 is (CH2)0-iNRaRb, where Ra and Rb 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-4alkyl 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. Examples of suitable R9 groups include:
In another preferred embodiment of the present invention, there is provided the compound of formula (lab):
or a pharmaceutically acceptable salt thereof, wherein R3 is as defined in relation to formula (I) and R9 is as defined in relation to formula (Iaa).
Preferably, R3 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy or halogen. More preferably, R3 is hydrogen or halogen. Most preferably, R3 is fluorine, chlorine or bromine.
Preferably, R9 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. Examples of suitable R9 groups include:
The independent syntheses of any optical isomers or their chromatographic separations may be achieved as known in the art. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
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. As used herein, the term "Ci-6alkyl" 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-6alkoxy" and "d-4alkoxy". The term "C2-6alkenyl" 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).
The term "C2-6alkynyl" 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).
The term "C3-8cycloalkyl" means a cyclic alkane ring having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to phenyl and naphthyl. The term "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.
The term "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.
The terms "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.
These compounds and those defined by the immediately preceding definitions are useful in therapy, particularly as NK-3 antagonists.
The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
The term "subject," (alternatively referred to herein as "patient") as used herein 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. The term "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, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the present invention, 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, N5N1- dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
Also, in the case of an alcohol group being present, pharmaceutically acceptable 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. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical 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. In general, 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. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "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. These 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. For example, 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.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 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 monooleate. 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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, 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. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) The pharmaceutical composition and method 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. In the treatment or prevention of conditions which require NK-3 receptor modulation 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. Preferably, 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. For oral administration, 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.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Thus there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
Likewise there is provided the use of a compound of formula (I) for the manufacture of a medicament for treating a neurokinin-3 mediated disease.
There is also disclosed 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. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from 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 such as Alzheimer's disease); post-traumatic stress disorder; attention deficit hyperactive disorder (ADHD); cognitive impairment (e.g. the treatment of impairment of cognitive functions 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 (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy); disorders of eating behaviours (including anorexia nervosa and bulimia nervosa); neurodegenerative diseases (such as Alzheimer's disease, ALS, motor neuron disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic-induced
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 neuralgia and trigeminal neuralgia; sympathetically maintained pain and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis; reflex sympathetic dystrophy such as shoulder/hand syndrome), acute pain (e.g. 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-eclampsia and stroke. Preferably, 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 IC50 of less than lμM and preferably less than 10OnM.
Details of the 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. solution (EFDS) is added and the factory is maintained for 10 min at room temperature. The cells are dislodged and the suspension poured into 500ml centrifuge bottles. The process is repeated with 200ml EFDS and the mixtures pooled giving 6 bottles in all, which are spun in a centrifuge for 10 min at 2200 rpm.
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.
40ml cold Tris with inhibitors is used to resuspend and combine the pellets which are again spun as above. The supernatants are again transferred to Sorvall tubes which, with those above, are spun at 18000 rpm for 20 min.
The supernatants are discarded and the pellets resuspended in a Storage Buffer consisting of 2.50ml IM Tris pH7.4, 50μl 100Ox protease inhibitors (4mg/ml leupeptin (Sigmo), 40mg/ml Bacitracin (Sigma) and 1OmM phosphoranidon (Peninsula) all dissolved in water) plus 0.5ml 0.5M MnCl2 made up to 50ml with H2Od<j. A 10ml syringe is used with 20-, 23- and 25-gauge needles sequentially.
A Bradford protein assay in conducted on 2-10μl aliquots with BSA as standard before 500- lOOOμl aliquots are snap-frozen in liquid nitrogen for storage at -8O0C. The membrane binding assay is carried out as follows. The amount of membranes needed to specifically bind < 10% of 125I-NeurokinB is predetermined. The frozen stocks are then diluted to allow addition in 50μl.
The test compounds are dissolved in DMSO. An automated apparatus (Tecan) is programmed to add 5μl of compound or DMSO, approximately 100,000 cpm of isotope in 20μl buffer which is prepared from 50μMTris, pH7.5, 150μM NaCl, bovine serum albumin to 0.02%, and protease inhibitors as in the storage buffer, made up as 0.5M stock, and 175μl assay buffer (as the storage buffer but containing 5μM MnCl2 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 50μl of cell membranes. The tubes are incubated with shaking for Ih at r.t. and filtered on a Tomtec 96 well cell harvester using Mach III filtermats (Tomtec) or using either a Packard 96-well harvester or Tomtec 9600 using Unifilter GF/C (Packard), presoaked in 0.25% polyethyleneimine and washed five times with IX wash buffer (O.lM.Tris, pH7.4 and IM NaCl, IX = 100ml of 1OX stock per litre of cold distilled water). If using Unifilter plates, 60μl Microscint 20 (Packard) is added to each well and the plate is then heat-sealed before counting in a Packard Topcount. Alternatively the filters from the filtermat are placed in 75xl00mm plastic tubes and counted on a Cobra gamma counter.
For the assay, typically lOμg of membrane is used at 25,000 cpm which is filtered over a Unifilter GF/C presoaked in 0.5% BSA.
Compounds of the present invention may be prepared by methods disclosed in the documents hereinbefore referred to and by methods known in the art of organic synthesis and the Schemes set forth below.
According to a general process (A), 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):
(H) (HI) where A, B, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in relation to formula (I). The reaction is conveniently preformed in the presence of a hydride source, such as a sodium triacetoxyborohydride, and a mild acid, such as acetic acid, in a suitable solvent, such as 1,2- dichloroethane. Where they are not commercially available, the starting materials of formulae (II) and (III) may be prepared by methods illustrated in the following Schemes, by methods analogous to those described in the accompanying Descriptions and Examples, or by standard methods well known from the art. For example, compounds of formula (II) can be made from known compounds using procedures analogous to those found in published International applications WO 2002/081435, WO 2004/031137 and WO 2004/031139 (all Merck Sharp & Dohme Limited).
It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
For instance, a compound of formula (I) where R4 is bromine may be transformed into a compound of formula (I) where R4 is hydrogen by hydrogenation using, for example, a palladium on carbon catalyst and hydrogen gas, in a suitable solvent, such as ethyl acetate.
In addition, a compound of formula (I) where R7 is methoxybenzyl may be transformed into a compound of formula (I) where R7 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.
Also, a compound of formula (Iaa) where R9 is a BOC-protected amine, may be transformed to a compound of formula (Iaa) where R9 is an amine by treatment with acid, such as hydrochloric acid, in a suitable solvent, such as 1,4-dioxane. The resultant compound of formula (Iaa) may be transformed into a compound of formula (Iaa) whereR9 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.
General synthetic schemes:
Scheme 1
Cfe & Trans
Reagents: i) Et3N, CH2Cl2; ϋ) mCPBA, CH2Cl2; iii) 2,2-bis(2-iodoethyl)-l,3-dioxolane, NaH, DMF; iv)pTsOH, AcOH, H2O, 50 °C; v) R7R8NH, NaBH(OAc)3, AcOH, 1,2-dichloroethane; vi) separate isomers
Scheme 2
Reagents: i) MeMgBr, THF, -78 °C.
Scheme 3
Reagents: i) NaH, DMF
Scheme 4
R4 Br
Reagents: i) l,4-dioxa-spiro[4.5]dec-8-yl methanesulfonate, CsF, DMF, 60 0C; ii) mCPBA, CH2Cl2; iii) nBuLi, THF; iv)/?TsOH, AcOH, H2O, 50 °C.
Scheme 5
Reagents: i) BF3OEt2, CH2Cl2; U)^TsOH, AcOH, H2O, 50 °C; iii) NaIO4, MeOH, H2O.
Scheme 6
Reagents: i) MeSO2Cl, Et3N, CH2Cl2; ii), Et3N, DMF, 80 0C; iii) mCPBA, CH2Cl2; ήOpTsOH, AcOH, H2O, 50 °C.
Scheme 7
e ring C = aryl, heteroaryl Reagents: i) haloacetyl chloride, ii) ethanolamine, iii) di-tert-butyl azodicarboxylate, nBu3P, EtOAc.
The following abbreviations are used in the Schemes, Descriptions and Examples: DMF: N,N- dimethylformamide; DMSO: dimethylsulfoxide; Et2O: diethyl ether; EtOAc: ethyl acetate; h: hour(s); MeCN: acetonitrile; MeOH: methanol; min: minute(s); RT: room temperature; THF: tetrahydrofuran
The following Descriptions and Examples illustrate the present invention.
Description 1: l-Chloro-4-[(4-fluorobcnzyl)thio]bcnzcnc
Triethylamine (6.3 mL, 45.1 mmol) was added dropwise to a stirred solution of 4-chlorothiophenol (5 g, 34.7 mmol) and 4-fluorobenzyl bromide (6.9 g, 36.4 mmol) in CH2Cl2 (60 mL) over 5 min. The mixture was stirred for Ih at ambient temperature then partitioned between CH2Cl2 and water. The organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (8.78 g, 100%). 1H NMR (500MHz, CDCl3): δ 7.23-7.19 (6H, m), 6.96 (2H, t, J8.6), 4.04 (2H, s).
Description 2: 2-[4-(4-Chlorobenzylsulfanyl)phenyl]propan-2-ol
A solution of 4-(4-chlorobenzylsulfanyl)benzoic acid methyl ester (prepared according to the method of Description 1) (3 g, 10.2 mmol) in THF (50 mL) was cooled to -78 C. Methyl magnesium bromide (3M in Et2O, 10 mL, 30 mmol) was added dropwise. The mixture was stirred at this temperature for 30 min, then warmed to RT. Water and EtOAc were added and the phases separated. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The title compound (2.71 g, 90%) was obtained after column chromatography on silica gel (Gradient: EtOAc in hexanes 10% to 30%). 1H NMR (360MHz, CDCl3): δ 7.37 (d, J 8.4, 2H); 7.24 (m, 6H); 4.05 (s, 2H); 1.55 (s, 6H).
