OA10601A - Antiviral nucleoside analogues containing a substituted benzimidazole base attached to a carbocyclicring - Google Patents

Antiviral nucleoside analogues containing a substituted benzimidazole base attached to a carbocyclicring Download PDF

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OA10601A
OA10601A OA60973A OA60973A OA10601A OA 10601 A OA10601 A OA 10601A OA 60973 A OA60973 A OA 60973A OA 60973 A OA60973 A OA 60973A OA 10601 A OA10601 A OA 10601A
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methyl
piperidine
furo
carbonyl
indole
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OA60973A
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Leroy B Townsend
Susan Mary Daluge
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Wellcome Foundation Ltd The Re
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Priority claimed from US08/304,006 external-priority patent/US5534535A/en
Application filed by Wellcome Foundation Ltd The Re filed Critical Wellcome Foundation Ltd The Re
Publication of OA10601A publication Critical patent/OA10601A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical

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Abstract

Antiviral nucleoside analogues contain a substituted benzimidazole base attached to a carbocyclic ring in place of the conventional sugar residue. In formulae (I) and (I-1), R<1> is H, CH3 or CH2OH; R<2> is H or OH; R<3> is H or OH; or R<2> and R<3> together form a bond; R<4> is amino, cyclopropylamino, cyclobutylamino, isopropylamino, tert-butylamino or -NR<8>R<9> where R<8> and R<9> together with the nitrogen atom to which they are attached form a 4, 5 or 6-membered heterocyclic ring; R<5> is H and R<6> and R<7> are Cl, excluding the compound (+/-)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1<u>H</u>-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol and provided that at least one of R<1>, R<2> and R<3> is or contains OH. The compounds have activity against herpes virus especially cytomegalovirus and also hepatitis B virus infections.

Description

010610
TETRACYCLIC SPIRO COMPOUNDS PROCESS FOR THEIR PREPARATIONAND THEIR USE AS 5HT1D RECEPTOR ANTAGONISTS
The présent invention relates to novel piperidine dérivatives, processes for theirpréparation, and pharmaceutical compositions containing them. EPA 0 533 266/7/8 disclose a sériés of benzanilide dérivatives which are said topossess 5HTid receptor antagonist activity. These compounds are said to be of use in thetreatment of various CNS disorders. A structurally distinct class of compounds hâve now been discovered and hâvebeen found to exhibit 5HTjp) antagonist activity. In a first aspect, the présent inventiontherefore provides a compound of formula (I) or a sait or N-oxide thereof:
R 3
A (I)
in which
Rl is hydrogen, halogen, Cj.galkyl, C3_6cycloalkyl, COCj.^alkyl, Cj.galkoxy, hydroxy,hydroxyCi_6alkyl, hydroxyCi.galkoxy, Cj.galkoxyCi.galkoxy, acyl, nitro,trifluoromethyl, cyano, SR9, SOR9, SO2R9, SO2NR10rH, CO2R10, NR^SO^1CONRJOR11, CC^NRW ξ CONR^(CH2)pCO2R^, (CH2)pNR10Rn,(CH2)pCONR10r11, (CH2)pNRl0cORll, (CH2)«CO2C1.6alkyl, CO2(CH2)pORl0,CONHNR1 OrI 1, NR1 OR11, NR1 °CO2R11, NR10cO(CH2)pNRl OR11,NRiOCONRÏÛRll, CR10=NORn, CNR^NOR1 !, where R9, R10 and R11 areindependently hydrogen or Cj.^alkyl and p is 1 to 4; or R1 is an optionally substituted 5 to7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen,nitrogen or sulphur; R2 and R3 are independently hydrogen, halogen, Ci.galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, Cj.galkoxy, hydroxy Cj.galkyl, Ci.galkylOCj.galkyl, acyl, aryl,acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R^, CONR^R1 NR^R1 1 whereRIO and R11 are independently hydrogen or Cj.galkyl; R^ is hydrogen or Cj^alkyl; R5 and R^ are independently hydrogen or Cj.^alkyl; A is (CR13r14) where q is 2, 3 or 4 and R13 and R14 are independently hydrogen or Cj. 6alkyl or A is (CR13R14)r-D where r is 0,1, 2 or 3 and D is oxygen, sulphur or CR13=CR14· B is oxygen, CR13R1(1 or NR1? where R1^, r16 anj r17 independently hydrogen or
Cj.galkyl or B is S(C% where b is 0, 1 or 2; 2 010610 m is 1,2 or 3; and n is 1, 2 or 3.
Cj.galkyl groups, whether alone or as part of another group, may be straight chainor branched.
Suitably R.1 is hydrogen, halogen, Cj.galkyl, C3_6cycloalkyl, COCj.^alkyl,Cj.galkoxy, hydroxy, hydroxyCj.galkyl, hydroxyCj.^alkoxy, Ci.galkoxyCj.galkoxy,acyl, nitro, trifluoromethyl, cyano, SR9, SOR9, SO2R9, SO2NR10rH, CO2r19, NR1 OS02R11, CONR1 ÛR11, CO^R1 oR] 1, CONR1 °(CH2)pCO2R11, (CH2)pNR10Rn, (CH2)pCONR10Rll, (CH^pNR^COR1 !, (CH2)pCO2C1.6alkyl,CO2(CH2)pORl θ CONHNR1 OR11, NR1 ÛR1 1, NR19CO2R1 1, NR10CO(CH2)pNR10R11, NR^CONR^R1 !, CR^NOR11, CNR^NOR1 ζ whereR9, RIO and R11 are independently hydrogen or Cj.galkyl and p is 1 to 4. Preferredgroups include cyano, COCj.galkyl, CR19=NOR11, (CH^pNR^COR11, C02RlO,nr] °so2r 1 1, SO2NRl 0r1 1, CONRl Ori 1, CONHNR1 °r1 1, NR1 0co2r! 1,NRlOcONRiOR1 !, CONHNR1 Or11 or SO2R9. Preferably alkyl groups, including R10and R11, are methyl and ethyl.
When Rl is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatomsselected from oxygen, nitrogen or sulphur suitable heterocyclic rings include thienyl, furyl,pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl,isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. The heterocyclic rings can belinked to the remainder of the molécule via a carbon atom or, when présent, a nitrogenatom. Suitable substituents for these rings include R“ and R^ groups as defined above.Preferably Rl is optionally substituted triazolyl, thiazolyl, isoxazolyl, pyrazinyl oroxadiazolyl. Most preferably R1 is optionally substituted oxadiazolyl. Preferredsubstituents for such oxadiazolyl groups include Cj.galkyl such as methyl or ethyl, andNR10Rn as defined above, preferably where R19 and R1 1 are Cj.galkyl. Mostpreferably R1 is a 5-methyl-l,2,4-oxadiazol-3-yl group or a 5-methyl-l,3,4-oxadiazol-2-ylgroup.
Suitably R^ and R^ are independently hydrogen, halogen, Cj.galkyl,C3_6cycl°alkyl, C3_6cycloalkenyl, Ci_6alkoxy, hydroxyCi.galkyl, Ci-galkylOCj.galkyl,acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R19, CONR^R11,NRIOrI 1 where R19 and R1 1 are independently hydrogen or Cj-galkyl. Preferably R^ ishydrogen or Cj.^alkyl, in particular methyl. Preferably R^ is hydrogen.
Suitably R^ is hydrogen or C i .galkyl. Preferably R^ is hydrogen, methyl or ethyl, most preferably R^ is methyl. Preferably m is 2 forming a spiro-piperidine ring,
Suitably R$ and R^ are independently hydrogen or Ci.galkyl. Preferably R^ and R6 are both hydrogen. 3 010610
Suitably A is (CR^rI 4)^ where q is 2, 3 or 4 and R^ and R^4 are independentlyhydrogen or Cj.galkyl or A is (CR^rI 4)r.p> where r is 0, 1, 2 or 3 and D is oxygen,sulphur or CR^=CR^· Preferably A is (CH2)2 or (CH2)3-
Suitably B is oxygen, CR^r16 Or NR^ where R^? r16 ancj r17 areindependently hydrogen or Cj.galkyl or B is S(O)b where b is 0, 1 or 2. Preferably B isoxygen or sulphur, most preferably B is oxygen.
Suitably n is 1, 2 or 3, preferably n isl.
Particularly preferred compounds of the invention include: r-Methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-l'-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl- 4- carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], 5- (2'-Methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahy dro spiro [furo [2,3 -f] indole-3,4'-piperidine], r-Ethyl-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], l'-Methyl-5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(4'-(5-Dimethylamino-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl)-r-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Methyl-5-[4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 2,3-Dihydro-1 '-methyl-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbony 1) spiro [furo [2,3-f] indole-3,4'-piperidine], 5-[4'-Cyano-2’-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f] indole-3,4'-piperidine], 5-(4'-Acetyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f] indole-3,4'-piperidine], 5-(4'-(l -(Methoxyamino)ethyl)-2'-methylbiphenyl-4-carbonyl)-1 '-methyl-2,3,6,7-tetrahydro spiro [furo [2,3 -f] indole-3,4'-piperidine],5-(4'-Acetamidomethyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 3.5.6.7.8.9- Hexahydro-r-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)spiro [2H-furo [2,3 -h]benzazepine-3,4'-piperidine], r-Methyl-5-(2'-methyl-4'-(3-methyl-l,2,4-oxadiazol-5-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahy dro spiro [furo [2,3 -f] indole-3,4' -piperidine], l'-Methyl-5-(2'-methyl-4'-(l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7- tetr ahydrospiro[furo[2,3-f] indole-3.4'-piperidine, 4 010610 5-[4'-(5-Ethyl-l,3,4-oxadiazol-2-yl)-2'-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[2'-Methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 2,3-Dihydro-l'-methy 1-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)bipheny 1-4-carbonyl)spiro[furo[2,3-f|indole-3,4'-piperidine], 5-(2,2'-Dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-r-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(2,3'-Dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-l'-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],l'-Methyl-5-(2'-methyl-4'-(4-methylthiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],5-(4'-Methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro [furo[2,3 -f]indole-3,4'-piperidine],5-(5'-Methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7-tetrahy drospiro [furo [2,3 -f] indole-3,4' -piperidine], 5-[4'-(Methanesulphonamino)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(4'-Hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7- tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], r-Ethyl-5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], l'-Methyl-5-(2'-methyl-5'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(4'-Carboxamido-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7- tetrahy dro spiro [furo [2,3 -f] indole-3,4' -piperidine], 5-(4'-Acetamido-2'-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7- tetrahy dro spiro [furo [2,3 -f] indole-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-5-(4'-methanesulphonamino-2'-methylbiphenyl-4-carbonyl)-l·-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine], l'-Methyl-5-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f] indole-3,4'-piperidine], 1.2.3.5.6.7- Hexahydro-1 '-methyl-1 -(2'-methyl-4'-(5 -methyl-1,3,4-oxadiazol-2-yl)biphenyl- 4- carbonyl)spiro[indeno[5,6-b]pyrrole-7,4'-piperidine], 5- [4'-(N-methanesulphonyl-N-methylamino)-2'-methylbiphenyl-4-carbonyl]-l'- methyl- 2.3.6.7- tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 010610 5-[4'-(Dimethylaminosulphonyl)biphenyl-4-carbonyl]-l '-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-[4'-(Methanesulphonyl)biphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f] indole-3,4'-piperidine], 5-[4'-(N ,N-Dimethylcarbamoylamino)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f] indole-3,4'-piperidine], 5-[4'-(Ethoxycarbonylamino)-2'-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f] indole-3,4'-piperidine], 5-[4'-(4,5-Dimethyl-l,2,4-triazol-3-yl)-2'-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-6-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,7,8-tetrahydrospiro [4H-pyrano [2,3 -f]indole-4,4'-piperidine], 1 '-Methyl-5-(2'-methyl-4'-(5-methyl-l ,3,4-thiadiazol-2-yl) biphenyl-4-carbonyl)-2,3,6,7-tetrahy drospiro [furo [2,3 -f] indole-3,4' -piperidine], 5-(2'-Methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-r-n-propyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], l'-Methyl-5-(2'-methyl-4'-(5-methyloxazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], r-Methyl-5-(2'-methyl-4'-(3-methylisoxazol-5-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-5-(2'-methyl-4'-(5-methylisoxazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahy drospiro [furo [2,3 -f]indole-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-l'-methyl-5-(4'-(5-dimethylamino-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(4'-(5-ethyl-l,3,4-oxadiazol-2-yl)-2'-methylbiphenyl-4-carbonyl)spiro [furo [2,3 -g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(4'-methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)spiro [furo[2,3-g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-l'-methyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)spiro [furo [2,3 -g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(2'-methyl-4'-(l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], l'-Methyl-5-(2'-methyl-4'-pyrazinylbiphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3- f]indole-3,4'-piperidine], r-Methyl-5-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazolyl-3-yl)biphenyl-4-carbonyl]-l-oxo- 2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine],r-Ethyl-5-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 010610 l'-Methyl-5-[2'-methyl-4'-(l-methylimidazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Methyl-5-[2'-methyl-4'-(l-methylimidazol-5-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[4'-(5-Elydroxymethyl-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl]-l'-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-l'-oxo- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],l'-Methyl-5-[2'-methyl-4'-(l,2,4-triazin-3-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3 -f] indole-3,4'-piperidine], 2,3,6,7,8,9-Hexahydro-l'-methyl-6-(2'-methyl-4'-(5-methyl -l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[4H-pyrano[2,3-g]quinoline-4,4' piperidine],l'-Ethyl-5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-l'-oxo- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Ethyl-5-[4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], r-Ethyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[4'-(Acetylhydrazinocarbonyl)-2'-methylbiphenyl-4-carbonyl]-l '-ethyl-2,3,6,7-tetrahydrospiro [furo [2,3 -fjindole-3,4'-piperidine], 5-[4'-(5-Methoxymethyl-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl]-l'-methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-[4'-(4,5-Dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carbonyl]-l '-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-[4'-(2-(N,N-Dimethylamino)acetamido)-2'-methylbiphenyl-4-carbonyl]-l'-methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] 5-[4'-(Ethoxycarbonylamino)-2'-methylbiphenyl-4-carbonyl]-l'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-[4'-(Acetylhydrazinocarbonyl)-2’-methylbiphenyl-4-carbonyl]-l,-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(4'-(5-methylfuran-2-yl)-2'-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7- tetrahydrospiro [furo [2,3 -f] indole-3,4'-piperidine], or pharmaceutically acceptable salts thereof.
Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides,phosphates, acétates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonatesand p-toluenesulphonates. 010610
Certain compounds of formula (I) are capable of existing in stereoisomeric forms.It will be understood that the invention encompasses ail géométrie and optical isomers ofthe compounds of formula (I) and the mixtures thereof including racemates. Tautomersand mixtures thereof also form an aspect of the invention.
In a further aspect the présent invention provides a process for the préparation of acompound of formula (I) which comprises. (a) reaction of a compound of formula (II):
R
•CO in which R?, R^ and R^ are as defined in formula (I) and L is a leaving group.with a compound of formula (III):
wherein R A R A r6 a, B, m and n are as defined in formula (I) and optionally thereafter inany order: • converting a compound of formula (I) into another compound of formula (I) • forming a pharmaceutically acceptable sait.
Suitable activated carboxylic acid dérivatives of formula (II) include acyl halidesand acid anhydrides. Activated compounds of formula (II) can also be prepared byreaction of the corresponding carboxylic acid with a coupling reagent such ascarbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide Preferablythe group L is halo, particularly chloro. A compound of formulae (II) and (III) are typically reacted together in an inertorganic solvent such as DMF, THF or dichloromethane at ambient or elevated températurein the presence of a base such as an alkali métal hydroxide, triethylamine or pyridine.
Intermediate compounds of formulae (II) can be prepared using standardprocedures such as those outlined in EPA 533266/7/8. Certain intermediate compounds offormula (III) are novel and form a further aspect of the invention. 010610
Alternatively L is an ester forming group such that the resulting esters of formula(II) can be reacted with compounds of formula (III) in the presence of an organo-aluminium reagent such as trimethylaluminium. Such a reaction is typically carried out inthe presence of an inert solvant such as toluene.
It will be appreciated to those skilled in the art that it may be necessary to protectcertain reactive substituents during some of the above procedures. Standard protectionand deprotection techniques can be used. For example, primary amines can be protectedas phthalimide, benzyl, benzyloxycarbonyl or trityl dérivatives. These groups can beremoved by conventional procedures well known in the art.
Carboxylic acid groups can be protected as esters. Aldéhyde or ketone groups canbe protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved usingstandard conditions. 5HTj£) Antagonists, and in particular the compounds of the présent invention, areexpected to be of use in the treatment of CNS disorders such as mood disorders, includingdépréssion, seasonal effective disorder and dysthymia; anxiety disorders, includinggeneralised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsivedisorder and post-traumatic stress disorder; memory disorders, including dementia,amnestic disorders and age-associated memory impairment; and disorders of eatingbehaviours, including anorexia nervosa and bulimia nervosa. Other CNS disorders includemotor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatrie disorders. 5HTid Antagonists, and in particular compounds of the présent invention, mayalso be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in thetreatment of vasospasm (particularly in the cérébral vasculature) and hypertension, as wellas disorders in the gastrointestinal tract where changes in motility and sécrétion areinvolved. They may also be of use in the treatment of sexual dysfunction andhypothermia.
Therefore, the présent invention provides a compound of general formula (I) or aphysiologically acceptable sait or solvaté thereof for use in therapy.
The présent invention also provides a compound of general formula (I) or aphysiologically acceptable sait or solvaté thereof for use in the treatment of theaforementioned disorders.
In another aspect the invention provides the use of a compound of general formula(I) or a pharmaceutically acceptable sait or solvaté thereof for the manufacture of amédicament for the treatment of the aforementioned disorders.
In a further aspect the invention provides a method of treating the aforementioneddisorders which comprises administering an effective amount to a patient in need of such 010610 treatment of a compound of general formula (I) or a pharmaceutically acceptable sait orsolvaté thereof.
In particular the invention provides a compound of general formula (I) or aphysiologically acceptable sait or solvaté thereof for use in the treatment or prophylaxis ofdépréssion.
It will be appreciated by those skilled in the art that the compounds according to theinvention may advantageously be used in conjunction with one or more other therapeuticagents, for instance, different antidepressant agents.
The présent invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptable sait thereof, and apharmaceutically acceptable carrier. A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient température and atmospheric pressure, is usually adaptedfor oral, parentéral or rectal administration and, as such, may be in the form of tablets,capsules, oral liquid préparations, powders, granules, lozenges, reconstitutable powders,injectable or infusible solutions or suspensions or suppositories. Orally administrablecompositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and maycontain conventional excipients, such as binding agents, fillers, tabletting lubricants,disintegrants and acceptable wetting agents. The tablets may be coated according tomethods well known in normal pharmaceutical practice.
Oral liquid préparations may be in the form of, for example, aqueous or oilysuspension, solutions, émulsions, syrups or élixirs, or may be in the form of a dry productfor reconstitution with water or other suitable vehicle before use. Such liquid préparationsmay contain conventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives, and, if desired,conventional flavourings or colorants.
For parentéral administration, fluid unit dosage forms are prepared utilising acompound of the invention or pharmaceutically acceptable sait thereof and a stérilevehicle. The compound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions, the compound can bedissolved for injection and filter sterilised before filling into a suitable vial or ampoule andsealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and bufferingagents are dissolved in the vehicle. To enhance the stability, the composition can be frozenafter filling into the vial and the water removed under vacuum. Parentéral suspensions areprepared in substantially the same manner, except that the compound is suspended in thevehicle instead of being dissolved, and stérilisation cannot be accomplished by filtration.The compound can be sterilised by exposure to ethylene oxide before suspension in a 10 010610 stérile vehicle. Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to60% by weight, of the active material, depending on the method of administration. 5 The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer,and other similar factors. However, as a general guide suitable unit doses may be 0.05 to1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more thanonce a day, for example two or three a day. Such therapy may extend for a number of 10 weeks or months.
The following Examples illustrate the préparation of compounds of the invention. 11
Description 1 4-(Hydroxymethyl)-l-methyl-l,2,3,6-tetrahydropyridine 010610
To a solution of ethyl l-methyl-l,2,3,6-tetrahydro-4-pyridinecarboxylate (10.0 ml, 0.061mole) in THF (200 ml) was added, maintaining température below 25° C, lithiumaluminium hydride (2.76g, 0.073 mole). After stirring for a further 15 min, water (2.75ml), 10% NaOH (4 ml) and water (4 ml) were successively added, and the mixture wasfiltered. The filtrate was dried (F^SOzQ and evaporated in vacuo to give the titlecompound as an amber oil (6.30g, 81%), which solidified on standing. iH NMR (200 MHz, CDC13) Ô(ppm): 5.63 (m, 1H), 4.01 (s, 2H), 2.94 (m, 2H), 2.55 (t,2H), 2.35 (s, 3H), 2.20 (m, 2H)
Description 2 4-(2-IodophenoxymethyI)-l-methyl-l,2,3,6-tetrahydropyridine 4-(Hydroxymethyl)-l-methyl-l,2,3,6-tetrahydropyridine (Dl, 5.63g, 0.044 mol), 2-iodophenol (7.80g, 0.035 mol) and triphenylphosphine (11.61g, 0.044 mol) were stirred indry THF (200 ml) under Ar as diethyl azodicarboxylate (7.0 ml, 0.044 mol) was addedportionwise. The solution was stirred for lh, concentrated, diluted with ethyl acetate, andextracted with dil. HCl. The extract was basified (sat. K2CO3 solution) and extracted withethyl acetate. This organic extract was dried (Na2SÛ4) and evaporated to give a brownoil. Purification by chromatography on silica gel, eluting with 0-10% methanol/chloroform (gradient) gave the title compound (7.65g, 65%) as an amber oil. !h NMR (200 MHz, CDCI3) ô(ppm): 7.76 (dd, 1H), 7.27 (m, 1H), 6.81 (dd, 1H), 6.68 (td,1H), 5.84 (m, 1H), 4.47 (s, 2H), 2.99 (m, 2H), 2.58 (t, 2H), 2.4-2.25 (m, 5H).
Description 3 2,3-Dihydro-l'-methyIspiro[benzofuran-3,4'-piperidine] 4-(2-Iodophenoxymethyl)-l-methyl-l,2,3,6-tetrahydropyridine (D2, 8.72g, 0.026 mol) andAIBN (0.20g, 0.0012 mol) were stirred at reflux under Ar in benzene (500 ml) astributyltin hydride (14.3 ml, 0.053 mol) was added dropwise in benzene (100 ml) over 1 h.The mixture was stirred at reflux for a further 4.5 h, cooled and evaporated. The residuewas dissolved in ethyl acetate, and extracted with dil. HCl. The extract was basified (sat.K2CO3 solution) and extracted with ethyl acetate. This organic extract was dried(Na2SÛ4) and evaporated to give a brown solid, which was chromatographed on silica gel, 12 010610 eluting with 0-8% methanol/chloroform (gradient) to give the title compound (3.86g, 69%)as a light yellow solid. *H NMR (250 MHz, CDC13) ô(ppm): 7.15 (m, 2H), 6.88 (t, 1H), 6.79 (d, 1H), 4.35 (s, 2H), 2.87 (m, 2H), 2.33 (s, 3H), 2.02 (m, 4H), 1.78 (m, 2H)
Description 4 2.3- Dihydro-l'-methyl-5-nitrospiro[benzofuran-3,4'-piperidine] 2.3- Dihydro-r-methylspiro[benzofuran-3,4'-piperidine] (D3, 2.72g, 0.013 mol) wasdissolved in acetic anhydride (40 ml) and stirred, standing in a cold water bath, as coppernitrate trihydrate (4.30g, 0.018 mol) was added portionwise over lh. The mixture wasstirred for 16 h, poured into Na2CO3 solution, treated with excess ammonia solution, andextracted with ethyl acetate. The extract was dried (Na2SÛ4) and evaporated to give abrown oil, which was purified by chromatography on silica gel, eluting with 0-5%methanol/dichloromethane (gradient), to give the title compound (1.63g, 79%) as a yellow-brown solid. lH NMR (200 MHz, CDC13) Ô(ppm): 8.11 (dd, 1H), 8.03 (d, 1H), 6.83 (d, 1H), 4.53 (s,2H), 2.91 (m, 2H), 2.34 (s, 3H), 2.02 (m, 4H), 1.81 (m, 2H).
Description 5 5-Amino-2,3-dihydro-r-methylspiro[benzofuran-3,4’-piperidine] 2.3- Dihydro-T-methyl-5-nitrospiro[benzofuran-3,4'-piperidine] (D4, 0.98g, 4.0 mmol) washydrogenated over 10% palladium on charcoal (0.18g) in éthanol (50 ml) for 6 h. Catalystwas filtered off onto kieselguhr, and the fîltrate was evaporated and chromatographed onsilica gel, eluting with 0-25% methanol/chloroform (gradient), to give the title compound(0.52g, 60%) as a cream solid. hl NMR (250 MHz, d6DMSO) ô(ppm): 6.42 (m, 2H), 6.33 (dd, 1H), 4.22 (s, 2H), 2.84(d, 2H), 2.29 (s, 3H), 2.12 (t, 2H), 1.82 (td, 2H), 1.61 (d, 2H) 13 010610
Description 6 6-(Cyanomethyl)-2,3-dihydro-r-methyl-5-nitrospiro[benzofuran-3,4-piperidine] 2,3-Dihydro-l'-methyl-5-nitrospiro[benzofuran-3,4-piperidine] (D4, 0.70g, 2.8mmol) and4-chlorophenoxyacetonitrile (0.90g, 5.4mmol) were dissolved in dry DMF (15ml) andadded to potassium t-butoxide (1.60g, 14.3mmol). The mixture was stirred under Ar for6h, diluted with water (150ml), acidified (5M HCl) and washed with ethyl acetate. It wasthen basified (saturated K2CO3 solution) and extracted with ethyl acetate. This extractwas dried (Na2SÛ4) and evaporated to give the title compound (0.35g, 43%) stillcontaining some spirocyclic starting material (ca 30%, NMR). lH NMR (200MHz, CDCI3) ô(ppm): 8.05 (s, 1H), 7.07 (s, 1H), 4.56 (s, 2H), 4.19 (s, 2H),2.9 (m, 2H), 2.34 (s, 3H), 2.1-1.7 (m, 6H).
