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WO2001098267A1 - 3-azabicyclo (3.1.0) hexane derivatives having opioid receptor affinity - Google Patents

3-azabicyclo (3.1.0) hexane derivatives having opioid receptor affinity Download PDF

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Publication number
WO2001098267A1
WO2001098267A1 PCT/IB2001/001035 IB0101035W WO0198267A1 WO 2001098267 A1 WO2001098267 A1 WO 2001098267A1 IB 0101035 W IB0101035 W IB 0101035W WO 0198267 A1 WO0198267 A1 WO 0198267A1
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Prior art keywords
alkyl
aryl
optionally substituted
halogen
alkoxy
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PCT/IB2001/001035
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French (fr)
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WO2001098267A8 (en
Inventor
Bernard Joseph Banks
Douglas James Critcher
Ashley Edward Fenwick
David Morris Gethin
Stephen Paul Gibson
Graham Lunn
Original Assignee
Pfizer Limited
Pfizer Inc.
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Publication date
Priority to EA200201269A priority Critical patent/EA005117B1/en
Priority to HU0301228A priority patent/HUP0301228A3/en
Priority to CA002412188A priority patent/CA2412188A1/en
Priority to AU62591/01A priority patent/AU781837B2/en
Priority to MXPA02012878A priority patent/MXPA02012878A/en
Priority to IL15342701A priority patent/IL153427A0/en
Priority to NZ523141A priority patent/NZ523141A/en
Priority to DZ013368A priority patent/DZ3368A1/en
Priority to JP2002504223A priority patent/JP2004512263A/en
Priority to EP01936728A priority patent/EP1292574A1/en
Priority to SK1717-2002A priority patent/SK17172002A3/en
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Priority to BR0111867-6A priority patent/BR0111867A/en
Priority to APAP/P/2002/002698A priority patent/AP2002002698A0/en
Priority to PL01365956A priority patent/PL365956A1/en
Priority to UY26787A priority patent/UY26787A1/en
Priority to UA20021210406A priority patent/UA73176C2/en
Publication of WO2001098267A1 publication Critical patent/WO2001098267A1/en
Priority to BG107329A priority patent/BG107329A/en
Priority to IS6637A priority patent/IS6637A/en
Priority to HR20020998A priority patent/HRP20020998A2/en
Priority to NO20026168A priority patent/NO20026168L/en
Publication of WO2001098267A8 publication Critical patent/WO2001098267A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors).
  • opiate receptors e.g. mu, kappa and delta opioid receptors.
  • Compounds that bind to such receptors are likely to be useful in the treatment of diseases modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans.
  • Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and head trauma.
  • Pruritus is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.
  • Certain 4-arylpiperidine-based compounds are disclosed in ter alia European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists.
  • International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.
  • Y 2 is H, Ci _g alkyl, C ⁇ .g alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Hetl),
  • Yl is C ⁇ _ ⁇ o alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, C ⁇ _4 alkoxy, C ⁇ -6 alkanoyloxy, CONH2, C ⁇ . ⁇ alkoxycarbonyl, NH2, aryl, mono- or di(C ⁇ _4 alkyl)amino, C3.8 cycloalkyl, phthalimidyl, Het ), Hefl, aryl (optionally substituted by one or more substituents independently selected from C ⁇ _4 alkyl, Ci _4 haloalkyl and halogen), NH2, N(C ⁇ _6 alkyl)2 or NH(C ⁇ _6 alkyl),
  • Hetl is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more substituents independently selected from Cj.g alkyl, C . alkoxy, C3.6 cycloalkyl, Ci .g haloalkoxy, C ⁇ .
  • haloalkyl, C3.6 halocycloalkyl, 0, OH, halogen, NO 2 , SiR ⁇ aR ⁇ bR ⁇ c, C ON 0 R20b NR20a R 20b ) s 21a NR 2 lbsO 2 R 22 , NR2 cC(0)OR22b ; NR21 c ⁇ R22d ; an Ci _ 6 alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a -S-, S(O)- or -S(O2)- group, and carbon atoms in the ring can be present as a part of a carbonyl moiety;
  • Rl9a s Rl9b 5 R19C eac h independently represent Ci _g alkyl or aryl
  • R21a, b, c and d eac h independently represent H, C ⁇ . ⁇ alkyl, aryl or Ci .4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Ci -,4 alkyl, Ci _4 alkoxy, OH, NO2, halogen, H2,
  • R22a, b and c e ach independently represent Ci .g alkyl, aryl or C1 -4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Ci .4 alkyl, C1.4 alkoxy, OH, NO2, halogen, NH2,
  • A is C1.4 alkylene, C2.4 alkenylene or C2.4 alkynylene, each of which is optionally substituted by one or more C ⁇ _4 alkyl, C1.4 alkoxy, halogen and/or OH,
  • AD is CN, NR 2 5R 2 6 CONR 25 R 26 ,
  • R 7 is COR30, C0 2 R 3 1a , S0 2 R 31b ,
  • R 2 8 and R 2 ⁇ re each independently H, Ci . ⁇ alkyl, C3.8 cycloalkyl, aryl or C ⁇ . 4alkylphenyl, each of which Ci .g alkyl, C3.8 cycloalkyl, aryl and Ci .4 alkylphenyl are optionally substituted by one or more NO2, halogen, Ci .4 alkyl, Ci .4 alkoxy (each of which latter Ci .4 alkyl and Ci .4 alkoxy are optionally substituted by one or more halogen),
  • R30 is H, C ⁇ _4 alkyl, C3_g cycloalkyl, Ci .4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, Ci .4 alkylphenyl, phenyl(C ⁇ _4 )alkoxy, (each of which C ⁇ _4 alkyl, C3_g cycloalkyl, C ⁇ _4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, Ci .4 alkylphenyl and phenyl(C ⁇ _4 )aIkoxy are optionally substituted by one or more NO2, halogen, Ci .4 alkyl, C1.4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)),
  • R31 an d R31b are eac h independently C1.4 alkyl, C3.8 cycloalkyl, aryl or C1..4 alkylphenyl, each of which is optionally substituted by one or more NO2, halogen, C1.4 alkyl or C 1.4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen
  • E is H, CONR 2 R33 5 CSNR3 R33, C0R34 C0 2 R 34 , COCH(R 3 a)NH 2j R 35 ? CH 2 C ⁇ 2R 35a , CHR35bco 2 R 35a , CH20C02R35 C , CHR35d 0 C ⁇ 2R 35c , COCHR 3 6CHR37NH 2 , or PO(OR38) 23
  • R 32 and R3 are each independently H, C3.10 alkylalkenyl, C3.7 cycloalkyl (optionally substituted by C ⁇ _4 alkyl), phenyl (optionally substituted by (X) n ), CI _IQ alkyl (optionally substituted by C4.7 cycloalkyl (optionally substituted by C1..4 alkyl) or phenyl optionally substituted by (X) n ),
  • R3 2 and R3 can be taken together with the N atom to which they are attached and can form a 5- to 8-men bered heterocycle optionally comprising further hetero atoms selected from N, O and S, which heterocycle is optionally substituted by C1.4 alkyl, optionally substituted by one or more halogen,
  • R 4 is H, C4.7 cycloalkyl (optionally substituted by one or more C ⁇ _4 alkyl), phenyl (optionally substituted by (X) n , C1..4 alkanoyloxy, NR 3 2R33 S CONR 2 R33 an d/or OH), or C ⁇ _6 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or moire C1.4 alkyl), or phenyl (optionally substituted by (X) n , C1..4 alkanoyloxy, NR3 2 R33, CONR 2 R33 an d/or OH)),
  • R 3 4a is H, Ci . ⁇ alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or more Cj_4 alkyl), or phenyl (optionally substituted by (X) n , C ⁇ _4 alkanoyloxy, NR 32 R33 J C0NR 32 R33 an d/ or OH)), C4.7 cycloalkyl (optionally substituted by one or more C ⁇ _4 alkyl), phenyl (optionally substituted by (X) n , C1 -4 alkanoyloxy, NR32R33 ; CONR 3 R33 an d/or OH) or a naturally occuring amino acid substituent,
  • R 5 is C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, phenyl (optionally substituted by one or more (X) n , C ⁇ _4 alkanoyl, NHR 2 , CON(R 32 ) 2 , and/or OH), C ⁇ _6 alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl (optionally substituted by one or more (X) n , C ⁇ _4 alkanoyl, NHR32 ; CON(R 32 )2, and/or OH)), C ⁇ _4 alkoxy(C ⁇ _4 alkyl), phenyl(C ⁇ _4)alkyloxy(C ⁇ _4)a ⁇ kyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,
  • R35a,b,c and d are eac h independently H, C4.7 cycloalkyl optionally substituted by one or more Ci-4 alkyl, phenyl optionally substituted by one or more (X) n or ⁇ . alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, or phenyl optionally substituted by one or more (X) n ),
  • R36 an d R3 e ach independently represent H, C3.6 alkylalkenyl, C4..7 cycloalkyl, phenyl optionally substituted by one or more (X) n , or C 1.6 alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C ⁇ _4 alkyl, or phenyl optionally substituted by one or more (X) n ))
  • R38 is C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl optionally substituted by one or more (X) n , or C g alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, or phenyl optionally substituted by one or more (X) n ),
  • R 2 when taken alone is H or halogen
  • Rl and R 2 when attached to adjacent carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Het la ;
  • R 2 3 and R 24 when taken alone independently represent H, C1.4 alkyl, or Ci.4 haloalkyl
  • R 2 3 and R 24 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, Ci .4 alkyl, Ci .4 haloalkyl, C1.4 alkoxy and/or C1.4 haloalkoxy groups,
  • R 3 is H, CN, halogen, Ci _g alkoxy, C ⁇ _g alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, c 3-8 cycloalkyl, C3_g cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR 12 R 13 , CONR 12 Rl3, NY 2 WYi, C ⁇ _6 alkyl, C2-10 alkenyl, C 2 . ⁇ o alkynyl, (each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or more CN, halogen, OH, C ⁇ . ⁇ alkoxy, C ⁇ _6 alkoxycarbonyl, C2-6 alkyloxycarbonyloxy, Ci.g alkanoyl, Ci . ⁇ alkanoyloxy, C3_ cycloalkyl, C3_g
  • R 4 is C ⁇ _ ⁇ o alkyl, C3.10 alkenyl or C3..10 alkynyl, each of which groups is linked to the N atom via a sp3 carbon, and which group is substituted by one or more substituents selected from:
  • C2-6 alkoxy [substituted by one or more groups selected from OH, NR 5R26 J C0N 25R26 J halogen, Ci .g alkoxy, C2.4 alkynyl, C2-4 alkenyl, heteroaryl 1, aryl*, COCH2CN, CO(heteroaryl !), CO(aryl 1), C0 2 (heteroaryl 1), COCH2(aryl 1), COCH2(heteroaryl 1), C0 2 CH 2 (aryll), C0 2 CH 2 (heteroaryll), S(0) n (C ⁇ _ 6 alkyl), S(O) n (aryll), S(0) n (heteroaryl 1 ), SO2NR 5R26 an d cycloalkyll],
  • S(0) n C ⁇ _6 alkyl [optionally substituted by one or more groups selected from OH, NR 2 5R 6 5 CONR25R26 J halogen, Cj.g alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl 1, aryll, COCH2CN, CO(heteroaryll), COCaryl 1 ), C0 2 (heteroaryll), COCH2(aryll), COCH 2 (heteroaryll), C0 2 CH2(aryl 1 ), C02CH 2 (heteroaryll), S(0) n (C ⁇ _ 6 alkyl), S(0) n (aryll), S0 2 NR25R26 and cycloalkyl 1],
  • aryl 2 is phenyl optionally fused to a C5.7 carbocyclic ring, which group is substituted by one or more substituent selected from Ci .g alkyl(substituted by OH), CONR 5R26 5 CH 2 CONR25R26, NR 5 R 26 , NHCONR 2 5R 2 6, CO(C ⁇ _ 6 alkyl), COaryl, COheteroaryl, S0 2 NR 2 5R 6 S(0) n (C!. 6 alkyl), S(0) n (aryl), S(O) n (heteroaryl), C0 2 (C ⁇ _6 alkyl),
  • cycloalkyl 1 is a C3_ ⁇ o carbocyclic system with one or two rings and which is substituted by C ⁇ _6 alkyl, aryl, C ⁇ _ 6 alkoxy, CH 2 (aryll), C1.4 haloalkyl, halogen, OH, CN orNR 2 6,
  • Z is a direct bond, CO or S(0) n group
  • B is (CH 2 ) p ,
  • Rl 2 and Rl3 each independently represent H or C1.4 alkyl
  • Rl2 and Rl3 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR1 , O and/or S, and which is optionally substituted by one or more C1.4 alkyl,
  • R i4 and Rl5 each independently represent H, C ⁇ _ ⁇ o alkyl, C3.10 alkenyl, C3_ ⁇ o alkynyl, C3-8 cycloalkyl, aryl or heteroaryl,
  • Rl and Rl5 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR! 6, O and/or S, and which is optionally substituted by one or more C1.4 alkyl,
  • Rl6 is H, C ⁇ _6 alkyl, C3_g cycloalkyl, (C ⁇ _6 alkylene)(C3_g cycloalkyl) or (C ⁇ _g alkylene)aryl,
  • R ⁇ when taken separately are each independently H, C ⁇ . ⁇ alkyl,
  • R5 and R ⁇ can be taken together with the carbon atoms to which they are joined to form a C3-8 cycloalkyl ring,
  • R5 and R° or R' can be taken together with the carbon atoms to which they are joined to form a C3_g cycloalkyl ring,
  • X is halogen, C1.4 alkyl, C1.4 alkoxy, C .4 haloalkyl or C1.4 haloalkoxy,
  • n 1 or 2;
  • q is 0 or 1
  • “Naturally occuring amino acid substituent” means the -substituent that occurs in any one of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline;
  • Heteroaryl represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if a S atom is present in the ring, it can be present as part of a - S-, S(O)- or -S(0) 2 - group, and which may be joined to the remainder of the compound via any available atom(s);
  • Heterocycle is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms;
  • Aryl including in the definitions of "aryloxy”, etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.);
  • Alkyl alkenyl and alkynyl groups can be linear or branched if the number of carbon atoms allows;
  • Cycloalkyl groups can be polycyclic if the number of carbon atoms allows;
  • fused heterocyclic group can be attached to the remainder of the compound via .any available atom(s).
  • Haloalkyl can contain more than one halogen atom, and for instance can be per-halogenated.
  • Certain of the compounds of the invention can exist in one or more geometric and/or stereoisomeric forms.
  • the present invention includes all such individual isomers and salts and prodrugs thereof.
  • Certain compounds of the present invention may exist in more than one tautomeric form. Similarly certain compounds of the invention may have zwitterionic forms. It is to be understood that the invention embraces all such tautomers, zwitterions and their derivatives.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and rj-toluenesulphonate salts.
  • Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.
  • bases which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.
  • prodrug It will further be appreciated by those skilled in the art that certain moieties known to those skilled in the art as “pro-moieties”, for example as described in "Design of
  • Prodrugs by H Bundgaard (Elsevier) 1985, may be placed on appropriate functionalities when such functionalities are present in compounds of formula (I), also to form a "prodrug".
  • the "Ar” ring represents phenyl or pyridyl. Most preferably the "Ar” ring represents a group of formula:
  • R 1 when taken alone is OH, CN, halogen, N0 2 , NH 2 , NY 2 WYl or Het 1 .
  • Rl when taken alone is OH, CN, I, CI, NH 2 , N0 , optionally benzo-fused heteroaryl, NHSO2Y 1 , NHCOY 1 or NHCO2Y 1 .
  • R 1 when taken alone is OH, CN, I, CI, NH2, N ⁇ 2,l, 2 ,3 ⁇ triazolyl, 1,2,4- triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl,
  • Rl is OH, NHSO2CH3, NHSO2C2H5, NHS ⁇ 2(n-C3H7), NHS ⁇ 2(i-
  • R 1 is OH, NHS0 2 CH3, NHS0 2 C 2 H5 or imidazol-2-yl.
  • R 2 when taken alone is H.
  • Rl and R 2 when taken together with the carbon atoms to which they are attached are preferably an optionally benzo-fused 5- to 7-membered heteroaryl ring optionally substituted by C i-4 alkyl or C 1.4 haloalkyl.
  • Rl and R 2 when taken together with the carbon atoms to which they are attached are a -membered heteroaryl moiety optionally substituted by C 1.4 alkyl or C 1.4 haloalkyl.
  • Rl and R 2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2-substituted by CF3.
  • X is CI.
  • n is 0.
  • q is 0.
  • R3 is H, CN, C ⁇ _6 lkyl (optionally substituted by one or more halogen, OH, C _ ⁇ alkoxy, C ⁇ . ⁇ alkoxycarbonyl, C 2 . ⁇ alkanoyl, C _6 alkanoyloxy, C 2 -6 alkyloxycarbonyloxy, NR 1 Ri3, CO R12R13 and/or NY 2 W ⁇ !).
  • R is H, CH3, C 2 H5, i-C3H7, n-C3H 7 or CH 2 OCH3.
  • R is CH3.