Description 3: 5-{[(4-Chlorophenyl)methyl]thio}-2-(trifluoromethyl) pyridine NaH (60% dispersion in mineral oil, 1.2 g, 30 mmol) was added to a stirred, cooled (0 0C) solution of 4- chlorobenzenemethanethiol (4.22 g, 26.5 mmol) in DMF (50 mL). The mixture was stirred at 0 0C for 10 min, then 5-bromo-2-(trifluoromethyl)pyridine (5 g, 22.1 mmol) was added. The mixture was stirred at RT for 4 h, then water was added. The mixture was extracted with EtOAc and the combined organic fractions were washed with water and brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (6.74 g, 100%). m/z (ES+) 304 (M+l).
The following compounds were prepared according to the method of Description 3.
Description 6: l-Chloro-4-[(4-fluorobenzyl)sulfonyl]benzene
3-Chloroperbenzoic acid (15.1 g, 87.5 mmol) was added in portions to a stirred, cooled (0 0C) solution of l-chloro-4-[(4-fluorobenzyl)thio]benzene (Description 1; 8.78 g, 34.7 mmol) in CH2Ck (80 mL). The mixture was warmed to RT and stirred overnight. The mixture was cooled in ice and Ca(OH)2 (9.7 g, 131 mmol) was added. The mixture was stirred for 20 min, filtered through Hyflo™ and the solvent was evaporated under reduced pressure to give the title compound (9.34 g, 95%).
1H NMR (500MHz, CDCl3): δ 7.55 (d, J 8.6, 2H); 7.43 (d, J 8.6, 2H); 7.08 (dd, J 5.4, 8.7, 2H); 7.00-6.94 (m, 2H); 4.27 (s, 2H).
Description ?: 8-[(4-Chlorophenyl)sulfonyl]-8-(4-fluorophenyl)-l,4-dioxaspiro[4.5]decane
NaH (60% in mineral oil, 1.53 g, 39 mmol) was added to a solution of l-chloro-4-[(4- fluorobenzyl)sulfonyl]benzene (Description 6; 4.67 g, 16.3 mmol) in DMF (120 mL) and the mixture was stirred at RT for 10 min. 2,2-Bis(2-iodoethyl)-l,3-dioxolane (6.85 g, 17.9 mmol) was added and the mixture was stirred at RT overnight. The mixture was cooled in ice and water was added. Aqueous NaHCO3 (saturated) was added and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15 - 20% EtOAc/hexane to give the title compound (4.00 g, 59%).
1H NMR (500MHz, CDCl3): δ 7.33 (d, J8.5, 2H); 7.23 (m, 4H); 7.00 (t, J8.6, 2H); 3.95 (t, J6.0, 2H); 3.88 (t, J5.9, 2H); 2.59-2.53 (m, 2H); 2.48 (d, J 12.9, 2H); 1.75 (d, J 13.1, 2H); 1.44-1.38 (m, 2H).
Description β: 4-[(4-Chlorophenyl)sulfonyl]-4-(4-fluorophenyl)cyclohexanone
/?-Toluenesulfonic acid monohydrate (3.03 g, 15.9 mmol) was added to a stirred, heated (50 "C) solution of 8-[(4-chlorophenyl)sulfonyl]-8-(4-fluorophenyl)-l,4-dioxaspiro[4.5]decane (Description 7; 4.00 g,
9.73 mmol) in acetic acid (90 mL) and water (10 mL) and the mixture was stirred at 50 °C overnight. The mixture was cooled, diluted with EtOAc and neutralised with K2CO3. The mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (3.3 g, 90%).
1H NMR (500MHz, CDCl3): δ 7.37-7.30 (m, 4H); 7.25 (m, 2H); 7.10-7.04 (m, 2H); 2.80 (m, 2H); 2.72- 2.66 (m, 2H); 2.50 (m, 2H); 2.22-2.15 (m, 2H).
The following compounds were prepared according to the methods of Descriptions 1-8.
The following compounds were prepared according to the methods of Descriptions 1-8.
Description 36: 8-[4-(Trifluoromcthyl)phcnylthio]-l,4-dioxa-spiro[4.5]dccanc
Cesium fluoride (10.2 g, 67.7 mmol) was heated to 180 0C under vacuum for 2 h, cooled to RT, placed under a N2 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 0C for 3 h, cooled and water and EtOAc were added. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (100:0 increasing to 90:10) to give the title compound (3.51 g, 50%). 1H NMR (500MHz, CDCl3): δ 7.52 (d, J 8.1, 2H); 7.42 (d, J 8.1, 2H); 3.93 (s, 4H); 3.31 (m, IH); 2.02 (m, 2H); 1.85 (m, 2H); 1.75 (m, 2H); 1.62 (m, 2H).
Description 37: 8-[4-(Trifluoromcthyl)bcnzcncsulfonyl]-l,4-dioxa-spiro[4.5]dccanc
Prepared from 8-[4-(trifluoromethyl)phenylthio]-l,4-dioxa-spiro[4.5]decane (Description 36) according to the method of Description 6.
1H NMR (500MHz, CDCl3): δ 8.05 (d, J8.1, 2H); 7.87 (d, J8.1, 2H); 3.93 (m, 4H); 2.95 (m, IH); 2.08 (m, 2H); 1.90-1.75 (m, 4H); 1.55 (m, 2H).
Description 38: 8-(4-Bromo)phcnylmcthyl-8-[4-(trifluoromcthyl)bcnzcncsulfonyl]-l,4-dioxa- spiro[4.5]dccanc n-Butyllithium (1.6M in hexanes, 1.7 mL, 2.7 mmol) was added dropwise to a stirred, cooled (-78 °C) solution of 8-[4-(trifluoromethyl)benzenesulfonyl]-l,4-dioxa-spiro[4.5]decane (Description 37, 1 g, 2.86 mmol) in THF (10 mL) and the mixture was stirred at -78 0C for 20 min. A solution of 4- bromobenzyl bromide (1.43 g, 5.7 mmol) in THF (4 mL) was added dropwise and the mixture was stirred at -78 0C for 2 h. Water and EtOAc were added, the mixture warmed to RT and the layers were separated. The organic layer was washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (95:5 increasing to 85:15) to give the title compound (1.16 g, 78%). 1H NMR (500MHz, CDCl3): δ 7.95 (d, J8.1, 2H); 7.80 (d, J8.1, 2H); 7.40 (d, J8.2, 2H); 7.13 (d, J8.2, 2H); 3.82 (s, 4H); 3.10 (s, 2H); 1.95 (m, 6H); 1.68 (m, 2H).
Description 39: 4-(4-Bromo)phcnylmcthyl-4-[4-(trifluoromcthyl)bcnzcncsulfonyl]cyclohcxanonc
Prepared from 8-(4-bromo)phenylmethyl-8-[4-(trifluoromethyl)benzenesulfonyl]- 1 ,4-dioxa- spiro[4.5]decane (Description 38) according to the method of Description 8. 1H NMR (500MHz, CDCl3): δ 8.09 (d, J8.1, 2H); 7.90 (d, J8.1, 2H); 7.42 (d, J8.2, 2H); 6.98 (d, J8.2, 2H); 2.96 (s, 2H); 2.84 (m, 2H); 2.43 (m, 2H); 2.15-2.00 (m, 4H).
Description 40: 4-(4-Bromo)phenylmethyl-4-[4-(chloro)benzenesulfonyl] cyclohcxanonc
Prepared from l,4-dioxa-spiro[4.5]dec-8-yl methanesulfonate and 4-chlorobenzenethiol according to the method of Descriptions 36-39.
1H NMR (500MHz, CDCl3): δ 7.88 (d, J8.1, 2H); 7.60 (d, J8.1, 2H); 7.42 (d, J8.2, 2H); 6.98 (d, J8.2, 2H); 2.95 (s, 2H); 2.82 (m, 2H); 2.41 (m, 2H); 2.10 (m, 2H); 2.01 (m, 2H).
Description 41: 8-Phcnyl-l,4-dioxaspiro[4.5]dccanc-8-mcthyl Methanesulfonate Triethylamine (0.57 g, 0.0056 mol) then methanesulfonyl chloride (0.57 g, 0.00495 mol) were added dropwise to 8-phenyl-l,4-dioxaspiro[4.5]decane-8-methanol (Bioorganic & Medicinal Chemistry Letters 2002, 12, 1755-1758, 0.82 g, 0.0033 mol) in CH2Cl2 (10 mL) and the mixture was stirred at RT for 16 h. The mixture was diluted with CH2Cl2, washed with water and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound. 1H NMR (360MHz, CDCl3): δ 1.52-1.70 (4H, m), 1.88-1.97 (2H, m), 2.30-2.34 (2H, m), 2.55 (3H, s), 3.88-3.97 (4H, m), 4.10 (2H, s), 7.24 (IH, m), 7.35-7.43 (4H, m).
Description 42 : 8-Phenyl-8-[(phenylthio)methyl] ] -1 ,4-dioxa-spiro [4.5] decane
Thiophenol (0.22 g , 0.002 mol) followed by triethylamine (0.2 g, 0.002 mol) were added to 8-phenyl-l,4- dioxaspiro[4.5]decane-8-methyl methanesulfonate (Description 41, 0.5 g, 0.0015 mol) in DMF (8 mL) and the mixture was stirred at 80 0C for 16 h. The mixture was cooled, diluted with water and extracted with EtOAc. The combined organic fractions were washed with water, and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound (0.21 g, 42%).