Description 7 2,3-Dihydro-r-methyIspiro[furo[2,3-flindole-3,4’-piperidine] 6-(Cyanomethyl)-2,3-dihydro-l'-methyl-5-nitrospiro[benzofuran-3,4'-piperidine] (D6,0.35g, 1.2mmol) was hydrogenated at 50psiH2 over 10% palladium on charcoal (0.30g) ina mixture of éthanol (18ml), water (2ml) and acetic acid (0.15ml) for 24h. Catalyst wasfiltered off onto kieselguhr, and the filtrate was evaporated to dryness. Chromatographyon silica gel, eluting with 0-12% methanol/chloroform (gradient) gave the title compound(0.020g, 10%) as a pale orange solid. iH NMR (250MHz, CDCI3) ô(ppm): 8.70 (b, 1H), 7.18 (m, 2H), 6.99 (s, 1H), 6.43 (m,1H), 4.40 (s, 2H), 3.05 (m, 2H), 2.46 (s, 3H), 2.3-1.7 (m, 6H).
Description 8 r-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4-piperidine] 2,3-Dihydro-l'-methylspiro[furo[2,3-f]indole-3,4'-piperidine] (D7, 0.056g, 0.23mmol) wasstirred in acetic acid (5ml) as sodium cyanoborohydride (0.044g, 0.70mmol) was addedportionwise over 10min. The solution was stirred for 2h, diluted with water (20ml),basified with saturated K2CO3 solution, and extracted with ethyl acetate. The extract wasdried (Na2SC>4) and evaporated to give the title compound (0.030g, 53%) as a white solid. hd NMR (200MHz, CDCI3) ô(ppm): 6.61 (s, 1H), 6.46 (s, 1H), 4.31 (s, 2H), 3.53 (t, 2H),2.96 (t, 2H), 2.9 (m, 3H), 2.33 (s, 3H), 1.99 (m, 4H), 1.74 (m, 2H). 010610 14
Description 8 - alternative préparation r-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (a) A stirred suspension of powdered l-acetyl-6-bromo-2,3-dihydro-lH-indol-5-ol(Tetrahedron, 1973,29 (8), 1115) (19g, 0.074 mole) in dry THF (1700 ml) at room temp.under argon was treated with triphenylphosphine (19.6g, 0.075 mole) and 1-methyl- 1.2.3.6- tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) (9.5g, 0.075 mole),followed by the dropwise addition over 15 mins. of a solution of diethyl azodicarboxylate(11.8 ml, 0.075 mole) in THF (40 ml). A mild exotherm occured and the insoluble materialdissolved. The solution was warmed at 32°C for 1 hour, then concentrated in vacuo toapprox. 500 ml volume. The solid which had formed was filtered off and dried affording16.1g of beige solid. The filtrate was concentrated in vacuo and the residue treated withethyl acetate (700 ml) and IM HCl acid (500 ml), shaken well and the acid layer separated.This was washed with ethyl acetate, then basified with 40% NaOH and extracted withethyl acetate, followed by chloroform. The combined extracts were dried (Na2SO4) andconcentrated in vacuo to leave a yellow solid, which was recrystallised from ethyl acetate(3.8g) giving a total yield of 19.9g (74%) of l-acetyl-6-bromo-2,3-dihydro-5-(l-methyl- 1.2.3.6- tetrahydropyridin-4-ylmethoxy)-l H-indole. 'H NMR (250 MHz, CDC13) δ (ppm): 8.42 (s, 1H), 6.72 (s, 1H), 5.80 (br s, 1H), 4.41 (s,2H), 4.04 (t, 2H), 3.12 (t, 2H), 2.97 (br s, 2H), 2.58 (t, 2H), 2.38 (s, 3H), 2.28 (br s, 2H),2.18 (s, 3H). b) A stirred suspension of the product from (a) (20.8g, 0.057 mole) in benzene (1500 ml)was treated with AIBN (400 mg) and heated to 75 °C under argon, then treated dropwiseover 0.5 h with a solution of tributyltin hydride (23 ml, 0.085 mole) in benzene (200 ml).The mixture was heated under reflux for 6 hours, then concentrated in vacuo. The residuewas treated with 2M HCl acid (900 ml) and ethyl acetate (600 ml), then shaken well andthe acid layer separated, washed with ethyl acetate and then basified with 40% NaOHsolution, keeping the temp. below 20°C. A white precipitate was formed which wasfiltered off, washed with water and dried to afford 14.8g (91%) of 5-acetyl-l'-methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]. ’H NMR (250 MHz, CDC13) δ (ppm): 8.11 (s, ÎH), 6.60 (s, 1H), 4.36 (s, 2H), 4.03 (t, 2H),3.10 (t, 2H), 2.92-2.78 (m, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 2.15-1.90 (m, 4H), 1.80-1.63(m,2H). 15 010610 c) A stirred solution of the product from (b) (14.5g, 0.051 mole) in a mixture of 5M HCl(250 ml) and éthanol (100 ml) was heated under reflux under argon for 2 hours followedby 16 hours at room temp. The éthanol was removed by concentration in vacuo and theremaining solution cooled in an ice bath and basified to pH 12 by addition of 40% NaOHsolution. The white precipitate which formed was filtered off, washed with water anddried to afford 6.0g of the title compound. The filtrate was extracted with ethyl acetate,followed by chloroform. The combined extract was dried (Na2SO4) and concentrated invacuo leaving a beige solid (6.2g) and affording a total of 12.2g (99%) of title compound(D8).
Description 9
Spiro[2,3-dihydro-l’-methylfuro[2,3-g]quinoline-3,4-piperidine]
Spiro[5-amino-2,3-dihydro-1 '-methyl-1 -benzofuran-3,4-piperidine] (D5, 0.316g, 1.45mmol), glycerol (0.20g, 2.2mmol) and iodine (0.008g, 0.03mmol) were stirred asconc. sulphuric acid (0.23ml) was added. The dark mixture was then stirred at 180°C forlh, cooled, and partitioned between ethyl acetate and 10% sodium hydroxide solution.
After séparation, the organic portion was dried (Na2SO4) and evaporated to give the titlecompound (0.182g, 49%) as a brown gum. ÏHNMR (250MHz, CDCI3) ô(ppm): 8.62 (dd, 1H), 7.90 (d, 1H), 7.77 (s, 1H), 7.21 (dd,1H), 6.95 (s, 1H), 4.39 (s, 2H), 2.72 (m, 2H), 2.28 (s, 3H), 2.04 (m, 4H), 1.78 (m, 2H).
Description 10
Spiro[2,3,5,6,7,8-hexahydro-l'-methylfuro[2,3-g]quinoline-3,4-piperidine]
Spiro[2,3-dihydro-r-methylfuro[2,3-g]quinoline-3,4'-piperidine] (D9, 0.182g, 0.72mmol)and platinum dioxide (0.077g, 0.34mmol) were hydrogenated at 50psiH2 in éthanol (25ml)for 72h. Catalyst was filtered off onto kieselguhr, and the filtrate was evaporated to givethe title compound (0.151g, 81%) as a brown gum. iHNMR (200MHz, CDCI3) ô(ppm): 6.44 (s, 1H), 6.32 (s, 1H), 4.26 (s, 2H), 3.7-3.1 (b,1H), 3.24 (t, 2H), 2.82 (m, 2H), 2.73 (t, 2H), 2.31 (s, 3H), 1.94 (m, 6H), 1.73 (m, 2H)Description 11 2’-Methyl-4'-(5-methyH,3,4-°xadiazol-2-yl)biphenyl-4-carboxylic acid A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-l,3,4-oxadiazole (EP 0533268Al) (0.21g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was 16 010610 treated with 4-boronobenzoic acid (0.14g, 0.0008 mole), sodium carbonate (0.39g, 0.0037mole) and tetrakis (triphenylphosphine)palladium (0) (16 mg), then heated under reflux for4 hours. The mixture was acidified with IM hydrochloric acid and extracted with ethylacetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave the titlecompound as a white solid (0.19g, 78%). NMR (250 MHz, CDCI3 + d6DMSO) ô(ppm): 8.02 (d, 2H), 7.86 (s, 1H), 7.80 (br d,1H), 7.32 (d, 2H), 7.27 (d, 1H), 2.54 (s, 3H), 2.26 (s, 3H)
Description 12 4-Bromo-3-methyIbenzamide oxime
Methanol (20 ml) at 5° C was treated portionwise over 5 min. with stirring with potassiumt-butoxide (1.68g, 0.015 mole), then after a further 5 mins the solution was treated withhydroxylamine hydrochloride (1.11 g, 0.016 mole). The resulting mixture was allowed towarm to room température, stirred for 1 h, then treated with a solution of 4-bromo-3-methylbenzonitrile (2.0g, 0.010 mole) in methanol (10 ml) and heated under reflux for 3 h.The mixture was allowed to cool, then filtered through kieselguhr and the filtrateconcentrated in vacuo to afford the title compound as a white solid (1.56g, 100%). iH NMR (250 MHz, d^DMSO) δ (ppm): 7.67 (d, 1H), 7.56 (d, 1H), 7.42 (dd, 1H), 5.85(br s, 2H), 2.35 (s, 3H).
Description 13 2-(4-Bromo-3-methylphenyl)-5-(dimethylaniino)-l,2,4-oxadiazole 4-Bromo-3-methylbenzamide oxime (D12, 1.5g, 0.0065 mole) was added portionwise over10 min with stirring to trichloroacetic anhydride (18 ml) at 10° C under argon. Thereaction mixture was allowed to warm up to room température and stir for 4 h, then addedslowly to a well stirred mixture of excess aqueous sodium bicarbonate solution and ethylacetate at ice bath température. When effervescence had ceased, the ethyl acetate layerwas separated, dried (Na2SÛ4) and concentrated in vacuo to leave the 5-trichloromethyloxadiazole as a pale yellow solid. This was treated with a 33% solution ofdimethylamine in IMS (25 ml) and heated under reflux for 18 h, then concentrated invacuo. The residue was treated with 10% Na2CÜ3 solution (20 ml) and extracted withethyl acetate (2 x 30 ml). The combined extract was dried (Na2SC>4), concentrated invacuo and the residue chromatographed on silica gel eluting with 1:1 ether/60-80 petrol toafford the title compound as a white solid (1.14g, 62%). 17 010610 ^H NMR (250 MHz, CDC13) δ (ppm): 7.88 (d, 1H), 7.69 (dd, 1H), 7.58 (d, 1H), 3.20 (s,6H), 2.44 (s, 3H).
Description 14 2'-Methyl-4'-(5-dimethylamino-l,2,4-oxadiazoI-3-yl)biphenyl-4-carboxylic acid
The title compound was prepared from 2-(4-bromo-3-methylphenyl)-5-(dimethylamino)-1,2,4-oxadiazole (DI3) using a similar procedure to Description 11 (64%) as a white solid. 1h NMR (250 MHz, d6DMSO) δ (ppm): 13.1 (br s, 1H), 8.03 (d, 2H), 7.85 (s, 1H), 7.80(d, 1H), 7.52 (d, 2H), 7.37 (d, 1H), 3.15 (s, 6H), 2.30 (s, 3H).
Description 15 4'-(5-Methyl-l,2,4-oxadiazol-3-yI)biphenyl-4-carboxylic acid
The title compound was prepared from l-bromo-4-(5-methyl-l,2,4-oxadiazol-3-yl)benzene[EP 0533268Al] (0.58g) and 4-boronobenzoic acid (0.4 g) as described in Description 11as a white solid (0.64g, 97%). iH NMR (250 MHz, d6DMSO) δ (ppm): 12.8-13.3 (br s, 1H), 7.8-8.2 (m, 8H), 2.7 (s, 3H).
Description 16 4'-Cyano-2'-methylbiphenyl-4-carboxylic acid 4-bromo-3-methylbenzonitrile (5g, 0.026 mol) was suspended in 1,2-dimethoxyethane(100 ml) and treated with 4-boronobenzoic acid (4.2g, 0.026 mol) followed by a solutionof sodium carbonate (11.65g, 0.11 mmol) in water (100 ml). The mixture was flushed withargon and tetrakis(triphenylphosphine)palladium (0) (0.55g) was added. The reactionmixture was then heated to reflux with stirring. After 24h, the 1,2-dimethoxyethane wasremoved by évaporation under reduced pressure and the aqueous residue was washed withethyl acetate. The aqueous layer was then acidified to pHl and the résultant solid wasfiltered off and was dried in vacuo to give the title compound as a white solid (4.16g, 69%). !h NMR (250 MHz, dÔDMSO) δ (ppm): 8.02 (d, 2H), 7.82 (s, 1H), 7.40 (dd, 1H), 7.52-7.40 (m, 4H), 2.28 (s, 3H) 18 010610
Description 17 N-Methoxy-N-methyl-4-bromo-3-methylbenzamide A stirred suspension of 4-bromo-3-methylbenzoic acid (5.0g, 0.023 mole) in thionylchloride (20 ml) was heated under reflux for 2 hours, then concentrated in vacuo. Theresidual acid chloride was dissolved in dichloromethane (100 ml) and added dropwise over10 minutes to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (2.4g, 0.025mole) and pyridine (5.6 ml, 0.069 mole) in dichloromethane (150 ml) and acetonitrile (20ml) at -20° C. The reaction mixture was allowed to warm to room température over 3 hoursthen treated with 10% Na2CC>3 solution and extracted with dichloromethane. The extractwas dried (Na2SÛ4) and concentrated·in vacuo to afford the title compound as a paleyellow oil (5.9g, 100%). JH NMR (200 MHz, CDC13) δ (ppm): 7.60-7.50 (m, 2H), 7.37 (dd, 1H), 3.54 (s, 3H), 3.35(s, 3H), 2.42 (s, 3H)
Description 18 4-Bromo-3-methylacetophenone A solution of N-methoxy-N-methyl-4-bromo-3-methylbenzamide (D17) (1.50g, 0.0057mole) in dry ether (30 ml) was added dropwise over 10 minutes to a stirred solution ofméthylmagnésium iodide (0.0075 mole) in dry ether (15 ml) under argon. The mixturewas then heated under reflux for 1 hour, allowed to cool and poured into well stirred IMHCl (50 ml). The mixture was extracted with ethyl acetate and the extract washed with10% Na2CC>3 solution, dried (Na2SÛ4) and concentrated in vacuo to afford the titlecompound as a pale yellow oil (1.14g, 94%). !h NMR (250 MHz, CDCI3) δ (ppm): 7.81 (s, 1H), 7.62 (s, 2H), 2.57 (s, 3H), 2.45 (s, 3H)
Description 19 4'-Acetyl-2'-methylbiphenyl-4-carboxylic acid
The title compound was prepared from 4-bromo-3-methylacetophenone (DI8) using aprocedure similar to Description 11 (80%). !hNMR (250 MHz, CDCI3) δ (ppm): 8.13 (d, 2H), 7.88 (d, 1H), 7.84 (d, 1H), 7.40 (d,2H), 7.34 (d, 1H), 2.65 (s, 3H), 2.34 (s, 3H). 19 010610
Description 20 4’-Acetamidomethyl-2’-methylbiphenyl-4-carboxylic acid 4-Bromo-3-methylbenzylamine (EP 532266) (7.36g, 0.037 mol) was dissolved in 1,2-dimethoxyethane (DME) (180 ml), with stirring, and was treated with 4-boronobenzoicacid (6.14g, 0.037 mol), followed by a solution of sodium carbonate (17.65g, 0.167 mol) inwater (180 ml). The reaction mixture was then flushed with argon and tetrakis(triphenylphosphine)palladium (O) (1.00g) was added. The reaction mixture was thenheated to reflux under argon. After 16h, the reaction mixture was allowed to cool and theDME was removed by évaporation under reduced pressure. The aqueous residue was thendiluted with water (-200 ml) and washed with EtOAc (2x150 ml). The aqueous layer wasthen treated with acetic anhydride (6.98 ml, 0.074 mol) and stirred for lh at roomtempérature. The resulting pale brown solution was filtered through kieselguhr to give apale yellow solution, which was acidified to pH5 using conc. HCl to give an off whiteprecipitate. This was filtered off, washed with water and dried in vacuo to give the titlecompound as an off white solid (5.85g, 56%). 1h NMR (200 MHz, d6DMSO) δ (ppm): 8.45 (t, 1H), 7.95 (d, 2H), 7.32 (d, 2H), 7.15 (m,3H), 4.28 (d, 2H>, 2.20 (s, 3H), 1.90 (s, 3H)
Description 21
Methyl 4'-acetamidomethyl-2'-methylbiphenyl-4-carboxylate
Thionyl chloride (0.119ml, 1.63 mmol) was added dropwise to MeOH (5 ml) at 0° C,followed by a solution of 4-acetamidomethyl-2'-methylbiphenyl-4-carboxylic acid (D20)(0.345g, 1.22 mmol) in MeOH (10 ml). The mixture was heated under reflux for 1.5 hrand the solvent removed in vacuo. The residue was dissolved in CH2CI2 (30 ml) andwashed with aq. Na2CO3 followed by water. The organic extract was dried (Na2SO4) andconcentrated in vacuo to give a colourless oil, which was purified by columnchromatography on silica gel eluting with EtOAc to give a colourless oil that crystallisedon standing (0.242g, 68%). !h NMR (200 MHz, CDCI3) δ (ppm): 8.1 (d, 2H), 7.38 (d, 2H), 7.23-7.14 (m, 3H), 5.90- 5.80 (bs, 1H), 4.45 (d, 2H), 3.90 (s, 3H), 2.28 (s, 3H), 2.05 (s, 3H).
Description 22 7-Methoxy-2,3,4,5-tetrahydro-lH-benzazepine 010610 20
6- Methoxytetralone (6.86g, 39 mmol), hydroxylamine hydrochloride (8.15g, 117 mmol)and sodium acetate trihydrate (25g, 184 mmol) were stirred at reflux in a mixture oféthanol (200 ml) and water (50 ml) for 45 min, concentrated in vacuo, and diluted withwater (200 ml). The white solid (6-methoxytetralone oxime, 7.44g) was collected anddried. A portion of this (6.31g, 33 mmol) was stirred in dry THF (150 ml) under argon aslithium aluminium hydride (1.80g, 47 mmol) was added portionwise. This mixture wasstirred at reflux for 3h, cooled, and treated successively with water (1.5 ml), 10% NaOH (1.5 ml) and water (4.5 ml). The solids were filtered off, and the filtrate was evaporated togive an amber oil. This was chromatographed on silica, eluting with ethyl acetate, givingthe title compound (2.96g, 50%). iHNMR (250 MHz, CDCI3) δ (ppm): 6.78 (m, 2H), 6.60 (dd, 1H), 3.75 (s, 3H), 3.3 (vbroad, 1H), 2.98 (t, 2H), 2.74 (t, 2H), 1.80 (m, 2H), 1.63 (m, 2H).
Description 23 7- Acetoxy-l-acetyl-2,3,4,5-tetrahydro-lH-benzazepine 7-Methoxy-2,3,4,5-tetrahydro-lH-benzazepine (D22, 2.96g, 17 mmol) was stirred at refluxin 48% HBr for 16 h, cooled and evaporated to dryness, giving a brown solid. Thismaterial was stirred in dichloromethane (200 ml) as triethylamine (9.4 ml, 68 mmol) andacetyl chloride (3.6 ml, 51 mmol) were added. The solution was stirred for lh, washedwith dilute HCl, dried (Na2SO4) and evaporated to give an oil. This was chromatographedon silica, eluting with 0-50% ethyl acetate/ dichloromethane, giving the title compound(3.88g, 94%) as an amber syrup which crystallised on standing. ]H NMR (250 MHz, CDCI3) δ (ppm): 7.14 (d, 1H), 7.0 (m, 2H), 4.69 (dt, 1H), 2.85-2.55(m, 3H), 2.31 (s, 3H), 2.10-1.75 (m, 3H), 1.88 (s, 3H), 1.44 (m, 1H)
Description 24 l-Acetyl-7-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine 7-Acetoxy-l-acetyl-2,3,4,5-tetrahydro-lH-benzazepine (D23, 3.88g, 16 mmol) was stirredin éthanol (40 ml) as NaOH (1.26g, 32 mmol) was added in water (5 ml). After stirring for30 min, the mixture was diluted with water (500 ml), and acidified with 5M HCl. The tanprecipitate was filtered off and dried, yielding 2.02g (63%) of the title compound. Afurther 0.80g (25%) of this material was isolated by dichloromethane extraction of thefiltrate. 21 010610 1η NMR (250 MHz, ÇDCI3) δ (ppm): 6.98 (d, 1H), 6.83 (bs, 1H), 6.75 (m, 2H), 4.67 (dt,1H), 2.8-2.5 (m, 3H), 2.05-1.7 (m, 3H), 1.89 (s, 3H), 1.42 (m, 1H)
Description 25 l-Acetyl-8-bromo-7-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine l-Acetyl-7-hydroxy-2,3,4,5-tetrahydro-lH-benzazepine (D24, 2.81g, 14 mmol) was stirredin glacial AcOH (50 ml) as N-bromosuccinimide (2.69g, 15 mmol) was added portionwiseover 20 min. The mixture was stirred for 30 min, diluted with ethyl acetate (500 ml),washed with water, K2CO3 solution and brine, dried (Na2SC>4) and evaporated to give atan solid, shown by NMR and TLC to be a mixture of dibromo and mono-bromo isomers.Chromatography on silica, eluting with 0-25% ethyl acetate/ dichloromethane, yieldedpure title compound (1.22g, 31%) as a cream solid. ÎH NMR (250 MHz, d6DMSO) δ (ppm): 7.43 (s, 1H), 6.84 (s, 1H), 4.43 (dt, 1H), 2.6-2.4(m, 3H), 1.90 (m, 1H), 1.73 (s, 3H), 1.68 (m, 2H), 1.28 (m, 1H)
Description 26 l-Acetyl-8-bromo-7-(l-methyl-l,2,3,6-tetrahydro-4-pyridyl)methoxy -2,3,4,5-tetrahydro-lH-benzazepine
The title compound was prepared from l-acetyl-8-bromo-7-hydroxy-2,3,4,5-tetrahydro-ΙΗ-benzazepine (D25) and 4-(hydroxymethyl)-l-methyl-l,2,3,6-tetrahydropyridine (Dl)following the procedure of Description 2. lH NMR (250 MHz, CDCI3) δ (ppm): 7.32 (s, 1H), 6.76 (s, 1H), 5.85 (m, 1H), 4.65 (dt,1H), 4.51 (s, 2H), 3.02 (m, 2H), 2.8-2.5 (m, 3H), 2.40 (s, 3H), 2.33 (m, 2H), 1.89 (s, 3H),2.05-1.7 (m,3H), 1.38 (m, 1H)
Description 27 5-AcetyI-3,5,6,7,8,9-hexahydro-r-methylspiro[2H-furo[2,3-h]benzazepine-3,4'- piperidine]
The title compound was prepared from l-acetyl-8-bromo-7-(l-methyl-l,2,3,6-tetrahydro-4-pyridyl)methoxy-2,3,4,5-tetrahydro-lH-benzazepine (D26) following the procedure ofDescription 3. 22 0106 î ο ]HNMR (200 MHz, CDCI3) δ (ppm): 6.84 (s, 1H), 6.64 (s, 1H), 4.65 (dt, 1H), 4.39(ABq, 2H), 2.84 (m, 2H), 2.64 (m,3H), 2.33 (s, 3H), 1.83 (s, 3H), 2.1-1.7 (m, 9H). 1.40 (m,1H)
Description 28 3,5,6,7,8,9-Hexahydro-r-methyIspiro[2H-furo[2,3-h]benzazapine-3,4'-piperidine] 5-Acetyl-3,5,6,7,8,9-hexahydro-l'-methylspiro [2H-furo[2,3-h]benzazepine-3,4'-piperidine] (D27, 0.25g, 0.82 mmol) was stirred at reflux under Ar in c. HCl (15 ml) for 4days. It was then evaporated to dryness, dissolved in dichloromethane, washed withK2CO3 solution, dried (Na2SOq) and evaporated to give the title compound (0.203g) as abrown gum, still containing ca. 15% of amide (NMR). Chromatography on silica, elutingwith 0-15% methanol in dichloromethane, give purer material (0.107g, 49%) ^H NMR (250 MHz, CDCI3) δ (ppm): 6.58 (s, 1H), 6.51 (s, 1H), 4.30 (s, 2H), 3.5 (b, 1H),2.99 (t, 2H), 2.82 (m, 2H), 2.70 (m, 2H), 2.31 (s, 3H), 1.98 (m, 4H), 1.74 (m, 4H), 1.59 (m,2H).
Description 29 2’-Methyl-4'-(3-methyI-l,2,4-oxadiazol-5-yI)biphenyl-4-carboxylic acid A stirred solution of 5-(4-bromo-3-methylphenyl)-3-methyl-l,2,4-oxadiazole (EP 0533268Al) (0.65g, 0.0026 mole) in a mixture of DME (30 ml) and water (30 ml) under argon wastreated with 4-boronobenzoic acid (0.43g, 0.0026 mole), sodium carbonate (1.16g, 0.011mole) and tetrakis (triphenylphosphine)palladium(O) (40 mg), then heated under reflux for4 hours. The mixture was acidified with IM hydrochloric acid and extracted with ethylacetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave the titlecompound as a white solid (0.61g, 80%). *H NMR (250 MHz, d6DMSO) δ (ppm): 8.12-7.95 (m, 4H), 7.60-7.45 (m, 3H), 2.44 (s,3H), 2.35 (s, 3H).
Description 30 4-Bromo-3-methylbenzoic hydrazide
The title compound was prepared from methyl 4-bromo-3-methylbenzoate using a similarprocedure to Description 35, as a white solid (69%). 23 010610 'h NMR (200MHz, CDC13 + d6DMSO) δ (ppm): 9.05 (br s, 1H), 7.75 (d, 1H), 7.58 (d,1H), 7.50 (dd, 1H), 4.10 (br s, 2H), 2.42 (s, 3H)
Description 31 5 2-(4-Bromo-3-methylphenyl)-5-ethyl-l,3,4-oxadiazole
The title compound was afforded as a beige crystalline solid (1.65g) as per method ofDescription 35, using 4-bromo-3-methylbenzoic hydrazide (D31) (1.30g) and triethylorthopropionate (13.0 ml). 10 'H NMR (200 MHz, CDC13) δ (ppm): 7.91 (s, 1H), 7.68 (m, 2H), 2.96 (q, 2H), 2.49 (s,3H), 1.45 (t,3H).
Description 32 15 4'-(5-Ethyl-l,3,4-oxadiazol-2-yl)-2'-methylbiphenyl-4-carboxylic acid
The title compound was afforded as a white solid (82%) as per method of Description 11from 2-(4-bromo-3-methylphenyl)-5-ethyl-l,3,4-oxadiazole (D31). 20 ’H NMR (400MHz, d6DMSO) δ (ppm): 12.98 (s, 1H), 8.00 (d, 2H), 7.89 (s, 1H), 7.82 (d,1H), 7.48 (d, 2H), 7.38 (d, 1H), 2.90 (q, 2H), 2.28 (s, 3H), 1.29 (t, 3H). 24 010610
Description 33 4-Borono-3-methyIbenzoic acid A stirred solution of 4-bromo-3-methylbenzoic acid (5.0g, 0.02 mole) in dry THF (250 ml)at -78°C under argon was treated with 1.6M n-butyllithium in hexane (36.3 ml, 0.05 mole).The mixture changed from a clear solution to an orange suspension. This was stirred at -78°C for 0.25h, then treated with triisopropyl borate (13.4 ml, 0.05 mole) and stirred at -78°C for a further lh. The mixture was allowed to warm to room temp. and stir for 19h,then treated with water (25 ml) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10% methanol/ dichloromethane to afford thetitle compound as a white solid (2.63g, 67%). ‘H NMR (200 MHz, d6DMSO) δ (ppm): 7.72-7.63 (m, 2H), 7.50 (d, 1H), 2.43 (s, 3H).