  • R 4 is C ⁇ _ ⁇ o alkyl substituted by one or more substituents selected from:
  • C 2 _6 alkoxy [substituted by one or more groups selected from OH, NR 2 5R 2 6, C0NR 2 5R26 3 halogen, C ⁇ . ⁇ alkoxy, C 2 _4 alkynyl, C 2 -4 alkenyl, heteroaryl 1, aryl 1 , COCH 2 CN, COheteroaryl 1 ), CO(aryll), ⁇ (heteroaryl 1 ), COCH2(aryl 1 ), COCH 2 (heteroaryl 1 ), C0 2 CH 2 (aryl 1 ), C ⁇ 2CH 2 (heteroaryl 1 ), S(0) n (C ⁇ _ 6 alkyl), S(O)n(a ⁇ yll), S(0)n(heteroaryI ), S02NR 2 5R26 an d cycloalkyl 1 ],
  • S(0) n C ⁇ _6 alkyl [optionally substituted by one or more groups selected from OH, NR25 26 ) CONR 25 R 2 6, halogen, C ⁇ . ⁇ alkoxy, C2.4 alkynyl, C 2 _4 alkenyl, heteroaryl 1 , aryl 1 , COCH 2 CN, COheteroaryl 1 ), CO(aryl 1 ), C0 2 (heteroaryl 1 ), COCH2(aryl 1 ), COCH ⁇ heteroaryl 1 ), C0 2 CH 2 (aryl 1 ), C0 2 CH 2 (heteroaryl 1 ), S(0) n (C ⁇ _6 al kyl), S(0) n (aryl 1 ), S ⁇ heteroaryl 1 ), S0 2 NR 2 5R 2 6 an d cycloalkyl 1 ],
  • R 4 is CJ.JO alkyl substituted by cycloalkyl 1 .
  • R 4 is C 2 -4 alkyl substituted by cycloalkyl 1 .
  • R 4 is propyl substituted by cycloalkyl ! .
  • R 4 is propyl substituted by a C3.10 carbocyclic system with one or two rings and which is substituted by OH.
  • R 4 is propyl substituted by (cyclohexyl substituted by OH)
  • R 4 is (l-hydroxycyclohexyl)prop-3-yl.
  • R 4 takes the values as specified in the Examples 145-203 below.
  • R ⁇ , R6, R7, R8 R9 and R 1 ⁇ are each taken separately and are H.
  • a preferred group of substances are those in which the "Ar" ring, R 1 , R 2 , R3, R 4 , R5 3 6 ; R7, R8, R9, R 1 ) q and (X) n have the values as detailed in the Examples below.
  • the invention further provides synthetic methods for the production of compounds and salts of the invention, which are described below and in the Examples and Preparations.
  • the skilled man will appreciate that the compounds of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as
  • tert-butyldimethylsilyl tgrt-butyldiphenylsilyl or trimethylsilyl
  • Suitable protecting groups for amino include tert-butyloxycarbonyl, 9- fluorenylmethoxycarbonyl or benzyloxycarbonyl.
  • Suitable protecting groups for carboxylic acid include Ci. alkyl or benzyl esters. In the Methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I).
  • the invention provides a process for the preparation of compounds of formula I as defined above, or a pharmacutically or veterinarily acceptable derivative thereof, which comprises: (a) for compounds of formula I in which q is 0 and R 1 represents NY 2 WY 1 , reacting a compound of formula II,
  • Z 1 is a suitable leaving group, such as halogen or Y S ⁇ 2 ⁇ - ; (b) for compounds of formula I in which q is 0 and R ⁇ and R7 both represent H, reduction of a compound of formula IV,
  • R a CH2 takes the same meaning as R 4 as defined above;
  • the reaction may be carried out at between 0°C and room temperature in the presence of a suitable base (e.g. pyridine) and an appropriate organic solvent (e.g. dichloromethane) .
  • a suitable base e.g. pyridine
  • an appropriate organic solvent e.g. dichloromethane
  • reaction in the presence of a suitable reducing agent, such as lithium aluminium hydride.
  • a suitable reducing agent such as lithium aluminium hydride.
  • the reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent (e.g. tetrahydrofuran).
  • Compounds of formula XI and XII may be prepared by reduction of the corresponding -N0 2 compounds under conditions that are well known to those skilled in the art (e.g. using H /Raney Ni or in the presence of CaCl and iron powder, in the presence of a suitable solvent system (e.g. EtOH, EtOAc and/or water)).
  • a suitable solvent system e.g. EtOH, EtOAc and/or water
  • the said corresponding -NO2 compounds may be prepared by reaction of a compound of formula XII or formula XIV, as appropriate,
  • L 1 represents a suitable leaving group [such as halo (e.g. chloro or bromo)]
  • L 2 represents a suitable leaving group (such as C 1.3 alkoxy)
  • R 3 is as defined above, with a compound of formula XV,
  • the reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable base (e.g. NaHC03) and an appropriate organic solvent (e.g. dimethylformamide), or at a higher temperature (e.g. between 50 and 200°C, preferably between 100 and 160°C) in the presence of neat compound of formula XV.
  • a suitable base e.g. NaHC03
  • an appropriate organic solvent e.g. dimethylformamide
  • reaction may be carried out at room temperature in the presence of a suitable catalyst [e.g. Rh 2 (OAc)4] and an appropriate non-protic organic solvent (e.g. dichloromethane).
  • a suitable catalyst e.g. Rh 2 (OAc)4
  • an appropriate non-protic organic solvent e.g. dichloromethane
  • XX for example by performing a Wittig reaction using an appropriate provider of the nucleophilic group R02C-CR5H _ or RO2C-CR8H- (wherein R represents lower (e.g. C1..3) alkyl), as appropriate, under conditions that are well known to those skilled in the art.
  • R represents lower (e.g. C1..3) alkyl)
  • the - CO2R group of the resulting compound may be converted to an appropriate -CH2L 1 group using standard techniques (e.g. reduction of the ester to the primary alcohol and conversion of the latter to an alkyl halide) under conditions that are well known to those skilled in the art.
  • suitable reducing agents include lithium aluminium hydride.
  • the reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent (e.g. tetrahydrofuran).
  • L3 represents a group that is capable of undergoing functional group transformations (e.g. cyano) using standard functional group substitution or conversion techniques.
  • Compounds of formula IV and V in which R 1 represents l,2,4-triazol-3-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 represents -CN with HCI (gas) in the presence of an appropriate lower alkyl alcohol (e.g. ethanol), for example at between 0°C and room temperature, followed by reaction of the resultant intermediate with formic acid hydrazide (e.g. at reflux temperature, with or without the presence of a suitable organic solvent (e.g. methanol), followed by, if necessary, removing the solvent and heating the resultant residue to a high temperature (e.g. about 150°C)).
  • an appropriate lower alkyl alcohol e.g. ethanol
  • formic acid hydrazide e.g. at reflux temperature, with or without the presence of a suitable organic solvent (e.g. methanol)
  • a suitable organic solvent e.g. methanol
  • R 1 represents imidazol-2-yl
  • R 1 represents imidazol-2-yl
  • R 1 represents imidazol-2-yl
  • an appropriate compound of formula XXI or XXII in which L3 represents -CN with HCI (gas) in the presence of an appropriate lower alkyl alcohol (e.g. ethanol), for example at between 0°C and room temperature, followed by reaction of the resultant intermediate with aminoacetaldehyde dialkylacetal (e.g. dimethylacetal) (e.g. at or around reflux temperature in the presence of an appropriate solvent, such as methanol).
  • an appropriate lower alkyl alcohol e.g. ethanol
  • aminoacetaldehyde dialkylacetal e.g. dimethylacetal
  • R 1 represents l,2,3-triazol-5-yl
  • R 1 represents l,2,3-triazol-5-yl
  • diazomethane or a protected (e.g. trialkylsilyl) derivative thereof, for example at between 0°C and room temperature in the presence of a suitable base (e.g. n- BuLi) and, optionally, an appropriate organic solvent (e.g. THF), followed by removal of the protecting group as necessary.
  • a suitable base e.g. n- BuLi
  • an appropriate organic solvent e.g. THF
  • Het 1 is defined above. Further details may be found in Preparations 67, 68, etc. in WO00/39089, herein incorporated by reference in its entirety.
  • reaction may be carried out by heating under reflux, with or without the presence of an appropriate organic solvent.
  • Compounds of formula VI may be prepared using known techniques.
  • compounds of formula VI may be prepared by nitration (at the 4-position) of a corresponding 3-aminobenzene compound (a compound of formula II), which latter compound may be activated by converting the 3-amino group to a 3-amido group, followed by hydrolysis of the amide and reduction of the 4-nitrobenzene compound. All of these reactions may be performed using techniques that are familiar to the skilled person, and are illustrated in Preparations 45-48, etc. below.
  • suitable leaving groups that Lg may represent include halogen, such as bromine, or a sulphonate group such as tosylate, mesylate or triflate.
  • the reaction may be carried out in a polar solvent that does not adversely affect the reaction, at a suitable temperature, e.g. 0-150°C, in the presence of a base.
  • a catalyst such as sodium iodide may optionally be added.
  • R 4 -Lg CI or Br
  • Lg CI or Br
  • base 2.0- 4.0 eq
  • K2CO3, NaHC ⁇ 3, or a tertiary amine such as triethylamine or Hunigs base
  • a polar solvent such as THF, DMF, or MeCN
  • a catalyst such as Nal or KI, for 2-24 hr.
  • RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), p 397, and references cited therein.
  • Compounds of formula VIII may be prepared from compounds of formula XXV,
  • Suitable protecting groups include allyl, which may be removed using a palladium (0) catalyst and N,N-dimethylbarbituric acid (see Preparation 53, etc. below).
  • Compounds of formula XXV may be prepared using analogous methods to those described herein for the preparation of compounds of formula I.
  • suitable reducing agents include lithium aluminium hydride.
  • the reaction may be carried out in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), at an elevated temperature (for example the reflux temperature of the solvent).
  • Compounds of formula X may be prepared by reacting a compound of formula XXVI with a compound of formula XXVII in the presence of an oxidizing agent.
  • Suitable oxidizing agents include manganese dioxide.
  • the reaction may be carried out in a solvent that does not adversely affect the reaction (for example dioxan), at an elevated temperature such as the reflux temperature of the solvent (for example see Preparation 77, WO00/39089).
  • the intermediate compounds XXTXa are isolatable using suitable conditions (e.g. see Preparation 58, WO00/39089).
  • Process (f) is particularly useful when Ar represents an optionally benzo-fused 5- or 6- membered heteroaryl ring.
  • a similar methodology may be used to obtain compounds of formula II: the precursor nitro compound may be prepared from a compound of formula XX, as defined above, using the steps described above (see for example Preparations 57-61, WO00/39089).
  • the reaction may be carried out in a solvent that does not adversely affect the reaction (for example ethanol), first below room temperature and then at an elevated temperature (Examples 79, etc. WO00/39089, provides further details).
  • suitable acids include dilute aqueous hydrochloric acid and concentrated hydrochloric acid, respectively.
  • the reaction may be carried out at or around room temperature, finishing at ' an elevated temperature (for example 90°C).
  • Example 51 WO00/39089 provides further details.
  • the compound of formula XXXI may be prepared by acylation of the compound of formula VIII as defined above, with an acylating agent of the formula R 4a CO- Lg, where Lg is a suitable leaving group as defined above with respect to (e), and includes halogen, (alkyl, haloalkyl or aryl)sulphonate, OCOR 4a (i.e. an acid anhydride) and the like, well known to those practising in the art. See for example the conditions used for Preparation 47.
  • the coupling can optionally be carried out in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein.
  • a catalyst for example DMAP
  • a suitable solvent see RC Larrock in "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein.
  • a catalyst for example DMAP
  • a suitable solvent see RC Larrock in "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein.
  • the carboxylic acid 0.9-1.1 eq
  • l-(3- dimethylaminopropyl)-3-ethylcarbodiimide l-(3- dimethylaminopropyl)-3-ethylcarbodiimi
  • the amide bond can be reduced with a suitable reducing agent, for example lithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-100°C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), pp 432-434, and references cited therein.
  • a suitable reducing agent for example lithium aluminium hydride or borane
  • THF ethereal solvent
  • the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C-RT, in THF, for 1-24 hr.
  • process (k) the appropriate aldehyde is reacted with an amine, optionally present as an acid addition salt, in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts).
  • a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts.
  • the reaction is suitably performed in the presence of acetic acid at 0-100°C in THF, methanol, DCM (dichloromethane), or DCE (1,2 -dichloroethane), for a suitable time such as 1-24 hr.
  • the amine salt such as the trifluoroacetic acid (TFA) salt
  • TFA trifluoroacetic acid
  • an organic base such as triethylamine or Hunigs base
  • the aldehyde (1-1.5 mole equivalents)
  • sodium triacetoxyborohydride (1-2.0 mole equivalents)
  • the aldehydes used in this process may be prepared from the corresponding alcohols using 0 suitable oxidising agents; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1234-1236 and 1238- 1247, and references cited therein.
  • Preferred oxidants are tetrapropylammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J. 15 Org. Chem., 1983, 48, 4155-4156).
  • Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432.
  • Suitable reducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride (LiAlH4, see Brown, Org. Reactions, 1951, 6,
  • Alcohols can be prepared from a corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1114-1116.
  • a suitable reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAlH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80°C, for 1-24 hr. - viz. reaction of the type:
  • Benzylacetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give benyloxyalcohols.
  • compounds of formula I may be converted to other compounds of formula I using known techniques.
  • compounds of formula I in which Y 1 represents alkoxycarbonyl may be converted to compounds in which Y 1 represents alkyl substituted by OH, by reduction using L-AIH4 (Example 57 provides further details).
  • intermediate compounds may be interconverted using known techniques (see for example Preparation 85).
  • intermediate compounds such as those of formulae III, XV, XVIII, XIX, XX, VII, IX, XXVI, XXVII and XXVIII, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
  • the invention further provides the intermediate compounds of formulae II, IV, V, VI, X, X a , XI, XII, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX, and XXXI as defined above.
  • the compound of formula (I) can be converted into a pharmaceutically acceptable salt thereof, conveniently by mixing together solutions of a compound of formula (I) and the desired acid or base, as appropriate.
  • the salt may be precipitated from solution and collected by filtration, or may be collected by other means such as by evaporation of the solvent. Both types of salt may also be formed or interconverted using ion-exchange resin techniques.
  • the compounds of the invention may be purified by conventional methods, for example separation of diastereomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of formula (I) or a salt thereof.
  • An individual enantiomer of a compound of formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereomeric salts formed by reaction of the corresponding racemate with a suitably optically active base or acid.
  • the compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals including humans. They are therefore indicated as pharmaceuticals and, in particular, for use as animal medicaments.
  • the compounds of the invention for use as medicaments, such as pharmaceuticals and animal medicaments, such as for the treatment of opiate-mediated diseases and conditions.
  • treatment this term includes both therapeutic (curative) and prophylactic treatment.
  • the substances of the invention have been found to be useful in the treatment of 5 diseases and conditions modulated via opiate receptors, such as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; and conditions characterised by having pruritis as a symptom.
  • opiate receptors such as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; and conditions characterised by having pruritis as a symptom.
  • the use of the compounds of the invention in the manufacture of a medicament for the treatment of a disease modulated via an opiate receptor.
  • the use of the compounds of the invention in the manufacture of a medicament for the treatment of as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses;
  • the compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in :0 animals and humans.
  • Other diseases and conditions which may be mentioned include contact dermatitis, psoriasis, eczema and insect bites.
  • the invention provides a method of treating or preventing a disease modulated via an opiate receptor. There is further provided a method of treating irritable bowel syndrome;
  • compositions will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses (see below).
  • the compounds are preferably employed in the form of a pharmaceutical, or veterinary, formulation comprising a pharmaceutically, or veterinarily, acceptable carrier, diluent or excipient and a compound of the invention.
  • the carrier, diluent or excipient may be selected with due regard to the intended route of administration and standard pharmaceutical, and/or veterinary, practice.
  • Pharmaceutical compositions comprising the compounds of the invention may contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
  • the methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (eg subcutaneously, intramuscularly or intravenously), or as an implant.
  • Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
  • the formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal.
  • typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal.
  • Preferably the range is 0.1 to 10 mg per kg.
  • the veterinary practitioner or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses.
  • the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
  • the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier.
  • Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice.
  • Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms.
  • agents which are provided by way of illustration and should not be construed as limiting
  • antiparasitics eg fipronil, lufenuron, imidacloprid, avermectins (eg abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, eg chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, eg fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, eg enroflaxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories eg pre
  • a pharmaceutical, or veterinary, formulation including a compound of the invention in admixture with a pharmaceutically, or veterinarily, acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also have the advantage that, in the treatment of human and/or animal patients, they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
  • the biological activities of the compounds of the present invention were determined by the following test method.