1H NMR (360MHz, CDCl3): δ 1.53-1.69 (4H, m), 1.94-2.02 (2H, m), 2.35 (2H, m), 3.16 (2H, s), 3.87- 3.96 (4H, m), 7.06-7.41 (1OH, m).
Description 43: 4-Phcnyl-4-[(phcnylsulfonyl)mcthyl]]cyclohcxanonc To an ice-bath-cooled solution of 8-phenyl-8-[(phenylthio)methyl]]-l,4-dioxa-spiro[4.5]decane (Description 42, 0.21 g, 0.00062 mol) in CH2Cl2 (8 mL) was added portionwise 3-chloroperbenzoic acid (70%, 0.36 g, 0.0015 mol). After allowing the mixture to warm to RT it was stirred for 16 h. Ca(OH)2 (0.068 g, 0.00092 mol) was added and the mixture was stirred at RT for 15 min. The mixture was filtered through celite and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (5 mL) and water (0.5 mL) and/?-toluenesulfonic acid monohydrate (176 mg, 0.00093 mol) was added. The mixture was heated at 50 0C for 16 h, cooled and EtOAc and water were added. The layers were separated and the organic layer was washed with water, and aqueous NaHCO3, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound (0.16 g, 80%). 1H NMR (360MHz, CDCl3): δ 2.26-2.48 (6H, m), 2.83 (2H, m), 3.45 (2H, m), 7.19-7.60 (1OH, m).
Description 44: 8-(4-Bromophcnyl)-8-[(4-trifluoromcthyl)phcnylthiol]-l,4-dioxa-spiro[4.5]dccanc Boron trifluoride diethyl etherate (1.82 g, 13 mmol) then 4-(trifluoromethyl)thiophenol (2.3 g, 13 mmol) were added dropwise to a stirred, cooled (-10 0C) solution of 8-(4-bromo-phenyl)-l,4-dioxa- spiro[4.5]decan-8-ol (prepared according to Zhang, Y.; Schuster, G.B. J. Org. Chem. 1994, 59, 1855.) (2 g, 6.4 mmol) in CH2Cl2 (32 mL) and the mixture was stirred at RT for 2 h. Water was added, the layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (98:2 increasing to 90:10) to give the title compound (0.4 g, 13%).
1H NMR (400MHz, CDCl3): δ 7.40 (m, 4H); 7.15 (d, J8.4, 2H); 7.05 (d, J8.4, 2H); 3.96 (m, 4H); 2.20- 1.50 (m, 8H).
Description 45: 4-(4-Bromophcnyl)-4-[(4-trifluoromcthyl)bcnzcncsulfϊnyl] cyclohcxanonc Sodium metaperiodate (131 mg, 0.7 mmol) in water (1 mL) was added to a solution of 4-(4- bromophenyl)-4-[(4-trifluoromethyl)phenylthio]cyclohexanone [prepared from 8-(4-bromophenyl)-8-[(4- trifluoromethyl)phenylthiol]-l,4-dioxa-spiro[4.5]decane (Description 44) according to the method of Description 8] (0.22 g, 0.51 mmol) in methanol (2 mL) and the mixture was stirred at RT overnight. The mixture was filtered and the solvent was evaporated under reduced pressure. Water and EtOAc were added and the layers were separated. The organic fraction was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with hexane/EtOAc (50:50) to give the title compound. 1H NMR (360MHz, CDCl3): δ 7.52 (m, 4H); 7.02 (m, 4H); 7.05 (d, J 8.4, 2H); 2.55 (m, 5H); 2.26 (m, 3H).
Description 46: 1-(1,1-Dimethylethyl) 4-Methyl 1,4-Pipcridincdicarboxylatc
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 CH2Cl2/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.
1H NMR (400MHz, CDCl3) δ 1.46 (s, 9H), 1.58-1.68 (m, 2H), 1.86-1.91 (m, 2H), 2.45 (tt, IH), 2.81-2.87 (m, 2H), 3.70 (s, 3H), 4.00-4.05 (m, 2H).
Description 47: 1-(1,1-Dimethylethyl) 4-Methyl 4-(Pent-4-en-l-yl)-l,4-piperidinedicarboxylate
A solution of l-(l,l-dimethylethyl) 4-methyl 1,4-piperidinedicarboxylate (Description 46, 25 g, 0.10 mol) in THF (250 mL) was added to a stirred, cooled (0 0C) solution of potassium bis(trimethylsilyl)amide (30.7 g, 0.15 mol) in THF (750 mL) and the mixture was stirred at 0 0C for 1 h. 5-Bromo-l-pentene (19.4 mL, 0.164 mol) was added and the mixture was allowed to warm to RT and stirred for 1.5 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc (3x). The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure to give the title compound (30.9 g) which was used in the next step without further purification.
1H NMR (400MHz, CDCl3) δ 1.26-1.40 (m, 4H), 1.46 (s, 9H), 1.50-1.54 (m, 2H), 1.99-2.06 (m, 2H), 2.11-18 (m, 2H), 2.80-2.98 (m, 2H), 3.72 (s, 3H), 3.87-3.95 (m, 2H), 4.95-5.02 (m, 2H), 5.72-5.80 (m, IH).
Description 48: 1-(1,1-Dimethylethyl) 4-Methyl 4-(4-Oxobut-l-yl)-l,4-pipcridincdicarboxylatc
A solution of l-(l,l-dimethylethyl) 4-methyl 4-(pent-4-en-l-yl)- 1,4-piperidinedicarboxylate (Description 47, 29.4 g, 0.0945 mol) in methanol (1000 mL) was cooled to -78 0C and ozone was bubbled into the solution until a blue color persisted. The excess ozone was removed with a stream OfN2, then methyl sulfide (69 mL, 0.95 mol) was added, the cooling bath was removed, and the mixture was allowed to warm to RT over 1.5 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography, eluting with 2: 1 heptane/EtOAc, to give the title compound (23.0 g).
1H NMR (400MHz, CDCl3) δ 1.29-1.40 (m, 2H), 1.46 (s, 9H), 1.50-1.57 (m, 4H), 2.09-2.13 (m, 2H), 2.41-2.44 (m, 2H), 2.82-2.95 (m, 2H), 3.73 (s, 3H), 3.86-3.89 (m, 2H), 9.74 (s, IH). Description 49: l-[(l,l-Dimcthylcthoxy)carbonyl]-4-(mcthoxycarbonyl)-4-pipcridincbutanoic acid
Jones reagent (2.6M , 28.2 mL) was added via syringe to a solution of l-(l,l-dimethylethyl) 4-methyl 4- (4-oxobut-l-yl)-l,4-piperidinedicarboxylate (Description 48, 23.0 g, 0.0734 mol) in acetone (775 mL). After 5 min, the solvent was evaporated under reduced pressure and the residue was taken up in water. The mixture was extracted with Et2O (3x) and the combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (23.4 g) which was used in the next step without further purification.
1H NMR (400MHz, CDCl3) δ 1.33-1.41 (m, 2H), 1.46 (s, 9H), 1.50-1.57 (br s, 4H), 2.09-2.19 (m, 2H), 2.32-2.34 (m, 2H), 2.85-2.89 (m, 2H), 3.73 (s, 3H), 3.81-3.89 (m, 2H).
Description 50: Methyl l-[(l,l-Dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4- piperidinebutanoate
Trimethylsilyldiazomethane (2.0M in hexane, 53 mL, 0.11 mol) was added to a stirred, cooled (0 0C) solution of l-[(l,l-dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-piperidinebutanoic acid
(Description 49, 23.4 g, 0.071 mol) in CH2Cl2MeOH (3:1, 480 mL). The mixture was stirred at RT for 15 min, then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title compound (20.1 g). 1H NMR (400MHz, CDCl3) δ 1.33-1.42 (m, 2H), 1.43 (s, 9H), 1.57-1.59 (m, 4H), 2.08-2.14 (m, 2H), 2.26-2.31 (m, 2H), 2.84-2.94 (m, 2H), 3.68 (s, 3H), 3.73 (s, 3H), 3.83-3.90 (m, 2H).
Description 51: (&S)-8-(l,l-Dimethylethyl) 2-Methyl l-Oxo-8-azaspiro[4.5]decane-2,8- dicarboxylatc
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexanes, 47 mL, 0.070 mol,) was added to a stirred, cooled (-78 0C) solution of methyl l-[(l,l-dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4- piperidinebutanoate (Description 50, 20.1 g, 0.058 mol) in THF (600 mL). The mixture was stirred at -78 0C for 25 min., then additional lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexanes, 31 mL) was added and the mixture was stirred at -78 0C for 20 min. The mixture was poured into saturated aqueous ammonium chloride and extracted with Et2O (3x). The combined organic fractions were washed with brine, dried (Na2SO4), and the solvent was evaporated under reduced pressure to give the title compound (19.9 g) which was taken on to the next step without further purification.
Description 52: 1,1-Dimethylethyl l-Oxo-8-azaspiro[4.5]dccanc-8-carboxylatc
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 0C for 60 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with CH2Cl2 (3x). The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title compound (9.41 g). 1H NMR (400MHz, CDCl3) δ 1.29-1.37 (m, 2H), 1.47 (s, 9H), 1.62-1.69 (m, 2H), 1.92-1.95 (m, 4H), 2.30-2.34 (m, 2H), 3.05-3.10 (m, 2H), 3.87-3.92 (m, 2H).