Description 34 2,2’-Dimethyl-4’-(5-methyl-l,354-oxadiazol-2-yl)biphenyl-4-carboxylic acid
The title compound was prepared from 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 Al) and 4-borono-3-methylbenzoic acid (D33) using a similarprocedure to Description 11 as a white solid (31%). ‘H NMR (250MHz, CDC13) δ (ppm): 8.10-7.97 (m, 3H), 7.92 (dd, 1H), 7.24 (d, 2H), 2.66(s, 3H), 2.13 (s, 6H).
Description 35 2-(4-Bromo-2-methyIphenyl)-5-methyl-l,3,4-oxadiazole A stirred solution of methyl 4-bromo-2-methylbenzoate (0.9g, 3.9 mmole) in methanol (10ml) was treated with hydrazine hydrate (1.0 ml, 21 mmole) and heated under reflux for 66h. The solution was concentrated in vacuo to leave the hydrazide as a white solid. Thiswas treated with triethyl orthoacetate (10 ml) and heated under reflux under argon for 4h,then concentrated in vacuo. The residue was chromatographed on silica gel eluting with1:1 ether/60-80 petrol to afford the title compound as a white solid (0.77g, 78%). H NMR (250 MHz, CDC13) δ (ppm): 7.76 (d, 1H), 7.51 (s, 1H), 7.45 (dd, 1H), 2.68 (s,3H), 2.62 (s, 3H). 25
Description 36 2,3'-DiinethyI-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid
The title compound was prepared from 2-(4-bromo-2-methylphenyl)-5-methyl-l,3,4-oxadiazole (D35) and 4-borono-3-methylbenzoic acid (D33) using a similar procedure toDescription 11 as a white solid (24%). ‘H NMR (250 MHz, CDC13 + d6DMSO) δ (ppm): 7.95-7.80 (m, 3H), 7.30-7.20 (m, 3H),2.68 (s, 3H), 2.59 (s, 3H), 2.26 (s, 3H).
Description 37 4-Bromo-3-methyl benzamide 4-Bromo-3-methylbenzoic acid (19g, 0.088 mole) was dissolved in dichloromethane (200ml) and treated with oxalyl chloride (12 ml, 0.013 mole), followed by DMF (3 drops). Thereaction mixture was stirred for 18 h at room température, after which the solvent wasremoved in vacuo. The acid chloride was added dropwise to 0.88 ammonia solution (250ml) with stirring. The resulting solid was fïltered off, washed with ether and dried toafford the title compound (18.03g, 96%). *H NMR (200 MHz, d6DMSO) δ (ppm): 8.02 (s, 1H), 7.88 (s, 1H), 7.69-7.61 (m, 2H),7.44 (s, 1H), 2.40 (s, 3H)
Description 38 4-Bromo-3-methylthiobenzamide 4-Bromo-3-methylbenzamide (D37, 1.0g, 0.0047 mole) was dissolved in THF (50 ml),treated with Lawessons reagent (0.95g, 0.0024 mole) and stirred under argon for 4h. Thesolvent was removed in vacuo and the residue purified by flash chromatography on silicagel eluting with 10% EtOH/CHCl3 to afford the title compound as a yellow solid (0.87g,80%). ’H NMR (200 MHz, CDC13) δ (ppm): 7.78 (s, 1H), 7.72 (br s, 1H), 7.63-7.45 (m, 2H), 7.19 (br s, 1H), 2.45 (s, 3H). 26
Description 39 010610 2-(4-Bromo-3-methylphenyl)-4-methylthiazole 4-Bromo-3-methylthiobenzamide (D38, 0.87g, 0.0038 mole) was dissolved in éthanol (60ml) and treated with chloroacetone (0.39 ml, 0.0049 mole). The reaction mixture washeated under reflux for 5 h, then more chloroacetone (0.39 ml, 0.0049 mole) was addedand the mixture heated under reflux for a further 3 h. After cooling to room température,the solvent was removed in vacuo to leave the title compound as a pale oil (1.00g, 98%). 'H NMR (200 MHz, CDC13) δ (ppm): 8.20 (d, 1H), 7.95 (dd, 1H), 7.69 (d, 1H), 7.22 (s,1H), 2.76 (s, 3H), 2.50 (s, 3H).
Description 40 2’ -Methyl-4' -(4-methylthiazol-2-yl)biphenyl-4-carboxylic acid
The title compound was prepared from 2-(4-bromo-3-methylphenyl)-4-methylthiazole(D39,1.00g, 0.0037 mole) using the method of Description 11 (0.77g, 67%). lH NMR (200 MHz, d6DMSO) δ (ppm): 8.03 (d, 2H), 7.89 (s, 1H), 7.82 (dd, 1H), 7.52 (d,2H), 7.40-7.22 (m, 2H), 2.46 (s, 3H), 2.32 (s, 3H).
Description 41 4’-Methoxycarbonyl-2’-methylbiphenyI-4-carboxylic acid A stirred solution of methyl 4-bromo-3-methylbenzoate (EP 0533268 Al) (1.0g, 0.0044mole) in dry DMF (10 ml) under argon was treated with 4-boronobenzoic acid (0.73g,0.0044 mole) and tetrakis (triphenylphosphine) palladium(O) (80 mg), followed bytriethylamine (1.8 ml, 0.016 mole), the mixture was heated at 100°C for 18 hours, thenconcentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10%NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethylacetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the titlecompound as a white solid (0.46g, 39%). ’H NMR (250 MHz, d6DMSO) δ (ppm): 13.1 (brs, 1H), 8.04 (d, 2H), 7.93 (s, 1H), 7.87(d, 1H), 7.51 (d, 2H), 7.38 (d, 1H), 3.87 (s, 3H), 2.30 (s, 3H). 27
Description 42 5'-Methoxycarbonyl-2'-methylbiphenyl-4-carboxyIic acid A stirred solution of methyl 3-bromo-4-methylbenzoate (2.6g, 0.011 mole) in dry DMF(20 ml) under argon was treated with 4-boronobenzoic acid (1.85g, 0.011 mole) andtetrakis (triphenylphosphine) palladium(O) (400 mg), followed by triethylamine (4.68ml,0.046 mole). The mixture was heated at 100°C for 18 hours, then concentrated in vacuo.The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. Thebasic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract wasdried (Na2SO4) and concentrated in vacuo to afford the title compound as a light orangesolid (2.12g, 85%). ’H NMR (250 MHz, d6DMSO) δ (ppm): 13.1 (br s, 1H), 8.09-8.00 (m, 2H), 7.92-7.75 (m,2H), 7.68-7.43 (m, 3H), 3.88 (s, 3H), 2.30 (s, 3H)
Description 43 N-[4-Bromo-3-methylphenyl]-methanesulphonamide
To a stirred solution of 4-bromo-3-methylaniline (3.32g, 17.8 mmol) in dry dichloromethane (150 ml) was added triethylamine (4.96 ml, 35.6 mmol), followed bymethanesulphonyl chloride (1.52 ml, 19.6 mmol). The complété reaction mixture wasstirred at room température under Ar for 18 hours. The mixture was then washed withwater, saturated potassium carbonate solution, and finally brine. The organic layer wasdried (Na2SO4) and concentrated in vacuo to afford a creamy orange solid. This wasdissolved in dichloromethane and shaken with 10% sodium hydroxide solution. Theaqueous layer was separated and acidified to pH6 using concentrated hydrochloric acid.This solution was then extracted using chloroform. The combined organic layers weredried (Na2SO4) and concentrated in vacuo to afford the title compound as a whtie solid(1.35 g, 30%). H NMR (250 MHz, CDC13) δ (ppm): 7.60-6.50 (vb, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 6.95 (dd, 1 H), 3.12 (s, 3H), 2.40 (s, 3H) 28 010610
Description 44 4'-(MethanesuIphonamino)-2'-methylbiphenyl-4-carboxylic acid
The title compound (44%) was afforded as a white solid as per method of Description 11from N-(4-bromo-3-methylphenyl]-methanesulphonamide (D43). ’H NMR (200 MHz, d6DMSO) δ (ppm): 13.0 (b, 1H), 9.80 (s, 1H), 7.98 (d, 2H), 7.43 (d,2H), 7.15 (m, 3H), 3.00 (s, 3H), 2.20 (s, 3H)
Description 45 2'-MethyI-5'-(5-methyl-l,3,4-oxadiazol-2-yI)biphenyl-4-carboxylic acid
The title compound was prepared from methyl 3-bromo-4-methylbenzoate foliowingsimilar procedures to those in Descriptions 35 and 11 as a beige solid. 'H NMR (200 MHz, d6DMSO) δ (ppm): 11.70 (s, 1H), 8.10-7.50 (m, 7H), 2.30 (s, 3H),1.90 (s, 3H).
Description 46 N- [4-Bromo-3-methylphenyl] -acetamide A stirred solution of 4-bromo-3-methylaniline (3.0g, 0.016 mole) and triethylamine (4.5ml, 0.032 mole) in dichloromethane (30 ml) at 0° C was treated with acetyl chloride (1.2ml, 0.017 mole) and allowed to warm to room température over lh. The mixture waswashed with water, then 5M HCl acid and dried (Na2SO4), then concentrated in vacuo toafford the title compound as a pale yellow solid (3.07g, 83%). 'H NMR (200 MHz, CDC13) δ (ppm): 7.50-7.35 (m, 2H), 7.19 (dd, 1H), 2.36 (s, 3H), 2.16(s, 3H).
Description 47 4’-Acetamido-2’-methylbiphenyI-4-carboxylic acid
The title compound was prepared from N-[4-bromo-3-methylphenyl]-acetamide (D46)using a similar procedure to Description 11 as a white solid (66%). lH NMR (200 MHz, d6DMSO) δ (ppm): 12.8 (br s, 1H), 9.98 (s, 1H), 7.98 (d, 2H), 7.55-7.40 (m, 4H), 7.16 (d, 1H), 2.20 (s, 3H), 2.05 (s, 3H) 29 010610
Description 48
Bis-(2,3-dihydro-6-iodo-lH-indoI-5-yI) disulphide A stirred suspension of 2,3-dihydro-6-iodo-lH-indole (0.600g, 2.45 mmol) (Heterocycles1987 26(11) 2817) in methanol (10 ml) under argon, was treated with potassiumthiocyanate (0.467g, 4.90 mmol) with stirring at 0° C. A solution of bromine (0.138 ml,2.69 mmol) in methanol (5 ml) was then added slowly. After 16 hours the reactionmixture was evaporated under reduced pressure. The residue was partitioned betweendichloromethane and potassium carbonate solution and the aqueous layer was extractedwith dichloromethane. The combined organic layers were then dried (Na2SO4) andevaporated under reduced pressure to give a brown solid which was suspended in a mixtureof 880 ammonia solution (18 ml) and dioxan (12 ml) and was heated to gentle reflux in air.After 24h, the reaction mixture was allowed to cool and was partitioned betweendichloromethane and water. The aqueous layer was then extracted with dichloromethane(IX) and the combined organic layers were dried (Na2SO4) and evaporated under reducedpressure to give the title compound as an orange oil which was dried in vacuo (0.410g,61%). ’H NMR (200 MHz, CDC13) Ô: 7.42 (s, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 7.05 (s, 1H), 3.62(t, 2H), 3.55 (t, 2H), 3.05 (t, 2H), 2.95 (t, 2H).
Description 49 l-AcetyI-2,3-dihydro-6-iodo-lH-indol-5-thiol
Bis-(2,3-dihydro-6-iodo-lH-indol-5-yl) disulphide (D48) (0.408g, 0.739 mmol) wassuspended in dichloromethane (30 ml) and was treated with triethylamine (0.226 ml, 1.62mmol) at 0°C, followed by acetic anhydride (0.153 ml, 1.62 mmol) with stirring underargon. After 24h the reaction mixture was washed with water (2X). The organic layer wasthen dried (Na2SO4) and was evaporated under reduced pressure to give an orange oil thatwas dried in vacuo (0.40g). The oil was then redissolved in a mixture of dioxan (20 ml)and water (4 ml) and triphenylphosphine (0.250g, 0.953 mmol) was added, followed byconc. HCl (1 drop). The mixture was flushed with argon, and then heated to reflux withstirring. After 2.5 hours, the reaction mixture was allowed to cool and was partitionedbetween 2% sodium hydroxide (20 ml) and dichloromethane (30 ml). The organic layerwas then washed with 2% sodium hydroxide (10 ml) and the combined aqueous layerswere acidified to pH5 using conc. HCl. The résultant suspension was then extracted withdichloromethane (3x15 ml). The combined extracts were then dried (Na2SO4) and 30 010610 evaporated under reduced pressure to give the title compound as a yellow solid which wasdried in vacuo (0.354g, 75%). ‘H NMR (200 MHz, CDC13) δ: 8.63 (s, 1H), 7.20 (s, 1H), 4.05 (t, 2H), 3.12 (t, 2H), 2.20(s, 3H).
Description 50 l-Acetyl-2,3-dihydro-6-iodo-5-(pyridin-4-yImethyIthio)-lH-indole l-Acetyl-2,3-dihydro-6-iodo-lH-indol-5-thiol (D49) (0.346g, 1.08 mmol) in dry DMF (5ml) was treated with potassium carbonate (0.374g, 3.71 mmol) followed by picolylchloride hydrochloride (0.186g, 1.13 mmol). After 65h stirring at room temp. the reactionmixture was evaporated under reduced pressure and was partitioned betweendichloromethane and water. The aqueous layer was then extracted with dichloromethaneand the combined organic layers were then dried (Na2SO4) and evaporated under reducedpressure to give the title compound as a pale brown solid which was dried in vacuo(0.392g, 89%). ‘H NMR (200 MHz, CDC13) Ô: 8.72 (s, 1H), 8.48 (d, 2H), 7.12 (d, 2H), 6.97 (s, 1H), 4.05(t, 2H), 3.95 (s, 2H), 3.03 (t, 2H), 2.21 (s, 3H).
Description 51 l-Acetyl-2,3-dihydro-6-iodo-5-[(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)methyIthio]- lH-indoIe l-Acetyl-2,3-dihydro-6-iodo-5-(pyridin-4-ylmethylthio)-lH-indole (D50) (0.390g, 0.951mmol) was dissolved in dry DMF (5 ml) and was treated with methyl iodide (0.089 ml, 1.430 mmol) with stirring. After 24 hours the reaction mixture was evaporated underreduced pressure and was triturated with ethyl acetate (~20 ml). The résultant brown solidwas then filtered off, washed with diethyl ether and dried in vacuo (0.513g). The solid wasthen redissolved in a mixture of éthanol (20 ml) and water (10 ml) and was cooled to 0° C.Sodium borohydride (0.069g, 1.824 mmol) was then added. After 0.5 h a further amountof sodium borohydride (0.035g, 0.912 mmol) was added . The reaction mixture was thenallowed to warm to room température. After 1.5 hours the reaction mixture was treatedwith sodium bicarbonate solution (~ 15 ml) and was partitioned between dichloromethaneand water. The aqueous layer was then extracted with dichloromethane (IX) and thecombined organic layers were dried (Na2SO4) and evaporated under reduced pressure to 31 010610 give a yellow solid which was purified by silica-gel chromatography (5% MeOH/CH2Cl2as eluant) to give the title compound as an off white solid (0.208g, 53%). 'H NMR (200 MHz, CDC13) δ: 8.70 (s, 1H), 7.12 (s, 1H), 5.48 (s, 1H), 4.08 (t, 2H), 3.45(s, 2H), 3.12 (t, 2H), 2.89 (s, 2H), 2.55 (t, 2H), 2.30 (s, 5H), 2.20 (s, 3H)
Description 52 5-Acetyl-l’-methyl-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine] A solution of tributyltin hydride (0.251 ml, 0.934 mmol) in benzene (10 ml) was addeddropwise over 30 minutes to a stirred solution of l-acetyl-2,3-dihydro-6-iodo-5-[(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)methylthio]-lH-indole (D51) (0.200g, 0.467 mmol)and AIBN (5 mg) in benzene (20 ml) under argon at reflux. Reflux was continued for afurther 0.75 h. The reaction mixture was then allowed to cool. Ethyl acetate (10 ml) wasthen added and the mixture washed with 2.5M HCl (3x10 ml). The combined aqueouswashings were then basified with solid potassium carbonate and the résultant suspensionwas extracted with dichloromethane (3x15 ml), The combined organic extracts were thendried (Na2SO4) and evaporated under reduced pressure to give a pale yellow solid whichwas dried in vacuo (QATlg). The solid was purified by prep. TLC (15% MeOH/CH2Cl2 aseluant) to give the title compound as a cream solid (0.047g, 33%). *HNMR (250 MHz, CDC13) δ: 8.12 (s, 1H), 6.98 (s, 1H), 4.05 (t, 2H), 3.30 (s, 2H), 3.12(t, 2H), 2.89 (m, 2H), 2.38 (s, 3H), 2.30 (m, 2H), 2.20 (s, 3H), 2.05 (m, 2H), 1.85 (m, 2H).
Description 53 l'-Methyl-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f|indole-3,4’-piperidine] 5-Acetyl-T-methyl-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine] (D52)(0.047g, 0.156 mmol) was dissolved in a mixture of éthanol (2 ml) and 5M HCl (4 ml) andwas heated to reflux with stirring under argon. Afiter 3 h, the reaction mixture was allowedto cool, was diluted with water (10 ml) and was basified using solid potassium carbonate.The resulting suspension (pH9) was then extracted with dichloromethane (3x10 ml) andthe combined extracts were dried (Na2SO4) and evaporated under reduced pressure to givethe title compound as an off white solid, which was dried in vacuo (0.029g, 71%). ’H NMR (250 MHz, CDC13) δ: 7.29 (s, 1H), 6.50 (s, 1H), 3.53 (t, 2H), 3.28 (s, 2H), 2.95(t, 2H), 2.82 (m, 2H), 2.31 (s, 3H), 2.10 (m, 2H), 1.87 (m, 4H). 32 010610
Description 54
Methyl 4'-[(N-methanesuIphonyl-N-methyI)amino]-2’-methylbiphenyl-4-carboxylate 4'-(Methanesulphonamino)-2'-methylbiphenyl-4-carboxylic acid (D44, 0.29g, 0.94 mmol),anhydrous K2CO3 (0.40g, 2.9 mmol) and iodomethane (0.18 ml, 2.9 mmol) were stirred indry DMF (5 ml) for 16 h. The mixture was diluted with ethyl acetate, washed with waterand brine, dried (Na2SO4) and evaporated to give the title compound (0.32g, quantitative)as a brown oil, containing residual solvent (NMR). 'H NMR (250 MHz, CDC13) δ (ppm): 8.10 (d, 2H), 7.38 (d, 2H), 7.27 (m, 3H), 3.96 (s,3H), 3.37 (s, 3H), 2.91 (s, 3H), 2.28 (s, 3H).
Description 55 4-Bromo-N,N-dimethylbenzenesulphonamide 4-Bromobenzenesulphonyl chloride (4.48g, 18 mmol) was stirred in dichloromethane, anddimethylamine (40% aqueous solution, 10 ml) was added portionwise. The mixture wasstirred for 2h, washed with dilute hydrochloric acid, dried (Na2SO4) and evaporated to givethe title compound (4.38g, 94%) as a white solid. 'H NMR (250 MHz, CDC13) δ (ppm): 7.67 (Abq, 4H), 2.72 (s, 6H).
Description 56 4'-(DimethyIaminosulphonyl)biphenyI-4-carboxylic acid
This was prepared from 4-bromo-N,N-dimethylbenzenesulphonamide (D55) following theprocedure of Description 11. This gave the title compound as a white solid (85%). ’H NMR (200 MHz, d6DMSO) δ (ppm): 8.08 (d, 2H), 8.02 (d, 2H), 7.90 (d, 2H), 7.86 (d,2H), 2.66 (s, 6H).
Description 57 4'-(Methanesulphonyl)biphenyI-4-carboxylic acid
This was prepared from 4-bromophenyl methyl sulphone, following the procedure ofDescription 11. This gave the title compound (72%) as a white solid. ’H NMR (250 MHz, d6DMSO) δ (ppm): 8.05 (m, 6H), 7.88 (d, 2H), 3.28 (s, 3H). 33 010610
Description 58 N’-(4-Bromo-3-methylphenyl)-N,N-dimethylurea 4-Bromo-3-methylaniline (5.00g, 27 mmol), triethylamine (3.9 ml, 28 mmol), 4-(dimethylamino)pyridine (0.5g, 4 mmol) and dimethylcarbamyl chloride (2.6 ml, 28mmol) were mixed in dichloromethane (100 ml), and left to stand for 2 weeks. Thesolution was then washed with dilute hydrochloric acid, dried (Na2SO4) and evaporated togive a solid. This was triturated with ether, and the solid was filtered off and dried,affording the title compound (2.51g, 36%) as an off-white solid. ‘H NMR (250 MHz, CDC13) δ (ppm): 7.40 (d, 1H), 7.35 (d, 1H), 7.07 (dd, 1H), 6.78 (bs,1H), 3.02 (s, 6H), 2.36 (s, 3H).
Description 59 4'-(N,N-Dimethylcarbamoylammo)-2'-methylbiphenyI-4-carboxylic acid
This was prepared from N'-(4-bromo-3-methylphenyl)-N,N-dimethylurea (D58), followingthe procedure of Description 11. This gave the title compound as a salmon-coloured solid(90%). ’H NMR (250 MHz, d6DMSO) δ (ppm): 8.34 (s, 1H), 7.98 (d, 2H), 7.45 (m, 4H), 7.10 (d,1H), 2.93 (s, 6H), 2.22 (s, 3H).
Description 60
Ethyl N-(4-bromo-3-methylphenyl)carbamate 4-Bromo-3-methylaniline (5.00g, 27 mmol) and triethylamine (4.5 ml, 32 mmol) werestirred in dichloromethane (200 ml) as ethyl chloroformate (3.1 ml, 32 mmol) was addeddropwise. The mixture was stirred for 2h, when water was added. After stirring for afurther 15 min, the white precipitate was filtered off, and the filtrate was separated. Theorganic portion was dried (Na2SO4) and evaporated to give the title compound (2.57g,37%) as an orange-brown oil. 'H NMR (250 MHz, CDC13) δ (ppm): 7.42 (d, 1H), 7.30 (d, 1H), 7.09 (dd, 1H), 6.60 (b s, 1H), 4.23 (q, 2H), 2.36 (s, 3H), 1.32 (t, 3H).
Description 61 34 4*-(Ethoxycarbonylamino)-2'-methylbiphenyl-4-carboxylic acid v ι u u ι u
This was prepared from ethyl N-(4-bromo-3-methylphenyl)carbamate (D60), following theprocedure of Description 11. This gave the title compound, after recrystallisation fromethyl acetate/petroleum ether (bp.60-80°C), as a white powder (63%). ’H NMR (200 MHz, d6DMSO) δ (ppm): 9.70 (s, 1H), 7.98 (d, 2H), 7.4 (m, 4H), 7.16 (d,1H), 4.14 (q, 2H), 2.22 (s, 3H), 1.26 (t, 3H)
Description 62 3- (4-Bromo-3-methyIphenyI)-5-methyl-l,2,4-triazole 4- Bromo-3-methylbenzoic hydrazide (D30, 3.06g, 13 mmol), ethyl acetimidatehydrochloride (2.48g, 20 mmol) and triethylamine (5.6 ml, 40 mmol) were stirred at refluxunder Ar for 24h, and then evaporated to dryness. The residue was chromatographed onsilica gel, eluting with dichloromethane/ethanol/ammonia (300:8:1). This gave the titlecompound (1.95g, 58%) as a white solid. ‘H NMR (200 MHz, CDCl3/d6DMSO) δ (ppm): 7.63 (s, 1H), 7.41 (d, 1H), 7.22 (d, 1H),2.15 (s, 3H), 2.10 (s, 3H).
Description 63 3-(4-Bromo-3-methylphenyl)-4,5-dimethyl-l,2,4-triazole 3-(4-Bromo-3-methylphenyl)-5-methyl-l,2,4-triazole (D62, 0.60g, 2.4 mmol) was stirredunder Ar in dry DMF (6 ml) as sodium hydride (80% dispersion, 0.21g, 7.2 mmol) wasadded. After stirring for 30 min, iodomethane (0.3 ml, 4.8 mmol) was added. Thismixture was stirred for lh, and treated with water (30 ml), giving a beige precipitate. Thiswas filtered off and dried, giving the title compound (0.49g, 77%) as a beige solid. !H NMR (250 MHz, d6DMSO) δ (ppm): 7.92 (s, 1H), 7.65 (m, 2H), 3.80 (s, 3H), 2.44 (s,3H), 2.39 (s, 3H).
Description 64 4’-(4,5-Dimethyl-l,2,4-triazol-3-yl)-2’-methylbiphenyl-4-carboxylic acid
This was prepared from 3-(4-bromo-3-methylphenyl)-4,5-dimethyl-l,2,4-triazole (D63),following the procedure of Description 11. This gave the title compound (53%) as a whitesolid. 35 010610 ‘h NMR (200 MHz, d6DMSO) δ (ppm): 13.0 (v b, 1H), 8.02 (d, 2H), 7.93 (s, 1H), 7.87 (d,1H), 7.53 (d, 2H), 7.30 (d, 1H), 3.84 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H).
Description 65 2-(4-Pyridyl)ethanol
This was prepared from ethyl 4-pyridylacetate, following the procedure of Description 1.This gave the title compound (95%) as a yellow oil. ‘H NMR (200 MHz, CDC13) δ (ppm): 8.43 (d, 2H), 7.17 (d, 2H), 3.90 (t, 2H), 3.0 (b, 1H),2.86 (t, 2H).
Description 66 l-Acetyl-6-bromo-2,3-dihydro-5-[2-(4-pyridyl)ethoxy]-lH-indole
This was prepared from l-acetyl-6-bromo-2,3-dihydro-lH-indol-5-ol (Tetrahedron 1973,29 (8), 1115) and 2-(4-pyridyl)ethanol (D65), following the procedure of Description 8a.This gave the title compound (84%), as a yellow solid. ’H NMR (200 MHz, CDC13) δ (ppm): 8.54 (d, 2H), 8.45 (s, 1H), 7.25 (d, 2H),6.70 (s, 1H),4.19 (t, 2H), 4.05 (t, 2H), 3.12 (m, 4H), 2.19 (s, 3H).