  • the reaction was terminated by rapid filtration using a Brandel Cell HarvesterTM through BetaplateTM GF/A glass fibre filters pre-soaked in 50 mM Tris pH 7.4, 0.1% polyethylenimine buffer. The filters were then washed three times with 0.5 ml ice-cold Tris pH 7.4 buffer. For mu and delta assays, washed filters were placed in bags and StarscintTM scintillant added, for the kappa assay MeltilexTM B/HS solid scintillant was used. Bags containing the filters and scintillant were heat sealed and counted by a BetaplateTM 1204 beta counter. Duplicate samples were run for each experimental compound and the data generated was analysed using IC50 analysis software in Graphpad Prism. Ki values were calculated using Graphpad Prism according to the following formula:
  • Ki IC 50 / 1 + [ 3 H ligand] / K D
  • IC50 is the concentration at which 50% of the 3H ligand is displaced by the test compound and Kj) is the dissociation constant for the 3H ligand at the receptor site.
  • Ki values of certain compounds of the present invention in the opioid receptor binding assays were determined, and were found to have Ki values of 4000 nM or less for the ⁇ receptor.
  • APCI atmospheric pressure chemical ionization
  • DMF dimethylformamide
  • DMSO dimethylsulphoxide
  • d in relation to time
  • day in relation to NMR
  • doublet ES in relation to MS
  • electrospray EtOAc ethyl acetate
  • ODS octadecylsilyl
  • the mass spectrometer which is used as a detector on the analytical HPLC-MS system is a Micromass VG Platform II, running on Masslynx/Openlynx software.
  • the system can run positive and negative ion with either Electrospray or APCI probes and is calibrated to 1972 Daltons, it collects full Diode array data from 190nm to 600nm.
  • HPLC means high performance liquid chromatography. HPLC conditions used were:
  • Condition 1 Rainin DynamaxTM column, 8 ⁇ ODS, 24 x 300 mm, column temperature 40°C, flow rate 45 ml/min, eluting with methanol : water (70 : 30), UV detection of product at 246 nm.
  • Condition 4 Phenomenex MagellanTM column, 5 ⁇ C 8 silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : OJM aqueous ammonium acetate buffer (30 : 70 to 95 : 5 over 10 min), UV detection of product at 220 nm.
  • Condition 7 Phenomenex MagellanTM column, 5 ⁇ g silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.05M aqueous ammonium acetate buffer (50 : 50 for 15 min then 50 : 50 to 90 : 10 over 5 min), UV detection of product at 220 nm.
  • Condition 8 Phenomenex Magellen ⁇ M column, 5 ⁇ Cig silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate buffer (15 : 85 to 85 : 15), UV detection of product at 220 nm.
  • Condition 9 Phenomenex MagellenTM column, 5 ⁇ ODS, 10 x 150 mm, column temperature 40°C, flow rate 5ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate buffer (5 : 95 to 30 : 70 over 5 min then 30 : 70 for a further 20 min), UV detection of product at 225nm.
  • Condition 10 Phenomenex MagellanTM column, 5 ⁇ Cjg silica, 21.2 x 150mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate (5 : 95 to 40 : 60 over 5 min then 40 : 60 for a further 25 min), UV detection of product at 210 nm.
  • Condition 11 Phenomenex MagellanTM column, 5 ⁇ ODS, 10 x 150mm, column temperature 40°C, flow rate 5 ml/min, eluting with a gradient of acetonitrile : water (5 : 95 to 55 : 45 over 5 min), UV detection of product at 210 nm.
  • the free base form of the azabicycles could be obtained from the hydrochloride or acetate salts, for example, in the following way.
  • the salt (0.3 mmol) was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (20 ml). The basic mixture was separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic extracts were dried (Na2S ⁇ 4) and concentrated in vacuo to give the free base.
  • SPE cartridge refers to a solid phase extraction cartridge. These can be commercially obtained from Varian (Mega Bond Elut ®) or IsoluteTM.
  • Examples numbered 1-144 are compounds related to the instant invention, but with different R 4 groups, and are disclosed as such in International Patent Application no. WOOO/39089, herein incorporated by reference in its entirety.
  • Treating an appropriate aldehyde R 4a CHO with an amine of formula VIII in the presence of a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts.
  • a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts.
  • the reaction is often performed in the presence of acetic acid at 0-100°C in THF, MeOH, DCM, or DCE (1 ,2 -dichloroethane), for 1-24 hr.
  • the amine salt is treated with an organic base (1-3 eq), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5 eq), followed by sodium triacetoxyborohydride (1-2.0eq), in dichloromethane or DCE, at room temperature for 2-24 hr.
  • organic base such as triethylamine or Hunigs base
  • aldehyde (1-1.5 eq)
  • sodium triacetoxyborohydride (1-2.0eq
  • DCE dichloromethane or DCE
  • the amide carbonyl can be reduced with a suitable reducing agent, for example lithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-100°C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic
  • the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C- RT, in THF, for 1-24 hr, e.g.:
  • Aldehydes used in process B can be prepared using suitable oxidising agents; see
  • oxidants are tetrapropylammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J. Org. Chem., 1983, 48, 4155-4156).
  • Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432. viz. reaction of the type:
  • Esters can be converted to the corresponding alcohol using a suitable reducing LO agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1117-1120 and references cited therein.
  • suitable reducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride (UAIH4, see Brown, Org. Reactions, 1951 , 6, 469).viz. reaction of the type:
  • alcohols used in process D can be prepared from the corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition,
  • the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAIH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80°C, for 1-24 hr.
  • Process I Alcohol to halide It should be appreciated that the R 4 Lg used in Process A can be prepared from the corresponding alcohol R 4 OH.
  • Benzyloxyalcohols can be prepared by refluxing the appropriate benzyl halide with sodium or sodium hydride and a polymethylene glycol in xylene, see J. Am. Chem.
  • Acetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give the benyloxyalcohols.
  • Example 199 ⁇ V-(3-(3-r3-(4-acetylphenyl)pro ⁇ yll-6-ethyl-3-azabicvclor3.1.0]hex-6- vUphenvDmethanesulfonamide - and formate salt
  • Example 200 ⁇ /-(3- ⁇ 3-r2-(benzvioxy)benzyll-6-ethyl-3-azabicvclor3.1.01hex-6- vPphenyQmethanesulfonamide
  • Example 201 A/- ⁇ 3-r3-(4-cvanobenzyl)-6-ethyl-3-azabicvclor3.1.0lhex-6- yllphenvDmethanesulfonamide
  • the compound above was prepared by a similar method to that of Example 167, using the trifluoroacetic acid salt of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide (100 mg, 0.25mmol) and 4-cyanobenzaldehyde (33mg, 0.25mmol) as the starting materials.
  • the product was purified using preparative HPLC (conditions 3) to afford the title compound (28 mg, 28 %) as an off-white solid.
  • Example 203 ⁇ /-(3-(6-ethyl-3-r(2-phenylcvclopropyl)methyll-3-azabicvclor3.1.Olhex- 6-yl ⁇ phenyl)methanesulfonamide
  • Aluminium chloride (15.0 g, 0.11 moles) and acetyl chloride (16.0 g, 0.20 moles) were dissolved in dichloromethane (50 ml) at room temperature. This mixture was then added dropwise to a solution 1-chloro-3-phenylpropane (15.5 g, 0.10 moles) in dichloromethane (25 ml) at room temperature over 15 minutes. The mixture was stirred for 1 hr and then poured cautiously onto ice. The aqueous layer was extracted with dichloromethane (450 ml). The organics were washed with water and brine, and then dried (MgSO 4 ) and concentrated in-vacuo to give the title compound (19.2 g, 98%) as an oil.
  • reaction mixture was cooled to between 0°C and 5°C and an aqueous solution of piperazine (198.5g, 2304mmol in 1.26L of water) added.
  • the reaction mixture was then heated under reflux for a period of 18hrs.
  • the THF was removed under vacuum, ethyl acetate
  • the reaction mixture was cooled to between 0°C and 5°C and an aqueous solution of piperazine (48.7g, 565mmoI in 320mls of water) added.
  • the reaction mixture was then heated under reflux for a period of 18hrs.
  • the THF was removed under vacuum, ethyl acetate (200mls) added, and the phases were separated.
  • the aqueous phase was extracted with a second portion of ethyl acetate (200mls).
  • the organic phases were combined and washed with 3 separate portions of water (3x400m!s). The organics were dried over MgSO 4 and evaporated in vacuo to yield the product as a white crystalline solid (33.5g, 94%).

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Abstract

Compounds of formula (I), where the substituents are as defined herein, and the pharmaceutically or veterinarily acceptable derivatives or prodrugs thereof, are pharmaceutically and veterinarily useful, in particular they bind to opiate receptors (e.g. mu, kappa and delta opioid receptors). They are likely to be useful in the treatment of diseases or conditions modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; pruritic dermatoses, such as allergic dermatitis and atopy; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage; and head trauma.

Description

3-AZABICYC O (3 . 1 . 0 ) HEXANE DERIVATIVES HAVING OPIOID RECEPTOR AFFINITY
This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors). Compounds that bind to such receptors are likely to be useful in the treatment of diseases modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and head trauma.
There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.
Existing treatments that have been employed in the treatment of pruritus include the use of corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatty acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success.
Thus, there is a continuing need for alternative and/or improved treatments of pruritus.
Certain 4-arylpiperidine-based compounds are disclosed in ter alia European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. In addition, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.
International Patent Application WO00/39089, filed before the priority date of the instant application, but published thereafter, is herein incorporated by reference in its entirety, and discloses azabicycloalkanes of similar structure to those described hereinbelow, with different R4 groups.
According to the invention there is provided a compound of formula I,
Figure imgf000003_0001
(I) wherein the "Ar" ring represents an optionally benzo-fused phenyl or 5- or 6-membered heteroaryl ring;
R1 when taken alone is H, halogen, NO2, NH2, NY2WYl, Het1, AD, CO2R7, C(O)R8, C(=NOH)R8, or OE,
Y2 is H, Ci _g alkyl, Cβ.g alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Hetl),
W is SO2, CO, C(0)O, P(Y1)=0, P(Y1)=S,
Yl is Cι_ιo alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, Cι _4 alkoxy, Cχ-6 alkanoyloxy, CONH2, C\.β alkoxycarbonyl, NH2, aryl, mono- or di(Cι_4 alkyl)amino, C3.8 cycloalkyl, phthalimidyl, Het ), Hefl, aryl (optionally substituted by one or more substituents independently selected from Cι _4 alkyl, Ci _4 haloalkyl and halogen), NH2, N(Cι _6 alkyl)2 or NH(Cι_6 alkyl),
Hetl is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more substituents independently selected from Cj.g alkyl, C . alkoxy, C3.6 cycloalkyl, Ci .g haloalkoxy, C\. haloalkyl, C3.6 halocycloalkyl, =0, OH, halogen, NO2, SiR^aR^bR^c, CON 0 R20b NR20aR20b) s 21a NR2lbsO2R22 , NR2 cC(0)OR22b; NR21 cθR22d; an Ci _6 alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a -S-, S(O)- or -S(O2)- group, and carbon atoms in the ring can be present as a part of a carbonyl moiety;
Rl9as Rl9b5 R19C each independently represent Ci _g alkyl or aryl,
R20a and R20b each independently represent H, Ci .β alkyl, aryl, (Ci .4 alkyl)phenyl, each of which alkyl, aryl and alkylphenyl are optionally substituted by one or more C1.4 alkyl, Ci _4 alkoxy, OH, NO2, NH2 and/or halogen, or R20a an(j R20b can be taken together with the N atom to which they are attached, to form a 4- to 6-membered ring optionally substituted by one or more substitutuents independently selected from one or more .4 alkyl, Ci .4 alkoxy, OH, =0, NO2, NH2 and/or halogen,
R21a, b, c and d each independently represent H, C\.β alkyl, aryl or Ci .4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Ci -,4 alkyl, Ci _4 alkoxy, OH, NO2, halogen, H2,
R22a, b and c each independently represent Ci .g alkyl, aryl or C1 -4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Ci .4 alkyl, C1.4 alkoxy, OH, NO2, halogen, NH2,
A is C1.4 alkylene, C2.4 alkenylene or C2.4 alkynylene, each of which is optionally substituted by one or more Cτ_4 alkyl, C1.4 alkoxy, halogen and/or OH,
D is H, OH, CN, NR25R26 CONR25R26 NHR27, C02R28, COR29 C(=NOH)R29J
or AD is CN, NR25R26 CONR25R26,
where R2^ and R2^ are either each independently H, Ci .3 alkyl, C3_g cycloalkyl, aryl, C1-.4 alkylphenyl (each of which Cι _3 alkyl, C3.8 cycloalkyl, aryl and C1.4 alkylphenyl are optionally substituted by one or more NO2, halogen, Cj_4 alkyl and/or Cχ_4 alkoxy, (each of which latter C1.4 alkyl and Ci .4 alkoxy is optionally substituted by one or more halogen)), or R2^ and R2^ are taken together with the N atom to which they are attached and can form a 4- to 7-membered heterocyclic ring optionally incorporating one or more further hetero atoms selected from N, O and 8, and which ring is optionally substituted by one or more Ci _ 4 alkyl, OH, =0, NO2, NH2 and/or halogen,
R 7 is COR30, C02R3 1a, S02R31b,
R28 and R2^ re each independently H, Ci .β alkyl, C3.8 cycloalkyl, aryl or C\. 4alkylphenyl, each of which Ci .g alkyl, C3.8 cycloalkyl, aryl and Ci .4 alkylphenyl are optionally substituted by one or more NO2, halogen, Ci .4 alkyl, Ci .4 alkoxy (each of which latter Ci .4 alkyl and Ci .4 alkoxy are optionally substituted by one or more halogen),
R30 is H, Cι _4 alkyl, C3_g cycloalkyl, Ci .4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, Ci .4 alkylphenyl, phenyl(Cι _4 )alkoxy, (each of which Cι_4 alkyl, C3_g cycloalkyl, Cι_4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, Ci .4 alkylphenyl and phenyl(Cι _4 )aIkoxy are optionally substituted by one or more NO2, halogen, Ci .4 alkyl, C1.4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)),
R31 and R31b are each independently C1.4 alkyl, C3.8 cycloalkyl, aryl or C1..4 alkylphenyl, each of which is optionally substituted by one or more NO2, halogen, C1.4 alkyl or C 1.4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen
E is H, CONR 2R335 CSNR3 R33, C0R34 C02R34, COCH(R3 a)NH2j R35? CH2Cθ2R35a, CHR35bco2R35a, CH20C02R35C, CHR35d0Cθ2R35c,
Figure imgf000005_0001
COCHR36CHR37NH2, or PO(OR38)23
R32 and R3 are each independently H, C3.10 alkylalkenyl, C3.7 cycloalkyl (optionally substituted by Cι _4 alkyl), phenyl (optionally substituted by (X)n), CI _IQ alkyl (optionally substituted by C4.7 cycloalkyl (optionally substituted by C1..4 alkyl) or phenyl optionally substituted by (X)n),
or R32 and R3 can be taken together with the N atom to which they are attached and can form a 5- to 8-men bered heterocycle optionally comprising further hetero atoms selected from N, O and S, which heterocycle is optionally substituted by C1.4 alkyl, optionally substituted by one or more halogen,
R 4 is H, C4.7 cycloalkyl (optionally substituted by one or more Cι _4 alkyl), phenyl (optionally substituted by (X)n, C1..4 alkanoyloxy, NR32R33S CONR 2R33 and/or OH), or Cι _6 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or moire C1.4 alkyl), or phenyl (optionally substituted by (X)n, C1..4 alkanoyloxy, NR32R33, CONR 2R33 and/or OH)),