Description 53: (U?S,2ftS)-l,l-Dimethylethyl 2-(l-Hydroxyprop-l-yl)-l-oxo-8-azaspiro[4.5]decane- 8-carboxylate
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 0C. Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 24 mL, 36 mmol,) was added and the mixture was stirred at -78 0C for 30 min. Propionaldehyde (2.6 mL, 36 mmol) was added and the mixture was stirred at -78 0C for 5 min. The mixture was diluted with Et2O, poured into saturated aqueous ammonium chloride and extracted with Et2O (3x). The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title compound (4.75 g).
1H NMR (400MHz, CDCl3) δ 0.97 (t, 3H), 1.33-1.37 (m, 2H), 1.47 (s, 9H), 1.54-1.68 (m, 5H), 1.75-1.78 (m, IH), 2.07-2.13 (m, 2H), 2.30-2.33 (m, IH), 2.95-3.15 (m, 2H), 3.62-3.63 (m, IH), 3.84-3.94 (m, 2H).
Description 54: 1,1-Dimethylethyl 2-(l-Oxoprop-l-yl)-l-oxo-8-azaspiro[4.5]decane-8-carboxylate
DMSO (2.6 mL, 37 mmol) was added slowly to a stirred, cooled (-78 0C) solution of oxalyl chloride (1.6 mL, 18.3 mmol) in CH2Cl2 (150 mL) and the mixture was stirred at -78 0C for 5 min. A solution of (IRS,2RS)- 1 , 1 -dimethylethyl 2-(l -hydroxyprop- 1 -yl)- 1 -oxo-8-azaspiro[4.5]decane-8-carboxylate
(Description 53, 4.75 g, 15.3 mmol) in CH2Cl2 (40 mL) was added via an addition funnel and the mixture was stirred at -78 0C for 45 min. Triethylamine (10.2 mL, 73.2 mmol) was added and the mixture was stirred at -78 0C for 5 min., then allowed to warm to RT for 1.5 h. The mixture was poured into water and extracted with CH2Cl2 (3x). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 15% EtOAc in hexanes, to give the title compound (3.98 g) as a pink oil.
Description 55: 1,1-Dimethylethyl l,3-Diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(lH),4'- piperidine]-l'-carboxylate Trifluoroacetate and 1,1-Dimethylethyl 2,3-Diethyl-4,5- dihydrospiro[cyclopentapyrazole-6(2H),4'-piperidine]-l'-carboxylate Trifluoroacetate Ethyl hydrazine oxalate (0.096 g, 0.640 mmol) was added to a solution of 1,1-dimethylethyl 2-(l- oxoprop-l-yl)-l-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 54, 0.165 g, 0.533 mmol) in ethanol (5 mL) and the mixture was stirred at 85 0C for 12 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was taken up in a minimal amount of 40:40:20 MeCN/water/DMSO solution and purified by Gilson reverse phase HPLC (Column: YMC-Pack Pro C 18, 100 X 20 mm I.D.; Gradient Eluent: 10:90 to 90: 10 v/v MeCN/water + 0.1% trifluoroacetic acid over 12.5 min; Detection: PDA, 210-400 nm; Flow rate: 20 mL/min) to give 1,1-dimethylethyl l,3-diethyl-4,5- dihydrospiro [cyclopentapyrazole-6(lH),4'-piperidine]-l '-carboxylate trifluoroacetate (0.220 g); 1H NMR (400MHz, CDCl3) δ 1.23 (t, 3H), 1.42 (t, 3H), 1.50 (s, 9H), 1.60-1.63 (m, 2H), 1.88-1.93 (m, 2H), 2.42-2.47 (m, 2H), 2.56-2.61 (m, 4H), 2.86-2.89 (m, 2H), 4.00 (q, 2H), 4.10-4.13 (m, 2H); m/z (ES+)
334 (M+l); and 1,1-dimethylethyl 2,3-diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(2H),4'-piperidine]- 1 '-carboxylate trifluoroacetate (0.016 g); 1H NMR (400MHz, CDCl3) δ 1.27 (t, 3H), 1.38 (t, 3H), 1.48 (s, 9H), 1.51-1.57 (m, 2H), 1.75-1.79 (m, 2H), 2.22-2.45 (m, 2H), 2.58-2.65 (m, 4H), 3.51-3.60 (m, 2H), 3.64-3.67 (m, 2H), 4.03 (q, 2H); m/z (ES+) 334 (M+l).
Description 56: l,3-Dicthyl-4,5-dihydrospiro[cyclopcntapyrazolc-6(lH),4'-pipcridinc]
Dihydrochloridc
Acetyl chloride (1.17 mL, 16.4 mmol) was added to a stirred, cooled (0 0C) 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. 1H NMR (400MHz, CDCl3) δ 1.32 (t, 3H), 1.54 (t, 3H), 2.00 (d, 2H), 2.37-2.45 (m, 2H), 2.66-2.69 (m, 2H), 2.73-2.82 (m, 4H), 3.18-3.24 (m, 2H), 3.47-3.52 (d, 2H), 4.41 (q, 2H).
Description 57: 1-(1,1-Dimcthylcthyl) 4-pipcridincdicarboxylatc Anhydride with lH-Imidazole-1- carboxylic Acid
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 CH2Cl2 (550 mL) and the mixture was stirred at 4 0C overnight. The mixture was poured into Et2O (2 L) and ice water (2 L), the layers were separated and the organic layer was washed with cold aqueous NaHCO3 (saturated, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (52 g).
Description 58: 1,1-Dimethylethyl 4-(l,3-Dioxobutyl)pipcridinccarboxylatc Acetone (41 mL) in THF (300 mL) was added dropwise to a stirred suspension of KH (30% in mineral oil, 75 g, 561 mmol) in THF (1.4 L) at RT. The mixture was cooled to -78 0C and treated with 1 -(1,1- dimethylethyl) 4-piperidinedicarboxylate anhydride with lH-imidazole-1-carboxylic acid (Description 57, 52 g) in THF (500 mL). The mixture was allowed to warm to RT and stirred overnight, then ethanol (50 mL) was added dropwise over 5 min. The mixture was poured into hydrochloric acid (IN, 2 L) and extracted with Et2O (2 xl L). The combined organic fractions were washed with aqueous NaHCO3 (saturated, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. Isohexane (1 L) and acetonitrile (500 mL) were added, the layers were separated and the isohexane layer was extracted with MeCN (500 mL). The MeCN layers were combined and the solvent was evaporated under reduced pressure. The residue was filtered through a silica pad, eluting with 0-20% EtOAc in hexanes, to give the title compound as a colorless solid (36 g, 72%). 1H NMR (CDCl3) δ 5.50 (IH, s), 4.18-4.11 (2H, m), 2.79-2.62 (2H, m), 2.34-2.27 (IH, m), 2.07 (3H, s), 1.80 (2H, brd, J 14.3), 1.60-1.51 (2H, m), 1.46 (9H, s).
Description 59: 1,1-Dimethylethyl 4-[l-(l,l-Dimethylethyl)-3-methyl-lH-pyrazol-5- yl]pipcridinccarboxylatc t-Butyl hydrazine hydrochloride (14.8 g, 118 mmol) then triethylamine (17 mL, 120 mmol) were added to a solution of 1,1-dimethylethyl 4-(l,3-dioxobutyl)piperidinecarboxylate (Description 58, 8 g, 29.7 mmol) in ethanol (200 mL) and the mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure and the residue was suspended in EtOAc (1 L), washed with aqueous NaOH (IN, 500 mL), water (500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (9.5 g). 1H NMR (CDCl3) δ 5.87 (IH, s), 4.27-4.18 (2H, m), 3.09-2.99 (IH, m), 2.79-2.68 (2H, m), 2.20 (3H, s), 1.85 (2H, brd, J 13.3), 1.63 (9H, s), 1.61-1.52 (2H, m), 1.48 (9H, s).
Description 60: 4-[l-(l,l-Dimethylethyl)-3-methyl-lH-pyrazol-5-yl]piperidine
Methanolic HCl (IN, 100 mL) was added to a solution of 1,1-dimethylethyl 4-[l-(l,l-dimethylethyl)-3- methyl- lH-pyrazol-5-yl]piperidinecarboxylate (Description 59, 9.5 g, 29 mmol) in MeOH (100 mL) and the mixture was stirred at RT for 4 h. The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc. The solid was collected, suspended in aqueous NaOH (4N, 20 mL) and extracted with CH2Cl2 (2 x 100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (6.4 g). 1H NMR (CDCl3) δ 5.91 (IH, s), 3.17 (2H, brd, J 13.0), 3.03 (IH, tt, J 13.0, 4.3), 2.69 (2H, dt, J 12.8, 3.5), 2.21 (3H, s), 1.86 (2H, brd, J 13.4), 1.67 (9H, s), 1.68-1.56 (2H, m).
Description 61 : 4-[l-(-(2,2,2-Trifluoroethyl))-3-methyl-lH-pyrazol-5-yl]piperidine
Prepared from 1,1-dimethylethyl 4-(l,3-dioxobutyl)piperidinecarboxylate (Description 58) according to the methods of Descriptions 59 and 60, substituting trifluoroethyl hydrazine oxalate for t-butyl hydrazine hydrochloride. 1H NMR (CDCl3) δ 5.91 (IH, s), 4.58 (2H, dd, J 16.4, 8.6), 3.17 (2H, brd, J 13.2), 2.70 (2H, dt, J 12.5, 2.4), 2.60 (IH, tt, J 12.1, 4.1), 2.23 (3H, s), 1.82 (2H, brd, J 14.4), 1.58 (2H, qd, J 12.5, 3.8).