Description 67 l-Acetyl-6-bromo-2,3-dihydro-5-[2-(4-pyridyl)ethoxy]-lH-indole methiodide l-Acetyl-6-bromo-2,3-dihydro-5-[2-(4-pyridyl)ethoxy]-lH-indole (D66) (3.15g, 8.7 mmol)and iodomethane (1.1 ml, 17.7 mmol) were mixed in dry DMF (30 ml) and left to stand for16 h. The suspension was then diluted with ethyl acetate (300 ml), and the solid wascollected and dried, affording the title compound (2.78g, 63%) as a yellow powder. 'H NMR (200 MHz, d6DMSO) δ (ppm): 8.93 (d, 2H), 8.19 (s, 1H), 8.14 (d, 2H), 7.13 (s,1H), 4.38 (t, 2H), 4.31 (s, 3H), 4.10 (t, 2H), 3.37 (t, 2H), 3.12 (t, 2H), 2.15 (s, 3H).
Description 68 l-Acetyl-6-bromo-2,3-dihydro-5-[2-(l-methyl-l,2,3,6-tetrahydro-4-pyridyl)ethoxy]- lH-indole 36 010610 l-Acetyl-6-bromo-2,3-dihydro-5-[2-(4-pyridyl)ethoxy]-lH-indole methiodide (D67) (2.78g, 5.5 mmol) was dissolved in éthanol (40 ml) and water (40 ml), cooled in ice, andtreated with stirring with sodium borohydride (0.31g, 8.2 mmol) portionwise over lh. Themixture was then basified with sodium hydroxide solution, diluted with water (100 ml),and extracted with chloroform. The extract was dried (Na2SO4) and evaporated to yieldthe title compound (1.95g, 96%) as a brown solid. *H NMR (200 MHz, CDC13) Ô (ppm):8.43 (s, 1H), 6.72 (s, 1H), 5.53 (m, 1H), 4.05 (m, 4H), 3.14 (t, 2H), 2.92 (m, 2H), 2.55 (m, 4H), 2.35 (s, 3H), 2.25 (m, 2H), 2.20 (s, 3H).
Description 69 6-Acetyl-l ’-methyl-2,3,7,8-tetrahydrospiro [4H-pyrano [2,3-0 indoIe-4,4’-piperidine]
This was prepared from l-acetyl-6-bromo-2,3-dihydro-5-[2-(l-methyl-l,2,3,6-tetrahydro- 4-pyridyl)ethoxy]-lH-indole (D68), following the procedure of Description 8b. This gave,after extensive purification, the title compound as a brown oil. 'H NMR (200 MHz, CDC13) δ (ppm): 7.96 (s, 1H), 6.86 (s, 1H), 4.40 (dt, 1H), 4.07 (t, 2H), 3.6 (m, 3H), 3.17 (t, 2H), 3.0 (m, 1H), 2.80 (s, 3H), 2.7 (m, 2H), 2.23 (s, 3H), 1.95(m, 5H).
Description 70 l’-Methyl-2,3,7,8-tetrahydrospiro[4H-pyrano[2,3-f|indole-4,4’-piperidine]
This was prepared from 6-acetyl-l'-methyl-2,3,7,8-tetrahydrospiro[4H-pyrano[2,3-f]indole-4,4'-piperidine] (D69), following the procedure of Description 8c. This gave thetitle compound (70%) as a brown oil. ’H NMR (250 MHz, CDC13) δ (ppm): 6.79 (s, 1H), 6.48 (s, 1H), 4.30 (dt, 1H), 3.55 (m,3H), 3.11 (m, 1H), 2.99 (t, 2H), 2.89 (m, 1H), 2.37 (s, 3H), 2.2 (m, 2H), 1.7-2.0 (m, 4H),1.57 (m, 1H), 1.34 (m, 1H), 0.85 (m, 1H).
Description 71 N’-Acetyl 4-bromo-3-methylbenzoic hydrazide 4-Bromo-3-methylbenzoic hydrazide (D30, 7.5g) was suspended in acetic anhydride (7 ml)giving rise to an exothermic reaction. The reaction mixture was cooled to roomtempérature and the product collected. The solid was washed with éthanol and diethylether to afford the title compound as a white powder (5.5g). 37 010610 'h NMR (250 MHz,d6DMSO) δ (ppm): 7.89 (d, 1H), 7.79 (d, 1H), 7.68 (dd, 1H), 3.36 (s,3H), 2.45 (s, 3H).
Description 72 2-(4-Bromo-3-methylphenyI)-5-methyl-l,3,4-thiadiazoIe N'-acetyl-4-bromo-3-methylbenzoic hydrazide (D71,3g) was converted to the crude titlecompound (1.6g) according to the literature method (P.B. Rasmussen et al, Bull. Soc.Chim. Fr., 1985, 62-65).
Description 73 2’-Methyl-4'-(5-methyl-l,354-thiadiazol-2-yI)biphenyl -4-carboxylic acid
The title compound was prepared from 2-(4-bromo-3-methylphenyl)-5-methyl-l,3,4-thiadiazole (D72) using the general procedure of Description 11. This was used in thenext step without purification.
Description 74 N-[2-(l,3-Dioxolan-2-yI)propyl]-4-bromo-3-methylbenzamide A stirred suspension of 4-bromo-3-methylbenzoic acid (2.15g, 10 mmol) in thionylchloride (15 ml) was heated under reflux for 1 hour, then concentrated in vacuo to leavethe acid chloride as a red oil. This was dissolved in dichloromethane (20 ml) and addeddropwise to a stirred solution of 2-(1,3-dioxalan-2-yl)propylamine (J. Org. Chem., 1972,37, 221) (2.34g, 20 mmole) and triethylamine (2.8 ml, 20 mmole) in a mixture ofdichloromethane (150 ml) and dry THF (50 ml) at 0°C under argon. The mixture wasallowed to warm to room temp. and stir for 18 hours, then concentrated in vacuo. Theresidue was dissolved in dichloromethane, washed with IM HCl, then dilute K2CO3solution and water, then dried (Na2SO4) and concentrated in vacuo to afford the titlecompound as a yellow solid (2.8g, 89%). ‘H NMR (250 MHz, CDC13) δ (ppm): 7.67 (d 1H), 7.60 (d, 1H), 7.42 (dd, 1H), 6.32 (br t, 1H), 4.06-3.96 (m, 4H), 3.61 (d, 2H), 2.45 (s, 3H), 1.39 (s, 3H).
Description 75 2-(4-Bromo-3-methylphenyl)-5-methyIoxazole 38 010610 N-[2-(l,3-Dioxolan-2-yl)propyl]-4-bromo-3-methylbenzamide (D74,2.8g, 8.9 mmole) wasadded portionwise over 5 minutes to well stirred polyphosphoric acid (50g) at 120°C underargon, then heated at 160°C for 35 minutes. The reaction mixture was allowed to cool,then treated with water (200 ml) and stirred well to dissolve the glassy mass. The mixture 5 was extracted with ethyl acetate and the extract washed with 10% Na2CO3 solution andwater, then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographedon silica gel eluting with 1:1 ether/60-80 petrol to afford the title compound as a paleyellow solid (2.0g, 89%). 10 *H NMR (250 MHz, CDC13) δ (ppm): 7.87 (s, 1H), 7.66 (dd, 1H), 7.58 (d, 1H), 6.82 (s, 1 H), 2.45 (s, 3H), 2.38 (s, 3H).
Description 76 2'-Methyl-4'-(5-methyloxazol-2-yl)biphenyI-4-carboxyIic acid 15
The title compound was prepared from 2-(4-bromo-3-methylphenyl)-5-methyloxazole(D75) using a similar procedure to Description 11 as a white solid (86%). ’H NMR (250 MHz, d6DMSO) δ (ppm): 8.02 (d, 2H), 7.88 (s, 1H), 7.83 (d, 1H), 7.51 (d, 20 2H), 7.38 (d, 1H), 7.02 (s, 1H), 2.40 (s, 3H), 2.31 (s, 3H). 39
Description 77 (4-Bromo-3-methyIphenyl)butane-l,3-dione 010610 A solution of 4-bromo-3-methylacetophenone (DI8) (2g, 0.0093 mol) in dry toluene (28ml) was treated under argon with sodium hydride (80% dispersion in minerai oil) (0.28g,0.0093 mol) and ethyl acetate (1.37 mis, 0.014 mol), followed by one drop of éthanol. Themixture was heated to reflux with stirring for 1 hour then cooled. Brine was added and themixture was extracted into ethyl acetate, the organic phase was dried (Na2SO4) andconcentrated in vacuo, and the residual crude mixture was purified by chromatography onsilica gel, eluting with dichloromethane and methanol, to afford the title compound as ayellow solid (623 mg, 26%). ’H NMR (enol form) (200 MHz, CDC13) δ (ppm): 16.1 (s, 1H), 7.75 (s, 1H), 7.6 (d, 1H),7.52 (d, 1H), 6.15 (s, 1H), 2.45 (s, 3H), 2.2 (s, 3H).
Description 78 5-(4-Bromo-3-methylphenyl)-3-methylisoxazoIe A solution of l-(4-bromo-3-methylphenyl)butane-l,3-dione (D77) (615 mg; 0.0024 mol)in éthanol (15 ml) was treated with hydroxylamine hydrochloride (170 mg; 0.0024 mol)and potassium carbonate (336 mg; 0.0024 mol), and the mixture heated at reflux for 2.5hours, then overnight at room température. The solvent was evaporated under reducedpressure and the residue partitioned between water and ethyl acetate. The organic phasewas dried (Na2SO4) and concentrated in vacuo to leave the crude isoxazole, which waspurified by chromatography on silica gel, eluting with pentane, 60-80 petroleum-ether andethyl acetate, to afford the title compound as a yellow crystalline material (477mg, 78%). ’H NMR (250 MHz, CDC13) δ (ppm): 7.65-7.56 (m, 2H), 7.4 (d, 1H), 6.35 (s, 1H), 2.45(s, 3H), 2.35 (s, 3H).
Description 79 2’-Methyl-4'-(3-niethylisoxazol-5-yl)biphenyl-4-carboxylic acid
The title compound was prepared from 5-(4-bromo-3-methylphenyl)-3-methylisoxazole(D78) using a similar procedure to Description 11 (48%) as a yellow solid. ‘H NMR (200 MHz, CDC13) δ (ppm): 8.04-7.9 (m, 2H), 7.78 (s, 1H), 7.7 (d, 1H), 7.4-7.2 (m, 3H), 6.9 (s, 1H), 2.4-2.2 (m, 6H). 010610 40
Description 80 4-Bromo-3-mcthylbenzaldehyde A solution of N-methoxy-N-methyl-4-bromo-3-methylbenzamide (D17) (12g; 0.046 mol)in dry tetrahydrofuran (120 ml) under argon, at -78°C was treated dropwise over 15minutes with diisobutylaluminium hydride (1.5m in toluene) (46 ml; 0.069 mol). After afurther 15 minutes the reaction mixture was added to 5N HCl (100 ml) and extracted intodiethyl ether. The organic phase was dried (Na2SO4) and evaporated under reducedpressure to give the title compound as a red oil (8.98g, 97%). ’H NMR (200 MHz, CDC13) δ (ppm): 9.95 (s, 1H), 7.76-7.65 (m, 2H), 7.55 (d, 1H), 2.48(s, 3H)
Description 81 4-Bromo-3-methylbenzaldehyde oxime A solution of 4-bromo-3-methylbenzaldehyde (D80) (lg; 0.005 mol) in methanol (20 ml)was treated with hydroxylamine hydrochloride (700 mg, 0.01 mol) and the mixture stoodat room température over a weekend. The solvent was evaporated under reduced pressureand the residual solid was partitioned between saturated K2CO3 solution and ethyl acetate.The organic phase was dried (Na2SO4), concentrated in vacuo and the residue purified bychromatography on silica gel eluting with 60-80 petroleum-ether and ethyl acetate, toafford the title compound as a pale pink powder (693 mg, 20%). *H NMR (200 MHz, CDC13) δ (ppm): 9.15 (br s, 1H), 7.8 (s, 1H), 7.67 (d, 1H), 7.59 (d,1H), 7.32 (s, 1H), 2.43 (s, 3H).
Description 82 3-(4-Bromo-3-methylphenyl)-5-methyIisoxazole A solution of 4-bromo-3-methylbenzaldehyde oxime (D81) (2.68g, 0.0125 mol) in drydimethylformamide (30 ml) was treated over 15 minutes with N-bromosuccinimide (636mg, 0.00357 mol), and reaction mixture stirred for 2.5 hours, then cooled to -15°C. 2-Chloropropene (3.45 ml, 0.0405 mol) was added in a single portion, followed by dropwiseaddition of triethylamine (1.35 ml, 0.0097 mol) in dry dimethylformamide (10 ml) over 0.5hours maintaining the temp. at -10°C. The mixture was stirred at 0°C for 1 hour, thenstirred at room température ovemight. The solvent was evaporated under reduced pressure 41 010610 and the residue partitioned between K2CO3 solution and chloroform. The organic phasewas dried (Na2SO4) and evaporated under reduced pressure and the residue purified bychromatography on silica gel eluting with 60-80 petroleum-ether and ethyl acetate, toafford the title compound (246 mg, 8%). 'H NMR (200 MHz, CDC13) δ (ppm): 7.68 (s, 1H), 7.6 (d, 1H), 7.43 (d, 1H), 6.26 (s, 1H),2.48 (s, 3H), 2.45 (s, 3H).
Description 83 2’-MethyI-4'-(5-methylisoxazol-3-yl)biphenyl-4-carboxylic acid
The title compound was prepared from 3-(4-bromo-3-methylphenyl)-5-methylisoxazole(D82) using a similar procedure to Description 11 (57%). ‘H NMR (250 MHz, d6DMSO) δ (ppm): 13.05 (br s, 1H), 8.04 (d, 2H), 7.82 (s, 1H), 7.75(d, 1H), 7.52 (d, 2H), 7.36 (d, 1H), 6.81 (s, 1H), 2.49 (s, 3H), 2.3 (s, 3H).
Description 84 (4-Bromo-3-methylphenyl) pyrazine A stirred solution of diisopropylamine (2.44 ml, 0.018 mol) in dry THF (40 ml) underargon was treated with n-butyllithium (1.6M) (10.1 ml, 0.016 mol) at -60°C. After 15minutes the résultant mixture was treated with methyl phenyl sulphoxide (1.68g, 0.014mol) in dry THF (15 ml). After a further 15 minutes a solution of N-methyl-N-methoxy-4-bromo-3-methyl-benzamide (DI7) (3.00g, 0.012 mol) in dry THF (30 ml) was addeddropwise and the reaction mixture was allowed to warm to room température over 2h andwas left stirring at room temp. for 18h, before 10% sodium carbonate solution (50 ml) wasadded. The reaction mixture was then concentrated in vacuo and the residue waspartitioned between water and dichloromethane. The aqueous layer was then extractedwith dichloromethane (IX) and the combined organic layers were dried (Na2SO4) andevaporated under reduced pressure to give an orange oil which was dried in vacuo (3.60g).The oil was then redissolved in dichloromethane (70 ml) and was cooled to 0°C underargon. Trifluoroacetic acid (0.960 ml, 0.013 mol) was then added, followed bytrifluoroacetic anhydride (3.53 ml, 0.025 mol). After 30 minutes, the reaction mixture wasevaporated under reduced pressure to give an orange oil. A solution of sodium hydrogencarbonate (3.70g, 0.044 mol) in water (75 ml) was then added, followed by éthanol (250ml). Ethylene diamine (0.840 ml, 0.013 mol) was then added to the résultant stirredsuspension. After 18 h, the reaction mixture was concentrated in vacuo and the residue 42 010610 was partitioned between dichloromethane and water. The aqueous layer was then extractedwith dichloromethane, and the combined organic layers were dried (Na2SO4) andevaporated under reduced pressure to give a dark red oil, which was dried in vacuo (3.65g).The oil was then redissolved in éthanol (80 ml) and was treated with potassium hydroxide(0.703g, 0.013 mol). The résultant solution was then heated to reflux. After 24h, thereaction mixture was allowed to cool and was evaporated under reduced pressure to give adark oil, which was partitioned between dichloromethane and water. The organic layerwas then dried (Na2SO4) and evaporated under reduced pressure to give a dark brown oil,which was purified by silica-gel chromatography (20% Et2O/pentane as eluant) to give thetitle compound as a pale yellow solid (0.583g, 21%). *H NMR (200 MHz, CDC13) δ (ppm): 9.00 (s, 1H), 8.62 (d, 1H), 8.51 (d, 1H), 7.90 (s, 1H), 7.70 (s, 2H), 2.50 (s, 3H).
Description 85 2'-Methyl-4'-pyrazinylbiphenyl-4-carboxylic acid (4-Bromo-3-methylphenyl) pyrazine (D84, 0.300g, 1.21 mmol) was converted to give thetitle compound (0.279g, 88%) as a white solid, according to the method described inDescription 11. ’H NMR (250 MHz, CD3SOCD3) δ (ppm): 9.30 (d, 1H), 8.72 (d, 1H), 8.62 (d, 1H), 8.12(s, 1H), 8.05 (m, 3H), 7.52 (d, 2H), 7.41 (d, 1H), 2.31 (s, 3H)
Description 86
Methyl 2'-methyl-4’-pyrazinylbiphenyl-4-carboxylate
Thionyl chloride (0.076 ml, 1.043 mmol) was added to methanol (7 ml) at 0°C. After 15minutes, 2'-methyl-4'-pyrazinylbiphenyl-4-carboxylic acid (D85, 0.216g, 0.745 mmol) wasadded and the mixture was heated to reflux. After 5 h, the reaction mixture was allowed tocool and was lefît at room température ovemight. The reaction mixture was thenevaporated under reduced pressure and the residue was partitioned between dichloromethane (25 ml) and 10% sodium carbonate solution (20 ml). The aqueous layerwas then extracted with dichloromethane (1x10 ml), and the combined organic layerswere then dried (Na2SO4) and evaporated under reduced pressure to give the titlecompound as a yellow/brown solid (0.146g, 65%). 43 010610 'HNMR (250 MHz, CDC13) δ (ppm): 9.10 (s, 1H), 8.68 (t, 1H), 8.52 (d, 1H), 8.13 (d,2H), 8.00 (s, 1H), 7.90 (dd, 1H), 7.45 (d, 2H), 7.40 (d, 1H), 3.98 (s, 3H), 2.38 (s, 3H).
Description 87
Methyl 4-bromo-3-raethylbenzimidate hydrochloride 4-Bromo-3-methylbenzonitrile (15.0g, 76.5 mmol) was dissolved in dry methanol (3.1 ml,76.5 mmol) and dry diethyl ether (108 ml), cooled to 0-5°, then saturated with HCl (g).Stirred for 18 hours at room température and the solid collected by filtration, then dried invacuo to yield the title compound as white needle-like crystals (19.3g, 95%). !H NMR (250 MHz, CDC13) δ (ppm): 12.7 (s, 1H), 12.0 (s, 1H), 8.35 (d, 1H), 8.05-8.00(m, 1H), 7.70 (d, 1H), 4.55 (s, 3H), 2.50 (s, 3H).
Description 88 2-(4-Bromo-3-methylphenyl)imidazole
Methyl 4-bromo-3-methylbenzimidate hydrochloride (D87, 5.0g; 21.9 mmol) wasdissolved in methanol (30 ml) and stirred during the addition of a solution of 2-aminoacetaldehyde dimethyl acetal (2.4 ml; 21.9 mmol) in methanol (10 ml) over 30minutes. Stirring was continued for 36 hours and evaporated in vacuo to yield an orangegum (7g crude). This crude hydrochloride was treated with cône. H2SO4 (12 ml) at 5°,then heated at 50° for 10 minutes. The solution was cooled in ice, diluted with H2O andbasified with 10% NaOH. The aqueous solution was extracted with chloroform (4 times)and the organics combined, dried over Na2SO4, filtered and evaporated in vacuo. Theresidue was purified by flash silica gel chromatography eluting with 1% MeOH/CHCl3 toyield the title compound as a white solid (1.55g; 44%). H NMR (250 MHz, CDC13) δ (ppm): 7.70 (d, 1H), 7.55-7.45 (m, 2H), 7.15 (s, 2H), 2.35 (s, 3H). 010610 44
Description 89 2-(4-Bromo-3-methylphenyl)-l-methylimidazole 2-(4-Bromo-3-methylphenyl)imidazole (D88, 900 mg; 3.8 mmol) was dissolved in dryTHF (30 ml) under argon and treated with sodium hydride (114 mg of an 80% dispersionin minerai oil; 3.8 mmol). After stirring for 30 minutes, iodomethane (237 ul; 3.8 mmol)was added and stirring continued for 18 hours. Evaporated in vacuo, the residuepartitioned between water and CHC13, the organic phase then dried over Na2SO4, filteredand evaporated in vacuo. The residue was purified by flash silica gel chromatographyusing CHC13 as eluant to yield the title compound as a clear, colourless gum (600 mg;63%). ’H NMR (200 MHz, CDCI3) δ (ppm): 7.60-7.50 (m, 2H), 7.30-7.20 (m, 1H), 7.10 (s, 1H),6.95 (s, 1H), 3.75 (s, 3H), 2.45 (s, 3H).
Description 90 2'-Methyl-4’-(l-methylimidazoI-2-yl)biphenyl-4-carboxylic acid 2-(4-Bromo-3-methylphenyl)-l-methylimidazole (D89, 600 mg, 2.39 mmol) was dissolvedin dimethoxyethane (15 ml) and H2O (15 ml) and treated with 4-boronobenzoic acid (397mg, 2.39 mmol), sodium carbonate (1.01g, 9.56 mmol), tetrakis (triphenylphosphine)palladium (O) (60 mg) and heated at reflux for 36 hours. Thedimethoxyethane was removed in vacuo, the aqueous residue treated with 10% Na2CO3(approx. 10 ml) and washed with ethyl acetate. The aqueous phase was acidified with 5NHCl and the solid that formed collected by filtration and dried in vacuo to yield the titlecompound as an off-white solid (620 mg, 89%). ‘H NMR (250 MHz, d6DMSO) δ (ppm): 8.10-8.00 (m, 3H), 7.95-7.75 (m, 3H), 7.65-7.50(m, 3H), 4.00 (s, 3H), 2.35 (s, 3H)
Description 91 (4-Bromo-3-methylbenzylidene)methylamine 4-Bromo-3-methylbenzaldehyde (D80, 3.7g, 18.6 mmol) was treated with methylamine inéthanol (33%, 100 ml) followed by 4Â molecular sieves and solid potassium carbonate(approx 4g) and the mixture stirred for 72 hours. Solvent was removed in vacuo, theresidue suspended in chloroform, and the solid removed by filtration. The filtrate wasevaporated in vacuo to yield the title compound as a red liquid (3.15g, 80%). 010610 45 'H NMR (250 MHz, CDC13) δ (ppm): 8.20 (s, 1H), 7.65-7.55 (m, 2H), 7.40-7.30 (m, 1H),3.50 (s, 3H), 2.45 (s, 3H).
Description 92 5-(4-Bromo-3-methyIphenyl)-l-methylimidazole (4-Bromo-3-methylbenzylidene)methylamine (D91, 2.15g, 10.1 mmol) was dissolved indry DME (30 ml) and methanol (70 ml) containing tosylmethylisocyanide (3.0g; 15.4mmol) and this solution was treated with potassium carbonate (2.8g, 20.3 mmol). Thewhole was heated at reflux for 48 hours, cooled and evaporated in vacuo. The residue waspartitioned between brine and chloroform (3 times), and the organics combined and driedover Na2SO4. The organics were filtered and evaporated in vacuo then the residue purifiedby flash silica gel chromatography (with chloroform as eluant) to yield the title compoundas an orange gum (1.52g, 60%). ’HNMR (250 MHz, CDC13) δ (ppm): 7.60 (d, 1H), 7.50 (s, 1H), 7.25 (s, 1H), 7.10-7.00(m, 2H), 3.65 (s, 3H), 2.45 (s, 3H).
Description 93 2'-Methyl-4'-(l-methylimidazoI-5-yl)biphenyI-4-carboxylic acid 5-(4-Bromo-3-methylphenyl)-l-methylimidazole (D92, 1.52g, 6.1 mmol) was dissolved inDME (50 ml) and water (50 ml), then treated with 4-boronobenzoic acid (1,0g, 6.1 mmol),sodium carbonate (2.57g, 24.2 mmol) and tetrakis(triphenylphosphine)palladium (O) (100mg). The mixture was heated at reflux (48 hours), cooled and the DME removed in vacuo.The aqueous residue was treated with 10% Na2CO3 (approx 30 ml), then washed with ethylacetate. The aqueous phase was acidified with 5N HCl and the solid that precipitated wascollected by filtration. This solid was dried in vacuo to yield the title compound as a whitesolid (600 mg, 34%). ‘H NMR (250 MHz, d6DMSO) δ (ppm): 9.20 (s, 1H), 8.05 (d, 2H), 7.85 (s, 1H), 7.60-7.40 (m, 5H), 3.90 (s, 3H), 2.30 (s, 3H). 46 010610
Description 94
Methyl 4’-(5-hydroxymethyl-l,2,4-oxadiazol-3-yI)biphenyl-4-carboxylate 3- (4-Bromo-3-methylphenyl)-l,2,4-oxadiazol-5-ylmethanol (EP 0533268A1) (1.0g, 3.7mmol) was reacted with 4-boronobenzoic acid using similar conditions to Description 11to afford 4'-(5-hydroxymethyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid. This wasdissolved in methanol (70 ml), treated with conc. sulphuric acid (2 ml) and heated underreflux for 4 hours. The solution was concentrated in vacuo and the residue basified with10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4)and concentrated in vacuo to afford the title compound (0.76g, 68%). ’H NMR (250 MHz, CDC13) δ (ppm): 8.12 (d, 2H), 8.04 (s, 1H), 7.96 (d, 1H), 7.42 (d, 2H), 7.35 (d, 1H), 5.00 (s, 2H), 3.96 (s, 3H), 3.0 (brs, 1H), 2.33 (s, 3H).
Description 95
Methyl 4'-[5-(t-butyldimethylsilyloxy)-l,2,4-oxadiazol-3-yl]-2'-methylbiphenyl-4-carboxylate A stirred solution of methyl 4'-(5-hydroxymethyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxylate (D94, 0.51g, 1.8 mmole) in dichloromethane (30 ml) was treated withtriethylamine (0.50 ml, 3.6 mmole), followed by a solution of t-butyldimethylsilyl chloride(0.29g, 1.8 mmole) in dichloromethane (5 ml), and 4-dimethylaminopyridine (29 mg).
