US20020143020A1 - Novel piperazine derivatives - Google Patents

Novel piperazine derivatives Download PDF

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Publication number
US20020143020A1
US20020143020A1 US10/010,058 US1005801A US2002143020A1 US 20020143020 A1 US20020143020 A1 US 20020143020A1 US 1005801 A US1005801 A US 1005801A US 2002143020 A1 US2002143020 A1 US 2002143020A1
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United States
Prior art keywords
piperazine
compound
carboxylic acid
fluoro
cis
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.)
Abandoned
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US10/010,058
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English (en)
Inventor
David Adams
Jonathan Bentley
James Davidson
Claire Dawson
Ashley George
Howard Mansell
Patrizio Mattei
Jacques Mizrahi
Matthias Nettekoven
Robert Pratt
Stephan Roever
Jonathan Roffey
Jean-Luc Specklin
Henri Stalder
Kerry Wilkinson
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.)
Ligand UK Research Ltd
Hoffmann La Roche Inc
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Assigned to VERNALIS RESEARCH LIMITED reassignment VERNALIS RESEARCH LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADAMS, DAVID REGINALD, BENTLEY, JONATHAN MARK, DAVIDSON, JAMES EDWARD PAUL, DAWSON, CLAIRE ELIZABETH, GEORGE, ASHLEY ROGER, MANSELL, HOWARD LANGHAM, PRATT, ROBERT MARK, ROFFEY, JONATHAN RICHARD ANTHONY, WILKINSON, KERRY
Assigned to HOFFMANN-LA ROCHE INC. reassignment HOFFMANN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MIZRAHI, JACQUES, NETTEKOVEN, MATTHIAS HEINRICH, ROEVER, STEPHAN, SPECKLIN, JEAN-LUC, STALDER, HENRI, MATTEI, PATRIZIO
Publication of US20020143020A1 publication Critical patent/US20020143020A1/en
Priority to US10/874,662 priority Critical patent/US7022707B2/en
Abandoned legal-status Critical Current

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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • BMI body mass index
  • m 2 body weight index
  • Overweight is defined as a BMI in the range 25-30 kg/m .
  • Obesity is a BMI greater than 30 kg/m
  • Orlistat a lipase inhibitor
  • Sibutramine a mixed 5-HT/noradrenaline re-uptake inhibitor
  • the serotonin releaser/re-uptake inhibitors fenfluramine (Pondimin®) and dexfenfluramine (ReduxTM) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
  • mCPP m-chlorophenylpiperazine
  • TFMPP trifluoromethylphenylpiperazine
  • CA-2132887 and CA-2153937 disclose that tricyclic 1-aminoethylpyrrole derivatives and tricyclic 1-aminoethyl pyrazole derivatives bind to 5-HT 2C receptors and may be used in the treatment of obesity.
  • WO-A-98/30548 discloses aminoalkylindazole compounds as 5-HT 2C agonists for the treatment of CNS diseases and appetite regulation disorders.
  • WO 0035922 discloses 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)ones as 5HT 2C agonists.
  • Aralkyloxycarbonyl-substituted piperazine derivatives have been repeatedly described as nitrogen-protected piperazine synthetic intermediates (e.g. Org. Lett., 2000, 2(8), 1049-1051.
  • the present invention is a new piperazine derivative, processes and intermediates for its preparation, to pharmaceutical compositions containing the compound of the invention and to a method of treatment using the compound.
  • the active compound of the present invention is useful in treating obesity and other disorders.
  • the invention is a compound of formula I or a pharmaceutically acceptable salt, solvate or ester therof
  • R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aryl and aralkyl or R 1 and R 2 together with the carbon atom to which they are attached form an unsubstituted 3- to 8-membered carbocyclic ring or a 3- to 8-membered ring which is substituted with alkyl;
  • R 3 and R 4 are independently selected from hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
  • a 1 is oxygen or sulfur, wherein in case A 1 is oxygen and A 2 is unsubstituted phenyl one of R 1 , R 2 , R 3 and R 4 is not hydrogen
  • a 2 is unsubstituted aryl, unsubstituted heteroaryl or unsubstituted cycloalkyl or aryl, heteroaryl or cycloalkyl each substituted with at least one substituent independently selected from the group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy, or wherein said alkyl,
  • n 1 or 2;
  • m is zero or 1;
  • alkyl signifies a straight-chain or branched-chain alkyl group with 1 to 10, preferably 1 to 8 carbon atoms, more preferably a straight or branched-chain alkyl group with 1-4 carbon atoms.
  • Examples of straight-chain and branched C 1 -C 8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl, ethyl, propyl and isopropyl. Particularly preferred are methyl and ethyl.
  • cycloalkyl signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms.
  • Examples of C 3 -C 8 cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methylcyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclo-propyl and particularly cyclopentyl.
  • alkoxy signifies a group of the formula alkyl-O— in which the term “alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy, preferably methoxy and ethoxy.
  • cycloalkoxy alone or in combination, signifies a group of the formula cycloalkyl-O— in which the term “cycloalkyl” has the previously given significance, such as cyclohexyloxy.
  • carbonyl refer to a group of the formula —C(O)—.
  • aryl signifies a phenyl or naphthyl group, preferably a phenyl group which optionally carries one or more, preferably one to three substituents each independently selected from halogen, trifluoromethyl, amino, alkyl, aryloxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy, carboxy, alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro and alkoxy, wherein alkoxy is optionally substituted with 1 to 3 halogen atoms.
  • Preferred is phenyl.
  • aryloxy alone or in combination, signifies a group of the formula aryl-O— in which the term “aryl” has the previously given significance. Phenyloxy is an example of such an aryloxy group.
  • heteroaryl signifies an aromatic 5 to 10, preferably 5- or 6-membered ring comprising 1 to 3 atoms independently selected from nitrogen, oxygen or sulfur such as e.g. furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl and benzothiadiazolyl.
  • furyl e.g. furyl
  • thienyl isoxazolyl
  • oxazolyl pyrrolyl and benzothiadiazolyl.
  • Preferred examples are pyridyl, thienyl, pyrazinyl, furyl, isoxazole, (1,2,4)oxadiazole and thiazolyl.
  • Particularly preferred are pyridyl and thienyl.
  • heteroarylalkoxy signifies an alkoxy group as defined before, wherein one or two, preferably one hydrogen atom is replaced by a heteroaryl group as defined before.
  • heteroarylalkoxy examples are pyridin-3-ylmethoxy, isoxazol-4-ylmethoxy, (1,2,4)oxadiazol-3-ylmethoxy, 3-furylmethoxy, thien-3-ylmethoxy, isoxazol-3-ylmethoxy, thien-2-methoxy, (2,1,3)benzothiadiazolylmethoxy, 2-thiophen-2-yl-ethoxy, 2-pyrrol-1-yl-ethoxy and thiazol-4-ylmethoxy.
  • aralkyl signifies an alkyl or cycloalkyl group as previously defined in which one or several, preferably one hydrogen atom has been replaced by an aryl group as previously defined. Preferred is benzyl.
  • 3- to 8-membered carbocyclic ring as used for the definition of R 1 and R 2 signifies a 3- to 8-membered, preferably 3 to 6 membered cycloalkane ring.
  • Examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane, preferably cyclopropane.
  • the term “5- to 7-membered carbocyclic ring” as used for the definition of A 2 signifies a cycloalkane ring with 5 to 7, preferably 6 carbon atoms optionally substituted with alkyl, alkoxy or halogen.
  • Examples are cyclopentane, methyl-cyclopentane, cyclohexane, methylcyclohexane, dimethyl-cyclohexane and cycloheptane preferably cyclohexane.