R34a is H, Ci .β alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or more Cj_4 alkyl), or phenyl (optionally substituted by (X)n, Cι _4 alkanoyloxy, NR32R33J C0NR32R33 and/or OH)), C4.7 cycloalkyl (optionally substituted by one or more Cι _4 alkyl), phenyl (optionally substituted by (X)n, C1 -4 alkanoyloxy, NR32R33; CONR3 R33 and/or OH) or a naturally occuring amino acid substituent,
R 5 is C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, phenyl (optionally substituted by one or more (X)n, Cι _4 alkanoyl, NHR 2, CON(R32)2, and/or OH), Cι _6 alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl (optionally substituted by one or more (X)n, Cι _4 alkanoyl, NHR32; CON(R32)2, and/or OH)), Cι _4 alkoxy(Cι _4 alkyl), phenyl(Cι _4)alkyloxy(Cι _4)aιkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,
R35a,b,c and d are each independently H, C4.7 cycloalkyl optionally substituted by one or more Ci-4 alkyl, phenyl optionally substituted by one or more (X)n or \. alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, or phenyl optionally substituted by one or more (X)n),
R36 and R3 each independently represent H, C3.6 alkylalkenyl, C4..7 cycloalkyl, phenyl optionally substituted by one or more (X)n, or C 1.6 alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Cι_4 alkyl, or phenyl optionally substituted by one or more (X)n))
R38 is C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl optionally substituted by one or more (X)n, or C g alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, or phenyl optionally substituted by one or more (X)n),
R2 when taken alone is H or halogen;
or Rl and R2, when attached to adjacent carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Hetla;
Het^3- is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (and is preferably an optionally benzo-fused 5- to 7- membered heterocyclic ring) and which group is optionally substituted by one or more substituents independently selected from OH, =0, halogen, Cι _4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and Ci .4 haloalkoxy, which C1.4 alkyl, C1 -4 haloalkyl, Cι _4 alkoxy and C1 -4 haloalkoxy groups can be optionally substituted by one or more C3.6 cycloalkyl, aryl(Cι _6)alkyl, which aryl group is optionally substituted by one or more halogen, C1 -4 alkyl, C1..4 haloalkyl, Cι _4 alkoxy and Ci .4 haloalkoxy, which latter C1 -4 alkyl, Ci.4 haloalkyl, C1.4 alkoxy and Cι _4 haloalkoxy groups can be optionally substituted by one or more NR2 R24 NR23s(0)nR24, NR23c(0)mR24, and if a S atom is present in a ring, it can be present as part of a -S-, S(O)- or -S(θ2)- group,
which R23 and R24 when taken alone independently represent H, C1.4 alkyl, or Ci.4 haloalkyl,
or R23 and R24 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, Ci .4 alkyl, Ci .4 haloalkyl, C1.4 alkoxy and/or C1.4 haloalkoxy groups,
R3 is H, CN, halogen, Ci _g alkoxy, Cι_g alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, c3-8 cycloalkyl, C3_g cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12Rl3, NY2WYi, Cι _6 alkyl, C2-10 alkenyl, C2.ιo alkynyl, (each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or more CN, halogen, OH, C\.β alkoxy, Cι _6 alkoxycarbonyl, C2-6 alkyloxycarbonyloxy, Ci.g alkanoyl, Ci .β alkanoyloxy, C3_ cycloalkyl, C3_g cycloalkyloxy, C4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R1 , CONR12R13 and/or NY2WY1),
R4 is C ι_ιo alkyl, C3.10 alkenyl or C3..10 alkynyl, each of which groups is linked to the N atom via a sp3 carbon, and which group is substituted by one or more substituents selected from:
C2-6 alkoxy [substituted by one or more groups selected from OH, NR 5R26J C0N 25R26J halogen, Ci .g alkoxy, C2.4 alkynyl, C2-4 alkenyl, heteroaryl 1, aryl*, COCH2CN, CO(heteroaryl !), CO(aryl 1), C02 (heteroaryl 1), COCH2(aryl 1), COCH2(heteroaryl 1), C02CH2(aryll), C02CH2(heteroaryll), S(0)n(Cι_6 alkyl), S(O)n(aryll), S(0)n(heteroaryl1), SO2NR 5R26 and cycloalkyll],
S(0)nCι_6 alkyl [optionally substituted by one or more groups selected from OH, NR25R 65 CONR25R26J halogen, Cj.g alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl 1, aryll, COCH2CN, CO(heteroaryll), COCaryl1), C02(heteroaryll), COCH2(aryll), COCH2(heteroaryll), C02CH2(aryl1), C02CH2(heteroaryll), S(0)n(Cι _6 alkyl), S(0)n(aryll),
Figure imgf000008_0001
S02NR25R26 and cycloalkyl 1],
aryl2,
Cθ2CH2(heteroaryll),
C02CH2(aryll)5 cycloalkyl 1,
CO heteroaryl1), CO(aryll),
OCO(aτyll),
OCO^eteroaryl1),
OCO(Cι_6 alkyl),
OCOCH2CN, Cθ2(heteroaryl1),
C02(aryll),
COCH2(heteroaryll),
S(0)naryll,
S(0)nCH2aryll, S(0)n(heteroaryll), S(0)nCH2(heteroaryl1),
NHSθ2aryl1,
NHS02(Cι.6 alkyl),
NHSθ2(heteroaryll), 5 NHS02CH2(heteroaryll),
NHS02CH2(aryll),
NHCOaryll,
NHCO^i.e alkyl),
NHCONHaryll, 10 NHCONH(Cι_6 alkyl),
NHCOheteroaryl1,
NHCONHheteroaryl1,
NHC02(aryll),
NHC02(Cι_6 alkyl), 15 NHCO2(heteroaryll), aryloxy, heteroaryl loxy,
C\.ζ alkoxycarbonyl substituted by Ci _6 alkyl, aryl, Ci _g alkoxy, CH2(aryll), Ci.4 haloalkyl, halogen, OH, CN or NR25R26; '.0 C2-6 alkanoyl substituted by C .β alkyl, aryl, C\. alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR25R ,
C2-6 alkanoyloxy substituted by C\.β alkyl, aryl, C\.β alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR 5R2 , cycloalkyloxy, :5 COcycloalkyl1, heterocycle substituted by one or more substituent selected from Ci _6 alkyl(substituted by
OH), CONR25R26J CH2CONR25R26; NR 5R265 NHC0NR25R263 CO(CI_6 alkyl),
S02NR25R26, S02(CI _6 alkyl), CO2(Cι.6 alkyl), CH2C02(Cι _6 alkyl), OGH2CO2(Ci.6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, .0 heterocyclyloxy substituted by one or more substituent selected from Cr.g alkyl(substituted by OH), C0NR 26, CH2CONR 5R26 NR25R26, NHCONR25R26) CO(CI.6 alkyl),
S02NR25R26S SO2(Cι_6 alkyl), C02(Cι _6 alkyl), CH2CO2(Cι.6 alkyl), OCH2C02(Cι _6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CNand C3.7 cycloalkyl, WHEREIN aryll is phenyl optionally fused to a C5.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C\.β alkyl(optionally substituted by OH, CN or halogen), C\.β haloalkoxy, OH, =0, NY2WYl, halogen, C\. alkoxy, CONR25R26; CH2CONR25R26; NR 5R 6; NHCONR25R265 CO(Cι_6 alkyl), COaryl, COheteroaryl, S02NR25R26> S(0)n(Cι_6 alkyl), S(0)n(aryl), S(0)n(heteroaryl), CO2(Cι_6 alkyl), C02(aryl), C02(heteroaryl), C02H, (CH2)l.4C02(Cι.6 alkyl), (CH2)i- 4CO2H, (CH2)l-4C02(aryl), (CH2)l-4C02(heteroaryl), 0(CH2)ι_4C02(Cι_6 alkyl), O(CH2)i-4CO2H, O(CH2)i-4C02(aryl), 0(CH2)1.4C02(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, 0(CH2)I_4CONR25R26 and C3.7 cycloalkyl,
aryl2 is phenyl optionally fused to a C5.7 carbocyclic ring, which group is substituted by one or more substituent selected from Ci .g alkyl(substituted by OH), CONR 5R265 CH2CONR25R26, NR 5R26, NHCONR25R26, CO(Cι_6 alkyl), COaryl, COheteroaryl, S02NR25R 6 S(0)n(C!.6 alkyl), S(0)n(aryl), S(O)n(heteroaryl), C02(Cι_6 alkyl),
5 CO2(aryl), CO2(heteroaryl), C02H, (CH2)i-4C02(C1.6 alkyl), (CH )i-4C02H, (CH2)ι . 4C02(aryl), (CH2)i.4C02(heteroaryl), 0(CH2)i-4C02(Cι.6 alkyl), 0(CH2)i-4C02H, 0(CH2)ι_4C0 (aryl), 0(CH2)i-4C02(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, 0(CH2)I-4CONR 5R26 and C3.7 cycloalkyl,
D heteroaryl 1 is heteroaryl optionally fused to a 05.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C\.β alkyl(optionally substituted by OH, CN or halogen), C\.β haloalkoxy, OH, =0, NY2WYΪ, halogen, C\.β alkoxy, CONR25R26, CH2CONR25R26, NR25R2 , NHCONR^R2^ CO(CI_6 alkyl), COaryl, COheteroaryl, S02NR25R26 S(0)n(Cμ6 alkyl), S(0)n(aryl), S(0)n(heteroaryl),
5 C02(Cι.6 alkyl), C02(aryl), C02(heteroaryl), CO2H, (CH2)l-4C02(Cι.6 alkyl), (CH2)i- 4C02H, (CH2)ι.4CO2(aryl), (CH2)l.4C02(heteroaryl), 0(CH2)ι.4C02(Cι.6 alkyl), O(CH2)i_4CO2H, 0(CH2)ι_4C0 (aryl), 0(CH2)i-4Cθ2(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, 0(CH2)I-4CONR25R26 and C3.7 cycloalkyl,
) cycloalkyl 1 is a C3_ιo carbocyclic system with one or two rings and which is substituted by Cι_6 alkyl, aryl, Cι_6 alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN orNR 26,
WITH THE PROVISO THAT THERE ARE NO N-R4 GROUPS WHEREIN THERE IS A HETERO- ATOM LINKED TO ANOTHER HETEROATOM VIA ONE SP3 CARBON
Z is a direct bond, CO or S(0)n group, B is (CH2)p,
Rl2 and Rl3 each independently represent H or C1.4 alkyl,
or Rl2 and Rl3 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR1 , O and/or S, and which is optionally substituted by one or more C1.4 alkyl,
Ri4 and Rl5 each independently represent H, Cι_ιo alkyl, C3.10 alkenyl, C3_ιo alkynyl, C3-8 cycloalkyl, aryl or heteroaryl,
or Rl and Rl5 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR! 6, O and/or S, and which is optionally substituted by one or more C1.4 alkyl,
Rl6 is H, Cι_6 alkyl, C3_g cycloalkyl, (Cι_6 alkylene)(C3_g cycloalkyl) or (Cι_g alkylene)aryl,
5 and R^ when taken separately are each independently H, C\.β alkyl,
R5 and R^ can be taken together with the carbon atoms to which they are joined to form a C3-8 cycloalkyl ring,
R6, R7, R and RlO when taken separately are H,
R5 and R° or R' can be taken together with the carbon atoms to which they are joined to form a C3_g cycloalkyl ring,
X is halogen, C1.4 alkyl, C1.4 alkoxy, C .4 haloalkyl or C1.4 haloalkoxy,
m is 1 or 2;
n is 0, 1 or 2; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
q is 0 or 1;
"Naturally occuring amino acid substituent" means the -substituent that occurs in any one of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline;
"Heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if a S atom is present in the ring, it can be present as part of a - S-, S(O)- or -S(0)2- group, and which may be joined to the remainder of the compound via any available atom(s);
"Heterocycle" is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms;
"Aryl", including in the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.);
"Alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbon atoms allows;
"Cycloalkyl" groups can be polycyclic if the number of carbon atoms allows;
or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
Where a fused heterocyclic group is present it can be attached to the remainder of the compound via .any available atom(s).
"Haloalkyl", "haloalkoxy" groups and the like can contain more than one halogen atom, and for instance can be per-halogenated. Certain of the compounds of the invention can exist in one or more geometric and/or stereoisomeric forms. The present invention includes all such individual isomers and salts and prodrugs thereof.
Certain compounds of the present invention may exist in more than one tautomeric form. Similarly certain compounds of the invention may have zwitterionic forms. It is to be understood that the invention embraces all such tautomers, zwitterions and their derivatives.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and rj-toluenesulphonate salts. Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be transformed after administration into or onto the body, for example by metabolism, to form compounds of formula (I) which are pharmacologically active. Such derivatives are included in the term
"prodrug". It will further be appreciated by those skilled in the art that certain moieties known to those skilled in the art as "pro-moieties", for example as described in "Design of
Prodrugs" by H Bundgaard (Elsevier) 1985, may be placed on appropriate functionalities when such functionalities are present in compounds of formula (I), also to form a "prodrug".
Further, certain compounds of formula I may act as prodrugs of other compounds of formula I.
All protected derivatives, and prodrugs, of the compounds of formula I are included within the scope of the invention.
Preferably the "Ar" ring represents phenyl or pyridyl. Most preferably the "Ar" ring represents a group of formula:
Figure imgf000014_0001
Preferably R1 when taken alone is OH, CN, halogen, N02, NH2, NY2WYl or Het1.
More preferably Rl when taken alone is OH, CN, I, CI, NH2, N0 , optionally benzo-fused heteroaryl, NHSO2Y1, NHCOY1 or NHCO2Y1.
Yet more preferably R1 when taken alone is OH, CN, I, CI, NH2, Nθ2,l,2,3~triazolyl, 1,2,4- triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl,
NHSO2(Ci_6 alkyl), NHSO2(Ci_6 alkyl substituted by methoxy, CONH2, OH, Cθ2(C2-6 alkyl), phthalimido, NH2 or halogen), NHSO2NH2, NHS02NH(Cι.6 alkyl), NHS0 N(Cι_6 alkyl)2, NHS02Hetia, NHCO(Cι_6 alkyl) or NHC02(Cι_g alkyl).
Even more preferably Rl is OH, NHSO2CH3, NHSO2C2H5, NHSθ2(n-C3H7), NHSθ2(i-
C3H7), NHS02(n-C H7), NHS02NH(i-C3H7), NHS02(N-methylimidazol-4-yl),
NHSθ2(CH2)2OCH3, NHS02(CH2)2OH, 1,2,4-triazolyl or imidazol-2-yl.
Most preferably R1 is OH, NHS02CH3, NHS02C2H5 or imidazol-2-yl.
Preferably R2 when taken alone is H.
Rl and R2 when taken together with the carbon atoms to which they are attached are preferably an optionally benzo-fused 5- to 7-membered heteroaryl ring optionally substituted by C i-4 alkyl or C 1.4 haloalkyl.
More preferably Rl and R2 when taken together with the carbon atoms to which they are attached are a -membered heteroaryl moiety optionally substituted by C 1.4 alkyl or C 1.4 haloalkyl.
Yet more preferably Rl and R2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2-substituted by CF3.
Preferably X is CI. Preferably n is 0.
Preferably q is 0.
Preferably R3 is H, CN, Cι_6 lkyl (optionally substituted by one or more halogen, OH, C _ β alkoxy, C\.β alkoxycarbonyl, C2.β alkanoyl, C _6 alkanoyloxy, C2-6 alkyloxycarbonyloxy, NR1 Ri3, CO R12R13 and/or NY2Wγ!).
More preferably R is H, CH3, C2H5, i-C3H7, n-C3H7 or CH2OCH3.
Most preferably R is CH3.
Preferably R4 is Cι_ιo alkyl substituted by one or more substituents selected from:
C2_6 alkoxy [substituted by one or more groups selected from OH, NR25R26, C0NR25R263 halogen, C\.β alkoxy, C2_4 alkynyl, C2-4 alkenyl, heteroaryl 1, aryl1, COCH2CN, COheteroaryl1), CO(aryll), ^(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), C02CH2(aryl1), Cθ2CH2(heteroaryl1), S(0)n(Cι_6 alkyl), S(O)n(aιyll), S(0)n(heteroaryI ), S02NR25R26 and cycloalkyl1],
S(0)nCι_6 alkyl [optionally substituted by one or more groups selected from OH, NR25 26) CONR25R26, halogen, C\.β alkoxy, C2.4 alkynyl, C2_4 alkenyl, heteroaryl1, aryl1, COCH2CN, COheteroaryl1), CO(aryl1), C02(heteroaryl1), COCH2(aryl1), COCH^heteroaryl1), C02CH2(aryl1), C02CH2(heteroaryl1), S(0)n(Cι_6 alkyl), S(0)n(aryl1), S^^heteroaryl1), S02NR25R26 and cycloalkyl1],
aryl2,
C02CH2(heteroaryl1),
C02CH2(aryl1), cycloalkyl1,
COheteroaryl1), CO(aryl1),
OCO(aryl1),
OCOOieteroaryl1),
OCO(Cι_6 alkyl),
OCOCH2CN, Cθ2(heteroaryl1), C02(aryl1),
COCH^heteroaryl1),
S(O)naιyll,
S(0)nCH2aryl1, S(0)n(heteroaryl1),
S(0)nCH2(heteroaryl1),
NHS02aryl1,
NHSO2(Ci_6 alkyl),
NHSθ2(heteroaryl1), NHS02CH2(heteroaryl1),
NHSθ2CH2(aryl1),
NHCOaryl1,
NHCO(Cι_6 alkyl),
NHCONHaryl1, NHCONH(Cι_6 alkyl),
NHCOheteroaryl1,
NHCONHheteroaryl1 ,
NHC02(aryl1),
NHCO2(Cι.6 alkyl), NHC02(heteroaryl1), aryl2oxy, heteroaryl ioxy,
C\.β alkoxycarbonyl substituted by C\.β alkyl, aryl, C\,β alkoxy, CH2(aryl1), C1.4 haloalkyl, halogen, OH, CN or NR25R26 C2-6 alkanoyl substituted by C\_ alkyl, aryl, C .β alkoxy, CH2(aryl1), C1.4 haloalkyl, halogen, OH, CN or NR25R26
C2.6 alkanoyloxy substituted by C\.β alkyl, aryl, Cι_6 alkoxy, CH^aryl1), C1.4 haloalkyl, halogen, OH, CN or NR25R26 cycloalkyloxy, COcycloalkyl1, heterocycle substituted by one or more substituent selected from Cγ.β alkyl(substituted by
OH), CONR25R26> CH2CONR25R26S NR25R26S NHCONR 5R26, CO(CI_6 alkyl),
S02NR25R26 SO2(Ci.6 alkyl), C02(Cι_6 alkyl), CH2C02(Cι.6 alkyl), OCH2C02(Cι.6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, heterocyclyloxy substituted by one or more substituent selected from Cι_6 alkyl(substituted by OH), CONR25R26, CH CONR25R26 NR2 26, NHCONR25R26 CO(Cι_6 alkyl), SO2NR25R26, S02(CI_6 alkyl), C02(Cι_6 alkyl), CH2C02(Cι.6 alkyl), OCH2C02(Cι.6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl,
More preferably R4 is CJ.JO alkyl substituted by cycloalkyl1.