Description 62: 1,1-Dimethylethyl 4-[(2-Oxocyclopcntyl)carbonyl]-l-pipcridinccarboxylatc Prepared from 1 -( 1 , 1 -dimethylethyl) 4-piperidinedicarboxylate anhydride with 1 H-imidazole- 1 - carboxylic acid (Description 57) according to the method of Description 58, substituting cyclopentanone for acetone.
1H NMR (CDCl3) δ 13.75 (IH, brs), 4.27-4.06 (2H, m), 2.78-2.69 (2H, m), 2.57 (2H, t, J6.2), 2.42 (2H, t, J7.2), 2.37-2.30 (IH, m), 1.96-1.89 (2H, m), 1.75-1.63 (4H, m), 1.46 (9H, s).
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. 1H NMR (CDCl3) δ 4.02 (2H, dd, J 14.5, 8.0), 3.18 (2H, brd, J 12.4), 2.72 (2H, dt, J 12.6, 2.5), 2.68-2.63 (5H, m), 2.40-2.33 (2H, m), 1.81 (2H, brd, J 13.6), 1.69 (2H, qd, J 12.6, 4.1), 1.42 (3H, t, J7.4).
Description 64: 1,1-Dimethylethyl 4-(l,3-Dioxo-2-mcthylbutyl)pipcridinccarboxylatc
NaH (60% in mineral oil, 75 mg, 1.9 mmol) was added to 1,1 -dimethylethyl 4-(l,3- dioxobutyl)piperidinecarboxylate (Description 58, 0.5 g, 1.9 mmol) in DMF (5 mL). The mixture was stirred at RT for 1 h, then added to a solution of iodomethane (0.59 mL, 9.5 mmol) in DMF (5 mL). Water (500 mL) was added and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 15-25% EtOAc in hexanes, to give the title compound (175 mg).
Description 65: 4-[l,3,4-Trimethyl-lH-pyrazol-5-yl]piperidine
Prepared from 1,1 -dimethylethyl 4-(l,3-dioxo-2-methylbutyl)piperidinecarboxylate (Description 64) according to the methods of Descriptions 59 and 60, substituting methyl hydrazine oxalate for t-butyl hydrazine hydrochloride.
1H NMR (CDCl3) δ 4.07 (2H, q, J7.6), 3.19 (2H, brd, J 11.8), 2.77-2.67 (3H, m), 2.14 (3H, s), 2.02 (3H, s), 1.92 (2H, qd, J 11.8, 4.1), 1.69 (2H, brd, J 13.0), 1.36 (3H, t, J7.4).
Description 66: l-Phenylmethyl-4-(3,5-diethyl-lH-pyrazol-l-yl)piperidine Triethylamine (3.54 mL, 25.5 mmol) was added to a stirred solution of 4-hydrazino-l-
(phenylmethyl)piperidine dihydrochloride (3.53 g, 12.7 mmol) in ethanol (50 mL) and the mixture was stirred at RT for 5 min. 3,5-Heptanedione (3.26 g, 25.5 mmol) was added and the mixture was stirred at RT for 4 days. The mixture was diluted with EtOAc, washed with aqueous NaOH (0.5M), brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 100% hexane to 100% Et2O, to give the title compound (2.7 g, 71%). 1H NMR (CD3OD) δ 7.35-7.20 (5H, m), 5.85 (IH, s), 4.02-3.94 (IH, m), 3.55 (2H, s), 2.99 (2H, d, J9.2), 2.63-2.51 (4H, m), 2.27-2.12 (4H, m), 1.73 (2H, t, J 11.8), 1.24-1.16 (6H, m).
Description 67: 4-(3,5-Diethyl-lH-pyrazol-l-yl)piperidine
Ammonium formate (5.73 g, 90 mmol) and Pd on C (300 mg) were added to a stirred solution of 1- phenylmethyl-4-(3,5-diethyl-lH-pyrazol-l-yl)piperidine (Description 66, 2.7 g, 9 mmol) in methanol (75 mL) and the mixture was stirred under reflux for 3 h. The mixture was cooled, filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residues was dissolved in MeOH and poured onto SCX cartridges (Varian Bond Elut™; 10 mL/500 mg). The cartridges were washed with MeOH, then eluted with methanolic ammonia (2M). The solvent was evaporated under reduced pressure to give the title product. (1.6 g, 85%).
1H NMR (CD3OD) δ 5.86 (IH, s), 4.18-4.10 (IH, m), 3.15 (2H, dd, J2.1, 10.9), 2.75-2.53 (6H, m), 2.07- 1.97 (2H, m), 1.79 (2H, d, J 14.0), 1.25-1.17 (6H, m).
Description 68: 1,1-Dimethylethyl l,2-Dihydro-l-(l-methylethyl)-2-oxospiro[3H-indole-3,4'- piperidine]-l'-carboxylate
NaH (60% in mineral oil, 344 mg, 8.6 mmol) was added in portions to a stirred, cooled (0 0C) solution of 1,1-dimethylethyl l,2-dihydro-2-oxospiro[3H-indole-3,4'-piperidine]-r-carboxylate (2.0 g, 6.6 mmol) in DMF (10 mL) and the mixture was stirred at 0 0C for 10 min. 2-Iodopropane (0.86 mL, 8.6 mmol) was added and the mixture was allowed to warm to RT and stirred overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic fractions were dried
(MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (70:30) to give the title compound as a solid (2.3 g). 1H NMR (CDCl3) δ 7.29-7.23 (2H, m), 7.06-7.02 (2H, m), 4.68-4.62 (IH, m), 3.88-3.76 (4H, m), 1.82- 1.74 (4H, m), 1.50 (9H, s), 1.47 (6H, d, J 7.3).
Description 69: l-(l-Methylethyl)spiro[3H-indole-3,4'-piperidin]-2(lH)-one Trifluoroacctatc
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 CH2Cl2 (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). 1H NMR (CDCl3) δ 9.01 (IH, s), 8.54 (IH, s), 7.32-7.28 (2H, m), 7.12 (IH, t, J7.12), 7.04 (IH, d, J 7.12), 4.65-4.59 (IH, m), 4.00 (2H, q, J 11.9), 3.45 (2H, d, J 12.4), 2.39-2.31 (2H, m), 1.90 (2H, d, J 14.8), 1.49 (6H, d, J 7.0).
Description 70: 1,1-Dimethylethyl 4-[(6-Mcthoxy-3-nitro-2-pyridinyl)amino]pipcridinccarboxylatc
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 0C 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%).
1H NMR (360MHz, CDCl3) δ 1.48 (9H, s), 1.52-1.62 (2H, m), 2.02-2.1 (2H, br m), 2.95-3.09 (2H, br m), 3.95 (3H, s), 4.00-4.10 (2H, br m), 4.23-4.35 (IH, m), 6.07 (IH, d, J9), 8.28 (IH, d, J 9), 8.63 (IH, br d).
Description 71: l,3-Dihydro-5-methoxy-3-(4-piperidinyl)-2H-imidazo[4,5-b]pyridin-2-one Dihydrochloridc
Platinum oxide (hydrated, 1.1 g) was added to a suspension of 1,1-dimethylethyl 4-[(6-methoxy-3-nitro- 2-pyridinyl)amino]piperidinecarboxylate (Description 70, 16.75 g, 47.52 mmol) in ethanol (250 mL) and the mixture was shaken under H2 (25 to 35 psi) for 4 h. CH2Cl2 (25 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (125 mL) and treated with N-ethyldiisopropylamine (24.40 mL, 18.42 g, 142.57 mmol) then N5N'- carbonyldiimidazole (8.48 g, 52.28 mmol) were added. The mixture was stirred at 90 0C for 24 h, cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with aqueous Na2CO3 (5%) and HCl (0.0 IN), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanolic HCl (3M, 200 mL) and stirred at RT for 90 min. The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc. The solid was collected and dried in vacuo to give the title compound as a purple solid (9.00 g, 59%). 1H NMR (400MHz, D6-DMSO) δ 1.87 (2H, br d, J 13), 2.75 (2H, qd, J 13, 4), 3.08 (2H, br q, J 11), 3.40 (2H, br d, J 13), 3.75 (3H, s), 4.45-4.55 (IH, m), 6.41 (IH, d, J8), 7.29 (IH, d, J8), 8.75 (1 H, br), 9.01 (1 H, br), 10.90 (IH, s).
Description 72: (3&S)-Ethyl l-(Phenylmethyl)-3-piperidinecarboxylate
Benzyl chloride (165 mL, 181 g, 1.43 mol) was added in one portion to an intensively stirred, cooled
(0 0C) mixture of (3&S)-ethyl 3-piperidinecarboxylate (200 mL, 201 g, 1.29 mol) and triethylamine
(200 mL, 145 g, 1.43 mol) in MeCN (400 mL) and the mixture was stirred at RT for 2.5 h. The solid was collected, washed with MeCN (2 x 200 mL) and dried in vacuo. The solid was dissolved in Et2O
(300 mL) and washed with water (2 x 300 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound as an oil (270 g, 85%). Description 73: (3&S)-l-(Phenylmethyl)-3-piperidinecarboxylic Acid Hydrazide
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 CHCl3 (2 x 300 mL). The combined organic fractions were dried (Na2SO4) the solvent was partly evaporated under reduced pressure until a precipitation occurred. The solid was collected, the filtrate was diluted with Et2O (200 mL) and further solid was collected. The combined solids were washed with Et2O and dried in vacuo to give the title compound as a solid (217 g, 92%).