  • aralkoxy signifies an alkoxy or cycloalkoxy group as previously defined in which one or several, preferably one hydrogen atom has been replaced by an aryl group as previously defined. Preferred is benzyloxy.
  • nitro alone or in combination, signifies a —NO 2 group.
  • cyano alone or in combination, signifies a —CN group.
  • alkoxycarbonyl alone or in combination, signifies an alkoxy-C(O)— group, wherein alkoxy is defined as before.
  • cycloalkoxycarbonyl alone or in combination, signifies an cycloalkoxy-C(O)— group, wherein cycloalkoxy is defined as before.
  • aryloxycarbonyl alone or in combination, signifies an aryloxy-C(O)— group, wherein aryloxy is defined as before.
  • aralkoxycarbonyl alone or in combination, signifies an aralkoxy-C(O)— group, wherein aralkoxy is defined as before.
  • heteroaryloxycarbonyl alone or in combination, signifies a heteroaryl-O—C(O)— group, wherein heteroaryl is defined as before.
  • amino signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents together forming a ring, such as, for example, —NH 2 , methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino and diethylamino and particularly primary amino.
  • halogen signifies fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine and particularly fluorine and chlorine.
  • carbamoyl alone or in combination refers to a group of the formula NH(R′)—C(O)—, wherein R′ means hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, adamantyl, alkenyl or alkyl substituted with halogen.
  • R′ means alkyl or aralkyl particularly preferred are isopropyl, benzyl and tert. butyl.
  • carbamoyloxy alone or in combination, signifies a carbamoyl-O— group, wherein carbamoyl is defined as before.
  • alkylsulfonyloxy alone or in combination, signifies a
  • alkyl is as previously defined.
  • An examples is propylsulfonyloxy.
  • arylsulfonyloxy alone or in combination, signifies a
  • alkenyl alone or in combination, signifies a straight-chain or branched-chain hydrocarbon group comprising an carbon-carbon double bond and 1 to 10, preferably 1 to 8 carbon atoms, more preferably 1-4 carbon atoms.
  • alkenyloxy alone or in combination, signifies an alkenyl-O— group, wherein alkenyl is defined as before.
  • alkynyl signifies a straight-chain or branched-chain hydrocarbon group comprising an carbon-carbon triple bond and 1 to 10, preferably 1 to 8 carbon atoms, more preferably 1-4 carbon atoms.
  • alkynyloxy alone or in combination, signifies an alkynyl-O— group, wherein alkynyl is defined as before.
  • Examples of pharmaceutically acceptable salts of the compounds of formula I are salts with physiologically compatible mineral acids such hydrochloric acid, sulfuric acid or phosphoric acid; or with organic acids such as methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • Preferred salts of compounds of formula I are hydrochloride salts, succinate salts and fumarate salts.
  • the compounds of formula I can also form salts with physiologically compatible bases. Examples of such salts are alkali metal, alkali earth metal, ammonium and alkylammonium salts such as the Na, K, Ca or tetramethylammonium salt.
  • the compound of formula I can also be present in the form of zwitterions.
  • the invention expressly includes pharmaceutically acceptable derivatives of the compounds of formula I.
  • hydroxy groups of compounds of formula I can be esterified.
  • esters are formate, acetate, propionate, butyrate, isobutyrate, valerate, 2-methylbutyrate, isovalerate and N,N-dimethylaminoacetate.
  • Preferred esters are acetate and N,N-dimethylaminoacetate.
  • solvates of compounds according to formula I such as for example hydrates.
  • the solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
  • lipase inhibitor refers to compounds that are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases.
  • orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are potent inhibitors of lipases.
  • Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin.
  • Other lipase inhibitors include a class of compound commonly referred to as panclicins. Panclicins are analogues of orlistat (Mutoh et al, 1994).
  • lipase inhibitor refers also to polymer bound lipase inhibitors for example described in International Patent Application WO99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterised in that they have been substituted with one or more groups that inhibit lipases.
  • lipase inhibitor also comprises pharmaceutically acceptable salts of these compounds.
  • lipase inhibitor preferably refers to orlistat.
  • Orlistat is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1, 1986, which also discloses processes for making orlistat and U.S. Pat. No. 6,004,996, which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described for example in International Patent Applications WO 00/09122 and WO 00/09123. Additional processes for the preparation of orlistat are disclosed in European Patent Applications Publication Nos. 185,359, 189,577, 443,449, and 524,495.
  • Orlistat is preferably orally administered from 60 to 720 mg per day in divided doses two to three times per day. Preferred is wherein from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day.
  • the subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater.
  • the lipase inhibitor be administered within about one or two hours of ingestion of a meal containing fat.
  • treatment be administered to a human who has a strong family history of obesity and has obtained a body mass index of 25 or greater.
  • Orlistat can be administered to humans in conventional oral compositions, such as, tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions.
  • carriers which can be used for tablets, coated tablets, dragées and hard gelatin capsules are lactose, other sugars and sugar alcohols like sorbitol, mannitol, maltodextrin, or other fillers; surfactants like sodium lauryl sulfate, Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maize starch or derivatives thereof; polymers like povidone, crospovidone; talc; stearic acid or its salts and the like.
  • Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
  • the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. They can also contain still other therapeutically valuable substances.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the pharmaceutical art. Preferably, orlistat is administered according to the formulation shown in the Examples and in U.S. Pat. No. 6,004,996, respectively.
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluent).
  • asymmetric carbon atom means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog-Convention the asymmetric carbon atom can be of the “R” or “S” configuration.
  • R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aryl and aralkyl or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 8-membered carbocyclic ring which is optionally substituted with alkyl;
  • R 3 and R 4 are independently selected from hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
  • a 1 is oxygen or sulfur, wherein in case A 1 is oxygen and A 2 is unsubstituted phenyl, one of R 1 , R 2 , R 3 and R 4 is not hydrogen;
  • a 2 is aryl, heteroaryl or cycloalkyl each optionally substituted with one or more substituents independently selected from halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl and carbamoyl, wherein alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and heteroaryloxycarbonyl are optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halogen and nitro, or two substituents of aryl,
  • n 1 or 2
  • More preferred compounds according to formula I are those wherein R 3 and R 4 are independently selected from hydrogen and alkyl,most preferably R 3 and R 4 are hydrogen.
  • R 3 and R 4 are both alkyl. Additional preferred compounds are those wherein R 3 and R 4 are methyl. Most preferred are the compounds according to formula I, wherein R 3 and R 4 are methyl and both methyl groups have the cis configuration. Preferred are the cis-2,6-dimethylpiperazine derivatives of the formula I, wherein R 3 and R 4 are methyl and R 1 , R 2 , A 1 , A 2 , m and n are defined as mentioned before.
  • a further preferred embodiment of the invention are compounds according to formula I, wherein one of R 3 and R 4 is methyl or ethyl and the other one is hydrogen.
  • R 5 is alkyl, particularly methyl or ethyl
  • R 1 , R 2 , A 1 , A 2 , m and n are defined as before.
  • Formula Ia means that the asymmetric carbon atom C*
  • [0072] is of the R configuration.
  • Also preferred compounds of formula I are those wherein R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aryl and aralkyl or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl ring which is optionally substituted with alkyl.
  • a particularly preferred embodiment of the invention comprises compounds of formula I, wherein R 1 and R 2 are independently selected from hydrogen, alkyl and aryl, preferably hydrogen, methyl and phenyl. Most preferred are those compounds, wherein R 1 and R 2 are both hydrogen.