Yet more preferably R4 is C2-4 alkyl substituted by cycloalkyl1.
Further more preferably R4 is propyl substituted by cycloalkyl ! .
Furthet yet more preferably R4 is propyl substituted by a C3.10 carbocyclic system with one or two rings and which is substituted by OH.
Even more preferably R4 is propyl substituted by (cyclohexyl substituted by OH)
Most preferably R4 is (l-hydroxycyclohexyl)prop-3-yl.
Another preferred group of compounds are those wherein R4 takes the values as specified in the Examples 145-203 below.
Preferably R^, R6, R7, R8 R9 and R1^ are each taken separately and are H.
A preferred group of substances are those in which the "Ar" ring, R1, R2, R3, R4, R53 6; R7, R8, R9, R1 ) q and (X)n have the values as detailed in the Examples below.
The invention further provides synthetic methods for the production of compounds and salts of the invention, which are described below and in the Examples and Preparations. The skilled man will appreciate that the compounds of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as
"Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, VCH (1989 or later editions), "Advanced Organic Chemistry - Reactions, Mechanisms and Structure", J.March, Wiley-
Interscience (3rd or later editions),
"Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions),
"Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To
Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.
It is to be understood that the synthetic transformation methods mentioned herein are exemplary only and they may be carried out in various different sequences in order that the desired compounds can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound. For example, substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinafter in conjunction with a particular reaction. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. The procedures may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks and to the examples provided hereinafter.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and refernces therein. Functional groups which may desirable to protect include oxo, hydroxy, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (e.g. ethylene ketals) and dithianes. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tgrt-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9- fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include Ci. alkyl or benzyl esters. In the Methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I).
The invention provides a process for the preparation of compounds of formula I as defined above, or a pharmacutically or veterinarily acceptable derivative thereof, which comprises: (a) for compounds of formula I in which q is 0 and R1 represents NY2WY1, reacting a compound of formula II,
II with a compound of formula III,
Zi-WY1 III wherein Z1 is a suitable leaving group, such as halogen or Y Sθ2θ- ; (b) for compounds of formula I in which q is 0 and R^ and R7 both represent H, reduction of a compound of formula IV,
Figure imgf000019_0002
IV using a suitable reducing agent;
(c) for compounds of formula I in which q is 0 and R9 and R1^ both represent H, reduction of a compound of formula V,
Figure imgf000020_0001
V using a suitable reducing agent;
(d) for compounds of formula I in which q is 0 and R1 and R2 are attached to adjacent carbon atoms and are taken together with the carbon atoms to which they are attached to represent Hetla, in which Hetla represents an imidazolo unit, reaction of a corresponding compound of formula VI,
Figure imgf000020_0002
VI with a compound of formula VII,
Figure imgf000020_0003
wherein RY represents H or any of the optional substituents on Hetla (as defined above), preferably H, C1-4 alkyl or C 1.4 haloalkyl;
(e) where q is 0, reacting a compound of formula VIII,
Figure imgf000021_0001
Nm with a compound of formula IX,
R4-Lg IX wherein Lg is a leaving group;
(f) for compounds of formula I in which q is 0 and R^, R7; R9 and RIO are all H, reduction of a compound of formula X,
Figure imgf000021_0002
X
with a suitable reducing agent;
(g) for compounds of formula I in which q is 0 and R1 represents OH, reacting a compound of formula II in which Y2 is H, as defined above, with fluoroboric acid and isoamyl nitrite; (h) for compounds of formula I in which q is 0 and R1 represents CI, reacting a compound of formula II in which Y2 is H, as defined above, with sodium nitrite in the presence of dilute acid, followed by reaction with copper (I) chloride in the presence of concentrated acid;
(i) for compounds of formula I in which q is 1, reacting a compound of formula I where q is 0 with a suitable oxidising agent such as aqueous hydrogen peroxide;
G) for compounds of formula I where q is 0, by reduction of a corresponding compound of formula XXXI,
Figure imgf000022_0001
XXXI
where R aCH2 takes the same meaning as R4 as defined above; or
(k) for compounds of formula (I) where q is 0, reductive amination reaction of the amine of formula VIII above with an aldehyde of formula R4a-CHO wherein R4aCH2 takes the same meaning as R4 as defined above, and where desired or necessary converting the resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa.
In process (a), the reaction may be carried out at between 0°C and room temperature in the presence of a suitable base (e.g. pyridine) and an appropriate organic solvent (e.g. dichloromethane) .
Compounds of formula II may be prepared by reduction of a corresponding compound of formula XI or formula XII,
Figure imgf000023_0001
in the presence of a suitable reducing agent, such as lithium aluminium hydride. The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent (e.g. tetrahydrofuran).
Compounds of formula XI and XII may be prepared by reduction of the corresponding -N02 compounds under conditions that are well known to those skilled in the art (e.g. using H /Raney Ni or in the presence of CaCl and iron powder, in the presence of a suitable solvent system (e.g. EtOH, EtOAc and/or water)). The skilled person will appreciate that, in preparing a compound of formula II, in which Y2 is H, from such a corresponding -N02 compound, the two above-mentioned reduction steps may be performed in the same step or sequentially in any order.
The said corresponding -NO2 compounds may be prepared by reaction of a compound of formula XII or formula XIV, as appropriate,
Figure imgf000023_0002
wherein L1 represents a suitable leaving group [such as halo (e.g. chloro or bromo)], L2 represents a suitable leaving group (such as C 1.3 alkoxy) and R3 is as defined above, with a compound of formula XV,
R4NH2 XV
The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable base (e.g. NaHC03) and an appropriate organic solvent (e.g. dimethylformamide), or at a higher temperature (e.g. between 50 and 200°C, preferably between 100 and 160°C) in the presence of neat compound of formula XV.
Compounds of formula XIII and XIV may be prepared in accordance with standard techniques. For example, compounds of formula XIII and XIV may be prepared by reacting a corresponding compound of formula XVI or XVII,
Figure imgf000024_0001
with a compound of formula XVIII or XIX respectively,
N2CHR5COL2 XVIII
N2CHR8C0L2 XIX wherein L2 is as defined above. The reaction may be carried out at room temperature in the presence of a suitable catalyst [e.g. Rh2(OAc)4] and an appropriate non-protic organic solvent (e.g. dichloromethane).
Compounds of formula XVI and formula XVII are available or can be prepared using known techniques. Compounds of formula XVI and formula XVII may, for example, be prepared from corresponding compounds of formula XX,
Figure imgf000025_0001
XX for example by performing a Wittig reaction using an appropriate provider of the nucleophilic group R02C-CR5H_ or RO2C-CR8H- (wherein R represents lower (e.g. C1..3) alkyl), as appropriate, under conditions that are well known to those skilled in the art. The - CO2R group of the resulting compound may be converted to an appropriate -CH2L1 group using standard techniques (e.g. reduction of the ester to the primary alcohol and conversion of the latter to an alkyl halide) under conditions that are well known to those skilled in the art.
In processes (b) and (c), suitable reducing agents include lithium aluminium hydride. The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent (e.g. tetrahydrofuran).
Compounds of formula II may be prepared by reduction of the corresponding compound of formula XXX,
Figure imgf000025_0002
XXX by analogy to the process steps mentioned above.
Compounds of formula IV and V may be prepared respectively from compounds of formula XXI and XXII,
Figure imgf000026_0001
wherein L3 represents a group that is capable of undergoing functional group transformations (e.g. cyano) using standard functional group substitution or conversion techniques.
For example:
(1) Compounds of formula IV and V in which R1 represents l,2,4-triazol-3-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 represents -CN with HCI (gas) in the presence of an appropriate lower alkyl alcohol (e.g. ethanol), for example at between 0°C and room temperature, followed by reaction of the resultant intermediate with formic acid hydrazide (e.g. at reflux temperature, with or without the presence of a suitable organic solvent (e.g. methanol), followed by, if necessary, removing the solvent and heating the resultant residue to a high temperature (e.g. about 150°C)).
(2) Compounds of formula IV and V in which R1 represents imidazol-2-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 represents -CN with HCI (gas) in the presence of an appropriate lower alkyl alcohol (e.g. ethanol), for example at between 0°C and room temperature, followed by reaction of the resultant intermediate with aminoacetaldehyde dialkylacetal (e.g. dimethylacetal) (e.g. at or around reflux temperature in the presence of an appropriate solvent, such as methanol).
(3) Compounds of formula IV and V in which R1 represents l,2,3-triazol-5-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 represents -CN with diazomethane, or a protected (e.g. trialkylsilyl) derivative thereof, for example at between 0°C and room temperature in the presence of a suitable base (e.g. n- BuLi) and, optionally, an appropriate organic solvent (e.g. THF), followed by removal of the protecting group as necessary.
(4) Compounds of formula IV and V in which R1 represents benzimidazol-2-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 represents C-NH(OEt) with 1,2-diaminobenzene. The reaction may be carried out in a solvent such as methanol, at an elevated temperature (such as the reflux temperature of the solvent). Preparations 81, etc. provide further details.
Compounds of formula IV and V in which R1 represents Het1 may also be prepared from compounds of formula XI and XII respectively according to the following scheme:
Figure imgf000027_0001
wherein Het1 is defined above. Further details may be found in Preparations 67, 68, etc. in WO00/39089, herein incorporated by reference in its entirety.
Compounds of formula XXI and XXII may be prepared in analogous fashion to methods described herein, for example those described hereinbefore for preparation of compounds of formula II.
Other compounds of formula (IV) and (V) may be prepared by analogy with methods described herein (e.g. by analogy with methods described hereinbefore for preparation of compounds of formula XI and XII (and especially the corresponding -NO2 compound)).
In process (d), the reaction may be carried out by heating under reflux, with or without the presence of an appropriate organic solvent.
Compounds of formula VI may be prepared using known techniques. For example, compounds of formula VI may be prepared by nitration (at the 4-position) of a corresponding 3-aminobenzene compound (a compound of formula II), which latter compound may be activated by converting the 3-amino group to a 3-amido group, followed by hydrolysis of the amide and reduction of the 4-nitrobenzene compound. All of these reactions may be performed using techniques that are familiar to the skilled person, and are illustrated in Preparations 45-48, etc. below.
In process (e), suitable leaving groups that Lg may represent include halogen, such as bromine, or a sulphonate group such as tosylate, mesylate or triflate. The reaction may be carried out in a polar solvent that does not adversely affect the reaction, at a suitable temperature, e.g. 0-150°C, in the presence of a base. A catalyst such as sodium iodide may optionally be added.
Preferable choices are a slight excess of R4-Lg, where Lg = CI or Br, an excess of base (2.0- 4.0 eq), such as K2CO3, NaHCθ3, or a tertiary amine, such as triethylamine or Hunigs base, in a polar solvent, such as THF, DMF, or MeCN, at between 40 and 120°C, optionally in the presence of a catalyst such as Nal or KI, for 2-24 hr. see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), p 397, and references cited therein. Compounds of formula VIII may be prepared from compounds of formula XXV,
Figure imgf000029_0001
XXV wherein Pg represents a suitable protecting group. Suitable protecting groups include allyl, which may be removed using a palladium (0) catalyst and N,N-dimethylbarbituric acid (see Preparation 53, etc. below). Compounds of formula XXV may be prepared using analogous methods to those described herein for the preparation of compounds of formula I.
In process (f), suitable reducing agents include lithium aluminium hydride. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), at an elevated temperature (for example the reflux temperature of the solvent).
Compounds of formula X may be prepared by reacting a compound of formula XXVI with a compound of formula XXVII in the presence of an oxidizing agent. Suitable oxidizing agents include manganese dioxide. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example dioxan), at an elevated temperature such as the reflux temperature of the solvent (for example see Preparation 77, WO00/39089). The intermediate compounds XXTXa are isolatable using suitable conditions (e.g. see Preparation 58, WO00/39089).
Figure imgf000030_0001
XXVI XXVII
XXIXa
Figure imgf000030_0002
XXIX
Compounds of formula XXVI may be prepared from compounds of formula XXVIII, by reaction of the corresponding ketone with hydrazine monohydrate using known techniques (and as described in Preparation 76, etc. WO00/39089).
Process (f) is particularly useful when Ar represents an optionally benzo-fused 5- or 6- membered heteroaryl ring. A similar methodology may be used to obtain compounds of formula II: the precursor nitro compound may be prepared from a compound of formula XX, as defined above, using the steps described above (see for example Preparations 57-61, WO00/39089). In process (g), the reaction may be carried out in a solvent that does not adversely affect the reaction (for example ethanol), first below room temperature and then at an elevated temperature (Examples 79, etc. WO00/39089, provides further details).
In process (h), suitable acids include dilute aqueous hydrochloric acid and concentrated hydrochloric acid, respectively. The reaction may be carried out at or around room temperature, finishing at' an elevated temperature (for example 90°C). Example 51 WO00/39089 provides further details.
In process (j), the compound of formula XXXI may be prepared by acylation of the compound of formula VIII as defined above, with an acylating agent of the formula R4aCO- Lg, where Lg is a suitable leaving group as defined above with respect to (e), and includes halogen, (alkyl, haloalkyl or aryl)sulphonate, OCOR4a (i.e. an acid anhydride) and the like, well known to those practising in the art. See for example the conditions used for Preparation 47. The coupling can optionally be carried out in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein. Preferably the carboxylic acid (0.9-1.1 eq), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide. HCI (1-1.5 eq) and 1-hydroxybenzotriazole (1.0 eq) are stirred in DMF or DCM at RT for 5-15 min and then the amine salt (1 eq) and base (NaHC03 or organic base , Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr at RT.
The amide bond can be reduced with a suitable reducing agent, for example lithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-100°C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), pp 432-434, and references cited therein. Preferably the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C-RT, in THF, for 1-24 hr.
In process (k) the appropriate aldehyde is reacted with an amine, optionally present as an acid addition salt, in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts). The reaction is suitably performed in the presence of acetic acid at 0-100°C in THF, methanol, DCM (dichloromethane), or DCE (1,2 -dichloroethane), for a suitable time such as 1-24 hr. Preferably the amine salt, such as the trifluoroacetic acid (TFA) salt, is treated with an organic base (1-3 mole equivalents), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5 mole equivalents), followed by sodium triacetoxyborohydride (1-2.0 mole equivalents), in DCM or DCE, at room temperature for 2-24 hr. see RC Larrock; 5 "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), p 835-842, and references cited therein, and Abdel-Magid et al, J. Org. Chem., 1996, 61, 3849.
The aldehydes used in this process may be prepared from the corresponding alcohols using 0 suitable oxidising agents; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1234-1236 and 1238- 1247, and references cited therein. Preferred oxidants are tetrapropylammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J. 15 Org. Chem., 1983, 48, 4155-4156).
Various functional group interconversions on compounds of formula (I), or intermediates thereto, may be carried out to give different compounds of formula (I) or intermediates. Some of these are mentioned below. >0
Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432.
!5 Esters can be converted to the corresponding alcohols using a suitable reducing agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1117-1120 and references cited therein. Suitable reducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride (LiAlH4, see Brown, Org. Reactions, 1951, 6,
,0 469) - viz. reaction of the type:
Figure imgf000032_0001
Alcohols can be prepared from a corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1114-1116. Preferably the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAlH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80°C, for 1-24 hr. - viz. reaction of the type:
Figure imgf000033_0001
Direct methods to prepare alkyl halides and alyl sulphonates from their alcohols are described by RC Larrock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 689-700, and references cited therein.
Benzylacetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give benyloxyalcohols.
For representative examples see Organic Preparations and Procedures, Int., 1991, 23, 4, 427-
431, ZrC14/LiAlH4; J. Org. Chem., 1987, 52, 2594, Zn(BH4)2/Me3SiCl; and Organic
Preparations and Procedures, Int., 1985, 17(1), 11-16, NaBH4/TFA. viz. reaction of the type:
Figure imgf000033_0002
It will be apparent to those skilled in the art that compounds of formula I may be converted to other compounds of formula I using known techniques. For example, compounds of formula I in which Y1 represents alkoxycarbonyl may be converted to compounds in which Y1 represents alkyl substituted by OH, by reduction using L-AIH4 (Example 57 provides further details). Similarly, intermediate compounds may be interconverted using known techniques (see for example Preparation 85). The intermediate compounds such as those of formulae III, XV, XVIII, XIX, XX, VII, IX, XXVI, XXVII and XXVIII, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
The invention further provides the intermediate compounds of formulae II, IV, V, VI, X, Xa, XI, XII, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX, and XXXI as defined above.