Description 74: (3&S)-l-(Phenylmethyl)-3-piperidinecarboxylic Acid 2- [(Mcthylamino)thioxomcthyl] hydrazide Methyl isothiocyanate (90 g, 1 43 mol) in toluene (50 mL) was added to a stirred solution of (3RS)-I - (phenylmethyl)-3-piperidinecarboxylic acid hydrazide (Description 73, 210 g, 0.90 mol) in toluene (500 mL) and the mixture was stirred at RT for 1 h. The solid was collected, washed with Et2O and dried in vacuo to give the title compound as a solid (245 g, 90%).
Description 75: (3ΛS)-l-(Phenylmethyl)-3-(4-methyl-5-thio-4H-l,2,4-triazol-3-yl)piperidine
Sodium (50 g, 2.18 mol) was added in portions to stirred, cooled (0 0C) MeOH (785 mL). Once the sodium had dissolved, (3&S)-l-(phenylmethyl)-3-piperidinecarboxylic acid 2-
[(methylamino)thioxomethyl]hydrazide (Description 74, 230 g, 0.76 mol) was added and the mixture was heated under reflux for 1 h. The mixture was cooled in ice and aqueous acetic acid (126 mL, 131 g, 2.19 mol) in water (400 mL) was added. The solid was collected, washed with Et2O and dried in vacuo to give the title compound as a solid (173 g, 79%).
Description 76: (3ΛS)-l-(Phenylmethyl)-3-(4-methyl-4H-l,2,4-triazol-3-yl)piperidine
(3R5)-l-(Phenylmethyl)-3-(4-methyl-5-thio-4H-l,2,4-triazol-3-yl)piperidine (Description 75, 160 g, 0.56 mol) was dissolved by portions of 15-20 g in stirred, cooled (0 0C) concentrated nitric acid (70%, 500 mL). The mixture was stirred at 0 0C for 1 h then poured into stirred, cooled (0 0C) aqueous KOH (600 g) with continuing addition of ice. The mixture was divided into 4 portions and each portion of 500 mL was extracted with CHCl3 (300 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound.
Description 77: (3&S)-3-(4-Methyl-4H-l,2,4-triazol-3-yl)piperidine Hydrochloride Pd on C (5%) was added to a mixture of (3RS)-l-(phenylmethyl)-3-(4-methyl-4H-l,2,4-triazol-3- yl)piperidine (Description 76) and hydrochloric acid (cone, 50 mL) in methanol (400 mL) and the mixture was shaken under an atmosphere OfH2 (100 atm.) at 90 0C for 24 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved at reflux in iso- propanol (100 mL) and hydrochloric acid (cone, 50 mL) was added. The mixture was cooled and stored at 5°C for 3 days. The solid was collected, washed with Et2O and dried in vacuo to give the title compound as a solid (103 g, 91%). 1H NMR (D6-DMSO) δ 9.80-9.40 (3H, m), 3.90 (3H, s), 3.80-2.80 (5H, m), 2.20-1.70 (4H, m).
Description 78: l-(3-Pyridinylmethyl)piperazine Trifluoroacetate
Sodium triacetoxyborohydride (254 g, 1.2 mol) was added in portions to a rigorously stirred solution of 1,1-dimethylethyl piperazinecarboxylate (186 g, 1 mol), acetic acid (120 mL, 2 mol) and 3- pyridinecarboxaldehyde (107 g, 1 mol) in CH2Cl2 (700 mL), keeping the mixture at slow reflux. The mixture was stirred overnight at RT, washed with aqueous acetic acid (5%, 2 x 150 mL) and dried (CaCl2). The solution was cooled in ice and trifluoroacetic acid (350 mL, 3.5 mol) was added with stirring. The mixture was stirred at RT until thin layer chromatography (silica gel; chloroform:ethanol:benzene; 7:2:1; ninhydrin development) indicated complete consumption of starting material. The solvent was partially evaporated under reduced pressure at 70 0C. The mixture was then allowed to crystallize (Et2O was added to help crystallization if needed). The solid was collected, washed with Et2O (2 x 100 mL), Et2O:EtOAc (2: 1, 100 mL), and again with Et2O (100 mL). The solid was dried in vacuo to give the title compound as a solid (390 g, 75%).
1H NMR (D6-DMSO) δ 8.85 (2H, br s), 8.70 (2H, m), 8.12 (IH, d), 7.69 (IH, t), 6.0 (IH, br s), 3.90 (2H, s), 3.20 (4H, m), 2.80 (4H, m).
Description 79: [1,2-Bis(hydroxyimino)propyl]piperazine
Piperazine (84 g, 0.96 mol) in distilled water (400 mL) was added dropwise to a solution of N-hydroxy-2- (hydroxyimino)propanimidoyl chloride (33 g, 0.24 mol) in ethanol (100 mL), maintaining the reaction temperature below 300C. The mixture was stirred at RT for 24 h, then filtered, washing with hot water (150 mL). The solvent was evaporated under reduced pressure to give a mixture of the title compound and piperazine, which was used without further purification.
Description 80: l-(4-Mcthyl-l,2,5-oxadiazol-3-yl)pipcrazinc Hydrochloride
NaOH (20 g, 0.5 mol) was added slowly to an intensively stirred solution of [1,2- bis(hydroxyimino)propyl]piperazine (Description 79) in water (350 mL). The mixture was placed in an autoclave (0.5 L) and stirred for 5 h at 190 0C. The mixture was cooled and stirred overnight. The mixture was extracted with Et2O (5 x 150 mL), and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in MeOH, acidified with hydrochloric acid (1 eq), and the solvent was evaporated under reduced pressure. The residue was recrystallized from isopropanol to give the title compound (5.8 g).
1H NMR (D6-DMSO) δ 9.50 (2H, br s), 3.50 (4H, t), 3.21 (4H, t), 2.38 (3H, s).
Description 81: 4-(Chloromcthyl)-4,5-dihydro-2-mcthyl-4-thiazolol
A mixture of thioacetamide (7.5 g, 0.1 mol), 1.3-dichloroacetone (14 g, 0.11 mol), sodium bicarbonate (9.3 g, 0.11 mol) and dichloroethane (60 mL) was stirred at RT for 48 h. The mixture was filtered, washing with dichloroethane (20 mL), to give a solution of the title compound which was used without further purification.
Description 82: 4-(Chloromcthyl)-2-mcthylthiazolc Hydrochloride
Thionyl chloride (13.1 g, 0.11 mol) in dichloroethane (60 mL) was added to an intensively stirred solution of 4-(chloromethyl)-4,5-dihydro-2-methyl-4-thiazolol in dichloroethane (Description 81), maintaining the reaction temperature below 30 0C. The mixture was stirred at 65-70 0C for 30 min, cooled and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc to give the title compound as a crystalline solid (17.12 g, 93%).
Description 83: l-[(2-Methyl-4-thiazolyl)methyl]piperazine
4-(Chloromethyl)-2-methylthiazole hydrochloride (Description 82, 92 g, 0.5 mol) in MeOH (400 mL) was added slowly to a stirred solution of piperazine (500 g, 5.81 mol) in methanol (800 mL) and the mixture was heated under reflux for 3 h. The mixture was cooled and methanolic KOH (1 mol in 400 mL) was added. The mixture was stirred at RT overnight, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in iso-propanol, filtered and purified by flash column chromatography on silica gel, eluting with iso-propanol-triethylamine (5:1) and the residue was vacuum distilled. A fraction with b.p. 123-127°C/~1 torr was collected to give the title compound as a light- yellow dense oil which formed hygroscopic low melting (~30 0C) crystals on standing (57.1 g, 58%). 1H NMR (D6-DMSO) δ 7.20 (IH, s), 3.45 (2H, s), 3.15 (IH, br s), 2.60 (4H, t), 2.50 (3H, s), 2.30 (4H, m).
Description 84: 1,1-Dimethylethyl 4-[2-(l-Hydroxy-l-methylethyl)-4-methyl-lH-imidazol-l-yl]-l- pipcridinccarboxylatc n-Butyllithium (1.6M in hexanes, 5.7 mL, 9.0 mmol) was added dropwise to a stirred, cooled (-78 0C) solution of 1,1-dimethylethyl 4-(4-methyl-lH-imidazol-l-yl)-l-piperidinecarboxylate (as prepared in WO93/19059, 2 g, 7.5 mmol) in THF (50 mL) and the mixture was stirred at -78 0C for 1 h. Ethyl bromide (0.7 mL, 9.0 mmol) was added and the mixture was stirred at RT for 5 h. Acetone (1.1 mL, 0.88 g, 15 mmol) was added and the mixture was stirred at RT overnight. Water was added and the mixture was extracted with EtOAc. The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2ZMeOH (100:0 increasing to 98:2), to give the title compound (0.9 g, 37%). m/z (ES+) 324 (M+l).
Description 85: 4-[2-(l-Hydroxy-l-methylethyl)-4-methyl-lH-imidazol-l-yl]piperidine 1,1 -Dimethylethyl 4-[2-( 1 -hydroxy- 1 -methylethyl)-4-methyl- 1 H-imidazol- 1 -yl]- 1 -piperidinecarboxylate (Description 84, 450 mg, 1.4 mmol) was dissolved in ethanolic HCl (4M, 6 mL) and stirred at RT overnight. The solvent was evaporated under reduced pressure, aqueous NaHCO3 (saturated) was added and the mixture was extracted with CHCl3/ iPrOH (85:15). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (257 mg, 83%).