  • a 2 is aryl, heteroaryl or cycloalkyl each optionally substituted with one or more, preferably one to four, particularly preferred one to three substituents independently selected from halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy, wherein alkyl, cycloalkyl, aryl
  • a 2 is phenyl, naphthalenyl, cycloalkyl, pyridyl, thienyl, pyrazinyl or furyl, each optionally substituted with one or more, preferably one to four substituents, independently selected from halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl and carbamoyl, wherein alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
  • a 2 is phenyl, naphthalenyl, cyclohexyl, pyridyl or thienyl each optionally substituted with one or more, preferably one to four substituents independently selected from halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl and carbamoyl, wherein alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and heteroaryloxycarbonyl are optionally substitute
  • substituents of phenyl, naphthalenyl, cyclohexyl, pyridyl and thienyl are trifluoromethoxyl, fluoro, chloro, bromo, nitro, phenylmethoxy, trifluoromethyl, methyl, tert-butyl, difluoromethoxy, cyano, methoxycarbonyl, benzyloxy, fluoro-benzyloxy, chlorobenzyloxy and nitrobenzyloxy.
  • Particularly preferred are compounds of formula I are those, wherein A 2 is phenyl, naphthalenyl, cyclohexyl, pyridyl or thienyl each optionally substituted with one or more, preferably one to four substituents independently selected from halogen, alkyl, aryl, alkoxy, aralkoxy, cyano, nitro, alkoxycarbonyl, wherein alkyl, alkoxy, aralkoxy and alkoxycarbonyl are optionally substituted with one to three substituents independently selected from halogen and nitro.
  • A is phenyl, optionally substituted with one to five, preferably one to three substituents independently selected from halogen, alkyl, aryl, alkoxy, aralkoxy, cyano, nitro, alkoxycarbonyl, wherein alkyl, alkoxy and aralkoxy optionally substituted with one to three substituents independently selected from halogen and nitro.
  • a further preferred object of the present invention are compounds according to formula I, wherein n is 1.
  • Another preferred object of the present invention are compounds according to formula I, wherein A 2 is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, alkynyloxy and cycloalkylalkoxy, wherein alkoxy, heteroarylalkoxy and alkenyloxy are optionally substituted with one to three substituents independently selected from alkyl and halogen.
  • a 2 is phenyl, optionally substituted with one to three substituents independently selected from fluoro, chloro, difluoromethoxy, propoxy, 3,5-dimethyl-isoxazol-4-ylmethoxy, 2-propenyloxy, 5-pentyloxy, cyclopropylmethoxy, 2-propynyloxy and NH(R′)—C(O)—O—, wherein R′ is isopropyl, benzyl or tert.-butyl.
  • Examples of preferred compounds of formula I include:
  • a compound of formula (VI) can be prepared by reaction of the piperazine carbamoyl chloride (III) with an alcohol (IV) or thiol (V) in the presence of a suitable base such as sodium hydride, triethylamine, PS-BEMP or pyridine in a solvent such as acetonitrile, N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran or dichloromethane.
  • a suitable base such as sodium hydride, triethylamine, PS-BEMP or pyridine
  • a solvent such as acetonitrile, N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran or dichloromethane.
  • P protecting group
  • tert-butoxycarbonyl 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyl, 3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and 9-fluorenylmethoxycarbonyl.
  • These protective groups may also be bound to a polymeric resin, e.g., polystyrene-PEG-bound trityl.
  • the protected piperazine-carbamoyl chloride (III) may be synthesized from a protected piperazine (II) by treatment with a reagent such as phosgene, diphosgene or triphosgene in the presence of a base such as pyridine in a suitable solvent, for instance dichloromethane.
  • a reagent such as phosgene, diphosgene or triphosgene
  • a base such as pyridine
  • a suitable solvent for instance dichloromethane.
  • protected piperazines (II) can be synthesized from commercially available monoalkyl- or dialkyl-piperazines by treatment with reagents known to introduce the desired protecting group e.g. di-tert-butyl dicarbonate or 9-fluorenylmethyl chloroformate.
  • Mono or dialkyl-piperazines may be prepared by those skilled in the art via a variety of methods which includes, but is not limited to: reduction of mono or dialkylpyrazines using e.g. catalytic hydrogenation or dissolved metal reagents; alkylation of ethylene diamine and alkylated analogues with e.g.
  • alkyl-substituted 1,2-dihaloethane compounds alkyl-substituted 1,2-ethanediol compounds or alkyl-substituted ethane-1,2-dialkylsulfonate compounds; reduction of a monoalkyl substituted 2,5-diketopiperazine with e.g. sodium or lithium borohydride or lithium aluminium hydride.
  • the alcohol (IV) may be commercially available or alternatively may be synthesized via reduction of an aldehyde, carboxylic acid, ester or amide derivative with a reagent such as sodium or lithium borohydride or lithium aluminium hydride in a suitable solvent or alternatively via Grignard addition of alkyl- or aryl-magnesium halides or alkyl- or aryl-lithium nucleophiles to aldehydes or carboxylic esters or amides.
  • the aldehydes, carboxylic acids, esters and amides may be commercially available or synthesized according to methods known to those skilled in the art. Such methods include but are not limited to formylation of an aryl or heteroaryl containing starting-material, vicarious nucleophilic substitution, hydrolysis of an alkyl halide or oxidation of an aryl-methyl (tolyl) group.
  • Thiols of formula (V) may be prepared from (IV) by a variety of methods e.g. displacement of an activated derivative of the hydroxyl of (IV) with a sulfur nucleophile such as thiolacetic acid followed by treatment with a reducing agent such as lithium aluminium hydride.
  • Activated hydroxyl derivatives include, but are not limited to, mesylates, tosylates and in situ activation with phosphorus compounds such as triphenylphosphine.
  • Thiols of formula (V) may be replaced by xanthogenates, which are prepared in situ from alcohol (IV) with carbon disulfide and a base such as sodium or potassium hydroxide in a solvent such as tetrahydrofuran or acetone.
  • Compounds of formula (I) may be prepared from compounds of formula (VI) by reaction with a reagent known to selectively remove the protecting group (P) e.g. tert-butoxycarbonyl, triphenylmethyl and 3,4-dimethoxybenzyl may be removed using an acid such as hydrochloric acid or trifluoroacetic acid and 9-fluorenylmethoxycarbonyl may be removed by treatment with a base such as morpholine.
  • a reagent known to selectively remove the protecting group (P) e.g. tert-butoxycarbonyl, triphenylmethyl and 3,4-dimethoxybenzyl may be removed using an acid such as hydrochloric acid or trifluoroacetic acid and 9-fluorenylmethoxycarbonyl may be removed by treatment with a base such as morpholine.
  • Such methods include, but are not limited to, conversion of an alcohol of formula (IV) where A 1 ⁇ O via treatment with triphenylphosphine and a halogen such as bromine; formation and displacement of an alkyl or arylsulfonate such as mesylate or tosylate with a halide salt such as sodium bromide in a solvent such as tetrahydrofuran or acetone and halogenation of an aralkyl or heteroaralkyl compound with a reagent such as N-bromosuccinimide optionally in the presence of a co-reagent such as AIBN (2,2′-azobisisobutyronitrile) or benzoyl peroxide.
  • a co-reagent such as AIBN (2,2′-azobisisobutyronitrile) or benzoyl peroxide.
  • Compounds of formula (VI) can be transformed into compounds of formula (I) by methods as described above in Reaction Scheme 1.
  • R 1 , R 2 , R 3 , R 4 and the substituent groups attached to A 2 are other than the one required, the substituent group may be converted to the desired substituent by known methods.
  • R 1 , R 2 , R 3 , R 4 and the substituent groups attached to A 2 may also need protecting against the conditions under which the reaction is carried out. In such a case, the protecting group may be removed after the reaction has been completed.
  • a compound of formula (VI) can be prepared by reaction of the piperazine (II) with an activated derivative (IX) or (X) of alcohol (IV) optionally in the presence of a suitable base such as triethylamine, PS-BEMP or pyridine in a solvent such as acetonitrile, N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran or dichloromethane.