The solution was left at room temp. for 14 h, then additional t-butyldimethylsilyl chloride(0.11 g, 0.7 mmole) and triethylamine (0.20 ml) were added and reaction left at room temp.for 4 days. The solution was washed rapidly with 0.5M HCl acid, then 10% Na2CO3solution, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed onsilica gel eluting with 10% ether/60-80 petrol to afford the title compound as a white solid(0.61g, 78%).
Description 96 4- Bromo-3-methylphenylamidrazone
Methyl 4-bromo-3-methylbenzimidate hydrochloride (D87, 24.6g, 0.093 mole) waspartitioned between ether (150 ml) and aqueous sodium hydroxide (5%, 160 ml). Theorganic layer was washed with water, dried (Na2SO4) and concentrated in vacuo. To theresidue was added hydrazine hydrate (4.51 ml, 0.093 mole) in ether (15 ml) and éthanol(75 ml). The solvent was concentrated in vacuo to afford the title compound as a solid (6g,28%). 47 010610 *H NMR (250 MHz, d6DMSO+D2O) δ (ppm): 8.05 (d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H),2.40 (s, 3H).
Description 97 3-(4-Bromo-3-methylphenyl)-l,2,4-triazine
Aqueous glyoxal (14 ml) was heated to 80°C and added to a suspension of 4-bromo-3-methylphenylamidrazone (D96, 10g, 0.044 mole) in water (50 ml). The mixture washeated at 70°C for 15 min, cooled and fïltered. The solid was suspended in methanol andstirred at ambient température for 72 hours. The mixture was fïltered through kieselguhrand the filtrate concentrated in vacuo. The residue was chromatographed on silica geleluting with 10% ethanol/chloroform to give the title compound as a yellow solid (2.36g,22%). *H NMR (250 MHz, CDC13) δ (ppm): 9.20 (d, 1H), 8.70 (d, 1H), 8.45 (d, 1H), 8.20 (d, 1 H), 7.70 (d, 1H), 2.50 (s, 3H).
Description 98 2’-Methyl-4'-(l,2,4-triazin-3-yl)biphenyl-4-carboxyIic acid 3- (4-Bromo-3-methylphenyl)-l,2,4-triazine (D97, lg, 0.004 mole) was converted to thetitle compound (260 mg, 22%) by the method of Example 11. 'H NMR (250 MHz, d6DMSO) δ (ppm): 13.1 (br s, 1H), 9.40 (d, 1H), 8.95 (d, 1H), 8.45(s, 1H), 8.35 (dd, 1H), 8.05 (d, 2H), 7.55 (d, 2H), 7.50 (d, 1H), 2.40 (s, 3H).
Description 99 4- (2-(2-Iodophenoxy)ethyl)pyridine A stirred solution of 2-iodophenol (8.8g, 0.040 mole), triphenylphosphine (10.5g, 0.040mole) and 2-(4-pyridyl)ethanol (D65, 5.5g, 0.045 mole) in THF (200 ml) at 0°C underargon was treated with a solution of diethyl azodicarboxylate (6.3 ml, 0.040 mole) in THF(30 ml). The solution was allowed to warm to room temp. and stirred for 4 h, thenconcentrated in vacuo and the residue treated with 10% Na2CO3 solution (80 ml) andextracted with ethyl acetate (2 x 80 ml). The combined organic was extracted with IMHCl acid (150 ml), then the acid extract basified by addition of potassium carbonate andextracted with ethyl acetate (2 x 100 ml). The combined extract was dried (Na2SO4) and 48 010610 concentrated in vacuo to leave a brown oil, which was chromatographed on silica geleluting with 0 to 15% ethyl acetate/ether to afford the title compound as a colourless oil(9.3g, 72%). 'H NMR (250 MHz, CDC13) δ (ppm): 8.58-8.51 (m, 2H), 7.76 (dd, 1H), 7.40-7.22 (m, 3H), 6.82-6.68 (m, 2H), 4.23 (t, 2H), 3.15 (t, 2H).
Description 100 4-(2-(2-Iodophenoxy)ethyl)-l-methyl-l,2,3,6-tetrahydropyridine A solution of 4-(2-(2-iodophenoxy)ethyl)pyridine (D99, 8.28g, 0.025 mole) in acetone(220 ml) was treated with iodomethane (3.7 ml, 0.059 mole) and kept at room températurefor 24 h, then concentrated in vacuo to leave the quatemary sait as a yellow oil. This wasdissolved in a mixture of éthanol (50 ml) and water (50 ml), cooled to 0°C under argon andtreated portionwise over 1 h with sodium borohydride (1.33g, 0.035 mole). The reactionmixture was kept at 0°C for a further 1 h, then treated with 10% NaOH solution (50 ml),diluted with water (120 ml) and extracted with ethyl acetate (2 x 200 ml). The combinedextract was dried (Na2SO4), concentrated in vacuo to leave an orange oil, which waschromatographed on silica gel eluting with 0 -10% methanol/chloroform to afford the titlecompound as a yellow oil (6.19g, 72%). 'H NMR (250 MHz, CDC13) δ (ppm): 7.76 (dd, 1H), 7.28 (dt, 1H), 6.79 (dd, 1H), 6.70 (dt,1H), 5.57 (m, 1H), 4.09 (t, 2H), 3.00-2.90 (m, 2H), 2.65-2.48 (m, 4H), 2.36 (s, 3H), 2.32-2.20 (m, 2H).
Description 101 2,3-Dihydro-r-methylspiro[4H-benzopyran-4,4'-piperidine] A stirred solution of 4-(2-(2-iodophenoxy)ethyl)-l-methyl-l,2,3,6-tetrahydropyridine(D100, 6.3g, 0.018 mole) and AIBN (50 mg) in benzene (700 ml) was heated to refluxunder argon, then treated dropwise over 1 h with a solution of tributyltin hydride (9.7 ml,0.036 mole) in benzene (100 ml). The reaction mixture was heated under reflux for afurther 3 h after completing the addition, then more tributyltin hydride (3.8 ml, 0.014mole) and AIBN (30 mg) were added and heating under reflux was continued for 4 h. Thereaction mixture was allowed to cool, then concentrated in vacuo and the residue treatedwith 2M HCl acid (150 ml), washed with ethyl acetate (100 ml), basified with potassiumcarbonate and extracted with ethyl acetate (2 x 100 ml). The combined extract was dried(Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on 49 010610 silica gel eluting with O to 2% methanol/chloroform to afford the title compound (2.3g ofapprox. 86% purity, 51%). ’h NMR (250 MHz, CDC13) Ô (ppm): 7.38 (dd, 1H), 7.08 (dt, 1H), 6.90 (dt, 1H), 6.79 (dd,1H), 4.18-4.10 (m, 2H), 2.83-2.70 (m, 2H), 2.45-2.25 (m, 4H), 2.35 (s, 3H), 2.05-1.95 (m,2H), 1.70-1.55 (m, 2H).
Description 102 2.3- Dihydro-r-ethoxycarbonylspiro[4H-benzopyran-4,4'-piperidine] A stirred solution of 2,3-dihydro-T-methylspiro[4H-benzopyran-4,4'-piperidine] (DI01,1.0g, 0.0046 mole) and diisopropylethylamine (1.2 ml, 0.0070 mole) in dichloroethane (20ml) was treated with 1 -chloroethyl chloroformate (0.64 ml, 0.0060 mole) and kept at roomtemp. for 1 h followed by 20 mins at reflux. The solution was then concentrated in vacuoand the residue treated with methanol (20 ml) and heated under reflux for 2 h. Thereaction mixture was concentrated in vacuo to leave a beige solid, which was dissolved indichloromethane (50 ml) and THF (10 ml) and treated with triethylamine (0.84 ml, 0.0060mole) followed by ethyl chloroformate (0.44 ml, 0.0046 mole). The solution was stirred atroom température for 2 h, then treated with 10% Na2CO3 solution (20 ml) and extractedwith dichloromethane (2 x 40 ml). The combined extract was dried (Na2SO4) andconcentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:1ether/60-80 petrol to afford the title compound as a yellow oil (1.3g, 100%). *H NMR (250 MHz, CDC13) Ô (ppm): 7.25 (dd, 1H), 7.10 (dt, 1H), 6.90 (dt, 1H), 6.80 (dd,1H), 4.25-4.00 (m, 6H), 2.98 (br t, 2H), 2.10-1.92 (m, 4H), 1.70-1.53 (m, 2H), 1.28 (t, 3H).
Description 103 2.3- Dihydro-l’-ethoxycarbonyI-6-and 8-nitrospiro[4H-benzopyran-4,4'piperidine] A stirred solution of 2,3-dihydro-T-ethoxycarbonylspiro[4H-benzopyran-4,4'-piperidine](DI02, 1.3g, 0.0046 mole) in acetic anhydride (30 ml) at 0°C under argon was treatedportionwise over 15 minutes with copper (II) nitrate hemipentahydrate (1.16g, 0.0050mole). The reaction mixture was kept at 0°C for a total of 1.5h, then allowed to warm toroom température over 0.5h. The mixture was poured into water/ice (300 ml) and basifiedby careful addition of potassium carbonate, then extracted with ethyl acetate (2 x 100 ml).The combined extract was dried (Na2SO4) and concentrated in vacuo to afford an orangeoil (1.5g, 100%), which was approximately a 1:1 mixture of 6- and 8-nitro isomers. Thiswas used without purification. 50 010610 'h NMR (250 MHz, CDC13) δ (ppm): 8.24 (d, 1H 6-isomer), 8.00 (dd, 1H 6-isomer), 7.64(dd, 1H 8-isomer), 7.52 (dd, 1H 8-isomer), 6.98 (t, 1H 8-isomer), 6.90 (d, 1H 6-isomer),4.35-4.05 (m, 6H), 3.00 (br t, 2H), 2.25-1.95 (m, 4H), 1.75-1.60 (m, 2H), 1.35-1.22 (m, 3 H).
Description 104 6-Amino-2,3-dihydro-r-ethoxycarbonylspiro[4H-benzopyran-4,4'-piperidine] A solution of 2,3-dihydro-l'-ethoxycarbonyl-6- and 8-nitrospiro[4H-benzopyran-4,4'-piperidine] (D103, 1.5g, 0.0046 mole) in éthanol (100 ml) was hydrogenated over 10% Pd-C (300 mg) at atmospheric température and pressure until uptake of hydrogen ceased. Thecatalyst was removed by filtration through kieselguhr and the filtrate concentrated invacuo. The mixture of 6- and 8-amino isomers was separated by chromatography on silicagel eluting with ether to afford the 6-amino compound as the lower rf component (420 mg,32%). ’H NMR (250 MHz, CDC13) δ (ppm): 6.66 (d, 1H), 6.60 (d, 1H), 6.50 (dd, 1H), 4.25-4.00(m, 4H), 4.17 (q, 2H), 3.45 (br s, 2H), 2.98 (br t, 2H), 2.08-1.88 (m, 4H), 1.70-1.55 (m, 2H), 1.30 (t, 3H).
Description 105 6-Amino-2,3-dihydro-l'-methylspiro[4H-benzopyran-4,4’-piperidine] A stirred suspension of lithium aluminium hydride (76 mg, 0.0020 mole) in THF (15 ml)at 0°C under argon was treated with a solution of 6-amino-2,3-dihydro-T-ethoxycarbonylspiro[4H-benzopyran-4,4'-piperidine] (DI04, 300 mg, 0.0010 mole) in THF(5 ml). The reaction mixture was allowed to warm to room temp. and stir for 1.5 h, thentreated with more lithium aluminium hydride (38 mg, 0.0010 mole) suspended in THF (5mi). The mixture was heated under reflux for 0.75 h, then cooled in an ice bath and treatedwith water (0.10 ml), 10% NaOH solution (0.10 ml) and water (0.30 ml). The resultingmixture was filtered through kieselguhr and the filtrate concentrated in vacuo to afford thetitle compound as a yellow oil (200 mg, 84%). 'H NMR (200 MHz, CDC13) δ (ppm): 6.73 (d, 1H), 6.65 (d, 1H), 6.48 (dd, 1H), 4.10-4.00(m, 2H), 3.3 (br s, 2H), 2.85-2.70 (m, 2H), 2.35 (s, 3H), 2.30-1.90 (m, 6H), 1.75-1.53 (m,2H). 51 010610
Description 106 2,3-Dihydro-l'-methylspiro[4H-pyrano[2,3-g]quinoline-4,4' piperidine] A stirred suspension of 6-amino-2,3-dihydro-l'-methylspiro[4H-benzopyran- 4,4'piperidine] (D105, 330 mg, 0.0014 mole) in glycol (1 ml) at room température wastreated with a catalytic amount of iodine (7 mg) and concentrated sulphuric acid (0.5 ml).An exothermic reaction took place, which was well controlled and required no cooling.
The reaction mixture was then heated to 175°C for 2 hrs and allowed to cool to 100°Cbefore water (20 ml) was added. The mixture was basified with 5M sodium hydroxide andthen extracted with ethyl acetate (3 x 100 ml). The combined extracts were dried (Na2SO4)and concentrated in vacuo. The residue was purified by chromatography on silica geleluting with 25-30% methanol/dichloromethane to afford the title compound as a whitesolid (150 mg, 39%). ‘H NMR (200 MHz, CDC13) δ (ppm): 8.73 (dd, 1H), 8.16 (s, 1H), 7.98 (d, 1H), 7.28 (dd,1H), 7.16 (s, 1H), 4.26 (dd, 2H), 2.83 (br dd, 2H), 2.38 (s, 3H), 2.35-2.15 (m, 6H), 1.79 (brd, 2H).
Description 107 2,3,6,7,8,9-Hexahydro-l'-methylspiro[4H pyrano[2,3-g]quinoline-4,4' piperidine] A solution of 2,3-dihydro-T-methylspiro[4H-pyrano[2,3-g]quinoline-4,4' piperidine] (DI06, 150 mg, 0.0006 mole) in éthanol (50 ml) and glacial acetic acid (2 ml) washydrogenated over PtO2 (35 mg) at 50 psi for 2 days. The catalyst was removed byfiltration through kieselguhr and the filtrate concentrated in vacuo. The residue waspurified by chromatography on silica gel eluting with 30% MeOH/dichloromethane with1% ammonia solution to afford the title compound (150 mg, 99%). ‘H NMR (200 MHz, CD3OD) δ (ppm): 6.59 (s, 1H), 6.41 (s, 1H), 4.05 (dd, 2H), 3.45-3.15(m, 6H), 2.91 (s, 3H), 2.69 (t, 2H), 2.37 (td, 2H), 2.05 (dd, 2H), 2.00-1.79 (m, 4H).Description 108 l-Ethyl-l,2,3,6-tetrahydropyridine-4-methanol
The title compound was prepared from 4-pyridylcarbinol and iodoethane following asimilar procedure to that described for the 1-methyl analogue in J. Med. Chem., 1988, 31,545 (92%). 52 010610 ’HNMR (200 MHz, CDC13) δ (ppm): 5.63 (m, 1H), 4.00 (s, 2H), 3.14 (br s, 1H), 2.97 (m,2H), 2.58 (t, 2H), 2.50 (q, 2H), 2.18 (m, 2H), 1.13 (t, 3H).
Description 109 l'-Ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-flindole-3,4'-piperidine]
This was prepared from l-acetyl-6-bromo-2,3-dihydro-lH-indol-5-ol (Tetrahedron, 1973,29 (8), 1115) and l-ethyl-l,2,3,6-tetrahydropyridine-4-methanol (D108), following theprocedure of Description 8 (alternative préparation), steps a), b), and c). This gave the titlecompound (overall yield: 45%) as a fine grey powder. 'H NMR (200 MHz, CDC13) δ (ppm): 6.61 (s, 1H), 6.48 (s, 1H), 4.32 (s, 2H), 3.53 (t, 2H),2.96 (m, 4H), 2.45 (q, 2H), 1.98 (m, 4H), 1.73 (m, 2H), 1.12 (t, 3H).
Description 110 2-(4“Bromophenyl)-5-methyI-l,3,4-oxadiazole
The title compound was prepared from 4-bromobenzoic hydrazide and triethyl orthoacetatefollowing a similar procedure to that of Description 35, to afford fine white crystals (77%). ‘H NMR (250 MHz, CDC13) δ (ppm): 7.92 (d, 2H), 7.67 (d, 2H), 2.63 (s, 3H).
Description 111 4'-(5-MethyI-l,3,4-oxadiazol-2-yI)biphenyl-4-carboxylic acid
The title compound was prepared from a stirred solution of 2-(4-bromophenyl)-5-methyl- 1.3.4- oxadiazole (DI 10) and 4-boronobenzoic acid using a similar procedure toDescription 11, as a white crystalline solid (68%). ‘H NMR (250 MHz, d6DMSO) δ (ppm): 8.10 (d, 2H), 8.06 (d, 2H), 7.98 (d, 2H), 7.89 (d,2H), 2.62 (s, 3H).
Description 112 4'-(5-Methoxymethyl-l,2,4-oxadiazol-3-yl)-2'-methyIbiphenyl-4-carboxylic acid
The title compound was prepared from 3-(4-bromo-3-methylphenyl)-5-methoxymethyl- 1.2.4- oxadiazole (EP 0533268A1) using a similar procedure to Description 11, as an offwhite solid (49%). 010610 53 ’H NMR (250 MHz, d6DMSO) δ (ppm): 13.06 (br s, 1H), 8.10-7.98 (m, 3H), 7.94 (dd, 1H), 7.55 (d, 2H), 7.45 (d, 1H), 4.87 (s, 2H), 3.45 (s, 3H), 2.34 (s, 3H).
Description 113 4’-(4,5-Dihydrooxazol-2-yl)-2'-methylbiphcnyl-4-carboxylic acid
This was prepared from 2-(4-bromo-3-methylphenyl)-4,5-dihydrooxazole (WO94/15920-Al) using the procedure of Description 11. This gave the title compound (85%) as a whitepowder. ‘H NMR (250 MHz, d6DMSO) δ (ppm): 8.02 (d, 2H), 7.7-7.9 (m, 2H), 7.52 (d, 2H), 7.36(d, 1H), 4.49 (t, 2H), 4.01 (t, 2H), 2.29 (s, 3H).
Description 114
Methyl 4'-(4,5-dihydrooxazol-2-yI)-2’-methylbiphenyI-4-carboxylate 4'-(4,5-Dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carboxylic acid (DI 13) (0.92g, 3.3mmol) was stirred under Ar in dry DMF (20 ml), and sodium hydride (80% in minerai oil,0.15g, 5.0 mmol) was added. This mixture was stirred for 30 min, and then treated withiodomethane (0.22 ml, 3.5 mmol). After a further 15 min, the mixture was diluted withethyl acetate (200 ml), washed with water and brine, dried (Na2SO4) and evaporated. Thecrude product was purified by chromatography on silica gel, eluting with 0-2%methanol/dichloromethane. This gave the title compound (0.15g, 15%) as a white solid. ’H NMR (250 MHz, CDC13) δ (ppm): 8.10 (d, 2H), 7.89 (s, 1H), 7.82 (d, 1H), 7.41 (d, 2H), 7.27 (d, 1H), 4.47 (t, 2H), 4.08 (t, 2H), 3.94 (s, 3H), 2.30 (s, 3H).
Description 115 4'-Amino-2'-methylbiphenyl-4-carboxylic acid
This compound was prepared from 4-bromo-3-methylaniline, following the procedure ofDescription 11. This gave the title compound (91%) as a mauve powder. 'H NMR (250 MHz, d6DMSO) δ (ppm): 7.93 (d, 2H), 7.39 (d, 2H), 6.93 (d, 1H), 6.50 (m, 2H),2.16(s, 3H).
Description 116 010610 54 4'-(2-ChIoroacetamido)-2'-methyIbiphenyI-4-carboxylic acid 4'-Amino-2'-methylbiphenyl-4-carboxylic acid (DI 15,2.45g, 10.8 mmol) andtriethylamine (3.8 ml, 27.3 mmol) were stirred in dichloromethane (50 ml) as chloroacetyl 5 chloride (1.05 ml, 13.2 mmol) was added dropwise. This mixture was stirred for 3 h, whenwater (20 ml) was added. After vigorous stirring for 15 min and basification withpotassium carbonate solution, the mixture was separated. The aqueous portion waswashed with dichloromethane, and acidified with conc. hydrochloric acid. Theprecipitated solid was filtered off and dried, giving the title compound (1.33g, 40%) as a 10 greypowder. ’h NMR (250 MHz, d6DMSO) δ (ppm): 13.0 (vb), 10.38 (s, 1H), 8.00 (d, 2H), 7.55 (m,2H), 7.46 (d, 2H), 7.21 (d, 1H), 4.27 (s, 2H), 2.23 (s, 3H). 15 Description 117 5-(4-Bromo-3-methylphenyl)-2-furaldehyde
Using a method similar to that of Davis and Lougheed (J.Het. Chem. 1976, 4(1), 153-4),4-bromo-3-methylaniline (20g, 0.107 mol) was converted to the title compound as an 20 orange powder (2.93g, 10%). H NMR (200 MHz, CDC13) δ (ppm): 9.64 (s, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 7.48 (d, 1H),7.3 (d, 1H), 6.82 (d, 1H), 2.45 (s, 3H). 55
Description 118 5-(4-Bromo-3-methylphenyl)-2-methylfuran 010610
Using a method similar to that of Oleinik et al (Khim-Farm. Zh., 1971 5(7) 19-22), 5-(4-bromo-3-methylphenyl-2-furaldehyde (DI 17) (1.5g, 5.66 mmol) was converted to the titlecompound as a yellow powder (1.12g, 79%). 'H NMR (200 MHz, CDC13) δ (ppm): 7.55-7.41 (m, 2H), 7.29 (d, 1H), 6.5 (d, 1H), 6.06(m, 1H), 2.4 (s, 3H), 2.35 (s, 3H).
Description 119 2'-Methyl-4'-(5-methylfuran-2-yl)biphenyl-4-carboxylic acid 5-(4-Bromo-3-methylphenyl)-2-methylfuran (DI 18) (600 mg, 2.39 mmol) and 4-boronobenzoic acid (397 mg, 2.39 mmol) were converted to the title compound using amethod similar to that of Description 11, as a pale yellow solid (207 mg, 30%). ‘H NMR (200 MHz, d6DMSO) δ (ppm): 13.0 (br s, 1H), 8.0 (d, 2H), 7.65-7.44 (m, 4H),7.25 (d, 1H), 6.86 (d, 1H), 6.2 (d, 1H), 2.35 (s, 3H), 2.28 (s, 3H).
Example 1 l'-Methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyI)- 2,3,6,7-tetrahydrospiro[furo[2,3-flindole-3,4'-piperidine] A stirred solution of 2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxylicacid (EP 0533268A1) (36 mg, 0.12 mmol) in thionyl chloride (3 ml) was heated at refluxunder argon for 20 minutes, then concentrated in vacuo to leave the acid chloride as ayellow solid. This was dissolved in dichloromethane (2 ml) and added to a stirred solutionof r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f)indole-3,4'-piperidine] (D8, 30 mg, 0.12mmol) and triethylamine (0.06ml, 0.43 mmol) in dichloromethane (2 ml) and kept at roomtempérature for 3 days. The mixture was washed with aq K2CO3 solution and brine, thendried (Na2SÛ4) and concentrated in vacuo. The residue was chromatographed on silicagel eluting with 0 to 11% methanol/dichloromethane to afford the title compound as acolourless gum (19 mg, 30%). This was converted to its oxalate (mp 232°C) andhydrochloride (mp >250°C) salts. 56 010610 JH NMR (oxalate sait) (400 MHz, d6DMSO) ô(ppm): 7.95-7.85 (m, 3H), 7.62 (d, 2H),7.47 (d, 2H), 7.39 (d, 1H), 6.72 (s, 1H), 4.44 (s, 2H), 4.01 (t, 2H), 2.99 (t, 2H), 2.90 (m),2.66 (m), 2.64 (s, 3H), 2.31 (s, 3H), 2.02 (m, 2H), 1.84 (m, 2H)
Example 2 2,3,5,6,7,8-Hexahydro-l'-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)spiro[fïiro[2,3-g]quinoline-3,4-piperidine]
The title compound was prepared from 2,3,5,6,7,8-hexahydro-l'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10), using a procedure similar to that of Example 1, in 87%yield. The oxalate sait was precipitated from acetone by addition of ether, as a whitepowder. lH NMR (oxalate sait) (250MHz, d6DMSO) ô(ppm): 7.9 (m, 2H), 7.3 (m, 5H), 6.68 (s, 1H), 6.5 (b, 1H), 4.34 (s, 2H), 3.80 (m, 2H), 3.12 (m, 2H), 2.9-2.6 (m, 12H), 2.29 (s, 3H),1.97 (t, 2H), 1.60 (m, 4H).
Example 3 5-(2'-Methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-fJindole-3,4’-piperidine] A stirred solution of T-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (El, 350 mg, 0.67mmole) in 1,2-dichloroethane (15 ml) under argon was treated with diisopropylethylamine(0.14 ml, 0.80 mmole) and 1-chloroethyl chloroformate (0.09ml, 0.80 mmole). Themixture was stirred at room température for 2 h followed by lh at reflux température.Additional diisopropylethylamine (0.10 ml, 0.57 mmole) and 1-chloroethyl chloroformate(0.06 ml, 0.53 mmole) was added and reaction maintained at reflux for a further 1 h. Thesolution was concentrated in vacuo and the residue treated with methanol (20 ml) andheated under reflux for 1 h. The solution was concentrated in vacuo and the residue treatedwith conc. K2CO3 solution (25 ml) and chloroform (25 ml), shaken well and thechloroform solution separated, dried (Na2SO4) and concentrated in vacuo to afford thetitle compound as a beige solid (340 mg, 100%). The hydrochloride sait was preparedfrom acetone/ether as a white solid mp 203-210° C. 1h NMR (free base) (250 MHz, CDCI3) δ (ppm): 8.12 (br s, 1H - low intégration), 8.00 (s,1H), 7.95 (d, 1H), 7.62 (d, 2H), 7.43 (d, 2H), 7.35 (d, 1H), 6.68 (s, 1H), 4.45 (br s, 2H), 57 010610 4.30-3.95 (br m, 4H), 3.40-3.15 (br, 2H), 3.08 (t, 2H), 2.90-2.72 (br, 2H), 2.68 (s, 3H), 2.35 (s, 3H), 2.15-1.95 (br, 2H), 1.90-1.70 (br, 3H).