1H NMR (500MHz, CDCl3) δ 6.84, 6.53 (total IH, each s), 5.25, 4.83 (total IH, each s), 3.16 (2H, m), 2.69 (2H, s), 2.18 (IH, m), 2.11 (3H, s), 1.98-1.79 (3H, m), 1.60, 1.59 (total 6H, each s).
Description 86: 2-Chloro-N-(l-ethyl-3-methyl-lH-pyrazol-5-yl)acetamide Chloroacetyl chloride (3.1 mL, 40 mmol) was added to a stirred mixture of l-ethyl-3-methyl-lH-pyrazol- 5-amine (4.5 g, 36 mmol) and K2CO3 (9.9 g, 72 mmol) in CH2Cl2 (75 mL). The mixture was stirred at RT for 15 min, diluted with MeOH and filtered. The solvent was evaporated under reduced pressure to give the title compound (5.6 g, 77%). 1H NMR (CD3OD) δ 6.72 (IH, s), 4.33 (4H, dd, J0.0, 7.0), 2.43 (3H, s), 1.47 (3H, t, /7.3).
Description 87: N-(l-Ethyl-3-methyl-lH-pyrazol-5-yl)-2-[(2-hydroxyethyl)amino]acetamide Ethanolamine (1.04 mL, 17 mmol) was added to a stirred mixture of 2-chloro-N-(l-ethyl-3-methyl-lH- pyrazol-5-yl)acetamide (Description 86, 872 mg, 4.3 mmol) and NaI (50 mg) in MeCN (15 mL) and the mixture was stirred at 80 0C for 4.5 h. The mixture was cooled and CHCl3/ isopropyl alcohol (3:1) and water were added. The layers were separated and the aqueous layer was extracted with CHCl3/ isopropyl alcohol. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (0.534 g, 54%).
1H NMR (CD3OD) δ 6.08 (IH, s), 3.99 (2H, q, Jl.2), 3.67-3.63 (2H, m), 3.46 (2H, s), 2.79-2.73 (2H, m), 2.19 (3H, s), 1.33 (3H, t, J7.2).
Description 88: l-(l-Ethyl-3-methyl-lH-pyrazol-5-yl)piperazin-2-one
Di-tert-butyl azodicarboxylate (0.915 g, 4 mmol) and tri-n-butyl phosphine (1 mL, 4 mmol) were added to a stirred solution of N-(l-ethyl-3-methyl-lH-pyrazol-5-yl)-2-[(2-hydroxyethyl)amino]acetamide (Description 87, 0.3 g, 1.3 mmol) in EtOAc (10 mL) and the mixture was stirred at RT for 6 h. The mixture was poured onto SCX cartridges (Varian Bond Elut™; 10 mL/500 mg). The cartridges were washed with MeOH, then eluted with methanolic ammonia (2M). The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with CH2Cl2MeOH (100:0 increasing to 90:10), to give the title compound (190 mg, 40%). 1H NMR (CDCl3) δ 5.89 (IH, s), 3.92-3.86 (2H, m), 3.69 (2H, s), 3.60-3.56 (2H, m), 3.20 (2H, t, J 5.5), 2.25 (3H, s), 1.43-1.39 (3H, m).
Description 89: 2-Bromo-N-(3-fluorophenyl)acetamide
Bromoacetyl bromide (23.5 mL, 0.27 mol) was added slowly to a stirred, cooled mixture of 3- fluoroaniline (25 g, 0.225 mol) in EtOAc (250 mL) and aqueous KHCO3 (20%, 250ml). The mixture was allowed to warm to RT and the layers were separated. The organic layer was diluted with EtOAc, washed with aqueous citric acid (10%) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (51.72 g, 92%). 1H NMR (360MHz, CD3OD) δ 7.54 (IH, dt, J 11, 2), 7.34-7.24 (2H, m), 6.84 (IH, t, J 7), 3.96 (2H, s).
Description 90: l-(3-Fluorophenyl)piperazinone Hydrochloride Ethanolamine (4.5 mL, 75 mmol) was added to stirred 2-bromo-N-(3-fluorophenyl)acetamide
(Description 89, 5.0 g, 21 mmol) in EtOAc (25 mL) and the mixture was stirred at 60 0C for 2 h. The mixture was cooled, EtOAc and water were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was suspended in EtOAc (135 mL) and tributylphosphine (5.3 mL, 21 mmol) was added. The mixture was cooled to 0 0C and di-tert-butylazodicarboxylate (4.8 g, 21 mmol) was added dropwise over 1 h. The mixture was stirred at 0 0C for 0.5 h, then at 40 0C for 1.5 h. The mixture was cooled and ethanolic HCl (4M, 4.7 mL) was added. The mixture was stored at 0 0C for 0.5 h., and the solid was collected, washing with cold EtOAc, and dried in vacuo to give the title compound. 1H NMR (400MHz, CD3OD) δ 3.68-3.71 (2H, m), 3.97-4.00 (2H, m), 4.02 (2H, s), 7.12 (IH, m), 7.18- 7.22 (2H, m), 7.48 (IH, m).
Description 91: N-(l-Ethyl-3-methyl-lH-pyrazol-5-yl)-3-azetidinamine
A mixture of l-ethyl-3-methyl-lH-pyrazol-5-amine (1.0 g, 8.0 mmol), l-(diphenylmethyl)-3-azetidinyl methanesulfonate (2.5 g, 8.0 mmol) and K2CO3 (2.2 g, 16.0 mmol) in DMF (10 mL) was stirred at 60 0C for 24 h. The mixture was cooled, poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 mL), palladium hydroxide (200 mg) was added and the mixture was shaken under H2 (45 psi) for 72 h. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2MeOH (90: 10), to give the title compound as an oil. (168 mg, 12%).
1H NMR (CD3OD) δ 5.15 (IH, s), 4.17-4.15 (IH, m), 3.90-3.81 (4H, m), 3.58 (2H, m), 2.09 (IH, s), 1.28 (3H, t, J7.1). Description 92: 8-(l-Ethyl-3-methyl-lH-pyrazol-5-yl)-l,4-dioxa-8-azaspiro[4.5]decane
A mixture of l-ethyl-3-methyl-lH-pyrazol-5-amine (1 g, 8 mmol), 2,2-bis(2-iodoethyl)-l,3-dioxolane (3 g, 8 mmol) and K2CO3 were dissolved in MeCN (15 mL) and heated under reflux for 4 days. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was suspended in EtOAc (100 mL) and washed with water (50 mL). The organic fraction was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexanes/EtOAc (80:20), to give the title compound (470 mg).
Description 93: l-(l-Ethyl-3-methyl-lH-pyrazol-5-yl)-4-piperidinone
8-(l-Ethyl-3-methyl-lH-pyrazol-5-yl)-l,4-dioxa-8-azaspiro[4.5]decane (Description 92) in aqueous acetic acid (75%, 16 mL) was heated under reflux for 16 h. The mixture was cooled and aqueous NaHCO3 (saturated, 300 mL) was added slowly. The mixture was extracted with EtOAc (2 x 200 mL) and the combined organic fractions were washed with brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. Heptane was added and evaporated under reduced pressure to give the title compound as an oil (0.3 g).
1H NMR (CDCl3) δ 5.69 (IH, s), 4.05 (2H, g, Jl.2), 3.19 (4H, m), 2.59 (4H, m), 2.23 (3H, s), 1.42 (3H, t, Jl.3).
Example 1: Jrαns-l-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5- methyl-2H-pyrazol-3-yl)piperidine
Sodium triacetoxyborohydride (0.3 g, 1.4 mmol) and acetic acid (62 mg, 1 mmol) were added to a mixture of 4-(4-bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone (Description 14, 0.44 g, 1 mmol) and 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine (0.2 g, 1 mmol) in 1,2-dichloroethane (8 mL) and the mixture was stirred at RT for 16 h. Water and EtOAc were added and the layers were separated. The organic layer was washed with aqueous NaHCO3 (saturated), water, and brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/isohexane mixtures, to give the title compound. 1H NMR (360MHz, CDCl3) δ 1.185 (2H, m), 1.36 (3H, t, Jl.2), 1.60 (2H, m), 1.79-1.93 (2H, m), 2.14 (2H, t, J 11.3), 2.19 (3H, s), 2.30 (2H, t, J 13.7), 2.35-2.50 (2H, m), 2.58 (2H, m), 2.86 (2H, m), 3.96 (2H, q, Jl.2), 5.73 (IH, s), 7.09 (2H, d, J8.7), 7.22 (2H, d, J8.7), 7.34 (2H, d, J8.7), 7.43 (2H, d, J8.7). m/z (ES+) 603, 605 (M+l).
The following compounds were prepared according to the method of Example 1 substituting a suitable cyclohexanone for 4-(4-bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone and a suitable amine for 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine.
Example 122: rrøns-l-{4-Phenylmethyl-4-[4-(trifluoromethyl)benzenesulfonyl] cyclohexyl]-4-(2- ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
Pd on C (30 mg) was added to a solution of trans- l-{4-(4-bromophenylmethyl)-4-[4- (trifluoromethyl)benzenesulfonyl]cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine (Example 119, 57 mg, 87 μmol) in EtOAc (5 mL) and the mixture was vigorously stirred under a H2 atmosphere overnight. The mixture was filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with EtOAc/MeOH/NH3(Aq.) (98:2:0.2) to give the title compound (10 mg, 20%). 1H NMR (500MHz, CD3OD): δ 7.99 (d, J8.1, 2H); 7.89 (d, J8.1, 2H); 7.36 (d, J8.2, 2H); 7.24 (m, 3H); 5.83 (s, IH); 4.02 (q, Jl.2, 2H); 3.26 (s, 2H); 3.01 (d, J 11.3, 2H); 2.63 (m, IH); 2.35 (m, 3H); 2.16 (s, 3H); 2.10 (d, J 13.1, 2H); 1.90 (m, 6H); 1.63 (m, 4H); 1.33 (t, Jl.2, 3H). Example 123: rrα/ιs-4-(4-Bromophcnyl)-4-{[4-(trifluoromcthyl)phcnyl]sulfonyl}cyclohcxanaminc
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. The aqueous layer was separated and re-extracted with EtOAc. The combined organic layers were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography, eluting with 10% MeOH in CH2Cl2, to give the title compound (48 mg, 62%).