  • a suitable base such as triethylamine, PS-BEMP or pyridine
  • a solvent such as acetonitrile, N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran or dichloromethane.
  • P protecting group
  • tert-butoxycarbonyl 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyl, 3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and 9-fluorenylmethoxycarbonyl.
  • the activated derivative (IX) may be synthesizedsynthesized from alcohol (IV) with 1-chloroalkyl chloroformate, preferably 1-chloroethyl chloroformate, in the presence of a suitable base such as triethylamine, PS-BEMP or pyridine in a solvent such as acetonitrile, N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran or dichloromethane.
  • a suitable base such as triethylamine, PS-BEMP or pyridine
  • a solvent such as acetonitrile, N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran or dichloromethane.
  • the activated derivative (X) is either commercially available or may be synthesizedsynthesized from alcohol (IV) by treatment with a reagent such as phosgene, diphosgene, or triphosgene, optionally in the presence of a base such as pyridine, in a suitable solvent, e. g., dichloromethane or tetrahydrofuran.
  • a reagent such as phosgene, diphosgene, or triphosgene
  • a base such as pyridine
  • Compounds of formula (I) may be prepared from compounds of formula (VI) by reaction with a reagent known to selectively remove the protecting group (P) e.g. tert-butoxycarbonyl and 3,4-dimethoxybenzyl may be removed using an acid such as hydrochloric acid or trifluoroacetic acid and 9-fluorenylmethoxycarbonyl may be removed by treatment with a base such as morpholine.
  • a reagent known to selectively remove the protecting group (P) e.g. tert-butoxycarbonyl and 3,4-dimethoxybenzyl may be removed using an acid such as hydrochloric acid or trifluoroacetic acid and 9-fluorenylmethoxycarbonyl may be removed by treatment with a base such as morpholine.
  • the processes as described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds.
  • a further object of the present invention is the process for the preparation of a compound according to formula I comprising the deprotection of a compound according to formula
  • R 1 to R 4 , A 1 , A 2 , m and n are defined as before and (P) is a nitrogen protecting group.
  • nitrogen protecting groups are tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyl, 3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and 9-fluorenylmethoxycarbonyl.
  • a further object of the invention are compounds of formula I as described above for the production of medicaments for the prophylaxis and therapy of illnesses which are caused by disorders associated with the 5-HT 2 receptor, particularly with the 5-HT 2a , 5-HT 2b or 5-HT 2c subtype. Most preferred is the 5-HT 2c subtype.
  • an object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I and a therapeutically inert carrier.
  • a further object of the invention is a compound of formula I for the production of pharmaceutical compositions for the treatment and prophylaxis of eating disorders and obesity.
  • an object of the invention is the use of a compound according to formula I for the production of medicaments for the treatment of diabetes mellitus, Type I diabetes, Type II diabetes, diabetes secondary to pancreatic disease, diabetes related to steroid use, Type III diabetes, hyperglycaemia, diabetic complications and insulin resistance.
  • a further object of the invention is the use of a compound of formula I for the production of medicaments for the treatment of Type II diabetes.
  • Another object of the invention is the use of compounds in accordance with formula I for the production of medicaments for the treatment and prophylaxis of disorders of the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus and sleep apnoea.
  • an object of the invention is the above method of treatment, wherein the disorders of the central nervous system are selected from depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexia nervosa, premenstrual tension, trauma, stroke, neurodegenerative diseases, encephalitis and meningitis.
  • the disorders of the central nervous system are selected from depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracra
  • a further preferred embodiment of the present invention is the above mentioned method of treatment by administering the compounds according to formula I, wherein the cardiovascular disorder is thrombosis.
  • a further object of the invention are compounds in accordance with formula I, when manufactured according to the described process.
  • a further embodiment of the present invention is a method for the treatment and prophylaxis of disorders of the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, and sleep apnoea, which method comprises administering an effective amount of a compound of formula I as described.
  • the disorders of the central nervous system are selected from depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexia nervosa, premenstrual tension, trauma, stroke, neurodegenerative diseases, encephalitis and meningitis.
  • a preferred object of the invention is a method for the treatment and prophylaxis of eating disorders and obesity, which method comprises administering an effective amount of a compound of formula I.
  • Another object of the present invention is a method for the treatment and prophylaxis of disorders selected from diabetes mellitus, Type I diabetes, Type II diabetes, diabetes secondary to pancreatic disease, diabetes related to steroid use, Type III diabetes, hyperglycaemia, diabetic complications and insulin resistance, which method comprises administering an effective amount of a compound in accordance with formula I.
  • a method for the treatment and prophylaxis of Type II diabetes comprises administering an effective amount of a compound in accordance with formula I.
  • Particularly preferred is the above method for the treatment and prophylaxis of Type II diabetes.
  • Particularly preferred is a method for the treatment and prophylaxis of Type II diabetes.
  • a further preferred object is a method of treatment of obesity in a human in need of such treatment which comprises administration to the human a therapeutically effective amount of a compound according to formula I and a therapeutically effective amount of a lipase inhibitor, particularly, wherein the lipase inhibitor is orlistat.
  • an object of the invention are the method as described above for the simultaneous, separate or sequential administration.
  • a further object of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor and particularly, wherein the lipase inhibitor is orlistat.
  • Another object of the invention is the use of a compound according to formula I in the manufacture of a medicament for the treatment and prevention of diabetes mellitus, Type I diabetes, Type II diabetes, diabetes secondary to pancreatic disease, diabetes related to steroid use, Type III diabetes, hyperglycaemia, diabetic complications and insulin resistance in a patient who is also receiving treatment with a lipase inhibitor and particularly, wherein the lipase inhibitor is orlistat.
  • a compound according to formula I in the manufacture of a medicament for the treatment and prevention of Type II diabetes in a patient who is also receiving treatment with a lipase inhibitor and particularly, wherein the lipase inhibitor is orlistat.
  • an object of the invention is the pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, a therapeutically inert carrier and further a therapeutically effective amount of a lipase inhibitor, particularly, wherein the lipase inhibitor is orlistat.
  • the compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT 2 receptor function.
  • the compounds may act as receptor agonists or antagonists.
  • the compounds may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT 2b and/or 5-HT 2c receptor function.
  • the compounds may be used in the treatment (including prophylactic treatment) of disorders where a 5-HT 2c receptor agonist is required.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) transdermal or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • the affinity of the compounds for 5-HT 2C receptors in a CHO cell line was determined according to the procedure of D. Hoyer, G. Engel and H. O. Kalkman, European J. Pharmacol., 1985, 118, 13-23.
  • the affinity of the compounds for human 5-HT 2B receptors in a CHO cell line was determined according to the procedure of K. Schmuck, C. Ullmer, P. Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.
  • Preferred Ki (2C) values are below 10000 nM; especially preferred Ki (2C) values are below 1000 nM, particularly preferred Ki (2C) values are below 100 nM. Most preferred Ki (2C) values are below 50 nM.
  • the drug (dissolved in 50 ⁇ L of the assay buffer) was added at a rate of 70 ⁇ L/sec to each well of the FLIPR 96 well plate during fluorescence measurements. The measurements were taken at 1 sec intervals and the maximum fluorescent signal was measured (approx 10-15 secs after drug addition) and compared with the response produced by 10 ⁇ M 5-HT (defined as 100%) to which it was expressed as a percentage response (relative efficacy). Dose response curves were constructed using Graphpad Prism (Graph Software Inc.).
  • the compounds of formula (I) have activity at the h5-HT 2C receptor in the range of 10,000 to 0.1 nM.