Example 4 l'-Ethyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro [furo [2,3-f] indoIe-3,4'-piperidine] A stirred solution of 5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E3, 100 mg, 0.20 mmole) inglacial acetic acid (2 ml) at room température under argon was carefully treated withsodium borohydride pellets (50 mg, 1.3 mmole) and stirred for 24 h. Additional sodiumborohydride pellets were added (50 mg, 1.3 mmole) and reaction mixture stirred at roomtempérature for a further 72 h. The reaction mixture was then treated with water (20 ml),basified with 10% NaOH solution (20 ml) and extracted with dichloromethane. Theextract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed onsilica gel eluting with 3% MeOH/CHCl3. Crystallisation of the product from ethylacetate/60-80 petrol afforded the title compound as a white solid (55 mg, 52%) mp 202-204° C. 1h NMR (250 MHz, CDC13) δ (ppm): 8.17 (br s, 1H - low intégration), 8.00 (s, 1H), 7.95(d, 1H), 7.62 (d, 2H), 7.42 (d, 2H), 7.36 (d, 1H), 6.67 (s, 1H), 4.40 (br s, 2H), 4.10 (br s,2H), 3.07 (t, 2H), 3.10-2.80 (br m, 2H), 2.68 (s, 3H), 2.55-2.30 (br m, 2H), 2.35 (s, 3H),2.25-1.50 (br,m,6H), 1.10(brt,3H)
Example 5 r-Methyl-5-(2'-methyl-4’-(5-methyl-l,3,4-oxadiazoI-2-yI)biphenyI-4-carbonyl)- 2.3.6.7- tetrahydrospiro [furo [2,3-f] indole-3,4'-piperidine]
The title compound was prepared from l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (DI 1) using a procedure similar to that of Example 1 (23%). This wasconverted to the oxalate sait which precipitated from acetone/ether as a white solid (mp232-235°C), and hydrochloride sait (mp >250°C).
Ud NMR (oxalate sait) (250 MHz, d^DMSO) δ (ppm): 7.98-7.80 (m, 3H), 7.72-7.65 (m,2H), 7.58-7.49 (m, 3H), 6.80 (s, 1H), 4.51 (s, 2H), 4.11-4.04 (m, 4H), 3.09-3.01 (m, 2H),2.85-2.78 (m, 4H), 2.61 (s, 3H), 2.61-2.55 (m, 2H), 2.50 (s, 3H), 2.38 (s, 3H)
Example 6 58 010610 5-(4'-(5-Dimethylamino-l,2,4-oxadiazol-3-yl)-2’-methylbiphenyl-4-carbonyl)-r- methyl^^ô^-tetrahydrospiroIfuroP^-flindole-S^'-piperidine]
The title compound was prepared from l'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-(5-dimethylamino-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (DI4) using a procedure similar to that of Example 1(18%). This was converted to the oxalate sait, which precipitated from acetone/ether as awhite solid. !h NMR (free base) (200 MHz, CDC13) δ (ppm): 8.15 (br s, 1H), 7.96-7.84 (m, 2H), 7.62(d, 2H), 7.42 (d, 2H), 7.32 (d, 1H), 6.69 (s, 1H), 4.40 (br s, 2H), 4.20-4.00 (br m, 2H), 3.24(s, 6H), 3.08 (t, 2H), 2.97-2.77 (br m, 2H), 2.34 (s, 6H), 2.18-1.59 (br m, 6H)
Example 7 r-Methyl-5-[4'-(5-methyI-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3-f] indole-3,4'-piperidine]
The title compound was prepared from T-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxylicacid (DI 5), using a procedure similar to that of Example 1 (57%). !h NMR (250 MHz, CDCI3) δ (ppm): 8.17 (d, 3H), 7.79-7.62 (m, 6H), 6.67 (s, 1H), 4.40(br s, 2H), 4.15-4.00 (br m, 2H), 3.08 (t, 2H), 3.00-2.80 (br m, 2H), 2.70 (s, 3H), 2.48-1.45(br m, 9H)
Example 8 2,3-Dihydro-r-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4- carbonyl)spiro[furo[2,3-f[indoIe-3,4’-piperidine] A stirred suspension of 2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxylicacid (EP 0533268A1) (315 mg, 1.1 mmole) inthionyl chloride (10 ml) was heated underreflux for 0.5 h, then concentrated in vacuo to leave the acid chloride as a yellow solid. Astirred solution of 2,3-dihydro-T-methylspiro[furo[2,3-f]indole-3,4'-piperidine] (D7, 260mg, 1.1 mmole) in dry THF (10 ml) at room température under argon was treated withpotassium t-butoxide (125 mg, 1.1 mmole) and stirred for 0.25 h, then treated with asolution of the above acid chloride (1.1 mmole) in dry THF (5 ml). The mixture wasstirred at room température for 2 h, then concentrated in vacuo and the residue treated with10% Na2CÛ3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), 59 010610 concentrated in vacuo and the residue chromatographed on silica gel eluting with 3%MeOH/CHCl3· The pale yellow oil obtained was further purified by préparative TLC on asilica gel plate eluting with 10% MeOH/CHCl3 to afford the title compound (80 mg, 14%),which crystallised from ether mp 196-198° C. 1h NMR (250 MHz, CDC13) δ (ppm): 8.33 (s, 1H), 8.03 (s, 1H), 7.98 (d, 1H), 7.80 (d, 2H), 7.50 (d, 2H), 7.38 (d, 1H), 7.29 (d, 1H), 6.96 (s, 1H), 6.54 (d, 1H), 4.46 (s, 2H), 3.00-2.87 (m, 2H), 2.70 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H), 2.25-1.97 (m, 4H), 1.90-1.78 (m, 2H)
Example 9 5-[4'-Cyano-2'-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f|indole-3,4’-piperidine] A stirred suspension of 4'-cyano-2'-methylbiphenyl-4-carboxylic acid (DI6) (0.3g, 1.3mmole) in dichloromethane (10 ml) at room température under argon was treated withoxalyl chloride (0.12 ml, 1.43 mmole), followed by DMF (1 drop). The mixture wasstirred for 2h, then concentrated in vacuo to leave the acid chloride as a pale yellow solid.This was dissolved in dry THF (8 ml) and added to a stirred solution of l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) (0.3g, 1.3 mmole) and triethylamine(0.35 ml, 2.6 mmole) in dry THF (10 ml) at 5° C under argon. The reaction mixture wasallowed to warm to room température and then concentrated in vacuo. The residue wastaken up in 10% Na2CO3 solution (20 ml) and extracted with EtOAc (2 x 30 ml). Thecombined extract was dried (Na2SÛ4) concentrated in vacuo and the residuechromatographed on silica gel eluting with 1% methanol/dichloromethane to give the titlecompound (0.2g, 34%) as a white solid. ^H NMR (250 MHz, CDCI3) δ (ppm): 8.14 (br s, ΙΗ-low intégration), 7.68-7.52 (m, 4H), 7.39-7.32 (m, 3H), 6.68 (s, 1H), 4.40 (br s, 2H), 4.18-3.99 (br m, 2H), 3.08 (t, 2H), 2.94- 2.79 (br m, 2H), 2.31 (s, 6H), 2.12-1.71 (brm, 6H) 60 010610
Example 10 5-(4’-Acetyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-fJindole-3,4'-piperidine]
The title compound was prepared from T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f)indole-3,4'-piperidine] (D8) and 4'-acetyl-2'-methylbiphenyl-4-carboxylic acid (DI9) using aprocedure similar to that of Example 1 (35%). NMR (250 MHz, CDCI3) δ (ppm): 8.13 (br s, ΙΗ-low intégration), 7.92-7.80 (m, 2H),7.62 (d, 2H), 7.42-7.28 (m, 3H), 6.68 (s, 1H), 4.40 (s, 2H), 4.20-4.00 (m, 2H), 3.08 (t, 2H),2.97-2.80 (m, 2H), 2.60 (s, 3H), 2.45-1.54 (m, 12H)
Example 11 5-(4’-(l-(Methoxyamino)ethyl)-2'-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f|indole-3,4’-piperidine]
Methoxylamine hydrochloride (0.06g, 0.7 mmol) was added to a stirred solution ofpotassium t-butoxide (0.06g, 0.5 mmol) in methanol (10 ml) under argon. After 20minutes at room température, the solution was treated with a solution of 5-(4'-acetyl-2'-methylbiphenyl-4-carbonyl)-T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E10, 0.16g, 0.3 mmole) in methanol (10 ml) and stirred at room températurefor 18 hours, followed by 1 hour heating under reflux. The solution was allowed to cool,treated with 10% Na2CÜ3 solution (40 ml) and extracted with ethyl acetate. The extractwas dried (Na2SÛ4) and concentrated in vacuo to afford the title compound as a yellowsolid (0.16g, 94%). lH NMR (250 MHz, CDCI3) δ (ppm): 8.12 (br s, ΙΗ-low intégration), 7.62-7.48 (m, 4H),7.40 (d, 2H), 7.25 (d, 1H), 6.69 (s, 1H), 4.40 (s, 2H), 4.18-4.04 (m, 2H), 4.03 (s, 3H), 3.07(t, 2H), 2.94-2.89 (m, 2H), 2.31 (s, 6H), 2.26 (s, 3H), 2.13-1.52 (m, 6H)
Example 12 5-(4’-Acetamidomethyl-2’-methylbiphenyl-4-carbonyl)-l’-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidme] A stirred solution of T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine](D8, 85 mg, 0.35 mmole) in toluene (10 ml) at room température under argon was treatedwith 2M trimethylaluminium in hexane (0.74 ml, 1.5 mmole). The mixture was stirred for0.75 h, then treated with a solution of methyl 4'-acetamidomethyl-2'-methylbiphenyl-4- 61 010610 carboxylate (D21, 120 mg, 0.40 mmole) in toluene (5 ml) and heated at 90° C for 2 h. Thesolution was allowed to cool, then poured carefully into a stirred slurry of silica gel (10 g)in dichloromethane (30 ml) and stirring continued until the effervescence had ceased. Thesilica gel slurry was then packed into a chromatography column and eiuted with 0-10%MeOH/CH2Cl2 to afford the title compound (85mg, 48%). This was converted to theoxalate sait, which crystallised from acetone. 'H NMR (free base) (250 MHz, CDCI3) δ (ppm): 8.13 (br s, ΙΗ-low intégration), 7.58 (d,2H), 7.35 (d, 2H), 7.25-7.13 (m, 3H), 6.67 (s, 1H), 5.95 (br t, 1H), 4.46 (d, 2H), 4.38 (br s,2H), 4.20-4.00 (br, 2H), 3.05 (t, 2H), 2.95-2.75 (br, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 2.20-1.50 (br m, 6H), 2.05 (s, 3H).
Example 13 3,5,6,7,8,9-Hexahydro-l'-methyl-5-(2’-methyl-4’-(5-methyl-l,2,4-oxadiazol-3- yl)biphenyI-4-carbonyI)spiro[2H-furo[2,3-h]benzazepine-3,4'-piperidine]
The title compound was prepared from 3,5,6,7,8,9-hexahydro-T-methylspiro[2H-furo[2,3-h]benzazepine-3,4'-piperidine] (D28), using a procedure similar to that of Example 1. Theoxalate sait was precipitated from acetone by addition of ether, as a white solid. lH NMR (oxalate sait) (250 MHz, d6DMSO) δ (ppm): 7.9 (m, 2H), 7.4-7.2 (m, 5H), 6.72(s, 1H), 6.61 (b, 1H), 4.73 (d, 1H), 4.42 and 4.28 (ABq, 2H), 3.31 (m, 1H), 3.1-2.7 (m, 6H), 2.69 (s, 3H), 2.67 (s, 3H), 2.20 (s, 3H), 2.3-1.7 (m, 5H), 1.5-1.2 (m, 3H)
Example 14 l'-Methyl-5-(2’-methyl-4'-(3-methyl-l,2,4-oxadiazol-5-yl)biphenyl-4-carbonyl)- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indoIe-3,4'-piperidme]
The title compound was prepared from l'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(3-methyl-l,2,4-oxadiazol-5-yl)biphenyl-4-carboxylic acid (D29) using a similar procedure to Example 1. This was converted to itsoxalate sait, which was obtained as a yellow solid (3%). JH NMR (free base) (200 MHz, CDC13) δ (ppm): 8.15 (br s, ΙΗ-low intégration), 8.06 (s,1H), 8.00 (d, 1H), 7.62 (d, 2H), 7.48-7.33 (m, 3H), 6.66 (s, 1H), 4.40 (br s, 2H), 4.10 (br,2H), 3.06 (t, 2H), 2.85 (br, 2H), 2.50 (s, 3H), 2.36 (s, 3H), 2.30 (br s, 3H), 2.15-1.70 (m,6H). 62 010610
Example 15 r-Methyl-5-(2'-methyl-4'-(l,3,4-oxadiazol-2-yl)biphenyI-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-fJindole-3.4’-piperidine A stirred suspension of 5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-l'-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E25) (150 mg, 0.3 mmol) intriethyl orthoformate (10 ml) was heated at reflux for 2 h. The mixture cooled,concentrated in vacuo and chromatographed on silica gel, eluting with methanol andchloroform to give the title compound as a white foam (24 mg, 16%). This was convertedto its oxalate sait which was obtained as a white solid (mp 242-244°C) and hydrochloridesait (mp 298-302°C). ‘H NMR (free base) (200 MHz, CDC13) Ô (ppm): 8.5 (s, 1H), 8.25-7.92 (m, 3H), 7.70-7.57(m, 2H), 7.50-7.35 (m, 3H), 6.68 (s, 1H), 4.38 (br s, 2H), 4.20-4.00 (br m, 2H), 3.08 (t, 2H), 2.97-2.70 (m, 2H), 2.38 (s, 3H), 2.31 (s, 3H), 2.20-1.50 (m, 6H)
Example 16 5-[4’-(5-Ethyl-l,354-oxadiazol-2-yl)-2'-metliylbiplienyI-4-carbonyI]-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidme]
The title compound was afforded as a white solid (54%) from 4'-(5-ethy 1-1,3,4-oxadiazol- 2-yl)-2'-methylbiphenyl-4-carboxylic acid (D32) and l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) as per method of Example 1. Thiswas converted to its oxalate sait. 'H NMR (oxalate sait) (400 MHz, d6DMSO) δ (ppm): 7.95 (m, 2H), 7.90 (d, 1H), 7.66(m, 2H), 7.51 (m, 3H), 6.78 (s, 1H), 4.50 (s, 2H), 4.05 (t, 2H), 3.40 (b, 2H), 3.00 (m, 6H),2.77 (s, 3H), 2.38 (s, 3H), 2.10 (b, 2H), 1.87 (b, 2H), 1.34 (t, 3H).
Example 17 5-[2'-Methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidme]
The title compound was prepared from T-methyl-5-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (E5) following a similar procedure to Example 3 (100%). This was convertedto the oxalate sait, which precipitated from acetone/ether as a pale yellow solid. 63 010611 'h NMR (oxalate sait) (200 MHz, CDC13) δ (ppm): 8.00-7.85 (m, 3H), 7.65 (d, 2H), 7.557.42 (m, 3H), 6.78 (s, 1H), 4.50 (s, 2H), 4.05 (t, 2H), 3.03 (t, 2H), 2.61 (s, 3H), 2.37 (s, 3H), remaining signais not discernable from spectrum.
Example 18 2,3-Dihydro-l'-methyl-5-(2'-methyI-4'-(5-methyH,3,4_oxadiazol-2-yl)biphenyl-4- carbonyl)spiro[furo[2,3-f]indole-3,4'-piperidine]
The title compound was prepared from 2,3-dihydro-T-methylspiro[furo [2,3-f]indole-3,4'-piperidine] (D7) and 2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylicacid (DI 1) using a similar procedure to Example 8 (22%). This was converted to itsoxalate sait, which crystallised from acetone/methanol as a white solid mp 234-237°C. *HNMR (free base) (200 MHz, CDC13) δ (ppm): 8.33 (s, 1H), 8.02 (s, 1H), 7.94 (d, 1H),7.81 (d, 2H), 7.50 (d, 2H), 7.40 (d, 1H), 7.28 (d, 1H), 6.97 (s, 1H), 6.55 (d, 1H), 4.46 (s,2H), 2.98-2.85 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H), 2.25-1.95 (m, 4H), 1.90-1.75 (m, 2H).
Example 19 5-(2,2'-Dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyI-4-carbonyI)-l’-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]
The title compound was prepared from T-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 2,2'-dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D34) using a similar procedure to Example 1 (53%). Thiswas converted to its oxalate sait and crystallised from acetone/methanol as a white solidmp 222-224°C. *H NMR (free base) (200 MHz, CDC13) δ (ppm): 8.13 (br s, 1H), 7.98 (s, 1H), 7.90 (dd, 1H), 7.48 (s, 1H), 7.41 (d, 1H), 7.35-7.20 (m, 1H), 7.16 (d, 1H), 6.66 (s, 1H), 4.38 (br s, 2H), 4.10 (br, 2H), 3.07 (t, 2H), 2.85 (br, 2H), 2.64 (s, 3H), 2.32 (s, 3H), 2.20-1.70 (m, 6H), 2.15 (s, 3H), 2.08 (s, 3H). 64
Example 20 0 1 06 1 0 5-(2,3'-Dimethyl-4'-(5-methyI-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-r-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f|indole-3,4'-piperidine]
The title compound was prepared from l'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f|indole-3,4'-piperidine] (D8) and 2,3'-dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D36) using a similar procedure to Example 1 (31%). Thiswas converted to its oxalate sait and crystallised from acetone/methanol as a pale yellowsolid mp. 193-195°C. 'H NMR (free base) (250 MHz, CDC13) δ (ppm): 8.14 (br s, 1H), 7.97 (d, 1H), 7.48 (s,1H), 7.42 (d, 1H), 7.37-7.25 (m, 3H), 6.67 (s, 1H), 4.40 (br s, 2H), 4.08 (br s, 2H), 3.06 (t,2H), 2.87 (br, 2H), 2.77 (s, 3H), 2.65 (s, 3H), 2.32 (s, 6H), 2.20-1,90 (m, 4H), 1.85-1.60(m, 2H).
Example 21 l’-Methyl-5-(2'-methyl-4’-(4-methylthiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]
The title compound was prepared from 2'-methyl-4'-(4-methylthiazol-2-yl)biphenyl-4-carboxylic acid (D40) and T-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8), following the procedure of Example 1. The oxalate sait crystallised fromacetone as a buff powder. ’H NMR (oxalate sait) (250 MHz, d6DMSO) δ (ppm): 7.8-8.0 (m, 3H), 7.67 (d, 2H), 7.52(d, 2H), 7.40 (m, 1H), 7.38 (s, 1H), 6.78 (s, 1H), 4.51 (s, 2H), 4.06 (t, 2H), 3.40 (m, 2H),3.04 (t, 2H), 3.0 (m, 2H), 2.77 (s, 3H), 2.44 (s, 3H), 2.37 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H).
Example 22 5-(4'-Methoxycarbonyl-2’-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-fJindole-3,4’-piperidine]
The title compound was prepared from l'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3- f]indole-3,4'-piperidine] (D8) and 4'-methoxycarbonyl-2'-methyl biphenyl-4-carboxylic acid (D41) using a procedure similar to that of Example 1 (76%). 65 010610 *H NMR (200 MHz, CDC13) δ (ppm): 8.12 (br s, 1H- low intégration), 7.99 (s, 1H), 7.91(d, 1H), 7.61 (d, 2H), 7.39 (d, 2H), 7.31 (d, 1H), 6.68 (s, 1H), 4.40 (s, 2H), 4.10 (br, 2H),3.95 (s, 3H), 3.08 (t, 2H), 2.90 (br s, 2H), 2.34 (s, 6H), 2.20-1.65 (m, 6H)
Example 23 5-(5'-Methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]
The title compound was prepared from T-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 5'-methoxycarbonyl-2'-methylbiphenyl-4-carboxylicacid (D42) using a similar procedure to Example 1 (51%). *H NMR (250 MHz, CDC13) δ (ppm): 8.12 (br s, 1H - low intégration), 7.98-7.89 (m, 2H),7.62 (d, 2H), 7.41-7.28 (m, 3H), 6.63 (s, 1H), 4.38 (br s, 2H), 4.09 (br s, 2H), 3.90 (s, 3H),3.09 (t, 2H), 2.90 (br s, 2H), 2.32 (s, 6H), 2.20-1.62 (m, 6H).
Example 24 5-[4'-(Methanesulphonamino)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine]
The title compound was afforded as a white solid (38%) from 4'-(methane sulphonamino)-2'-methylbiphenyl-4-carboxylic acid (D44) as per method of Example 1 and converted toits oxalate sait. ’H NMR (oxalate sait) (250 MHz, d6DMSO) δ (ppm): 9.82 (b, 1H), 7.96 (b, 1H), 7.65 (d,2H), 7.45 (d, 2H), 7.20 (m, 3H), 6.78 (s, 1H), 4.50 (s, 2H), 4.15 (t, 2H), 3.39 (m, 2H), 3.05(m, 4H), 2.78 (s, 3H), 2.40-2.00 (b, 2H), 2.27 (s, 3H), 2.10 (s, 3H), 1.89 (m, 2H).
Example 25 5-(4'-Hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahy drospiro [furo [2,3-fJ indole-3,4’ -piperidine] A solution of 5-(4'-methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)-T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E22, 0.75g, 1.5 mmole) inmethanol (25ml) was treated with hydrazine monohydrate (1.05 ml) and heated under reflux for 18 h.The reaction mixture was allowed to cool, then poured into water (50 ml) and the solidwhich precipitated out was filtered off and dried (0.61g, 81%). A 50 mg portion was 66 01 061 0 purified by préparative TLC on silica gel eluting with 20% methanol/chloroform to affordthe title compound as a white solid mp. 130-135°C. 'H NMR (250 MHz, CDC13 + CD3OD) δ (ppm): 8.11 (br s, 1H), 7.75 (s, 1H), 7.67 (dd,1H) 7.62 (d, 2H), 7.42 (d, 2H), 7.31 (d, 1H), 6.70 (s, 1H), 4.40 (br s, 2H), 4.12 (br t, 2H), 3.10 (t, 2H), 2.94 (br, 2H), 2.38 (br s, 3H), 2.33 (s, 3H), 2.30-2.00 (m, 4H), 1.90-1.70 (m,2H).
Example 26 l'-Ethyl-5-[2'-methyI-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3-fJ indole-3,4 ’-piperidine] A stirred suspension of 2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylicacid (DI 1, 0.53g, 1.8 mmole) in thionyl chloride (8 ml) was heated at about 45°C for 30minutes, then concentrated in vacuo. The yellow solid was dissolved in THF (10ml)/dichloromethane (5 ml) and added to a stirred solution of 1 ’-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D109, 0.46g, 1.8 mmole) andtriethylamine (0.50 ml, 3.6 mmole) in THF (15 ml) at 5°C under argon. The solution wasstirred at room temp. for 2 h, then concentrated in vacuo. The residue was treated with10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4),concentrated in vacuo and the residue chromatographed on silica gel eluting with 3%methanol/chloroform and the yellow oil obtained passed through a short basic aluminacolumn eluting with ethyl acetate to afford the title compound as a beige foam (0.62g,68%). This was converted to its hydrochloride (mp 269-273°C) and mesylate (mp 275-279°C) salts. *H NMR (free base) (250 MHz, CDC13) δ (ppm): 8.18 (br s, 1H - low intégration), 7.98 (d,1H), 7.91 (dd, 1H), 7.63 (d, 2H), 7.42 (d, 2H), 7.37 (d, 1H), 6.66 (s, 1H), 4.40 (br s, 2H), 4.10 (br m, 2H), 3.08 (t, 2H), 3.05-2.90 (br m, 2H), 2.65 (s, 3H), 2.55-2.35 (br m, 2H),2.36 (s, 3H), 2.20-1.50 (m, 6H), 1.13 (brt, 3H).
Example 27 l’-Methyl-5-(2'-methyl-5'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]
The title compound was prepared from 2'-methyl-5'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D45) and l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3- 67 010610 f]indole-3,4'-piperidine] (D8) using a similar procedure to Example 1 as a brown oil(10%). This was converted to its oxalate sait which was obtained as a white solid. ’H NMR (oxalate sait) (400 MHz, d6DMSO)8 (ppm): 7.98 (br s, 1H), 7.91 (d, 1H), 7.80(s, 1H), 7.68 (m, 2H), 7.58 (d, 1H), 7.54 (d, 2H), 6.77 (s, 1H), 4.50 (s, 2H), 4.07 (br t, 2H),3.50-3.35 (br, 2H), 3.10-2.95 (m, 4H), 2.78 (s, 3H), 2.58 (s, 3H), 2.35 (s, 3H), 2.20-2.00(m, 2H), 1.97-1.84 (m, 2H).