Where desired or necessary, the compound of formula (I) can be converted into a pharmaceutically acceptable salt thereof, conveniently by mixing together solutions of a compound of formula (I) and the desired acid or base, as appropriate. The salt may be precipitated from solution and collected by filtration, or may be collected by other means such as by evaporation of the solvent. Both types of salt may also be formed or interconverted using ion-exchange resin techniques.
The compounds of the invention may be purified by conventional methods, for example separation of diastereomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of formula (I) or a salt thereof. An individual enantiomer of a compound of formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereomeric salts formed by reaction of the corresponding racemate with a suitably optically active base or acid.
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals including humans. They are therefore indicated as pharmaceuticals and, in particular, for use as animal medicaments.
According to a further aspect of the invention there is provided the compounds of the invention for use as medicaments, such as pharmaceuticals and animal medicaments, such as for the treatment of opiate-mediated diseases and conditions. By the term "treatment", this term includes both therapeutic (curative) and prophylactic treatment.
In particular, the substances of the invention have been found to be useful in the treatment of 5 diseases and conditions modulated via opiate receptors, such as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; and conditions characterised by having pruritis as a symptom.
0 Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a disease modulated via an opiate receptor. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses;
5 depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage' and/or head trauma; and conditions characterised by having pruritis as a symptom.
The compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in :0 animals and humans. Other diseases and conditions which may be mentioned include contact dermatitis, psoriasis, eczema and insect bites.
Thus, the invention provides a method of treating or preventing a disease modulated via an opiate receptor. There is further provided a method of treating irritable bowel syndrome;
:5 constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; or a medical condition characterised by pruritus as a symptom in an animal (e.g. a mammal), which comprises administering a therapeutically effective amount of a compound of the invention to an animal in need of such treatment.
0
The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses (see below).
While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical, or veterinary, formulation comprising a pharmaceutically, or veterinarily, acceptable carrier, diluent or excipient and a compound of the invention. The carrier, diluent or excipient may be selected with due regard to the intended route of administration and standard pharmaceutical, and/or veterinary, practice. Pharmaceutical compositions comprising the compounds of the invention may contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (eg subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg.
In any event, the veterinary practitioner, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
For veterinary use, the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses. As an alternative for treating animals, the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice.
Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be construed as limiting) include antiparasitics, eg fipronil, lufenuron, imidacloprid, avermectins (eg abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, eg chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, eg fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, eg enroflaxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories eg prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, eg gamma-linoleic acid; and emollients. Therefore, the invention further provides a product containing a compound of the invention and one or more selected compounds from the above list as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases modulated via opiate receptors
The skilled person will also appreciate that compounds of the invention may be taken as a single dose or on an "as required" basis (i.e. as needed or desired).
Thus, according to a further aspect of the invention there is provided a pharmaceutical, or veterinary, formulation including a compound of the invention in admixture with a pharmaceutically, or veterinarily, acceptable adjuvant, diluent or carrier.
Compounds of the invention may also have the advantage that, in the treatment of human and/or animal patients, they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
The biological activities of the compounds of the present invention were determined by the following test method.
Biological Test
Compounds of the present invention have been found to display activity in three opioid receptor binding assays selective for the mu, kappa and delta opioid receptors in dog brain. The assays were conducted by the following procedure.
Laboratory bred beagles were used as a source of dog brain tissue. Animals were euthanaised, their brains removed and the cerebellum discarded. The remaining brain tissue was sectioned into small pieces approximately 3 g in weight and homogenised in 50mM Tris pH 7.4 buffer at 4°C using a Kinematica Polytron tissue homogeniser. The resulting homogenate was centrifuged at 48,400 x g for 10 minutes and the supernatant discarded. The pellet was resuspended in Tris buffer and incubated at 37°C for 10 minutes. Centrifugation, resuspension and incubation steps were repeated twice more, and the final pellet was resuspended in Tris buffer and stored at -80°C. Membrane material prepared in this manner could be stored for up to four weeks prior to use.
For mu, kappa and delta assays, increasing concentrations of experimental compound (5 x lO"12 to 10"5M), Tris buffer and 3H ligand, (mu = [D-Ala2,N-Me-Phe4,Gly-ol5]- Enkephalin, DAMGO; kappa = U-69,593; delta = Enkephalin, [D-pen >5] DPDPE), were combined in polystyrene tubes. The reaction was initiated by the addition of tissue, and the mixture was incubated at room temperature for 90 minutes. The reaction was terminated by rapid filtration using a Brandel Cell Harvester™ through Betaplate™ GF/A glass fibre filters pre-soaked in 50 mM Tris pH 7.4, 0.1% polyethylenimine buffer. The filters were then washed three times with 0.5 ml ice-cold Tris pH 7.4 buffer. For mu and delta assays, washed filters were placed in bags and Starscint™ scintillant added, for the kappa assay Meltilex™ B/HS solid scintillant was used. Bags containing the filters and scintillant were heat sealed and counted by a Betaplate™ 1204 beta counter. Duplicate samples were run for each experimental compound and the data generated was analysed using IC50 analysis software in Graphpad Prism. Ki values were calculated using Graphpad Prism according to the following formula:
Ki = IC50 / 1 + [3H ligand] / KD
where IC50 is the concentration at which 50% of the 3H ligand is displaced by the test compound and Kj) is the dissociation constant for the 3H ligand at the receptor site.
Biological Activity
The Ki values of certain compounds of the present invention in the opioid receptor binding assays were determined, and were found to have Ki values of 4000 nM or less for the μ receptor.
It is believed that the methods used in the following Examples produce compounds having the relative stereochemistry shown below, and such compounds are preferred:
Figure imgf000039_0001
wherein R1-4 and (X)n are as defined above. 3 The invention is illustrated by the following Examples and Preparations in which the following abbreviations may be used:
APCI = atmospheric pressure chemical ionization DMF = dimethylformamide j DMSO = dimethylsulphoxide d (in relation to time) = day d (in relation to NMR) = doublet ES (in relation to MS) = electrospray EtOAc = ethyl acetate
EtOH = ethanol h = hour
MeOH = methanol min = minute
MS = mass spectrum n-BuOH = n-butanol
ODS = octadecylsilyl
THF = tetrahydrofuran
TSP = thermospray
Melting points were determined using a Gallenkamp melting point apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectral data relate to ^R and were obtained using a Varian Unity 300 or 400 spectrometer, the observed chemical shifts (δ) being consistent with the proposed structures. Mass spectral (MS) data were obtained on a Fisons Instruments Trio 1000, or a Fisons Instruments Trio 1000 APCI, or a Finnigan Navigator MS, or a Micromass Platform LC spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass. Room temperature means 20 to 25°C. The mass spectrometer which is used as a detector on the analytical HPLC-MS system is a Micromass VG Platform II, running on Masslynx/Openlynx software. The system can run positive and negative ion with either Electrospray or APCI probes and is calibrated to 1972 Daltons, it collects full Diode array data from 190nm to 600nm.
HPLC means high performance liquid chromatography. HPLC conditions used were:
Condition 1: Rainin Dynamax™ column, 8μ ODS, 24 x 300 mm, column temperature 40°C, flow rate 45 ml/min, eluting with methanol : water (70 : 30), UV detection of product at 246 nm.
Condition 2: Rainin Dynamax™ column, 5μ ODS, 21.6 x 250 mm, column temperature
40°C, flow rate 5 ml/min, eluting with acetonitrile : water (50 : 50), UV detection of product at 246 nm.
Condition 3: Rainin Dynamax™ column, 8μ ODS, 41 x 250 mm, column temperature 40°C, flow rate 45 ml/min, eluting with acetonitrile : 0.1M aqueous ammonium acetate buffer (50 :
50), UV detection of product at 235 nm. Condition 4: Phenomenex Magellan™ column, 5μ C 8 silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : OJM aqueous ammonium acetate buffer (30 : 70 to 95 : 5 over 10 min), UV detection of product at 220 nm. Condition 5: Phenomenex Magellan™ column, 5μ ODS, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate buffer (5 : 95 to 95 : 5 over 20 min), UV detection of product at 215 nm. Condition 6: Phenomenex Magellan™ column, 5μ g silica, 4.6 x 150 mm, column temperature 40°C, flow rate 1 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous heptanesulphonic acid (10 : 90 to 90 : 10 over 30 min), UV detection of product at 220 nm. Condition 7: Phenomenex Magellan™ column, 5μ g silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.05M aqueous ammonium acetate buffer (50 : 50 for 15 min then 50 : 50 to 90 : 10 over 5 min), UV detection of product at 220 nm.
Condition 8: Phenomenex Magellen^M column, 5μ Cig silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate buffer (15 : 85 to 85 : 15), UV detection of product at 220 nm. Condition 9: Phenomenex MagellenTM column, 5μ ODS, 10 x 150 mm, column temperature 40°C, flow rate 5ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate buffer (5 : 95 to 30 : 70 over 5 min then 30 : 70 for a further 20 min), UV detection of product at 225nm.
Condition 10: Phenomenex MagellanTM column, 5μ Cjg silica, 21.2 x 150mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate (5 : 95 to 40 : 60 over 5 min then 40 : 60 for a further 25 min), UV detection of product at 210 nm.
Condition 11: Phenomenex MagellanTM column, 5μ ODS, 10 x 150mm, column temperature 40°C, flow rate 5 ml/min, eluting with a gradient of acetonitrile : water (5 : 95 to 55 : 45 over 5 min), UV detection of product at 210 nm.
The free base form of the azabicycles could be obtained from the hydrochloride or acetate salts, for example, in the following way. The salt (0.3 mmol) was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (20 ml). The basic mixture was separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic extracts were dried (Na2Sθ4) and concentrated in vacuo to give the free base. SPE cartridge refers to a solid phase extraction cartridge. These can be commercially obtained from Varian (Mega Bond Elut ®) or IsoluteTM.
NB "Examples" numbered 1-144 are compounds related to the instant invention, but with different R4 groups, and are disclosed as such in International Patent Application no. WOOO/39089, herein incorporated by reference in its entirety.
A number of further Examples, such as those in the table below, can be made via the processes A-K outlined below and in the experimental details following the table
Process A
All viation Alkylation of the amine of formula VIII or a salt thereof with R4Lg, where Lg is a suitable leaving group, such as a halogen, triflate, mesylate, etc., in the presence of a base, optionally in the presence of a catalyst, in a polar solvent, at between 0 and
150°C.
Preferably the alkylation is carried out with R4Lg (slight excess), where Lg =CI or Br, an excess of base (2.0-4.0 eq), such as K2CO3, NaHCO3, or a tertiary amine, such as triethylamine or Hunigs base, in a polar solvent, such as THF, DMF, or MeCN, at between 40 and 120°C, optionally in the presence of a catalyst such as Nal or KI, for
2-24 hr. see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), p 397, and references cited therein.
For Example:
Figure imgf000043_0001
Lg=Br or CI
Conditions: Amine salt (1.0 eq), RX (1.1 eq), NaHCO3 (2-4.0 eq), DMF, Nal (cat), 4(
Process B
Reductive amination
Treating an appropriate aldehyde R4aCHO with an amine of formula VIII in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts). The reaction is often performed in the presence of acetic acid at 0-100°C in THF, MeOH, DCM, or DCE (1 ,2 -dichloroethane), for 1-24 hr.
Preferably the amine salt is treated with an organic base (1-3 eq), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5 eq), followed by sodium triacetoxyborohydride (1-2.0eq), in dichloromethane or DCE, at room temperature for 2-24 hr. see RC Larrock; "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), p 835-842, and references cited therein, and Abdel-Magid et al, J. Org. Chem., 1996, 61 , 3849. For example:
Figure imgf000044_0001
Conditions: Amine salt (1.0 eq), RCHO (1-1.5eq), Et3N (1-3 eq), Na(OAc)3BH (1-2 eq), DCM RT.
Process C
Reduction of Amide of Formula XXXI
The amide carbonyl can be reduced with a suitable reducing agent, for example lithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-100°C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic
Transformations-A Guide to Functional Group Preparations", VCH, (1989), pp 432-
434, and references cited therein.
Preferably the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C- RT, in THF, for 1-24 hr, e.g.:
Figure imgf000044_0002
Process D
Oxidation
Aldehydes used in process B can be prepared using suitable oxidising agents; see
RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional
Group Preparations", second edition, (1999), pp 1234-1236 and 1238-1247, and references cited therein. Preferred oxidants are tetrapropylammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J. Org. Chem., 1983, 48, 4155-4156).
Figure imgf000045_0001
Process E
Acid/ amine salt coupling to give amides of formula XXXI
Either using an acid chloride + amine in a suitable solvent or the acid activated by a suitable agent, optionally in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein. Preferably the carboxylic acid (0.9-1.1 eq), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide. HCI (1-1.5 eq) and 1- hydroxybenzotriazole (1.0 eq) are stirred in DMF or DCM at RT for 5-15 min and then the amine salt (1 eq) and base (NaHCO3 or organic base , Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr at RT. For Example:
Figure imgf000045_0002
Process F
Urea formation
Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432. viz. reaction of the type:
Figure imgf000046_0001
Process G
Ester to an alcohol
Esters can be converted to the corresponding alcohol using a suitable reducing LO agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1117-1120 and references cited therein. Suitable reducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride (UAIH4, see Brown, Org. Reactions, 1951 , 6, 469).viz. reaction of the type:
Figure imgf000046_0002
Process H
.0 Acid to alcohol
It should be appreciated that the alcohols used in process D can be prepared from the corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition,
-5 (1999), pp 1114-1116. Preferably the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAIH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80°C, for 1-24 hr.
Figure imgf000046_0003
50
Process I Alcohol to halide It should be appreciated that the R4Lg used in Process A can be prepared from the corresponding alcohol R4OH.
Direct methods to prepare alkyl halides and alkyl sulphonates from their alcohols are described by RC Larock, Comprehensive Organic Transformations-A Guide to
Functional Group Preparations, second edition, (1999), pp 689-700, and references cited therein.
Process J
Benzyl halides to benzyloxyalcohols
Benzyloxyalcohols can be prepared by refluxing the appropriate benzyl halide with sodium or sodium hydride and a polymethylene glycol in xylene, see J. Am. Chem.
Soc, 1951 , 3159-3162.viz. reaction of the type:
Figure imgf000047_0001
X = halide
Process K
Acetals to benzyloxyalcohols
Acetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give the benyloxyalcohols.
For representative examples see Organic Preparations and Procedures, Int., 1991 ,
23, 4, 427-431 , ZrCI4/LiAIH4; J. Org. Chem., 1987, 52, 2594, Zn(BH4)2/Me3SiCI; and Organic Preparations and Procedures, Int., 1985, 17(1 ), 11-16, NaBH4/TFA.viz. reaction of the type:
Figure imgf000047_0002
Figure imgf000047_0003
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Example 199: ■V-(3-(3-r3-(4-acetylphenyl)proρyll-6-ethyl-3-azabicvclor3.1.0]hex-6- vUphenvDmethanesulfonamide - and formate salt
Figure imgf000065_0002
To a solution of the trifluoroacetic acid salt of Λ/-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide (106 mg, 0.27 mmol) in N,N- dimethylformamide (4 ml) was added sodium hydrogen carbonate (90mg, 1.1 mmol), 1-[4-(3- chloropropyl)phenyl]ethanone (58 mg, 0.29 mmol) and sodium iodide (catalytic) and the reaction mixture was heated at 70 °C for 20 h. After cooling, the solvent was removed in-vacuo to give a crude residue. This was purified by silica (14 g) column chromatography eluting with ethyl acetate: hexane (75:25) and then with neat ethyl acetate. Combination and evaporation of the appropriate fractions gave the partially purified product. This material was further purified by preparative HPLC (condition 1) to afford the formate salt of title compound (16 mg, 12%) as a yellow oil.
Η-NMR (300MHz, CDCI3, data for formate salt) : 0.85 (t, 3H), 1.70 (q, 2H), 2.05 (quintet, 2H), 2.15 (s, 2H), 2.55 (s, 3H), 2.70 (t, 2H), 2.80-2.85 (m, 4H), 2.95 (s, 3H), 3.70-3.80 (m, 2H), 7.00 (d, 1H), 7.05-7.10 (m, 2H), 7.20-7.28 (m, 3H), 7.90 (d, 2H), 8.40 (s, 1H). MS (Electrospray) : M/Z (M-H) 439; C^^OsS - H requires 439.2.
Example 200 : Λ/-(3-{3-r2-(benzvioxy)benzyll-6-ethyl-3-azabicvclor3.1.01hex-6- vPphenyQmethanesulfonamide
Figure imgf000066_0001
To a solution of 2-benzyloxybenzaldehyde (27mg, 0.13mmol) in dichloromethane (5 ml) at room temperature was added the trifluoroacetic acid salt N-[3-(6-ethyl-3- azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (50mg, 0.13 mmol) and triethylamine (0.05 ml, 0.38 mmol). The reaction was left to stir at room temperature for 2h. At this point sodium triacetoxyborohydride (40.8 mg, 0.19 mmol) was added and the reaction was left to stir at room temperature for 16 h. Water (5ml) was then added to the reaction mixture and the two layers were separated using a Whatman filter tube (hydrophobic polytetrafluoroethylene membrane). The organic layer was then blown down to dryness under a steam of nitrogen. The residue was purified by column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with hexane: ethyl acetate (100:0, 1 :1 , 1 :3, 1:6, 1 :9 and 0:100) to afford the title compound (28 mg, 46%) as an oil.