  • Preferred activities at the h5-HT 2C receptor are below 10000 nM; especially preferred below 1000 nM, particularly preferred activities are below 100 nM. Most preferred activity at the h5-HT 2C receptor are below 50 nM.
  • the compounds of formula (I) have maximum functional activity at the h5-HT 2C receptor in the range of 0 to 100%.
  • Preferred maximal functional activity at the h5-HT 2C receptor as described above are above 30%; especially preferred above 50%, particularly preferred above 60%. Most preferred maximal functional activity at the h5-HT 2C receptor are above 70%.
  • the anorectic drug d-fenfluramine normally serves as a positive control.
  • the route of drug administration, drug volume and injection-test-interval are dependent upon the compounds used.
  • a palatable wet mash made by adding powdered lab chow and water in aratio of 1:2 and mixing to a smooth consistency, is presented in 120 mL glass jars for 60 minutes each day. Intake is measured by weighing before and after each session. Care is taken to collect all spillage. Animals are allowed to habituate to the wet mash meal for 10 days. After drug administration, animals are allowed to consume the wet mash. Food consumption is assayed at pre-determined time points (typically, 1, 2 and 4 hours after administration).
  • Food intake data are subjected to one-way analysis of variance (ANOVA) with drug as a between-subjects factor. A significant main effect is followed up by the performance of Dunnett's test in order to assess which treatment mean(s) are significantly different from the control mean. All statistical analyses were performed using Statistica Software, Version 5.0 (Statsofr Inc.) and Microsoft Excel 7.0 (Microsoft Corp.).
  • PS-BEMP 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazo-phosphorine on polystyrene
  • PS-NH2 4-(Aminomethyl)-polystyrene
  • (+/ ⁇ )4-Chlorocarbonyl-2-ethylpiperazine-1-carboxylic acid tert-butyl ester a solution of (RS) 4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g) and pyridine (1.64 ml) in DCM (35 ml) was added dropwise to a stirred solution of triphosgene (2.1 g) in DCM (100 ml) at 0° C. under Ar. The mixture was warmed to room temperature, stirred for 30 min then washed with water (100 ml) and brine (100 ml). The organic solution was dried (sodium sulfate) and concentrated in vacuo.
  • (+/ ⁇ )4-chlorocarbonyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester and (R)4-chlorocarbonyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester were prepared according to the above method from commercially available racemic 2-methylpiperazine and (R)2-methylpiperazine respectively.
  • Tetrabutylammonium hydrogencarbonate was prepared as described in St. C. Cheng, Ch. A. Blaine, M. G. Hill, K. R. Mann, Inorg. Chem. 35, 7704 (1996); C. Venturello, R. D'Aloisio, Synthesis 1985, 33.
  • N-Boc-piperazine is commercially available.
  • N-Fmoc-piperazine hydrobromide is commercially available.
  • 2-Fluoro-5-hydroxybenzyl alcohol was prepared according to the following procedure: 2-Fluoro-5-hydroxybenzaldehyde: to a stirred solution of 2-fluoro-5-methoxybenzaldehyde (18.3 g) in dichloromethane (200 mL) at 0° C. was added dropwise a solution of boron tribromide in dichloromethane (1M, 120 mL, 1 eq.). The mixture was stirred for 3 h then concentrated to a volume of ⁇ 50 mL and partitioned between ethyl acetate (500 mL) and water (500 mL).
  • Ethanethioic acid, S-[4-(tert-butyldimethylsilyloxy)benzyl]ester To an efficiently stirred solution of triphenylphosphine (81 g, 309 mmol) in THF (200 mL) was added diethyl azodicarboxylate (62.5 g, 309 mmol) at 0° C. The mixture was stirred for 30 min, after which time a thick white precipitate was obtained.
  • Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride A solution of 174 mg (0.49 mmol) piperazine-1,4-dicarboxylic acid tert-butyl ester 4-trifluoromethoxy-benzyl ester in 4.9 ml 1.5M HCl/Et2O and 0.98 ml abs. MeOH was stirred at rt for 3 h. Evaporation of the reaction mixture provided 189 mg as colourless powder.
  • Piperazine-1-carboxylic acid 3,4-difluoro-benzyl ester hydrochloride was prepared from 3,4-difluorobenzyl alcohol; MS (ISP): 257.1 MH + .
  • Piperazine-1-carboxylic acid 4-bromo-benzyl ester hydrochloride was prepared from 4-bromobenzyl alcohol; MS (ISP): 299.1 MH + .
  • Piperazine-1-carboxylic acid 2-trifluoromethoxy-benzyl ester hydrochloride was prepared from 2-trifluoromethoxy-benzyl alcohol; MS (ISP): 305.2 MH + .
  • Piperazine-1-carboxylic acid 2-chloro-5-nitro-benzyl ester hydrochloride was prepared from 2-chloro-5-nitro-benzyl alcohol; MS (ISP): 300.3 MH + .
  • Piperazine-1-carboxylic acid 2-chloro-benzyl ester hydrochloride was prepared from 2-chlorobenzyl alcohol; MS (ISP): 255.1 MH + .
  • Piperazine-1-carboxylic acid biphenyl-4-ylmethyl ester hydrochloride was prepared from 4-biphenylmethanol; MS (ISP): 297.3 MH + .
  • Piperazine-1-carboxylic acid 3-methoxy-benzyl ester hydrochloride was prepared from 3-methoxybenzyl alcohol; MS (ISP): 250.2 MH + .
  • Piperazine-1-carboxylic acid 3-trifluoromethyl-benzyl ester hydrochloride was prepared from 3-(trifluoromethyl)-benzyl alcohol; MS (ISP): 289.2 MH + .
  • Piperazine-1-carboxylic acid 4-trifluoromethyl-benzyl ester hydrochloride was prepared from 4-(trifluoromethyl)-benzyl alcohol; MS (ISP): 289.1 MH + .
  • Piperazine-1-carboxylic acid naphthalen-2-ylmethyl ester hydrochloride was prepared from 2-naphthalenemethanol; MS (ISP): 271.3 MH + .
  • Piperazine-1-carboxylic acid naphthalen-1-ylmethyl ester hydrochloride was prepared from 1-naphthalenemethanol; MS (ISP): 271.3 MH + .
  • Piperazine-1-carboxylic acid 2-methyl-benzyl ester hydrochloride was prepared from 2-methylbenzyl alcohol; MS (ISP): 235.4 MH + .
  • Piperazine-1-carboxylic acid 2,4-dichloro-benzyl ester hydrochloride was prepared from 2,4-dichlorobenzyl alcohol; MS (EI): 288.0 M + .
  • Piperazine-1-carboxylic acid 2,6-dichloro-benzyl ester hydrochloride was prepared from 2,6-dichlorobenzyl alcohol; MS (ISP): 289.1 MH + .
  • Piperazine-1-carboxylic acid 4-tert-butyl-benzyl ester hydrochloride was prepared from 4-tert.-butyl-benzyl alcohol; MS (ISP): 277.3 MH + .
  • Piperazine-1-carboxylic acid 2-fluoro-4-trifluoromethyl-benzyl ester hydrochloride was prepared from 2-fluoro-4-trifluoromethyl-benzyl alcohol; MS (ISP): 307.2 MH + .
  • Piperazine-1-carboxylic acid 2,4-difluoro-benzyl ester hydrochloride was prepared from 2,4-difluorobenzyl alcohol; MS (ISP): 257.1 MH + .
  • Piperazine-1-carboxylic acid 2-chloro-4-fluoro-benzyl ester hydrochloride was prepared from 2-chloro-4-fluorobenzyl alcohol; MS (ISP): 273.2 MH + .
  • Piperazine-1-carboxylic acid 4-fluoro-2-trifluoromethyl-benzyl ester hydrochloride was prepared from 4-fluoro-2-trifluoromethyl-benzyl alcohol; MS (ISP): 307.3 MH + .