Example 28 5-(4'-Carboxamido-2'-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] A suspension of 5-(4'-cyano-2'-methylbiphenyl-4-carbonyl)-T-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E9) (130 mg, 0.28 mmol) in methanol(5 ml) was treated with 30% hydrogen peroxide (0.1 ml) and 20% sodium hydroxidesolution (0.08 ml) and stirred at room température for 1.5 h. Sodium metabisulphite (60mg) was added, the mixture was concentrated in vacuo and the residue was partitionedbetween water and ethyl acetate. The organic phase was dried (Na2SO4) and concentratedin vacuo and the résultant solid chromatographed on silica gel eluting with methanol andchloroform, to give the title compound as a white solid (50 mg, 37%). ’H NMR (400 MHz, CDC13) δ (ppm): 7.75 (s, 1H), 7.65 (d, 1H), 7.60 (d, 2H), 7.4-7.35(m, 2H), 7.3 (d, 1H), 6.64 (s, 1H), 5.8 (br s, 2H), 4.35 (s, 2H), 4.1 (t, 2H), 3.05 (t, 2H),2.88-2.74 (m, 2H), 2.36-2.26 (m, 6H), 2.11-2.0 (m, 2H), 1.78-1.65 (m, 4H). (one aromaticproton not observed)
Example 29 5-(4’-Acetamido-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]
The title compound was prepared from 4'-acetamido-2'-methylbiphenyl-4-carboxylic acid(D47) and T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4,-piperidine] (D8)following a similar procedure to Example 1 using oxalyl chloride in place of thionylchloride, as a yellow oil (43%). This was converted to its oxalate sait which crystallised asa white solid from acetone. ’H NMR (oxalate sait) (400 MHz, d6DMSO) δ (ppm): 10.00 (s, 1H), 7.95 (br s, 1H), 7.62(d, 2H), 7.55-7.50 (m, 2H), 7.43 (d, 2H), 7.19 (d, 1H), 6.77 (s, 1H), 4.50 (s, 2H), 4.05 (t, 68 0 1 06 1 0 2H), 3.40 (br, 2H), 3.08-2.93 (m, 4H), 2.75 (br s, 3H), 2.25 (s, 3H), 2.17-2.00 (m, 2H), 2.06 (s, 3H), 1.94-1.80 (m, 2H)
Example 30 2.355.6.7.8- Hexahydro-l'-methyI-5-(2’-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[furo[2,3-g]quinoIine-3,4'-piperidine]
The title compound was prepared from 2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (DI 1) and 2,3,5,6,7,8-hexahydro-T-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a similar procedure to Example 1 as a white solid(62%). This was converted to its oxalate sait which was obtained as a white solid (mp 187-188° C) and hydrochloride sait (mp 176-180°C). !H NMR (free base) (200 MHz, CDC13) δ (ppm): 7.94 (s, 1H), 7.85 (d, 1H), 7.4-7.3 (m,2H), 7.28 -7.14 (m, 3H), 6.6 (s, 1H), 6.35 (br s, 1H), 4.26 (s, 2H), 3.94 (t, 2H), 2.78 (t, 2H),2.71-2.55 (m, 5H), 2.3 (s, 3H), 2.25 (s, 3H), 2.14-1.75 (m, 4H), 1.61-1.41 (m, 4H)
Example 31 2.3.5.6.7.8- Hexahydro-5-(4'-methanesulphonamino-2'-methylbiphenyl-4-carbonyl)-r-methylspiro[furo[2,3-g]qumoline-3,4'-piperidine]
The title compound was prepared from 4'-(methanesulphonamino)-2'-methylbiphenyl-4-carboxylic acid (D44) and 2,3,5,6,7,8-hexahydro-T-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a similar procedure to Example 1 as a white solid (46%). Thiswas converted to its oxalate sait which was obtained as a white powder. mp 165-170°C ’H NMR (free base) (200 MHz, CDC13) δ (ppm): 7.36-7.29 (m, 2H), 7.2-7.0 (m, 5H), 6.6(s, 1H), 6.37 (br s, 1H), 4.25 (s, 2H), 3.92 (t, 2H), 3.03 (s, 3H), 2.77 (t, 2H), 2.7-2.55 (m,2H), 2.25 (s, 3H), 2.2 (s, 3H), 2.12-1.78 (m, 4H), 1.57-1.41 (m, 4H) (one aromatic protonnot observed)
Example 32 l’-Methyl-5-[2'-methyl-4’-(5-methyl-l,2,4-oxadÎazol-3-yl)bîphenyl-4-carbonyl]- 2,3>6,7-tetrahydrospiro[thiopheno[2,3-flindole-3,4'-piperidine] l'-Methyl-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine] (D53) (0.029g,0.112 mmol) was transformed to give the title compound as a pale yellow oil (0.055g,93%) according to the method of Example 1. 69 010610 'h NMR (200 MHz, CDC13) δ (ppm): 8.00 (m, 3H), 7.62 (m, 2H), 7.40 (m, 3H), 7.05 (s,1H), 4.12 (m, 2H), 3.30 (s, 2H), 3.08 (t, 2H), 2.85 (br s, 2H), 2.30 (s, 3H), 2.35 (s, 6H),2.20 (br s, 4H), 1.85 (br s, 2H)
Example 33 1.2.3.5.6.7- Hexahydro-l'-methyl-l-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[indeno[5,6-b]pyrrole-7,4'-piperidine] 1.2.3.5.6.7- Hexahydro-r-methylspiro[indeno[5,6-b]pyrrole-7,4'-piperidine] is preparedfrom l-acetyl-2,3-dihydro-lH-indole-5-carboxaldehyde using a similar procedure to thatdescribed for compound 11 in Arch. Pharm. (Weinheim) 1991,323, 35 and then convertedto the title compound using a similar procedure to Example 1.
Example 34 5-[4'-((N-Methanesulphonyl-N-methyl)amino)-2'-methylbiphenyl-4-carbonyl]-r- methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]mdole-3,4'-piperidine]
This was prepared from methyl 4'-[(N-methanesulphonyl-N-methyl)amino]-2'-methylbiphenyl-4-carboxylate (D54) following the procedure of Example 12. This gavethe title compound as a white foam, which was converted into its oxalate sait, a light greypowder. ’H NMR (oxalate sait) (250 MHz, d6DMSO) δ (ppm): 7.97 (bs, 1H), 7.67 (d, 2H), 7.48 (d,2H), 7.40 (s, 1H), 7.32 (m, 2H), 6.79 (s, 1H), 4.52 (s, 2H), 4.07 (t, 2H), 3.39 (m, 2H), 3.28(s, 3H), 3.0 (m, 7H), 2.77 (s, 3H), 2.30 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H).
Example 35 5-[4'-(DimethylaminosuIphonyl)biphenyl-4-carbonyl]-l'-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f)indole-3,4’-piperidine]
This was prepared from 4'-(dimethylaminosulphonyl)biphenyl-4-carboxylic acid (D56)following the procedure of Example 1. This gave the title compound (88%) as a yellowishfoam, which was triturated in acetone to give a white powder. ‘H NMR (250 MHz, d6DMSO) δ (ppm): 8.0 (m, 3H), 7.86 (m, 4H), 7.7 (m, 2H), 6.72 (s,1H), 4.86 (s, 2H), 4.02 (t, 2H), 3.00 (t, 2H), 2.74 (b, 2H), 2.64 (s, 6H), 2.19 (s, 3H), 1.9 (m,4H), 1.65 (m, 2H). 70 010610
Example 36 5-[4'-(Methanesulphonyl)biphenyl-4-carbonyl]-r-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-fJindole-3,4’-piperidine]
This was prepared from 4'-(methanesulphonyl)biphenyl-4-carboxylic acid (D57),following the procedure of Example 1. This gave the title compound (73%) as a paleyellow foam, which was triturated with acetone/ether to give a white powder. ‘H NMR (250 MHz, d6DMSO) δ (ppm): 8.02 (m, 5H), 7.87 (d, 2H), 7.72 (d, 2H), 6.71 (s,1H), 4.37 (s, 2H), 4.03 (t, 2H), 3.28 (s, 3H), 3.01 (t, 2H), 2.75 (m, 2H), 2.20 (s, 3H), 1.9(m, 4H), 1.65 (m, 2H).
Example 37 5-[4'-(N,N-Dimethykarbamoylamino)-2’-methylbiphenyl-4-carbonyl]-r-methyl- 2,3,6,7-tetrahydrospiro [furo [2,3-f] indole-3,4' -piperidine]
This was prepared from 4'-(N,N-dimethylcarbamoylamino)-2'-methylbiphenyl-4-carboxylic acid (D59), following the procedure of Example 9, but using dichloromethaneas solvent throughout. This gave the title compound (35%) as a glass, which wasconverted to its oxalate sait, a cream solid. !H NMR (oxalate sait) (250 MHz, d6DMSO) δ (ppm): 8.32 (s, 1H), 7.95 (b s, 1H), 7.61 (d,2H), 7.45 (m, 4H), 7.12 (d, 1H), 6.77 (s, 1H), 4.46 (s, 2H), 4.05 (t, 2H), 3.3 (b, 2H), 3.1-2.9(m, 4H), 2.93 (s, 6H), 2.69 (s, 3H), 2.23 (s, 3H), 2.05 (m, 2H), 1.85 (m, 2H).
Example 38 5-[4’-(Ethoxycarbonylamino)-2’-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahy drospiro [furo [2,3-f[ indole-3,4’-piperidine]
This was prepared from 4'-(ethoxycarbonylamino)-2'-methylbiphenyl-4-carboxylic acid(D61), following the procedure of Example 9. This gave the title compound (75%) as alight yellow foam, which was converted to its hydrochloride sait, a white powder. ‘H NMR (HCl sait) (200 MHz, d6DMSO) δ (ppm): 10.5 (b, 1H), 9.70 (s, 1H), 8.94 (b s,1H), 7.62 (d, 2H), 7.43 (m, 4H), 7.18 (d, 1H), 6.78 (s, 1H), 4.51 (s, 2H), 4.14 (q, 2H), 4.07(t, 2H), 3.4 (m, 2H), 3.1 (m, 4H), 2.78 (s, 3H), 2.24 (s, 3H), 2.2 (m, 2H), 1.9 (m, 2H), 1.26(t, 3H) 71 010610
Example 39 5-[4'-(4,5-DimethyI-l,2,4-triazol-3-yl)-2’-methylbiphenyl-4-carbonyl]-l’-methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]
This was prepared from 4'-(4,5-dimethyl-l,2,4-triazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (D64), following the procedure of Example 9. This gave the titlecompound (27%) as a white solid. 'HNMR (200 MHz, CDC13) δ (ppm): 8.13 (b, 1H), 8.00 (s, 1H), 7.93 (d, 1H), 7.61 (d,2H), 7.42 (d, 2H), 7.29 (d, 1H), 6.66 (s, 1H), 4.38 (s, 2H), 4.11 (b, 2H), 3.87 (s, 3H), 3.07(t, 2H), 2.85 (m, 2H), 2.52 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H), 2.05 (m, 4H), 1.85 (m, 2H).
Example 40 r-Methyl-6-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]- 2.3.7.8- tetrahydrospiro[4H-pyrano[2,3-f|jndole-4,4'-piperidme]
This was prepared from T-methyl-2,3,7,8-tetrahydrospiro[4H-pyrano[2,3-f]indole-4,4'-piperidine] (D70), following the procedure of Example 5. This gave the title compound(27%), which was converted to the oxalate sait, a white solid. ‘H NMR (oxalate sait) (400 MHz, d6DMSO) δ (ppm): 7.96 (m, 2H), 7.89 (d, 1H), 7.69 (d,2H), 7.54 (d, 2H), 7.48 (d, 1H), 6.94 (s, 1H), 4.32 (m, 1H), 4.07 (t, 2H), 3.65 (m, 2H), 3.38(m, 2H), 3.06 (t, 2H), 3.0-3.2 (m, 2H), 2.85 (s, 3H), 2.61 (s, 3H), 2.38 (s, 3H), 1.92 (m,2H), 1.5-1.75 (m,3H)
Example 41 r-Methyl-5-(2'-methyl-4’-(5-methyl-l,3,4-thiadiazol-2-yl) biphenyl-4-carbonyl)- 2,3,6,7-tetrahydrospiro[furo[2,3-f|indole-3,4'-piperidine]
Crude 2'-methyl-4'-(5-methyl-l,3,4-thiadiazol-2-yl)biphenyl-4-carboxylic acid (D73, 500mg) and r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4,-piperidine] (D8) affordedthe title compound according to the general method of Example 1. Préparative HPLCafforded 10 mg of pure compound. *H NMR (400 MHz, CD3OD) δ (ppm): 8.02 (br s, 1H), 7.91 (s, 1H), 7.85 (d, 1H), 7.69 (d,2H), 7.52 (d, 2H), 7.41 (d, 1H), 6.76 (s, 1H), 4.56 (s, 2H), 4.18 (t, 2H), 3.62-3.51 (m, 2H),3.21-3.05 (m, 4H), 2.94 (s, 3H), 2.83 (s, 3H), 2.38 (s, 3H), 2.29-2.00 (m, 4H). 72 . , Λ, 010610
Example 42 5-(2’-MethyI-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-l'-n-propyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] 1-Bromopropane (0.07 ml, 0.80 mmole) and sodium carbonate (226mg, 2.13 mmole) wereadded to a stirred solution of 5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E3, 270mg, 0.53mmole) in éthanol (10 ml). This mixture was heated under reflux for 31 hours. Thereaction mixture was concentrated in vacuo and the residue treated with water (15 ml) andextracted with chloroform. The organic extract was dried (Na2SO4), concentrated in vacuoand the residue chromatographed on silica gel eluting with 0-6% methanol/chloroform toafford the title compound as a yellow gum (194mg, 67%). This was converted to itshydrochloride sait and crystallised from ether m.p. 263-266°C. H1 NMR (free base); (250 MHz, CDC13) δ (ppm): 8.15 (br s, 1H - low intégration), 7.99(s, 1H), 7.91 (dd, 1H), 7.64 (d, 2H), 7.42 (d, 2H), 7.37 (d, 1H), 6.67 (s, 1H), 4.40 (br s, 2H), 4.10 (br s, 2H), 3.07 (t, 2H), 2.94 (br s, 2H), 2.66 (s, 3H), 2.37 (s, 3H), 2.33 (br t, 2H),2.22-1.38 (br m, 8H), 0.92 (t, 3H).
Example 43 l'-Methyl-5-(2'-methyl-4'-(5-methyloxazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]mdole-3,4’-pipendme]
The title compound was prepared from 2'-methyl-4'-(5-methyloxazol.-2-yl)biphenyl-4-carboxylic acid (D76) and 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8)foliowing the procedure of Example 1 (58%). This was converted to its oxalate sait andcrystallised from acetone/methanol as a white solid m.p. 230-233°C. 'H NMR (free base) (250 MHz, CDC13) δ (ppm): 8.14 (br s, 1H - low intégration), 7.95 (s, 1H), 7.87 (d, 1H), 7.61 (d, 2H), 7.41 (d, 2H), 7.32 (d, 1H), 6.85 (s, 1H), 6.66 (s, 1H), 4.37 (br s, 2H), 4.10 (br m, 2H), 3.06 (t, 2H), 2.85 (br s, 2H), 2.42 (s, 3H), 2.35 (s, 3H), 2.31 (br s, 3H), 2.20-1.50 (m, 6H). 73 010610
Example 44 l'-Methyl-5-(2’-methyl-4'-(3-methylisoxazol-5-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-flindole-3,4'-piperidine]
The title compound was prepared from l'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-fJindole-3,4'-piperidine] (D8) and 2'-methyl-4'-(3-methylisoxazol-5-yl)biphenyl-4-carboxylic acid (D79) using a procedure similar to that of Example 1 (58%) m.p. 224-5°C. ‘H NMR (250 MHz, CDC13) δ (ppm): 8.15 (br s, 1H), 7.72-7.55 (m, 4H), 7.45-7.24 (m,3H), 6.67 (s, 1H), 6.4 (s, 1H), 4.38 (s, 2H), 4.20-4.0 (m, 2H), 3.07 (t, 2H), 2.95-2.71 (m,2H), 2.37 (s, 3H), 2.32 (s, 6H), 2.2-1.5 (m, 6H).
Example 45 r-Methyl-5-(2'-methyl-4'-(5-methylisoxazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f|indole-3,4'-piperidine]
The title compound was prepared from l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole3,4'-piperidine] (D8) and 2'-methyl-4'-(5-methylisoxazol-3-yl)biphenyl-4-carboxylic acid(D83) using a procedure similar to that of Example 1 (75%) m.p. 197-9°C. 'H NMR (200 MHz, CDC13) δ (ppm): 8.15 (br s, 1H), 7.78-7.55 (m, 4H), 7.45-7.2 (m,3H), 6.65 (s, 1H), 6.32 (s, 1H), 4.39 (s, 2H), 4.2-4.0 (m, 2H), 3.07 (t, 2H), 2.95-2.7 (m,2H), 2.49 (s, 3H), 2.3 (s, 6H), 2.2-1.55 (m, 6H).
Example 46 2,3,5,6,7,8-Hexahydro-r-methyï-5-(4’-(5-dimethylamino-l,2,4-oxadiazol-3-yl)-2’-methylbipheny l-4-carbonyl)spiro [furo [2,3-g] quinolme-3,4'-piperidine]
The title compound was prepared from 4'-(5-dimethylamino-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (D14) and 2,3,5,6,7,8-hexahydro-l'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a procedure similar to thatof Example 1 (26%). This was converted to the hydrochloride sait. M.p. 118-120°C. 'H NMR (free base) (200 MHz, CDC13) δ (ppm): 7.9 (s, 1H), 7.82 (d, 1H), 7.4-7.11 (m,5H), 6.6 (s, 1H), 6.35 (br s, 1H), 4.25 (s, 2H), 3.94 (t, 2H), 3.2 (s, 6H), 2.77 (t, 2H), 2.7-2.56 (m, 2H), 2.27 (s, 3H), 2.22 (s, 3H), 2.12-1.69 (m, 4H), 1.55-1.41 (m, 4H). 010610 74
Example 47 2.3.5.6.7.8- Hexahydro-l'-methyl-5-(4'-(5-ethyl-l,3,4-oxadiazoI-2-yl)-2’- methylbiphenyl-4-earbonyl)spiro[furo[2,3-g]quinoline-3,4’-piperidine]
The title compound was prepared from 4'-(5-ethyl-l,3,4-oxadiazol-2-yl)-2'- methylbiphenyl-4-carboxylic acid (D32) and 2,3,5,6,7,8-hexahydro-T- methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a procedure similar to thatof Example 1 (19%). This was converted to its hydrochloride sait, as a white solid. M.p.241-3°C. ’H NMR (free base) (200 MHz, CDC13) δ (ppm): 7.94 (s, 1H), 7.85 (d, 1H), 7.4-7.11 (m,5H), 6.59 (s, 1H), 6.36 (br s, 1H), 4.26 (s, 2H), 3.95 (t, 2H), 2.98 (q, 2H), 2.78 (t, 2H),2.71-2.58 (m, 2H), 2.3 (s, 3H), 2.25 (s, 3H), 2.14-1.61 (m, 4H), 1.58-1.35 (m, 7H).
Example 48 2,3j5,6,7,8-Hexahydro-l'-methyl-5-(4’-methoxycarbonyl-2’-methylbiphenyl-4-carbonyl)spiro [furo[2,3-g]quinoline-3,4'-piperidine]
The title compound was prepared from 2,3,5,6,7,8-hexahydro-l'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) and 4'-methoxycarbonyl-2'-methylbiphenyl-4-carboxylic acid (D41) using a procedure similar to that of Example 1 (46%). ’H NMR (200 MHz, CDC13) δ (ppm): 7.93 (s, 1H), 7.87 (d, 1H), 7.35 (d, 2H), 7.24-7.1 (m,3H), 6.6 (s, 1H), 6.35 (b s, 1H), 4.26 (s, 2H), 4.0-3.85 (m, 5H), 2.79 (t, 2H), 2.7-2.55 (m,2H), 2.3-2.2 (m, 6H), 2.15-1.99 (m, 2H), 1.97-1.65 (m, 2H), 1.58-1.4 (m, 4H).
Exampïe 49 2.3.5.6.7.8- Hexahydro-l’-methyl-5-(4’-hydrazinocarbonyl-2’-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine]
The title compound was prepared from 2,3,5,6,7,8-hexahydro-l'-methyl-5-(4'-methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine] (E48) and hydrazine monohydrate, using a procedure similar to that ofExample 25 (90%). 'H NMR (200 MHz, CDC13) δ (ppm): 7.7-7.5 (m, 3H), 7.35 (d, 2H), 7.25-7.1 (m, 3H), 6.6(s, 1H), 6.35 (br s, 1H), 4.25 (s, 2H), 4.1 (br s, 2H), 3.95 (t, 2H), 2.78 (t, 2H), 2.7-2.52 (m,2H), 2.3-2.19 (m, 6H), 2.14-1.7 (m, 4H), 1.57-1.4 (m, 4H). 010610 75
Example 50 2,3,5,6,7,8-Hexahydro-r-methyl-5-(2'-methyl-4'-(l,3,4-oxadiazol-2-yl)biphenyl-4- carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine] A suspension of 2,3,5,6,7,8-hexahydro-T-methyl-5-(4'-hydrazinocarbonyl-2'- methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine] (E49) (794 mg) intriethylorthoformate (25 ml) was heated at reflux overnight. The mixture was concentratedin vacuo and the residue refluxed overnight in xylene (40 ml) to complété cyclisation. Thexylene was evaporated under reduced pressure and the residue purified by chromatographyon silica gel, eluting with chloroform and methanol, to afford the title compound (470 mg,58%). The hydrochloride sait precipitated from acetone as a white solid. 'H NMR (free base) (200 MHz, CDC13) δ (ppm): 8.49 (s, 1H), 8.0 (s, 1H), 7.92 (d, 1H),7.38 (d, 2H), 7.3-7.15 (m, 3H), 6.6 (s, 1H), 6.38 (br s, 1H), 4.26 (s, 2H), 3.95 (t, 2H), 2.79(t, 2H), 2.72-2.58 (m, 2H), 2.3 (s, 3H), 2.26 (s, 3H), 2.15-1.41 (m, 8H).
Exemple 51 l'-Methyl-5-(2’-methyl-4'-pyrazinylbiphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine] l'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]mdole-3,4'-piperidine] (0.098g, 0.403 mmol)(D8) was dissolved in toluene (5 ml) and was treated with trimethylaluminium (2.0 M inhexane) (0.810 ml, 1.612 mmol) with stirring under argon. After 0.25h, a solution ofmethyl 2'-methyl-4'-pyrazinylbiphenyl-4-carboxylate (D86, 0.136g, 0.447 mmol) intoluene (5 ml) was added. The reaction mixture was then heated to 80°C. After 2h, thereaction mixture was allowed to cool and was stirred at room température. The reactionmixture was then poured onto a slurry of silica gel (9385 ~ 20 ml) in dichloromethane (30ml). After effervescence had ceased, the slurry was filtered and the filter pad was washedwith 20% MeOH/CH2Cl2 (-200 ml). The filtrate was then evaporated under reducedpressure to give a brown oil, which was purified by silica-gel chromatography (9385, 10%MeOH/CH2Cl2 as eluant) to give the title compound as a cream solid (0.091g, 44%). ’H NMR (250 MHz, CDC13) δ (ppm): 9.08 (s, 1H), 8.68 (t, 1H), 8.52 (d, 1H), 8.14 (br s,1H), 8.00 (s, 1H), 7.90 (dd, 1H), 7.62 (d, 2H), 7.42 (d, 2H), 7.38 (d, 1H), 6.70 (s, 1H), 4.40(br s, 2H), 4.10 (br s, 2H), 3.10 (t, 2H), 2.90 (br s, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 2.20 (brs,2H), 1.85 (brs,4H). 010610 76
Example 52 l'-Methyl-5-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazolyl-3-yl)biphenyl-4-carbonyl]-l- oxo-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4’-piperidine] A solution of T-methyl-5-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine] (E32, 0.100g,0.187 mmol) in methanol (10 ml) was treated with a solution of sodium periodate (0.200g,0.935 mmol) in water (1 ml) with stirring. After 20 h, water (10 ml) was added and themethanol présent was removed by évaporation under reduced pressure to give a whitesuspension. The suspension was then extracted with dichloromethane (3 x 25 ml). Thecombined organic layers were then dried (Na2SO4) and evaporated under reduced pressureto give a colourless oil, which was purified by préparative t.l.c. to give the title compoundas a white foam (0.055g, 53%) which was subsequently converted to its hydrochloride sait. ’HNMR (200 MHz, CDC13) (free base): 8.03 (s, 1H), 7.95 (d, 1H), 7.65 (s, 1H), 7.60 (d,2H), 7.40 (m, 4H), 4.21 (t, 2H), 3.25 (Abq, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.70 (s, 3H),2.40 (s, 3H), 2.35 (s, 3H), 2.15 (br m, 6H).
Example 53 r-Methyl-5-[2’-methyI-4'-(l-methylimidazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahy drospiro [furo [2,3-f] indole-3,4' -piperidine] 2'-Methyl-4'-(l-methylimidazol-2-yl)biphenyl-4-carboxylic acid (D90, 310 mg, 1.06mmol) was heated at reflux in thionyl chloride (10 ml) for 30 minutes, cooled, evaporatedin vacuo and the orange residue redissolved in dry THF (10 ml). l'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 260mg, 1.06 mmol) andtriethylamine (0.15 ml, 1.06 mmol) were added and the mixture stirred for 72 hours. Themixture was evaporated in vacuo, the residue partitioned between H2O and CHC13 (4times) and the organics combined, dried over Na2SO4, filtered and evaporated in vacuo.The residue was purified by flash silica-gel chromatography with 2% MeOH/CHCl3 aseluant to yield the title compound as a pale yellow gum (224 mg, 41%) which wasconverted to the hydrochloride sait. ‘H NMR (free base) (200 MHz, CDC13) Ô: 7.60-7.30 (m, 9H), 7.15 (s, 1H), 6.65 (s, 1H), 4.35 (d, 2H), 4.10 (s, 2H), 3.80 (s,3H), 3.10 (t, 3H), 2.90 (s, 2H), 2.35 (s, 6H), 2.15-2.00 (m, 4H), 1.90-1.70 (m, 2H).
Example 54 77 010610 r-Methyl-5-[2'-methyl-4'-(l-methylimidazol-5-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidinej 2'-Methyl-4'-(l-methylimidazol-5-yl)biphenyl-4-carboxylic acid (D93, 300 mg, 1.0 mmol)was heated at reflux in thionyl chloride (15 ml) for 1 hour, cooled and evaporated in vacuo.The residue was redissolved in dry THF (10 ml) and treated with l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 250 mg, 1.0 mmol) andtriethylamine (143ul, 1.0 mmol) then stirred for 18 hours. The reaction mixture wasevaporated in vacuo, partitioned between water and CHC13 (3 times) and the organicextracts combined. The organics were dried over Na2SO4 and evaporated in vacuo to anorange gum. The gum was purified by flash silica gel chromatography (eluting with3%MeOH/CHCl3) to yield the title compound as a pale yellow gum (200 mg, 38%) whichwas converted to the hydrochloride sait. ’H NMR (free base) (200 MHz, CDC13) δ (ppm): 7.65-7.50 (m, 3H), 7.40 (d, 2H), 7.35-7.20 (m, 4H), 7.15 (s, 1H), 6.65 (s, 1H), 4.35 (s, 2H), 4.10 (s, 2H), 3.75 (s, 3H), 3.05 (t,2H), 2.85 (s, 2H), 2.40-2.25 (m, 6H), 2.15-1.95 (m, 4H), 1.75 (s, 2H)
Example 55 5-[4'-(5-Hydroxymethyl-l,2,4-oxadiazoI-3-yl)-2’-methylbiphenyl-4-carbonyl]-r- methyl-2,3,6,7~tetrahydrospiro[furo[2,3-f]iiidole-3,4'-piperidme] A stirred solution of l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine](D8, 0.34g, 1.4 mmole) in toluene (10 ml) under argon was treated with 2Mtrimethylaluminuim in toluene (0.7 ml, 1.4 mmole) and kept at room temp. for 20 minutes.A solution of methyl 4'-[5-(t-butyldimethylsilyloxy)-l,2,4-oxadiazol-3-yl]-2'-methylbiphenyl-4-carboxylate (D95, 0.61g, 1.4 mmole) in toluene (10 ml) was added andthe stirred mixture heated under reflux for 3 hours. The solution was allowed to cool andthen poured into a stirred slurry of silica gel (10g) in dichloromethane (30 ml). This waspacked into a column and eluted with 10% methanol/chloroform. The concentrated eluant(0.8g) was dissolved in THF (50 ml) and treated with tetraethylammonium fluoride (100mg), then the mixture was stirred at room temp. for 1 hour, before concentrating undervacuum. The residue was treated with 10% Na2CO3 solution and extracted withdichloromethane. The extract was dried (Na2SO4), concentrated in vacuo, and the residuechromatographed on silica gel eluting with 0-5% methanol/chloroform to afford the titlecompound as pale yellow oil (0.28g, 30%). This was converted to its hydrochloride sait m.p. 273-278°C. 78 010610 'H NMR (250 MHz, CDC13) δ (ppm): 8.13 (br s, 1H - low intégration), 8.02 (s, 1H), 7.96(d, 1H), 7.60 (d, 1H), 7.40 (d, 2H), 7.32 (d, 1H), 6.67 (s, 1H), 4.96 (s, 2H), 4.40 (br s, 2H),4.10 (br m, 2H), 3.07 (t, 2H), 3.0-2.7 (br m, 2H), 2.31 (s, 6H), 2.4-1.6 (m, 7H). 5 Example 56 l'-Methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-r-oxo- 2,3,6,7-tetrahydrospiro [furo [ 2,3-fJ indole-3,4'-piperidine] A stirred solution of l'-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4- 10 carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (El, 300 mg, 0.57mmole) in chloroform (20 ml) at -20°C under argon was treated with a dried (Na2SO4)solution of 3-chloroperoxybenzoic acid (207 mg of 50-60% commercial purity) inchloroform (5 ml). The mixture was allowed to warm to room temp. over 20 minutes, thenwashed with 10% Na2CO3 solution, dried (Na2SO4) and concentrated in vacuo to leave a 15 beige solid. This was chromatographed on silica gel eluting with 0-20% methanol/chloroform and the product crystallised from acetone to afford the titlecompound as a white solid (120 mg, 39%) m.p. 223-229°C. *H NMR (250 MHz, CDC13) δ (ppm): 8.25 (br s, 1H - low intégration), 8.00 (d, 1H), 7.96 20 (dd, 1H), 7.62 (d, 2H), 7.42 (d, 2H), 7.37 (d, 1H), 6.70 (s, 1H), 4.45 (s, 2H), 4.12 (t, 2H),3.48-3.18 (m, 4H), 3.31 (s, 3H), 3.14-2.90 (m, 2H), 3.07 (t, 2H), 2.69 (s, 3H), 2.35 (s, 3H),1.80-1.63 (m, 2H). 010610 79
Example 57 l'-MethyI-5-[2’-methyI-4'-(l,2,4-triazm-3-yl)biphenyI-4-carbonyI]-2,356,7- tetrahydrospiro[furo[2,3-flindole-3,4'-piperidine]
The title compound (100 mg, 22%) was prepared from 2'-methyl-4'-(l,2,4-traizin-3-yl)biphenyl-4-carboxylic acid (D98, 0.25g, 0.80 mmol) according to the method ofExample 1. This was converted to its hydrochloride sait. 'H NMR (HCl sait) (250 MHz, CD3OD) δ (ppm): 9.30 (d, 1H), 8.90 (d, 1H), 8.50 (s, 1H),8.45 (d, 1H), 8.10 (br s, 1H), 7.75 (d, 2H), 7.60 (d, 2H), 7.50 (d, 1H), 6.80 (s, 1H), 4.60 (s,2H), 4.20 (m, 2H), 3.65-3.55 (m, 2H), 3.28-3.10 (m, 4H), 2.95 (s, 3H), 2.45 (s, 3H), 2.40-2.20 (m, 2H), 2.15-2.00 (m, 2H).