1H-NMR (300MHz, CDCI3): 0.85 (t, 3H), 2.80 (s, 2H), 2.00-2.10 (m, 2H), 2.85 (d, 2H), 3.00 (s, 3H), 3.10-3.20 (dd, 2H), 3.80 (s, 2H), 5.10 (s, 2H), 6.90-7.05 (m, 3H), 7.10 (m, 2H), 7.20-7.30 (m, 3H), 7.40-7.50 (m, 6H). MS (Electrospray) : M/Z (M+H) 477; C28H32N2O3S + H requires 477.
Example 201 : A/-{3-r3-(4-cvanobenzyl)-6-ethyl-3-azabicvclor3.1.0lhex-6- yllphenvDmethanesulfonamide
Figure imgf000067_0001
The compound above was prepared by a similar method to that of Example 167, using the trifluoroacetic acid salt of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonamide (100 mg, 0.25mmol) and 4-cyanobenzaldehyde (33mg, 0.25mmol) as the starting materials. The product was purified using preparative HPLC (conditions 3) to afford the title compound (28 mg, 28 %) as an off-white solid.
1H-NMR (300MHz, CDCI3): 0.85(t, 3H), 1.80 (s, 2H), 2.05 (q, 2H), 2.80 (d, 2H), 3.00 (s, 3H), 3.10 (d, 2H), 3.70 (s, 2H), 7.00-7.20 (m, 3H), 7.20 (m, 1 H), 7.40 (d, 2H), 7.60 (d, 2H) MS (Electrospray) : M/Z (M+H) 396; C22H25N3O2S-H requires 396.
Example 202j /V-(3-(3-r2-f4-cvclopropylphenoxy)ethvπ-6-ethyl-3- azabicvclor3.1.0lhex-6-yl}phenyl)methanesulfonamide
Figure imgf000068_0001
To a solution of the trifluoroacetic acid salt of Λ/-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesuIfonamide (75 mg, 0.19 mmol) in N,N- dimethylformamide (3 ml) was added sodium hydrogen carbonate (64 mg, 0.8 mmol), 1-(2-chloroethoxy)-4- cyclopropylbenzene (41 mg, 0.21 mmol) and sodium iodide (3 mg, catalytic) and the reaction mixture was heated at 60 °C for 20 h. After cooling, the solvent was removed in-vacuo to give a crude residue. This was purified by preparative HPLC (condition 2) to afford the formate salt of the title compound (4 mg, 5%) as a brown gum.
1H-NMR (300MHz, CDCI3, data for formate salt) : 0.55-0.60 (m, 2H), 0.80-0.95 (m, 5H), 1.80-1.90 (m, 3H), 2.25 (bs, 2H), 2.95 (s, 3H), 3.15 (d, 2H), 3.45 (t, 2H), 3.80- 3.90 (m, 2H), 4.20 (t, 2H), 6.90 (d, 2H), 7.00 (d, 2H), 7.05-7.15 (t, 2H), 7.20 (s, 1H), 7.30 (t, 1 H). MS (Electrospray) : M/Z (M-H) 439; C25H32N2O3S - H requires 439.2.
Example 203: Λ/-(3-(6-ethyl-3-r(2-phenylcvclopropyl)methyll-3-azabicvclor3.1.Olhex- 6-yl}phenyl)methanesulfonamide
Figure imgf000068_0002
To a mixture of -rans-2-phenylcyclopropylcarboxa!dehyde {ref. J. Org. Chem., 1992, 57, 1526} (30 mg, 0.2 mmol) and the trifluoroacetic acid salt of Λ/-[3-(6-ethyl-3- azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (50 mg, 0.13 mmol) in dry 1,2- dichloroethane was added Hunigs' base (0.02ml, 0.12mmol). The mixture was sonicated for 3 minutes and then stirred for a further 30 minutes followed by the addition of sodium triacetoxyborohydride (50 mg, 0.25mmol). After stirring for 72 hours, the reaction was diluted with ethyl acetate (50ml) and partitioned between saturated sodium bicarbonate (2 x 25ml). The organic layer was washed with brine (2 x 20ml), dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure to produce a yellow/brown oil. This oil was dissolved in the minimum of quantity of dichloromethane and purified using a Biotage™ 6 g cartridge eluting with a gradient of ethyl acetate:hexane (30:70) to ethyl acetate (100%) to afford the title compound (32 mg 62%) as an oil. Η-NMR (300MHz, CDCI3): 0.78-0.90 (m, 3H), 0.97 (m, 1H), 1.24 (m, 1H), 1.72 (m, 1H), 1.76-1.79 (m, 2H) 1.90-2.05 (m, 2H) 2.45 (dd, 1 H), 2.60 (dd, 1 H), 2.84-2.95 (m, 2H), 2.99 (s, 3H), 3.02-3.08 (m, 2H) 6.89-7.3 (m, 9H), MS (Electrospray) : M/Z (M+H) 411 ; C24H30SO2N2 + H requires 411
PREPARATIONS
NB Preparations 1 to 148 from International Patent Application publication no. WO00/39089 are herein incorporated by reference in their entirety, and the same numbering is adhered to herein.
Preparation 149
1-r4-(3-chloropropyl)phenvπethanone
Figure imgf000069_0001
Aluminium chloride (15.0 g, 0.11 moles) and acetyl chloride (16.0 g, 0.20 moles) were dissolved in dichloromethane (50 ml) at room temperature. This mixture was then added dropwise to a solution 1-chloro-3-phenylpropane (15.5 g, 0.10 moles) in dichloromethane (25 ml) at room temperature over 15 minutes. The mixture was stirred for 1 hr and then poured cautiously onto ice. The aqueous layer was extracted with dichloromethane (450 ml). The organics were washed with water and brine, and then dried (MgSO4) and concentrated in-vacuo to give the title compound (19.2 g, 98%) as an oil.
1H-NMR (300MHz, CDCI3): 2.10 (quintet, 2H), 2.60 (s, 3H), 2.85 (t, 2H), 3.55 (t, 2H),
7.30 (d, 2H), 7.90 (d, 2H).
MS (thermospray) : M/Z [M+NH4]+ 214; C^H^CIO + NH4 requires 214.1.
Preparation 150 1-(2-chloroethoxy)-4-cvclopropylbenzene
Figure imgf000070_0001
4-Cyclopropylphenol (6.75 g, 50.3 mmol, reference: Horrom et. al., Org. Prep. Proceed. Int., 1992, 24 (6), 696-698), 2-chloroethyl p-toluenesulfonate (17.71 g, 75.5 mmol), and potassium carbonate (10.4 g, 75.4 mmol) in anhydrous acetonitrile (500 ml) were stirred together under a nitrogen atmosphere at reflux for 30 hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (1000 ml). The organics were washed with water (3 x 250 ml), dried (MgSO4), filtered and concentrated in vacuo. This crude material was purified by silica column chromatography eluting with hexane : dichloromethane (4:1) and then with hexane : dichloromethane (3:1) to afford the title compound (8.7 g, 88%) as a solid. Mpt: 47-48°C
1H-NMR (300MHz, CDCI3): 0.60-0.70 (m, 2H), 0.85-0.95 (m, 2H), 1.80-1.95 (m, 1 H), 3.81 (t, 2H), 4.21 (t, 2H), 6.82 (d, 2H), 7.02 (d, 2H). MS (thermospray) M/Z (M) 196; CnH^OCI requires 196.1.
Preparation 151
1-Allyl-1H-pyrolle-2.5-dione (see J. Orα. Chem.. 1997. 62. 2652)
Figure imgf000071_0001
To a solution of. maleic anhydride (98 g, 1.00 mol) in dry toluene (3000 ml) at room temperature under a nitrogen atmosphere was added dropwise a solution of allylamine (57.1 g, 1.00 mol) in toluene (1000 ml) over one hour. The mixture was stirred at room temperature for 20 hours and then zinc chloride (136.3 g, 1.00 mol) was added and the reaction was heated to 80°C. 1 ,1 ,1 ,3,3,3-Hexamethyldisilazane (242 g, 1.5 mol) in toluene (1000 ml) was then added dropwise over one hour and the mixture was stirred at 80°C for another 4 hours. The mixture was cooled to room temperature and then poured onto 1N HCI (4000 ml). The two layers were separated and the organic layer was washed with water (2000 ml), saturated sodium bicarbonate (2000 ml) and brine (2000 ml). The organics were concentrated in vacuo to give the title compound (74 g, 54%) as a solid.
1H-NMR (300MHz, CDCI3): 4.05 (d, 2H), 5.00-5.15 (m, 2H), 5.60-5.80 (m, 1H), 6.65 (2H, s).
Preparation 152 1-(3-nitrophenyl)-1-propanone hvdrazone
Figure imgf000071_0002
To a solution of 3-nitropropiophenone (168 g, 0.93 mol) in ethanol (830 ml) at room temperature was slowly added hydrazine monohydrate (96.8 g, 1.93 mol) via a dropping funnel. The reaction mixture was heated at reflux for 4 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (750 ml) and water (750 ml). The two layers were separated and the organic layer was washed with brine (250 ml), dried (Na2SO4), filtered and concentrated in-vacuo to give an orange oil. This residue was crystallised from diisopropyl ether at -20°C to afford the title compound (110 g, 61%) as a yellow crystalline solid.
Mpt: 32°C
Η-NMR (300MHz, CDCI3): 1.20 (t, 3H), 2.70 (q, 2H), 5.65 (broad s, 2H), 7.50 (t, 1 H), 7.95 (d, 1 H), 8.10 (d, 1 H), 8.50 (s, 1 H).
MS (Electrospray) M/Z [MH]+ 194;
Figure imgf000072_0001
+ H requires 194.1.
Preparation 153 3-Allyl-6-ethyl-6-(3-nitrophenyl)-3-azabicvclor3.1.0lhexane-2,4-dione
Figure imgf000072_0002
To a stirred solution of 1-(3-nitrophenyl)-1-propanone hydrazone (84.7 g, 439 mmol) in 1 ,4-dioxane (1000 ml) was rapidly added manganese dioxide (grade CMD-1 from Sumitromo, 175 g, 2.01 mol) followed by a saturated solution of ethanolic potassium hydroxide (40 ml) at room temperature. The mixture was stirred at room temperature for 18 minutes and during this period the reaction temperature had risen from 19°C to 25°C. Stirring was then stopped and the mixture was allowed to settle. This mixture was then filtered through a pad of Celite® dropwise, directly into a solution of 1 -allyl-1 H-pyrolle-2,5-dione (57.3 g, 418 mmol) in 1 ,4-dioxane (200 ml). The Celite® pad was washed with 1 ,4-dixane (100 ml) to ensure complete addition of the reactants. After stirring at room temperature for one hour the mixture was heated at reflux for 20 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was then crystallised from diisopropyl ether (1000 ml) at 0°C to afford the title compound (83 g, 66%) as an off-white crystalline solid.
MPt: 128-129°C
Η-NMR (300MHz, CDCI3): 0.90 (t, 3H), 1.80 (q, 2H), 2.80 (s, 2H), 4.05 (d, 2H), 5.20 (d, 1H), 5.30 (d, 1H), 5.75-5.85 (m, 1H), 7.55 (t, 1H), 7.70 (dd, 1H), 8.20 (dd, 1H), 8.25 (s, 1 H).
Preparation 154 3-allyl-6-(3-aminophenyl)-6-ethyl-3-azabicvclor3.1.01hexane-2.4-dione
Figure imgf000073_0001
To a stirred suspension of 3-allyl-6-ethyl-6-(3-nitrophenyl)-3- azabicyclo[3.1.0]hexane-2,4-dione (93 g, 310 mmol) and iron powder (151 g, 2.70 mol) in ethanol (6.75 L) was added calcium chloride (16.7 g, 0.15 moi) in water (1.2 L). The mixture was heated at reflux for three hours and then cooled to room temperature before being filtered through Celite®. The filtrate was concentrated in vacuo to give a wet solid. This material was dissolved in dichloromethane (500 ml) and the two layers were separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid (81 g). This material was crystallised from ethyl acetate and hexane (1:1 ; 6ml per gram) at room temperature to afford the title compound (54 g, 65%) as a pale yellow crystalline solid.
1H-NMR (300MHz, CDCI3): 0.90 (t, 3H), 1.75 (q, 2H), 2.75 (s, 2H), 3.95 (broad s, 2H), 4.05 (d, 2H), 5.25 (d, 1 H), 5.35 (d, 1 H), 5.75-5.85 (m, 1 H), 6.65 (d, 1 H), 6.70 (s, 1 H), 6.75 (d, 1 H), 7.10 (t, 1 H).
Preparation 155
3-(3-Allyl-6-ethyl-3-azabicyclor3.1.01hex-6-yl)aniline
Figure imgf000074_0001
To a solution of lithium aluminium hydride (1 M solution in THF; 400 ml, 400 mmol) in tetrahydrofuran (400 ml) under a nitrogen atmosphere at -15°C was added 3-allyl-6- (3-aminophenyI)-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (44 g, 163 mmol) in tetrahydrofuran (250 ml) via a dropping funnel over 0.5 hours. The mixture was then allowed to slowly warm to room temperature over one hour. The mixture was heated at 50°C for 3 hours and then cooled to 5°C. Water (400 ml) was then cautiously added to the cooled (5°C) reaction mixture. The solids were removed by filtration through a pad of Celite® , washing with ethyl acetate (400 ml). The filtrate was dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (38.1 g, 96%) as a golden oil.
1H-NMR (300MHz, CDCI3): 0.85 (t, 3H), 1.80-1.95 (m, 4H), 2.85-3.00 (m, 4H), 3.15 (d, 2H), 3.60 (broad s, 2H), 5.10 (d, 1 H), 5.20 (d, 1 H), 5.80-5.95 (m, 1 H), 6.50 (d, 1 H), 6.60 (s, 1 H), 6.65 (d, 1 H), 7.05 (t, 1 H). MS (AP+) M/Z [MH]+ 243; C16H22N2 + H requires 243.2.
Preparation 156 A/-r3-(3-allyl-6-ethyl-3-azabicvclo[3.1.01hex-6-yl)phenvnmethanesulfonamide
Figure imgf000075_0001
To a solution of 3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)aniIine (41 g, 169 mmol) and triethylamine (34 g, 337 mmol) in dichloromethane (750 ml) at -40°C was added dropwise methanesulfonyl chloride (23.7 g, 206 mmol) via a dropping funnel. The reaction mixture was slowly allowed to warm to room temperature over 2 hours and was then stirred at room temperature for 20 hours. The organics were then washed with water (4 x 500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (59.0 g) as a crude gum.
1H-NMR (300MHz, CDCI3): 0.85 (t, 3H), 1.85 (s, 2H), 1.95 (q, 2H), 2.80-3.20 (m, 9H), 5.10-5.25 (m, 2H), 5.80-5.95 (m, 1H), 7.00-7.40 (m, 4H).
Preparation 157 Λ/-r3-(6-ethyl-3-azabicvclof3.1.01hex-6-yl)phenyl1methanesulfonamide
Figure imgf000076_0001
To a degassed solution of Λ/-[3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesuIfonamide (54.0 g, 169 mmol) and 1 ,3-dimethylbarbituric acid (80.0 g, 512 mmol) in dichloromethane (500 ml) under a nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol). The mixture was heated at reflux for 8 hours and then stirred at room temperature for 20 hours. The organics were then extracted with 2M HCI (2 x 100 ml) and water (100 ml). The combined aqueous layers were then washed with dichloromethane (4 x 100 ml) and freeze dried to give a crude solid. This material was purified by preparative HPLC (condition 4) to afford the trifluoroacetic acid salt of title compound (25.2 g, 53%) as a grey solid.
1H-NMR (300MHz, CD3OD): 0.90 (t, 3H), 1.65 (q, 2H), 2.30-2.40 (m, 2H), 2.90 (s, 3H), 3.25-3.35 (m, 2H), 3.70-3.80 (m, 2H), 7.10-7.15 (m, 2H), 7.20 (s, 1H), 7.30 (t, 1 H).
MS (AP+) : M/Z [MH]+ 281 ; C14H20N2O2S + H requires 281.1.
Preparation 158 : 3-Benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicvclor3.1.01hexane- 2.4-dione
To a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone (100g, 0.56mol), in dioxan (1 L) was added MnO2 (350g, 2.3mol) and the reaction mixture stirred at room temperature for 30mins. The slurry was filtered through celite and the celite pad washed with dioxan (200mls). The filtrate was returned to a pot and N-benzyl maleimide (110g,) added portionwise over a period of 20mins. The reaction mixture was stirred at room temperature for 4hrs before being heated under reflux for 16hrs. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was triturated in methanol (500mls) and the product isolated by filtration as a white crystalline solid ( 56%).