  • Piperazine-1-carboxylic acid 4-difluoromethoxy-benzyl ester hydrochloride was prepared from 4-difluoromethoxy-benzyl alcohol; MS (ISP): 287.2 MH + .
  • Piperazine-1-carboxylic acid 2,4-dimethyl-benzyl ester hydrochloride was prepared from 2,4-dimethyl-benzyl alcohol; MS (ISP): 248.2 MH + .
  • Piperazine-1-carboxylic acid 2-fluoro-benzyl ester hydrochloride Piperazine-1,4-dicarboxylic acid tert-butyl ester 2-fluoro-benzyl ester: A solution of 4.47 g N-Boc-piperazine in 40 ml acetonitrile was saturated with dry carbon dioxide gas at rt. To this solution was added dropwise in 5 min. a solution of 8.50 g (28 mmol) terabutylammonium hydrogencarbonate (dried at 50° C. at 0.1 mbar for 1 h) in 30 ml acetonitrile, and then carbon dioxide gas bubbled into the stirred solution at rt for 1 h.
  • Piperazine-1-carboxylic acid 4-cyano-benzyl ester hydrochloride was prepared from 4-cyano-benzyl bromide; MS (ISP): 246.3 MH + .
  • Piperazine-1-carboxylic acid 2-trifluoromethyl-benzyl ester hydrochloride was prepared from methanesulfonic acid 2-trifluoromethyl-benzyl ester that was prepared from 2-trifluoromethyl-benzyl alcohol and methanesulfonyl chloride following a text book procedure; MS (ISP): 289.2 MH + .
  • Piperazine-1-carboxylic acid 4-chloro-2-fluoro-benzyl ester hydrochloride was prepared from 4-chloro-2-fluoro-benzyl bromide; 1 H-NMR (d 6 -DMSO): 3.07 m, 4H and 3.59m, 4H, piperazine-H; 5.13 s, 2H, OCH 2 ; MS (ISP): 273.2 MH + .
  • Piperazine-1-carbothioic acid S-(4-benzyloxy-benzyl)ester hydrochloride 4-(4-Benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acid tert-butyl ester: Under argon 84 mg (1.5 mmol) of solid KOH was dissolved at rt in 214 mg (1 mmol) 4-(benzyloxy)-benzyl alcohol and 0.5 ml acetone. Then 76 mg (1.1 mmol) carbon disulfide was added and the mixture thoroughly stirred for 2 h.
  • Piperazine-1-carbothioic acid S-(4-bromo-benzyl)ester hydrochloride was prepared from 4-bromobenzyl alcohol; 1 H-NMR (d 6 -DMSO): 3.10 m, 4H and 3.68 m, 4H, piperazine-H; 4.12 s, 2H, SCH 2 ; MS (ISP): 317.1 MH + .
  • Piperazine-1-carbothioic acid S-(4-trifluoromethoxy-benzyl)ester hydrochloride was prepared from 4-trifluoromethoxy-benzyl alcohol; 1 H-NMR (d 6 -DMSO): 3.12 m, 4H and 3.70 m, 4H, piperazine-H; 4.21 s, 2H, SCH 2 ; MS (ISP): 321.3 MH + .
  • Piperazine-1-carbothioic acid S-(4-fluoro-benzyl)ester hydrochloride was prepared from 4-fluoro-benzyl alcohol; 1 H-NMR (d 6 -DMSO): 3.10 m, 4H and 3.68 m, 4H, piperazine-H; 4.14 s, 2H, SCH 2 ; MS (ISP): 255.1 MH + .
  • Piperazine-1-carbothioic acid S-(2,4-difluoro-benzyl)ester hydrochloride was prepared from 2,4-difluoro-benzyl alcohol; 1 H-NMR (d 6 -DMSO): 3.10 m, 4H and 3.68 m, 4H, piperazine-H; 4.14 s, 2H, SCH 2 ; MS (ISP): 273.2 MH + .
  • Piperazine-1-carbothioic acid S-(4-methoxy-benzyl)ester hydrochloride was prepared from 4-methoxy-benzyl alcohol; 1 H-NMR (d 6 -DMSO): 3.10 m, 4H and 3.67 m, 4H, piperazine-H; 3.72 s, 3H, OCH 3 ; 4.09 s, 2H, SCH 2 ; MS (ISP): 267.3MH + .
  • Piperazine-1-carbothioic acid S-(2,4-dimethyl-benzyl)ester hydrochloride was prepared from 2,4-dimethylbenzyl alcohol; 1 H-NMR (d 6 -DMSO): 2.23 s, 3H, and 2.27 s, 3H, 2 ⁇ CH 3 -aryl; 3.10 m, 4H and 3.66 m, 4H, piperazine-H; 4.10 s, 2H, SCH 2 ; MS (ISP): 265.3 MH + .
  • Piperazine-1-carbothioic acid S-(2-fluoro-4-trifluoromethyl-benzyl)ester hydrochloride was prepared from 2-fluoro-4-trifluoromethyl-benzyl alcohol; 1 H-NMR (d 6 -DMSO): 3.10 m, 4H and 3.67 m, 4H, piperazine-H; 4.24 s, 2H, SCH 2 ; MS (ISP): 323.3 MH + .
  • Piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester A solution of 274 mg (0.5 mmol) piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester 9H-fluoren-9-ylmethyl ester in 13 ml morpholine was stirred at rt for 1 h. Then 23 ml of chilled water was added, the suspension filtered and the filtrate extracted with TBME. The organic layer was washed with water, brine, dried over Na 2 SO 4 and evaporated: 54 mg piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester as light yellow, waxy solid.
  • Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester Prepared in analogy to piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester 9H-fluoren-9-ylmethyl ester (Example 41) from (RS)-carbonic acid 1-chloro-ethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester) and N-Fmoc-piperazine: yellow solid.
  • Piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl ester Prepared in analogy to piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester (Example 41) from piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester and morpholine: colourless, waxy solid: IR (Nujol): 3341 cm ⁇ 1 , 1689 cm ⁇ 1 .
  • Piperazine-1-carboxylic acid 4-methoxy-benzyl ester hydrochloride was prepared from 4-methoxy-benzyl alcohol via the Following Intermediates
  • 6-(3-Chlorobenzyloxy)nicotinic acid 6-chloronicotinic acid (1.0 g, 6.3 mmol)) was added portion-wise over 30 min to a stirred suspension of sodium hydride (60%, 0.76 g, 19 mmol) in toluene (10 mL. The mixture was stirred for 30 min then cooled to 0° C. A solution of 3-chloro-benzyl alcohol (0.69 g, 6.4 mmol) in toluene (5 mL) was added drop-wise over 10 min. The mixture was warmed to room temperature, DMF (20 mL) was added and the mixture was heated to 95° C. and stirred for 18 h.
  • Piperazine-1-carboxylic acid 5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester fumarate a solution of hydrogen chloride in dioxan (4 M, 0.9 mL, 3.6 mmol) was added drop-wise to a stirred solution of Piperazine-1,4-dicarboxylic acid 5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester (0.16 g, 0.35 mmol) in methanol (5 mL). The mixture was stirred for 18 h then concentrated in vacuo.
  • cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared in analogy to 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester from cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (A. Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by a modified procedure of Rhone-Poulenc DE 25 50 111 (Rhone-Poulenc).
  • cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared in analogy to 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester from cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (A. Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by a modified procedure of Rhone-Poulenc DE 25 50 111 (Rhone-Poulenc).