Example 58 2,3,6,7,8,9-Hexahydro-r-methyl-6-(2'-methyl-4'-(5-methyl -l,3,4-oxad’az°l-2-yl)biphenyl-4-carbonyI)spiro[4H-pyrano[2,3-g]quinoline-4,4' piperidine] A solution of 2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid(DI 1, 184 mg, 0.0006 mmole) in thionyl chloride (5 ml) under an argon atmosphère washeated to reflux for 20 minutes. The reaction mixture was allowed to cool and thenconcentrated in vacuo to leave an orange residue, which was dissolved in dichloromethane(5 ml) and treated with 2,3,6,7,8,9-hexahydro-T-methylspiro[4H-pyrano[2,3-g]quinoline-4,4' piperidine] (DI07, 150 mg, 0.0006 mole) in dichloromethane (5 ml) and triethylamine(100 ul, 0.0007 mole). The solution was stirred at room temp. for 15 hrs, thenconcentrated in vacuo. The residue was purified by chromatography on silica gel elutingwith 8% methanol/dichloromethane to afford the title compound (105 mg, 31%). 'H NMR (200 MHz, CDC13) δ (ppm): 7.93 (s, 1H), 7.87 (d, 1H), 7.40 (d, 2H), 7.27-7.20 (m, 3H), 6.62 (br s, 2H), 4.02 (dd, 2H), 3.95 (t, 2H), 2.77 (t, 2H), 2.63 (s, 3H), 2.56 (br d, 2H), 2.31 (s, 3H), 2.26 (s, 3H), 2.18-2.00 (m, 4H), 1.85 (dd, 2H), 1.48 (br d, 2H), 1.28 (br d, 2H). 80 Γ . «> 010610
Example 59 r-Ethyl-5-(2'-methyl-4’-(5-methyI-l,3,4-oxadiazoI-2-yl)biphenyl“4-carbonyI)-r-oxo- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] 5 The title compound was prepared from T-ethyl-5-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E26)using a similar procedure as in Example 56 to yield an off white solid (16%). 'H NMR (250 MHz, CDC13) δ (ppm): 8.22 (br s, 1H - low intégration), 7.98 (s, 1H), 7.91 10 (d, 1H), 7.64 (d, 2H), 7.48-7.30 (m, 3H), 6.69 (s, 1H), 4.48 (br s, 2H), 4.11 (brm, 2H), 3.57-2.76 (m, 10H), 2.66 (s, 3H), 2.36 (s, 3H), 1.72 (brd, 2H), 1.49 (brt, 3H).
Example 60 r-Ethyl-5-[4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-15 tetrahy drospiro [furo [2,3-f] indole-3,4’ -piperidine]
The title compound was prepared from 4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (Dll) and T-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (DI09) using a similar procedure as that outlined in Example 1, to afford the 20 title compound as a yellow gum (31%). This was converted to its hydrochloride sait toyield an off white solid m.p. 245-249°C. *H NMR (HCl sait) (400 MHz, d6DMSO) δ (ppm): 8.09 (d, 2H), 7.98 (d, 2H), 7.95 (br s,1H), 7.88 (d, 2H), 7.72 (d, 2H), 6.77 (s, 1H), 4.52 (s, 2H), 4.06 (t, 2H), 3.50 (br d, 2H), 25 3.12 (m, 2H), 3.10-2.93 (m, 4H), 2.61 (s, 3H), 2.25 (br m, 2H), 1.90 (br d, 2H), 1.29 (t, 3H).
Example 61 r-Ethyl-5-(4'-hydrazmocarbonyI-2’-methylbiphenyI-4-carbonyl)-2,3,6,7- 30 tetrahydrospiro[furo[2,3-f|indoIe-3,4'-piperidine] A stirred solution of T-ethyl-5-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E26, 2.5g, 4.7 mmole)in methanol (600 ml) was treated with IM hydrogen chloride in ether (30 ml, 30 mmole) 35 and kept at room temp. for 20 hours, then concentrated in vacuo. The residue was treatedwith 10% Na2CO3 solution (200 ml) and chloroform (500 ml), stirred well for 20 minutes,then the chloroform layer separated, dried and concentrated in vacuo. The residue was 81 010610 crystallised from ethyl acetate to afford the title compound as a beige solid (0.94g, 39%)m.p. 222-225°C. 'H NMR (250 MHz, CDC13) δ (ppm): 8.17 (br s, 1H - low intégration), 7.71 (s, 1H), 7.67-7.55 (m, 3H), 7.50 (br s, 1H), 7.38 (d, 2H), 7.28 (d, 1H), 6.67 (s, 1H), 4.50 (br s, 2H), 4.3-3.9 (br s, 4H), 3.09 (t, 2H), 2.98 (br s, 2H), 2.50-2.38 (m, 2H), 2.34 (s, 3H), 2.22-1.41 (m,6H), 1.13 (brt, 3H).
Example 62 5-[4'-(Acetylhydrazinocarbonyl)-2'-methylbiphenyl-4-carbonyl]-l'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]
To a stirred solution of T-ethyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)- 2,3,6,7-tetrahydrospiro[furo[2-3-f]indole-3,4'-piperidine] (E61, 1.00g, 1.96mmole) inchloroform (30 ml), acetic anhydride (5.76 ml, 0.06 mmole) was slowly added. Thesolution was stirred at room température for approximately 1 hour, then concentrated invacuo. Toluene was used to azeotrope out the excess acetic anhydride. The residue wasdissolved in chloroform, washed with 10% Na2CO3 solution and the organic phase dried(Na2SO4), then concentrated in vacuo. The residue beige solid was chromatographed onsilica gel, eluting with 0-12% methanol in chloroform to afford the title compound as ayellow solid (0.87g, 80%) m.p. 154-157°C. ’h NMR (250 MHz, CDC13) δ (ppm): 9.02 (br s, 1H), 8.17 (br s, ΙΗ-low intégration), 7.76(s, 1H), 7.71 (dd, 1H), 7.61 (d, 2H), 7.37 (d, 2H), 7.29 (d, 1H), 6.67 (s, 1H), 4.40 (br s,2H), 4.09 (br m, 2H), 3.06 (t, 2H), 2.98 (br m, 2H), 2.44 (br m, 2H), 2.31 (s, 3H), 2.15 (s,3H), 2.10-1.50 (m, 6H), 1.13 (brt,3H).
Example 63 5-[4'-(5-Methoxymethyl-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyI-4-carbonyl]-r- methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f|indole-3,4'-piperidine]
The title compound was prepared from 4'-(5-methoxymethyl-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (DI 12) and T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) using a similar procedure as described in Example 1. Thisafforded the title compound as a pale yellow solid (62%), which was converted to itshydrochloride sait to give an off white solid m.p. 247-251°C. 82 0 î 061 0 'H NMR (free base) (250 MHz, CDC13) δ (ppm): 8.15 (s, 1H - low intégration), 8.06 (s, 1H), 8.00 (dd, 1H), 7.63 (d, 2H), 7.42 (d, 2H), 7.36 (d, 1H), 6.68 (s, 1H), 4.79 (s, 2H), 4.41(br s, 2H), 4.10 (br m, 2H), 3.59 (s, 3H), 3.08 (t, 2H), 2.88 (br s, 2H), 2.38 (s, 3H), 2.32 (brs, 3H), 2.10-1.54 (m, 6H).
Example 64 5-[4’-(4,5-Dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carbonyl]-l’-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f|indoIe-3,4'-piperidine]
This was prepared from methyl 4'-(4,5-dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carboxylate (DI 14) and r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine(D8) following the procedure of Example 12. This gave the title compound (35%) as alight yellow solid. ’H NMR (200 MHz, CDC13) δ (ppm): 8.15 (b, 1H), 7.89 (s, 1H), 7.82 (d, 1H), 7.60 (d, 2H), 7.39 (d, 2H), 7.28 (d, 1H), 6.66 (s, 1H), 4.46 (t, 2H), 4.38 (s, 2H), 4.09 (t, 2H), 4.0-4.2(b, 2H), 3.06 (t, 2H), 2.87 (m, 2H), 2.32 (s, 6H), 1.9-2.3 (m, 4H), 1.6-1.9 (m, 2H).
Example 65 5-[4'-(2-(N,N-DimethyIammo)acetamido)-2’-methyIbiphenyl-4-carbonyl]-l'-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine] 4'-(2-Chloroacetamido)-2'-methylbiphenyl-4-carboxylic acid (DI 16, 0.34g), following theprocedure of Example 29, gave 5-[4'-(2-chloroacetamido)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (0.20g, 33%) as a lightyellow powder, but of low purity (HPLC). This was dissolved in éthanol (25 ml) anddichloromethane (10 ml), and dimethylamine (5.6 M in éthanol, 2 ml) was added. Thesuspension was stirred until homogenous, and then left to stand for 6 days. Solvents werethen evaporated off, and the residue was purified by chromatography on silica gel, elutingwith 0-20% methanol/dichloromethane. The crude product was dissolved in 10%methanol/dichloromethane, washed with dil. potassium carbonate solution, dried (Na2SO4)and evaporated to give the title compound (0.06g, 30%) as a colourless oil. This wasconverted into its dihydrochloride sait, a light cream powder. 'H NMR (free base) (250 MHz, CDC13) δ (ppm): 9.07 (s, 1H), 8.08 (b s, 1H), 7.51 (d, 2H),7.45 (m, 2H), 7.30 (d, 2H), 7.15 (d, 1H), 6.59 (s, 1H), 4.30 (s, 2H), 4.02 (b, 2H), 3.03 (s,2H), 2.99 (t, 2H), 2.79 (m, 2H), 2.32 (s, 6H), 2.26 (s, 3H), 2.22 (s, 3H), 1.9-2.1 (m,4H),1.1-1.3 (m,2H). 83 010610
Example 66 5-[4'-(Ethoxycarbonylamino)-2'-methylbiphenyl-4-carbonyl]-l'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine]
This compound was prepared from 4'-(ethoxycarbonylamino)-2'-methylbiphenyl-4-carboxylic acid (D61) and l'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (DI09), following the procedure of Example 29. This gave the title compound(61%) as a straw coloured foam, which was converted to its hydrochloride sait. ’H NMR (HCl sait) (200 MHz, d6DMSO) δ (ppm): 10.16 (b, 1H), 9.67 (s, 1H), 7.93 (s, 1H), 7.61 (d, 2H), 7.41 (m, 4H), 7.16 (d, 1H), 6.76 (s, 1H), 4.51 (s, 2H), 4.13 (q, 2H), 4.04(t, 2H), 3.5 (m, 2H), 2.9-3.2(m, 6H), 2.23 (s, 3H), 2.1-2.3 (m, 2H), 1.88 (d, 2H), 1.27 (t, 3H), 1.25 (t,3H).
Example 67 5-[4'-(Acetylhydrazmocarbonyl)-2'-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-i]indole-3,4'-piperidme]
The title compound was prepared from 5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E25) usinga similar procedure to Example 62 as a colourless oil (27%). HCl sait mp 235-238°C. *H NMR (250 MHz, CDC13) δ (ppm): 9.5 (br s), 8.13 (br s, 1H), 7.77 (s, 1H), 7.70 (d, 1H),7.60 (d, 2H), 7.34 (d, 2H), 7.23 (d, 1H), 6.66 (s, 1H), 4.40 (br s, 2H), 4.08 (br m, 2H), 3.06(t, 2H), 3.0-2.8 (br, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H), 2.2-1.5 (m, 6H).
Example 68 5-(4'-(5-methylfuran-2-yl)-2’-methylbiphenyl-4-carbonyl)-l’-methyl-2,3,6,7-tetrahydrospiro [furo [2,3-f] indole-3,4’-piperidine] 2’-Methyl-4’-(5-methylfuran-2-yl)biphenyl-4-carboxylic acid (DI 19) (160 mg, 0.55 mmol)and T-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8,134 mg, 0.55mmol) were converted to the title compound using the method outlined in Example 29, asan off-white foam (176 mg, 62%). ’H NMR (200 MHz, CDC13) δ (ppm): 8.12 (br s, 1H), 7.65-7.45 (m, 4H), 7.4 (d, 2H), 7.29-7.19 (m, 1H), 6.65 (s, 1H), 6.58 (d, 1H), 6.08 (d, 1H), 4.39 (br s, 2H), 4.21-4.0 (m, 2H), 010610 3.05 (t, 2H), 2.93-2.75 (m, 2H), 2.38 (s, 3H), 2.3 (s, 6H), 2.11-1.9 (m, 4H), 1.84-1.6 (m,2H). 10 85 010610
Pharmacological Data 5-HT 1D ALPHA AND 5-HT 1D BETA BINDING. 5 CHO cells expressing 5-HT 1D alpha receptors (0.563 x 108cells / ml) are homogenised inTris buffer and stored in 1ml aliquots. CHO cells expressing 5-HT 1D beta receptors (4 x 107cells / ml) are homogenised in Tris buffer and stored in 1.5ml aliquots. 0.4ml of a cell suspension was incubated with [3H]-5-HT (4nM) in Tris Mg HCl buffer10 (pH 7.7) and test drug, at 37°C for 45 minutes. Each test drug was tested at 10 concentrations (0.0 ImM to 0.3nM final concentration), with non-specific binding definedusing 0.0ImM 5-HT. The total assay volume was 0.5ml. Incubation was stopped by rapidfiltration using a Packard Filtermate (filters pre-soaked in 0.3% polyethylenimine) andradioactivity measured by Topcount scintillation counting. 15 The pKi values were calculated from the IC50 generated by an itérative least squares curvefitting programme.
Examples 1, 4, 5, 6, 8, 18,23, 26, 40, 45, 51, 54, 55, 57 and 66 had pKi values > 8.0 at 5-HT 1D beta receptors. 20

Claims (10)

010610 86 CLAIMS:
1. A compound of formula (I) or a sait or N-oxide thereof:
(I) in which R1 is hydrogen, halogen, Cj.^alkyl, C3_6cycloalkyl, COCj.galkyl, Cj.galkoxy, hydroxy,hydroxyCj.galkyl, hydroxyCj.galkoxy, Cj.galkoxyCi.galkoxy, acyl, nitro,trifluoromethyl, cyano, SR9, SOR9, SO2R9, SO2NR10R1 ξ CO2R10, NR10SO2r! !,CONRiOR1 !, CC^NRW1 !, CONR^CH^pCC^R1 !, (CH^pNR^R11,(CH2)pCONR10Rn, (CH^pNR^COR11, (CH2)pCO2C1.6alkyl, CO2(CH2)pOR10,CONHNR1 OR11, NR1 OR11, NR1 °CO2R11, NR1 OcOCCH^pNR1 OR11,NR19CONR19r1 1, CR10=NORl 1, CNR10=NOR1 !, where R9, RIO and R11 areindependently hydrogen or Cj.galkyl and p is 1 to 4; or R1 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen,nitrogen or sulphur; R^ and R3 are independently hydrogen, halogen, Cj^alkyl, C3_6cycloalkyl, C3_6cyeloalkenyl, Cj.galkoxy, hydroxyCj.galkyl, CpgalkylOCj.galkyl, acyl, aryl,acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R19, CONR^R1 NR19rJ 1 whereR10 and R11 are independently hydrogen or C^.^alkyl; R4 is hydrogen or Cj.galkyl; R3 and R^ are independently hydrogen or Cj.galkyl; A is (CR13R14)q where q is 2, 3 or 4 and R13 and R14 are independently hydrogen or Cj_galkyl or A is (CR13R14)r-D where r is 0,1, 2 or 3 and D is oxygen, sulphur orCR13=CR14· B is oxygen, CR15Rl6 or NR13 where R13, R1^ and R13 are independently hydrogen orCj.^alkyl or B is S(O)b where b is 0,1 or 2;m is 1, 2 or 3; and n is 1, 2 or 3.
2. A compound according to claim 1 in which R1 is COCj^alkyl,cr1o=nor11, (ch2)pnr10corU, CO2R10, NRlOS02Rn, sc^nrIQr11,CONrIOr1 !, CONHNR1 or! !, NR^CO^1 !, NR10CONR10Rh, CONHNR1 Or11 orSO2R9 or R1 is optionally substituted oxadiazole. 87 010610
3. A compound according to claim 1 or 2 in which R.2 is C^alkyl.
4. A compound according to any one of daims 1 to 3 in which m is 2.
5. A compound according to any one of daims 1 to 4 in which R.4 is hydrogen, methyl or ethyl.
6. A compound according to any one of daims 1 to 5 in which n is 1.
7 A compound according to claim 1 which is: l'-Methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-l'-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl- 4- carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], 5 -(2'-Methyl-4'-(5 -methyl-1,2,4-oxadiazol-3 -yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahy dro spiro [furo [2,3 -f] indole-3,4' -piperidine], r-Ethyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Methyl-5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyI)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5- (4'-(5-Dimethylamino-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl)-r-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 1 '-Methy 1-5 - [4 ' - (5 -methyl-1,2,4-oxadiazol-3 -yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-i]indole-3,4'-piperidine], 2,3-Dihydro-l'-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbony l)spiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[4'-Cyano-2'-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(4'-Acetyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(4'-(l-(Methoxyamino)ethyl)-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine],5-(4'-Acetamidomethyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 3.5.6.7.8.9- Hexahydro-l'-methyl-5-(2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl- 4- carbonyl)spiro[2H-furo[2,3-h]benzazepine-3,4'-piperidine],l'-Methyl-5-(2'-methyl-4'-(3-methyl-l,2,4-oxadiazol-5-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], l'-Methyl-5-(2'-methyl-4'-(l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahy dro spiro [furo [2,3 -f] indole- 3.4'-piperidine, 5- [4'-(5-Ethyl-l,3,4-oxadiazol-2-yl)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahy dro spiro [furo [2,3 -f] indole-3,4' -piperidine], 88 010610 5-[2'-Methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro [furo [2,3 -f] indole-3,4'-piperidine], 2,3-Dihydro-r-methyl-5-(2'-methyl-4,-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro [furo [2,3 -f]indole-3,4'-piperidine], 5-(2,2'-Dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-r-methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(2,3'-Dimethyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-r-methyl- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],r-Methyl-5-(2'-methyl-4'-(4-methylthiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],5-(4'-Methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine],5-(5'-Methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[4'-(Methanesulphonamino)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-(4'-Hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7- tetrahy dro spiro [furo [2,3 -f] indole-3,4' -piperidine], r-Ethyl-5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-5-(2'-methyl-5'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine],5-(4'-Carboxamido-2'-methylbiphenyl-4-carbonyl)-l '-methyl-2,3,6,7-tetrahy drospiro [furo [2,3 -f]indole-3,4'-piperidine],5-(4'-Acetamido-2'-methylbiphenyl-4-carbonyl)-r-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f] indole-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-5-(4'-methanesulphonamino-2'-methylbiphenyl-4-carbonyl)-l'-methyl spiro [furo [2,3 -g] quinoline-3,4'-piperidine], l'-Methyl-5-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine], 1.2.3.5.6.7- Hexahydro-r-methyl-l-(2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl- 4- carbonyl)spiro[indeno[5,6-b]pyrrole-7,4'-piperidine], 5- [4'-(N-methanesulphonyl-N-methylamino)-2'-methylbiphenyl-4-carbonyl]-1 '- methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],5-[4'-(Dimethylàminosulphonyl)biphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 89 010610 5-[4'-(Methanesulphonyl)biphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3- f]indole-3,4'-piperidine], 5-[4'-(N, N-Dimethylcarbamoylamino)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-[4'-(Ethoxycarbonylamino)-2'-methylbiphenyl-4-carbonyl]-l'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-[4'-(4,5-Dimethyl-l,2,4-triazol-3-yl)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], l'-Methyl-6-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,7,8-tetrahy drospiro [4H-pyrano [2,3-1] indole-4,4 ’-piperidine], l'-Methyl-5-(2'-methyl-4'-(5-methyl-l,3,4-thiadiazol-2-yl) biphenyl-4-carbony 1)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(2'-Methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-r-n-propyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine], r-Methyl-5-(2'-methyl-4'-(5-methyloxazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-5-(2'-methyl-4'-(3-methylisoxazol-5-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine], r-Methyl-5-(2'-methyl-4'-(5-methylisoxazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(4'-(5-dimethylamino-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(4'-(5-ethyl-l,3,4-oxadiazol-2-yl)-2'-methylbiphenyl-4-carbony l)spiro [furo [2,3 -g] quinoline- 3,4' -piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(4'-methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)spiro [furo [2,3 -g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], 2.3.5.6.7.8- Hexahydro-r-methyl-5-(2'-methyl-4'-(l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine], r-Methyl-5-(2'-methyl-4'-pyrazinylbiphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-5-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazolyl-3-yl)biphenyl-4-carbonyl]-l-oxo- 2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine], r-Ethyl-5-[2'-methyl-4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], r-Methyl-5-[2'-methyl-4'-(l-methylimidazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahy drospiro [furo [2,3-f]indole-3,4'-piperidine], 90 010610 r-Methyl-5-[2'-methyl-4'-(l-methylimidazol-5-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro [furo [2,3 -f] indole-3,4'-piperidine], 5-[4'-(5-Hydroxymethyl-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl]-l'-methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 1 '-Methyl-5 -(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-1 '-oxo- 2.3.6.7- tetrahydrospiro[furo[2,3-f)indole-3,4'-piperidine], l'-Methyl-5-[2'-methyl-4'-(l,2,4-triazin-3-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine], 2,3,6,7,8,9-Hexahydro-l'-methyl-6-(2'-methyl-4'-(5-methyl -l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)spiro[4H-pyrano[2,3-g]quinoline-4,4' piperidine], 1 '-Ethyl-5 -(2'-methyl-4'-(5 -methyl-1,3,4-oxadiazol-2-y l)biphenyl-4-carbonyl)-1 ’-oxo- 2.3.6.7- tetrahy drospiro [furo [2,3 -f]indole-3,4'-piperidine], r-Ethyl-5-[4'-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7- tetrahy drospiro [furo [2,3 -f]indole-3,4'-piperidine], r-Ethyi-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-2,3,6,7- tetrahy drospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[4'-(Acetylhydrazinocarbonyl)-2'-methylbiphenyl-4-carbonyl]-l '-ethyl-2,3,6,7-tetrahydro spiro [furo [2,3 -f] indole-3,4'-piperidine], 5-[4'-(5-Methoxymethyl-l,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carbonyl]-r-methyl- 2.3.6.7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-[4'-(4,5-Dihydrooxazol-2-yl)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[4'-(2-(N,N-Dimethylamino)acetamido)-2'-methylbiphenyl-4-carbonyl]-l'-methyl- 2.3.6.7- tetrahydrospiro[iuro[2,3-f)indole-3,4'-piperidine] 5-[4'-(Ethoxycarbonylamino)-2'-methylbiphenyl-4-carbonyl]-1 '-ethyl-2,3,6,7-tetrahy drospiro [furo [2,3 -f]indole-3,4'-piperidine], 5-[4'-(Acetylhydrazinocarbonyl)-2'-methylbiphenyl-4-carbonyl]-r-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], 5-(4'-(5-methylfuran-2-yl)-2'-methylbiphenyl-4-carbonyl)-l'-methyl-2,3,6,7- tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], or pharmaceutically acceptable salts or N-oxides thereof.
8. A process for the préparation of a compound of formula (I) which comprises: (a) reaction of a compound of formula (II): R
R CO 010610 91 (Π) ϊ in which , R^ and R^ are as defined in formula (I) and L is a leaving group. with a compound of formula (III): » 5
(III) 10 wherein R^, R$, r6 a, b, m and n are as defined in formula (I) and optionally thereafter inany order: • converting a compound of formula (I) into another compound of formula (I) • forming a pharmaceutically acceptable sait or N-oxide. 15
9. A compound according to any one of daims 1 to 7 for use in therapy.
10. A pharmaceutical composition which comprises a compound according to any one of daims 1 to 7 in association with a pharmaceutically acceptable carrier orexcipient.
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