1H NMR (400MHz, CDCl3 δ 1.02 (2H, q, J 12.4), 1.88 (2H, d, J 12.3), 2.32 (2H, m), 2.53 (2H, d, J 13), 2.84 (IH, m), 7.09 (2H, d, J8.2), 7.43 (4H, d, J8.1), 7.63 (2H, d, J8.0).
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-(7røns-4-(4-Chloropheiiyl)-4-{[4- (trifluoromcthyl)phcnyl]sulfonyl}cyclohcxyl)pipcridin-4-aminc Hydrochloride
Hydrogen chloride in dioxane (4N, 10 mL) was added to a stirred solution of 1,1-dimethylethyl [\-(trans- 4-(4-chlorophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl} cyclohexyl)-4-piperidinyl]carbamate (Example 100, 2.045 g, 3.4 mmol) in CH2Cl2 (10 mL) and the mixture was stirred at RT overnight. The solvent was evaporated under reduced pressure to give the title compound (1.73 g, 95%). 1H NMR (360MHz, CD3OD): δ 7.78 (t, 2H), 7.55 (d, 2H), 7.35 (q, 4H), 3.53 (d, 3H), 3.06 (t, 2H), 2.85 (d, 2H), 2.38 (t, 3H), 2.21 (d, 4H), 1.93 (d, 2H), 1.41 (d, 2H).
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 CH2Cl2 (5 mL) and the mixture was stirred at RT for 2 h. Water was added and the mixture was extracted with CH2Cl2. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound (40 mg, 36%).
1H NMR (500MHz, CD3OD): δ 7.77 (d, 2H), 7.53 (d, 2H), 7.31 (q, 4H), 3.37 (t, IH), 2.77 (d, 2H), 2.71 (d, 2H), 2.52 (s, IH), 2.25 (q, 4H), 1.99 (d, 2H), 1.79 (d, 2H), 1.29 (t, 2H), 1.26 (s, 9H), 1.21-1.13 (m, 2H).

Claims

Claims
1. A compound of formula (I):
wherein: rings A and B are independently aryl or heteroaryl; n is 0, 1 or 2;
X and Y are independently selected from a bond, -CH2-, and -N(Ci-4alkyl)-; Z is a bond, -CH2- or -CCd^alkyl);.-;
R1 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, hydroxy, Ci-6alkoxy, halogen, CN, CO2(Ci-6alkyl) or C(CH3)2OH, optionally substituted by 1 to 8 halogen atoms;
R2 is hydrogen, d_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or halogen; R3 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8CyClOaIlCyI, hydroxy, Ci-6alkoxy, halogen or CN, optionally substituted by 1 to 8 halogen atoms;
R4 is hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl or halogen; R5 and R6 are independently selected from hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3- gcycloalkyl, hydroxy, Ci-6alkoxy or halogen;
R7 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (CH2)0-2aryl, (CH2)0- 2heteroaryl 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 R8 is hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl or C3-8cycloalkyl; or R7 and R8, 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 Ci_6alkyl, C2- 6alkenyl, C2-6alkynyl or C3-8CyClOaIlCyI, hydroxy, oxo, (CH2)0-3Ci-6alkoxy, (CH2)o_3Oaryl, (CH2)o_3aryl, (CH2)o_3heteroaryl, (CH2)0-3Het, or (CH2)0-3NRaRb , wherein said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from Ci-6alkyl, hydroxy, oxo, Ci-6alkoxy or halogen, which Ci-6alkyl being optionally substituted by hydroxy or 1 to 5 halogen atoms, and where said aryl, heteroaryl and Het are also optionally fused to a 5- or 6-membered ring which optionally contains 1, 2 or 3 heteroatoms selected from N, O or S and which ring is optionally substituted by hydroxy, oxo, or halogen, and which heterocycle may optionally be fused to heteroaryl, which heteroaryl is optionally substituted by Ci-6alkyl or trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5- or 10-membered mono- or bi-cyclic ring system optionally containing 1, 2 or 3 heteroatoms selected from N, O and S, and further optionally containing 1, 2 or 3 double bonds and also optionally substituted by 1 to 3 groups independently selected from Ci-6alkyl, hydroxy, oxo, phenyl and SO2Ci-6alkyl;
Ra is hydrogen, Ci-6alkyl, C(O)Ci-6alkyl, C(O)OCi-6alkyl, C(O)NH(Ci-6alkyl), (CH2)0-3aryl, (CH2)o-3heteroaryl or SO2Ci-6alkyl, optionally substituted by Ci-6alkyl;
Rb is hydrogen, Ci-6alkyl or aryl; and pharmaceutically acceptable salts thereof.
2. A compound as claimed in Claim 1 wherein ring A is phenyl, pyridyl or pyrimidyl.
3. A compound as claimed in Claim 1 or Claim 2 wherein ring B is aryl or pyridyl.
4. A compound as claimed in any one of Claims 1 to 3 wherein n is 1 or 2.
5. A compound as claimed in any one of Claims 1 to 4 wherein X is a bond, -CH2- or
-CCd^alkyl),-.
6. A compound as claimed in any one of Claims 1 to 5 wherein Y is a bond, -CH2- or -CCd^alkyl),-.
7. A compound as claimed in any one of Claims 1 to 6 wherein Z is a bond or -CH2-.
8. A compound as claimed in any one of Claims 1 to 7 wherein R1 is hydrogen, Ci-6alkyl; hydroxy, Ci-6alkoxy, halogen, CN, CO2(Ci-4alkyl) or C(CH3)2OH, optionally substituted by 1 to 5 halogen atoms.
9. A compound as claimed in any one of Claims 1 to 8 wherein R2 is hydrogen or Ci-6alkyl.
10. A compound as claimed in any one of Claims 1 to 9 wherein R3 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, halogen or CN, optionally substituted by 1 to 5 halogen atoms.
11. A compound as claimed in any one of Claims 1 to 10 wherein R4 is hydrogen or halogen.
12. A compound as claimed in any one of Claims 1 to 11 wherein R5 is hydrogen, Ci-6alkyl, hydroxy, Ci-6alkoxy, or halogen.
13. A compound as claimed in any one of Claims 1 to 12 wherein R6 is hydrogen or Ci-6alkyl.
14. A compound as claimed in any one of Claims 1 to 13 wherein R7 is hydrogen, Ci-6alkyl, (CH2V 2aryl, or Het, optionally substituted by Ci-4alkyl, or heteroaryl, which heteroaryl is optionally substituted by 1 or 2 methyl or ethyl groups.
15. A compound as claimed in any one of Claims 1 to 14 wherein R8 is hydrogen or Ci-6alkyl.
16. A compound as claimed in any one of Claims 1 to 13 wherein R7 and R8, 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, CH2-O-phenyl, phenyl, heteroaryl, CH2heteroaryl, Het, NH2, (CH2)0-iNHRa or CH2N(phenyl)SO2CH3, where said aryl, heteroaryl, and Het are optionally substituted by 1, 2 or 3 groups selected from oxo or halogen, which Ci-4alkyl 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-4alkoxy, and which heterocycle may optionally be fused to pyridyl or triazolyl, optionally substituted by trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5-membered monocyclic or a 8- or 9-membered bicyclic ring system, optionally containing 1 or 2 N atoms, further optionally containing 2 or 3 double bonds and also optionally substituted by oxo, phenyl, or and Ra is as defined in Claim 1.
17. A compound as claimed in Claim 1 of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein ring A, n, X, Y, R1, R3, R4, R7 and R8 are as defined in Claim 1.
18. A compound as claimed in Claim 17 of formula (Iaa):
or a pharmaceutically acceptable salt thereof, wherein R1 and R3 are as defined in Claim 1, and R9 is (CH2)o-3NRaRb, where Ra and Rb are as defined in Claim 1, or (CH2)0-3heteroaryl or (CH2)o-3Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3 groups independently selected from Ci-6alkyl, hydroxy, oxo, Ci-6alkoxy or halogen, which Ci-6alkyl 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-4alkyl, hydroxy or
19. A compound as claimed in Claim 17 of formula (lab):
or a pharmaceutically acceptable salt thereof, wherein R3 is as defined in Claim 1 and R9 is as defined in Claim 18.
20. A compound as claimed in Claim 1 which is selected from Examples 1 to 126 or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
22. A compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof for use in therapy.
23. Use of a compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a NK-3 receptor mediated disease.
24. A method of treatment of a subject suffering from a NK-3 receptor mediated disease, which comprises administering to that patient a therapeutically effective amount of a compound of any one of Claims 1 to 20 or a pharmaceutically acceptable salt thereof.
25. The use of Claim 23 or the method of Claim 24 wherein the NK-3 receptor mediated disease is selected from: depression; anxiety disorders; phobias; psychosis and psychotic disorders; post-traumatic 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.
26. A method of preparing a compound of Claim 1 where Z is a bond by the reaction of a compound of formula (II) with a compound of formula (III):
(H) (HI)
where A, B, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in Claim 1.
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