  • Piperazine-1-carbothioic acid S-[4-(3-nitrobenzyl)oxy]benzyl ester A mixture [(4-tert-butyl-dimethylsilyloxy)benzylsulfanylcarbonyl]-piperazine-4-carboxylic acid tert-butyl ester (0.05 g), 3-nitrobenzyl bromide (0.028 g), cesium fluoride (0.033 g) and DMF (1 mL) was shaken for 48 h then partitioned between water (2 mL) and dichloromethane (2 mL).
  • Piperazine-1,4-dicarboxylic acid (3-tert-butyldimethylsilyloxy)benzyl ester tert-butyl ester A solution of 3-tert-butyldimethylsilyloxybenzyl alcohol (Tetrahedron Lett. 26, 681 (1985)) (5.0 g), triethylamine (8.7 mL), pyridine (1.65 mL) and 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester (5.1 g) in dichloromethane (200 mL) was stirred for 96 h.
  • Piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl ester tert-butyl ester a solution of tetrabutylammonium fluoride in THF (1 M, 4.4 mL, 4.4 mmol) and glacial acetic acid (0.76 mL, 13.3 mmol) were added sequentially to a stirred solution of piperazine-1,4-dicarboxylic acid (3-tert-butyldimethylsilyloxy)benzyl ester tert-butyl ester (0.50 g, 1.1 mmol) in anhydrous THF (10 mL) at 0° C .
  • Piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzyl ester tert-butyl ester potassium carbonate (0.072 g, 0.52 mmol) was added to a solution of piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl ester tert-butyl ester (0.16 g, 0.48 mmol) in acetone (5 mL) at 0° C. and the reaction mixture was stirred at 0° C. for 30 min. (2-Bromoethyl)-benzene (0.097 g, 0.52 mmol) was added and the reaction mixture was allowed to warm to room temperature and then heated under reflux for 24 h.
  • 6-(2-Fluorobenzyloxy)nicotinic acid to a stirred suspension of sodium hydride (60%, 0.63 g) in DMF (10 ml) at 0° C. was added portionwise over 10 min 6-chloronicotinic acid (1.0 g). The mixture was stirred for 30 min then a solution of 2-fluorobenzyl alcohol (0.84 g) in DMF (5 ml) was added dropwise over 10 min. The mixture was warmed to room temperature, stirred for 1 h then heated to 100° C. and stirred for a further 18 h then cooled to room temperature. To the mixture were added dropwise water (10 ml) and hydrochloric acid (2M, 10 ml).
  • Benzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and benzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a cream solid (0.0833 g, 15% overall); ⁇ max (nujol)/cm-1 2776, 2672, 2568, 2527, 1706, 1581, 1415, and 1329; ⁇ H (400 MHz, DMSO-d 6 ) 9.89 (1 H, br), 9.19 (1 H, br), 7.41-7.31(5 H, m), 5.13 (2 H, s), 4.34 (2 H, m), 3.17-3.08 (4 H, m), and 1.31 (6 H, d, J 7.2).
  • reaction mixture was heated to reflux for 19 h, then cooled to ambient temperature and partitioned between ethyl acetate (50 ml) and saturated aqueous ammonium chloride solution (50 ml). The organic phase was separated, washed with water and brine, dried (sodium sulfate) and the solvent evaporated under reduced pressure to afford the crude product as an oil, which was purified by silica gel chromatography (DIPE:heptane, 1:1) and used immediately.
  • DIPE:heptane silica gel chromatography
  • 6-(3-Methylbutoxy)nicotinic acid was prepared from 6-chloronicotinic acid (0.50 g), 3-methyl-1-butanol (0.36 ml) and sodium hydride (60%, 0.32 g) according to the method described in Example 54 to give the product as a white solid (0.25 g, 38%): ⁇ H (400 MHz, DMSO-d 6 ) 12.97 (1H, m), 8.71 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.87 (1H, d, J 8.5 Hz), 4.36 (2H, t, J 7 Hz), 1.75 (1H, nonet, J 6.5 Hz), 1.62 (2H, 1 , J 6.5 Hz) and 0.93 (6H, d, J 6.5 Hz); HPLC (XTERRA, 20/50, 220 nm) 99% (3.90 min).
  • [6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol was prepared from 6-(3-methylbutoxy)nicotinic acid (0.24 g) and lithium aluminium hydride (0.5M, THF, 3.5 ml) according to the method described in Example 54 to give the product as a yellow oil (0.19 g, 86%): ⁇ H (400 MHz, CDCl 3 ) 8.08 (1H, d, J 2.5 Hz), 7.59 (1H, dd, J 8.5, 2.5 Hz), 6.71 (1H, d, J 8.5 Hz), 4.60 (2H, s), 4.30 (2H, t, J 6.5 Hz), 1.81 (1H, nonet, J 6.7 Hz), 1.66 (3H, q, J 7 Hz) and 0.96 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80, 235 nm) 86% (2.54 min).
  • cis-2,6-dimethyl-piperazine-1-carboxylic acid 6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester fumarate was prepared from cis-2,6-dimethyl-piperazine-1-carboxylic acid 6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester (0.05 g) and HCl (4M, dioxane, 0.2 ml) according to the method described in Example 48 to give the product as a white solid (0.012 g, 28%): ⁇ H (400 MHz, DMSO-d 6 ) 8.15 (1H, d, J 2.5 Hz), 7.69 (1H, dd, J 8.5, 2 Hz), 6.79 (1H, d, J 8.5 Hz), 6.60 (2H, s), 5.02 (2H, s), 4.27 (2H, t, J 7 Hz), 3.95 (2H, m), 2.75 (2H, d, J 12 Hz), 2.68 (2
  • 6-(Cyclohexylmethoxy)nicotinic acid was prepared from 6-chloronicotinic acid (0.50 g), cyclohexylmethanol (0.41 ml) and sodium hydride (60%, 0.32 g) according to the method described in Example 54 to give the product as a white solid (0.42 g, 56%): ⁇ H (400 MHz, DMSO-d 6 ) 12.97 (1H, br), 8.70 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.88 (1H, d, J 8.5 Hz), 4.14 (2H, d, J 6 Hz), 1.81-1.60 (6H, m), 1.20 (3H, sept of triplets, J 12, 2.5 Hz) and 1.03 (2H, dq, J 11, 2.5 Hz); HPLC (XTERRA, 50/80, 220 nm) 100% (1.47 min).
  • 2,3-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,3-difluorobenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a white solid (0.1846 g, 57% overall); (Found: C, 52.4; H, 6.0; N, 8.6%.
  • 2,4-Dimethylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,4-dimethylbenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a hygroscopic white solid (0.1384 g, 44% overall); (Found: C, 60.9; H, 8.1; N, 8.9%.
  • (+/ ⁇ )-S-4-[(2-Butylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate hydrochloride was prepared from S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and (+/ ⁇ )sec-butyl isocyanate according to the method described in Example 71 to give the product as a white solid (41.2%); melting point 185.7-205.6° C.; NMR ⁇ H (400 MHz, DMSO-d 6 ) 0.871(3H, t, J 7.5 Hz), 1.090(3H, d, J 7.0 Hz), 1.440(2H, m), 3.115(4H, t), 3.455(1H, m), 3.672(4H, bt) 4.142(2H, s), 7.012(2H, d, J 8.5 Hz), 7.325(2H, d, J 8.5 Hz), 7.584(
  • (+/ ⁇ )-S-4-[[(1-Phenylethyl)amino]carbonyl]oxybenzyl piperazine-1-thiocarboxylate hydrochloride was prepared from S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and 1-phenylethyl isocyanate according to the method described in Example 71 to give the product as a white solid (54.2%); melting point 231.9-232.0° C.; NMR ⁇ H (400 MHz, DMSO-d 6 ) 1.411(3H, d, J 7.0 Hz), 3.101(4H, bt), 3.668(4H, bs) 4.132(2H, s), 4.701(1H, m), 7.00(2H, d, J 8.0 Hz), 7.327(6H, m), 8.297(1H, bd) and 9.175(2H, bs).
  • (RS) 1-Chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine a solution of (RS)4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g) and pyridine (1.64 ml) in DCM (35 ml) was added dropwise to a stirred solution of triphosgene (2.1 g) in DCM (100 ml) at 0° C. under Ar. The mixture was warmed to room temperature, stirred for 30 min then washed with water (100 ml) and brine (100 ml). The organic solution was dried (sodium sulfate) and concentrated in vacuo.
  • (+/ ⁇ )4-Difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate sodium borohydride (0.11 g) was added to stirred 4-difluoromethoxybenzaldehyde (1.0 g) in methanol (20 ml). The mixture was stirred for 2 h then concentrated in vacuo. The residue was partitioned between DCM (30 ml) and aqueous sodium hydroxide solution (2M, 30 ml). The organic layer was filtered through a PTFE membrane and concentrated in vacuo to give a clear oil (0.89 g).
  • (+/ ⁇ )-4-Difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate fumarate (+/ ⁇ )4-difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate (0.045 g) and HCl-dioxane (4M, 0.2 ml) were combined according to the method described for Example 48 to give the product as a white solid (0.023 g); ⁇ H (400 MHz, DMSO-d 6 ) 7.41 (1H, d, J 8 Hz), 7.21 (1H, t, J 74 Hz), 7.17 (1H, d, J 8.5 Hz), 6.56 (2H, s), 5.08 (1H, d, J 13 Hz), 5.04 (1H, d, J 13 Hz), 3.91 (lH, m), 3.78 (1H, m), 2.90 (3H, m), 2.73 (1H, m), 2.
  • 2,6-Difluoro-4-(2-propoxy)benzyl alcohol a mixture of 2,6-difluoro-4-hydroxybenzyl alcohol (0.20 g), cesium carbonate (0.22 g) and 2-iodopropane (0.14 ml) in DMF (10 ml) was heated to 40° C. and stirred for 18 h. The mixture was cooled to room temperature then poured into water (30 ml) and extracted with ethyl acetate (2 ⁇ 20 ml).
  • (+/ ⁇ )-2,6-Difluoro-4-propoxybenzyl 2-ethylpiperazine-1-carboxylate fumarate was prepared from (+/ ⁇ )1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine, 1-iodopropane and 2,6-difluoro-4-hydroxybenzyl alcohol according to the methods described for Examples 54 and 96 to give the product as a white solid (0.13 g, 42%); m.p. 145-165° C.
  • (+/ ⁇ )-2,6-Difluoro-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate fumarate was prepared from (+/ ⁇ )1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine and 2,6-difluoro-4-difluoromethoxybenzyl alcohol according to the methods described for Examples 54 to give the product as a white solid (0.084 g, 38%); m.p. 145° C. (decomp.); Found: C, 49.04; H, 4.78; N, 5.87%. C 19 H 22 F 4 N 2 O 7 requires: C, 48.93; H, 4.75; N, 6.00%.
  • (R)-2,6-Difluorobenzyl 2-methylpiperazine-1-carboxylate hydrochloride was prepared from 2,6-difluorobenzyl alcohol and (R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 52 and 54 to give the product as a white solid (0.217 g, 70% overall); (Found: C, 50.7; H, 5.65; N, 9.0.
  • (S) N-Benzyl-1-amino-2-propanol hydrochloride a mixture of (S) 1-amino-2-propanol (9.0 g), benzaldehyde (14.7 ml), magnesium sulfate and THF (200 ml) was stirred for 18 h then filtered and concentrated in vacuo. The residue was dissolved in ethanol (200 ml) and sodium borohydride (1.1 g) was added. The mixture was stirred for 2 h then a further portion of sodium borohydride (1.1 g) was added. The mixture was stirred for 18 h then concentrated in vacuo.
  • (R,R)1-Benzyl-3,5-dimethylpiperazine a solution of (R,R)1-benzyl-3,5-dimethylpiperazine-2-one (1.3 g) in THF (10 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.68 g) in THF (30 ml) at 0° C. under Ar. The mixture was stirred for 30 min then heated under reflux for a further 18 h. The mixture was cooled to 0° C. and diluted with ether (50 ml). To the stirred mixture were added water (2 ml) sodium hydroxide solution (2 ml) and water (2 ml).
  • (R,R)2,6-Dimethylpiperazine dihydrochloride a mixture of (R,R)4-Benzyl-2,6-dimethylpiperazine (0.95 g), palladium hydroxide/carbon (20%, 0.35 g) and methanol (30 ml) was shaken under hydrogen (45 p.s.i.) for 18 h. The mixture was filtered through a pad of kieselguhr, washing with methanol. The filtrate was treated with HCl-dioxane (4M, 5 ml), left to stand for 30 min then concentrated in vacuo.
  • the resin was washed 3 ⁇ each with THF, methanol and dichloromethane using the following automated sequence: 5 mL solvent added, wash for 5 minutes, drain for 2 minutes. To the washed resin was added 5% trifluoroacetic acid in dichloromethane (5 mL). The mixture was agitated for 1 h then drained. More TFA/DCM (5 mL) was added and the mixture was agitated for a further hour then drained again.
  • (+/ ⁇ )-2,6-Difluoro-4-(2-pyridylmethyl)oxybenzyl 2-methylpiperazine-1-carboxylate was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, 2-pyridylmethyl chloride hydrochloride and (+/ ⁇ )2-methylpiperazine resin according to the methods described for Example 126 to give the product as a yellow oil: ⁇ H (400 MHz, DMSO-d 6 ) 1.19 (3H, d, J 7.1 Hz), 2.85 (1H, m), 3.05-3.20 (4H, m), 3.90 (1H, m), 4.35 (1H, m), 5.10 (2H, m), 5.28 (2H, s), 6.92 (2H, m), 7.48 (1H, m), 7.62 (1H, m), 7.96 (1H, m), 8.65 (1H, m) and 9.15 (1H, br); HPLC (XTERRA, 50/80, 220 nm) 92% (1.
  • (+/ ⁇ )-2,6-Difluoro-4-(3-pyridylmethyl)oxybenzyl 2-methylpiperazine-1-carboxylate was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, 3-pyridylmethyl chloride hydrochloride and (+/ ⁇ )2-methylpiperazine resin according to the methods described for Example 126 to give the product as a yellow oil: ⁇ H (400 MHz, DMSO-d 6 ) 1.19 (3H, d, J 7.1 Hz), 2.85 (1H, m), 3.05-3.20 (4H, m), 3.90 (1H, m), 4.35 (1H, m), 5.10 (2H, m), 5.28 (2H, s), 6.92 (2H, m), 7.78 (1H, m), 8.25 (1H, m), 8.78 (1H, m), 8.84 (1H, m) and 9.20 (1H, br); HPLC (XTERRA, 50/80, 220 nm) 90.5%
  • (+/ ⁇ )-2-Methyl-piperazine-1-carboxylic acid 4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, 4-(3,5-dimethylisoxazolylmethyl chloride and (+/ ⁇ )2-methylpiperazine resin according to the methods described for Example 126 to give the product as a yellow oil: ⁇ H (400 MHz, DMSO-d 6 ) 1.20 (3H, d, J 7.1 Hz), 2.22 (3H, s), 2.42 (3H, s), 2.85 (1H, m), 3.05-3.20 (4H, m), 3.90 (1H, m), 4.35 (1H, m), 5.0 (2H, s), 5.10 (2H, m), 6.89 (2H, m), 8.60 (1H, br) and 9.20 (1H, br); HPLC (XTERRA,

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