NMR (CDCI3) d: 1.31 (s, 3H), 1.55 (s, 3H), 2.80 (s, 2H), 4.63 (s, 2H), 7.28-7.34 (m, 3H), 7.43-7.45 (d, 2H), 7.52-7.56 (t, 1 H), 7.63-7.65 (d, 1 H), 8.13-8.16 (d, 1H), 8.17 (s, 1H)
MS (APCI): m/z [MH+] 337.5 +H requires 337.3
Preparation 159: 6-(3-Aminophenyl)-3-benzyl-6-methyl-3-azabicvclor3.1.Olhexane- 2.4-dione
To a slurry of 3-benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4- dione (30g, 89mmol) in ethyl acetate (600mls) was added 5%Pt C (1.5g, 5wt%). The mixture was hydrogenated at 4 atm. (=60p.s.i.) / room temperature for 18hrs. The slurry was filtered through arbacel and the resulting solution evaporated in vacuo to yield the product as a white crystalline solid (24g, 88%). NMR (CDCI3) d: 1.26 (s, 3H), 2.74 (s, 2H), 3.7 (2H, bs), 4.60 (s, 2H), 6.56-6.58 (d, 1 H), 6.60 (s, 1 H), 6.65-6.67 (d, 1 H), 7.07-7.11 (t, 1 H), 7.26-7.33 (m, 3H), 7.42-7.44 (m, 2H).
MS (APCI): m/z [MH+] 307.5 +H requires 307.4
Preparation 160: N-{3-r3-Benzyl-6-methyl-2.4-dioxo-3-azabicvclol3.1.Olhex-6- yllphenvDmethanesulfonamide
To a solution of 6-(3-aminophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexane- 2,4-dione (24g, 78mmol) in ethyl acetate (480mls) was added pyridine (9.5mls, 118mmol) followed by the slow addition of methane sulfonyl chloride (9.1 mis, 118mmol). The reaction was stirred at room temperature for 2.5hrs. The reaction mixture was washed sequentially with 1M HCI solution (120mls) and water (120mls). The ethyl acetate was dried over MgSO4 and evaporated in vacuo to yield the product as an orange solid (30g, 99%).
NMR (CDCI3) d: 1.27 (s, 3H), 2.77 (s, 2H), 3.02 (s, 3H), 4.61 (s, 2H), 7.08-7.14 (m, 3H), 7.26-7.32 (m, 4H), 7.41-7.42 (d, 2H).
MS (APCI): m/z [MH+] 385.7 +H requires 385.5
Preparation 161 : N-f3-Benzyl-6-methyl-3-azabivclor3.1.01hex-6-vnphenyll methanesulfonamide
To a solution of N-{3-[3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6- yl]phenyl}methanesulfonamide (150g, 391 mmol), under nitrogen was added sodium borohydride (31 g, 820mmol). The reaction mixture was cooled to <10°C and the BF3.OEt2 (138.6mls, 1094mmol) added dropwise maintaining the temperature at <10°C. The reaction mixture was allowed to warm to room temperature over 2hrs before being heated under reflux for a further 8.5hrs. The reaction mixture was cooled to between 0°C and 5°C and an aqueous solution of piperazine (198.5g, 2304mmol in 1.26L of water) added. The reaction mixture was then heated under reflux for a period of 18hrs. The THF was removed under vacuum, ethyl acetate
(900mls) added, and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (450mls). The organic phases were combined and washed with water (750mls). The organics were dried over MgSO4 and evaporated in vacuo to yield the product as a white crystalline solid (129g, 93%).
NMR (CDCI3) d: 2.62 (s, 3H), 2.80-2.83 (d, 2H), 2.99 (s, 3H), 3.03-3.07 (d, 2H), 3.68 (s, 2H), 7.01-7.02 (s, 1H), 7.06-7.08 (m, 2H), 7.22-7.26 (m, 3H), 7.30-7.32 (m, 3H).
MS (APCI): m/z [MH+]357.5 +H requires 357.5
Preparation 162: N-f3-r6-methyl-3-azabicvcloF3.1.01hex-6- vπphenvDmethanesulfonamide To a solution of N-{3-benzyl-6-methyl-3-azabiyclo[3.1.0]hex-6-yl]phenyl} methanesulfonamide (20g, 56mmol), in methanol, was added ammonium formate (10.6g, 168mmol) and the reaction stirred for δminutes. 10% Pd/C (8g) was added and the resulting mixture heated at reflux for 16hrs. The mixture was allowed to cool and the catalyst removed by filtration through celite. The solvent was removed in vacuo to yield the product as a pale yellow oil, which solidified on standing (15.2g, 85%).
NMR (CDCI3) d: 1.27 (s, 3H), 1.85-1.88 (d, 2H), 2.93 (s, 3H), 3.07-3.10 (d, 2H), 3.39-3.44 (d, 2H), 6.92-6.97 (m, 2H), 7.06 (s, 1H), 7.20-7.23 (m, 1H).
MS (APCI): m/z [MH+] 267.4 +H requires 267.3
Preparation 163 : 3-Benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicvclor3.1.01hexane-2,4- dione
To a solution of 1-(3-nitrophenyl)-1-propanone hydrazone
(42.1gg, 217mmol), in dioxan (630mls) was added MnO2 (126g, 1440mmol) and the reaction mixture stirred at room temperature for 20mins. The slurry was filtered through celite and the celite pad washed with dioxan (200mls). The filtrate was returned to a pot and N-benzyl maleimide (44.9g, 239mmol) added portionwise over a period of 20mins. The reaction mixture was stirred at room temperature for 60hrs before being heated under reflux for 16hrs. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was heated to reflux in methanol (1200mls) for 3 hours and then cooled to room temperature. The product was isolated by filtration as a white crystalline solid (42.4g, 56%).
NMR (CDCI3) d: 0.69-0.73 (t, 3H), 1.47-1.49 (q, 2H), 2.78 (s, 2H), 4.64 (s, 2H), 7.3-7.32 (m, 2H), 7.43-7.44 (d, 1 H), 7.52-7.55 (t, 1 H), 7.62-7.65 (d, 2H), 8.17-8.18 (m, 3H). MS (APCI): m/z [MH+] 351.5 +H requires 351.3 Preparation 164: 6-(3-Aminophenyl)-3-benzyl-6-ethyl-3-azabicvclof3.1.01hexane-2.4- dione
To a slurry of 3-benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (42.1g, 120mmol) in ethyl acetate (850mls) was added 5%Pt C (2.1g, 5wt%). The mixture was hydrogenated at 60psi/ room temperature for 18hrs. The slurry was filtered through arbacel and the resulting solution evaporated in vacuo to yield the product as a white crystalline solid (34.1g, 89%).
NMR (CDCI3) d: 0.70-0.74 (t, 3H), 1.41-1.47 (q, 2H), 2.73 (s, 2H), 3.68 (bs, 2H),
4.61 (s, 2H), 6.55-6.57 (d, 1H), 6.60 (s, 1H), 6.66-6.68 (d, 1 H), 7.07-7.10 (t, 1H), 7.28-7.32 (m, 3H), 7.41-7.43 (d, 2H).
MS (APCI): m/z [MH+] 321.4 +H requires 321.4
Preparation 165: N-f3-r3-Benzyl-6-ethyl-2.4-dioxo-3-azabicyclor3.1.01hex-6- yllphenyl}methanesulfonamide
To a solution of 6-(3-aminophenyl)-3-benzyl-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4- dione (31.5g, 98mmol) in dichloromethane (250mls) was added pyridine (9.5mls, 118mmol) followed by the slow addition of methane sulfonyl chloride (9.1 mis, 118mmol). The reaction was stirred at room temperature for 16hrs. The reaction mixture was washed sequentially with 1 M HCI solution (250mls) and water (120mls). The dichloromethane was dried over MgSO4 and evaporated in vacuo to yield the product as a waxy pink solid (38.2g, 98%). NMR (CDCI3) d: 0.68-0.72 (t, 3H), 1.42-1.47 (q, 2H), 2.75 (s, 2H), 3.02 (s, 3H),
4.62 (s, 2H), 7.13-7.18 (m, 3H), 7.29-7.42 (m, 4H), 7.41-7.43 (d, 2H). MS (APCI): m/z [MH+] 399.6 +H requires 399.5
Preparation 166: N-(3-Benzyl-6-ethyl-3-azabicvclor3.1.OIhex-6-vnphenyl} methanesulfonamide
To a solution of N-{3-[3-benzyl-6-ethyI-2,4-dioxo-3-azabicyclo[3.1.0]hex-6- yl]phenyl}methanesulfonamide (38.2g, 95rnmol), in THF (200mls) under nitrogen was added sodium borohydride (7.46g, 201 mmol). The reaction mixture was cooled to <10 C and the BF3.OEt2 (38.1 mis, 268mmol) added dropwise maintaining the temperature at <10 C. The reaction mixture was allowed to warm to room temperature over 2hrs before being heated under reflux for a further 12hrs. The reaction mixture was cooled to between 0°C and 5°C and an aqueous solution of piperazine (48.7g, 565mmoI in 320mls of water) added. The reaction mixture was then heated under reflux for a period of 18hrs. The THF was removed under vacuum, ethyl acetate (200mls) added, and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (200mls). The organic phases were combined and washed with 3 separate portions of water (3x400m!s). The organics were dried over MgSO4 and evaporated in vacuo to yield the product as a white crystalline solid (33.5g, 94%).
NMR (CDCI3) d: 0.84-0.88 (t, 3H), 1.76-1.77 (d, 2H), 2.06-2-.12 (q, 2H), 2.79-2.81 (d, 2H), 2.99 (s, 3H), 3.06-3.08 (d, 2H), 3.67 (s, 2H), 7.01-7.03 (d, 1 H), 7.08-7.10 (d, 2H), 7.22-7.26 (m, 3H), 7.30-7.32 (m, 3H).
MS (APCI): m/z [MH+] 371.3 +H requires 371.5
Preparation 167: N-(3-r6-Ethyl-3-azabicvclor3.1.0lhex-6- yllphenvDmethanesulfonamide
To a solution of N-{3-benzyl-6-ethyl-3-azabiyclo[3.1.0]hex-6-yl]phenyl} methanesulfonamide (500mg, 1.34mmol), in methanol (30mls), was added ammonium formate (255mg, 4.05mmol) and the reaction stirred for 5minut.es. 10% Pd/C (200mg) was added and the resulting mixture heated at reflux for 2hrs. The mixture was allowed to cool and the catalyst removed by filtration through celite. The solvent was removed in vacuo to yield the product as a pale yellow oil, which solidified on standing (15.2g, 85%).
NMR (CDCI3) d: 0.80-0.84 (t, 3H), 1.64-1.69 (q, 3H), 1.82-1.86 (d, 2H), 2.98 (s, 3H), 3.12-3.18 (d, 2H), 3.21-3.26 (d, 2H), 7.01-7.06 (d, 1H), 7.10-7.14 (m, 2H), 7.25- 7.28 (m, 1 H).
MS (APCI): m/z [MH+] 281.7 +H requires 281.4 Other building block materials useful in synthesising compounds of formula (I) with various different R4 groups are available from the sources indicated in the table below, and routine derivatisation thereof, or analogy synthesis.
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001

Claims

1. A substance which is a compound of formula I,
Figure imgf000090_0001
(I) wherein the "Ar" ring represents an optionally benzo-fused phenyl or 5- or 6-membered heteroaryl ring;
R1 when taken alone is H, halogen, NO2, NH2, NY2WYl, Hetl, AD, CO R7, C(O)R8, C(=NOH)R8, or OE,
Y^ is H, C\.β alkyl, C3.6 alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Hetl),
W is SO2, CO, C(O)0, P(Y1)=0, P(Y1)=S,
Yl is Cι_ιo alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, C1.4 alkoxy, C\.β alkanoyloxy, CONH2, .β alkoxycarbonyl, NH2, aryl, mono- or di(Cι_4 alkyl)amino, C3.3 cycloalkyl, phthalimidyl, Hetl), Hetl, ary\ (optionally substituted by one or more substituents independently selected from Cι_4 alkyl, Ci _4 haloalkyl and halogen), H2, N(Cι _6 alkyl)2 or NH(Cι_6 alkyl),
Hetl js a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more substituents independently selected from C\.β alkyl, Cι _6 alkoxy, C3.6 cycloalkyl, C\.β haloalkoxy, C\.β haloalkyl, C3.6 halocycloalkyl, =O, OH, halogen, NO2, SiRl9 Rl9bRl9cj CON20aR20b NR20aR20b; sR21a Ml2lbSo2R a NR21cc(O)OR22b; NR2ldC0R22d, and Ci _6 alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a -S-, S(O)- or -S(02)- group, and carbon atoms in the ring can be present as a part of a carbonyl moiety;
Rl9a; Rl9b5 R19c each independently represent C\.β alkyl or aryl,
R2fJa an(j R20b eacn independently represent H, C\.β alkyl, aryl, (C1.4 alkyl)phenyl, each of which alkyl, aryl and alkylphenyl are optionally substituted by one or more C1.4 alkyl, C 1.4 alkoxy, OH, NO , NH2 and/or halogen, or R20a ancj R20b can tøe taken together with the N atom to which they are attached, to form a 4- to 6-membered ring optionally substituted by one or more substitutuents independently selected from one or more Ci .4 alkyl, C1.4 alkoxy, OH, =O, NO2, NH2 and/or halogen,
R 1a, b, c and d each independently represent H, C\.β alkyl, aryl or C 1.4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more C1.4 alkyl, Cι_4 alkoxy, OH, NO2, halogen, NH2,
R22a, b and c each independently represent Cι_6 alkyl, aryl or C1 -4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Ci .4 alkyl, Cι_4 alkoxy, OH, NO2, halogen, H2,
A is Cι_4 alkylene, C2-4 alkenylene or C2-4 alkynylene, each of which is optionally substituted by one or more Ci .4 alkyl, Ci .4 alkoxy, halogen and/or OH,
D is H, OH, CN, NR25R26 CONR25R26 NHR2 CO2R28, COR2?, C(=NOH)R29,
or AD is CN, NR25R26 CONR25R26,
where R25 and R2^ are either each independently H,'Cι_3 alkyl, C3.8 cycloalkyl, aryl, C\_ alkylphenyl (each of which C1.3 alkyl, C3.8 cycloalkyl, aryl and C1.4 alkylphenyl are optionally substituted by one or more NO2, halogen, C1.4 alkyl and/or Ci .4 alkoxy, (each of which latter Ci .4 alkyl and Ci _4 alkoxy is optionally substituted by one or more halogen)), or R ^ and R26 are taken together with the N atom to which they are attached and can fofm a 4- to 7-membered heterocyclic ring optionally incorporating one or more further hetero atoms selected from N, O and S, and which ring is optionally substituted by one or more Ci _ 4 alkyl, OH, =O, NO , NH2 and/or halogen,
R2? is COR30, CO R3 1a, SO2R3l ,
R28 and R2 are each independently H, C\.β alkyl, C3.8 cycloalkyl, aryl or Cι _ 4alkylphenyl, each of which C\.β alkyl, C3.8 cycloalkyl, aryl and C1.4 alkylphenyl are optionally substituted by one or more NO2, halogen, Cj_4 alkyl, C .4 alkoxy (each of which latter C1.4 alkyl and Ci .4 alkoxy are optionally substituted by one or more halogen),
R30 is H, Cι_4 alkyl, C3_g cycloalkyl, Cι _4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, C1.4 alkylphenyl, phenyl(Cι _4 )alkoxy, (each of which C1.4 alkyl, C3_8 cycloalkyl, C1.4 alkoxy, C3-8 cycloalkyloxy, aryl, aryloxy, Ci .4 alkylphenyl and phenyl(Cι_4 )alkoxy are optionally substituted by one or more NO2, halogen, C1.4 alkyl, Cχ_4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)),
R3 la and R3 b are each independently C1.4 alkyl, C3.8 cycloalkyl, aryl or C1.4 alkylphenyl, each of which is optionally substituted by one or more NO2, halogen, C1 -.4 alkyl or C 1.4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen
E is H, CONR32R335 CSNR32R33, COR34 C02R 4, COCH(R34a)NH2, R 5, CH2CO2R35a CHR35bco2R35a CH2OCO2R35c CHR35doCO2R35cs COCR36=CR37NH , COCHR36CHR3 NH2, or PO(OR38)2,
R32 and R are each independently H, C3.10 alkylalkenyl, C3.7 cycloalkyl (optionally substituted by C1.4 alkyl), phenyl (optionally substituted by (X)n), CI.JQ alkyl (optionally substituted by C4..7 cycloalkyl (optionally substituted by C1.4 alkyl) or phenyl optionally substituted by (X)n)=
or R 2 and R can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising further hetero atoms selected from N, O and S, which heterocycle is optionally substituted by C1.4 alkyl, optionally substituted by one or more halogen, R is H, C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), phenyl (optionally substituted by (X)n, C1.4 alkanoyloxy, NR32R33, CONR32R33 anαγor OH), or C\.β alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), or phenyl (optionally substituted by (X)n, C1 -4 alkanoyloxy, NR32R33, C0NR32R33 and/or OH)),
R34a is JJ, C\.β alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), or phenyl (optionally substituted by (X)n> C1.4 alkanoyloxy, NR32R33, CONR3 R 3 and/or OH)), C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), phenyl (optionally substituted by (X)n, C1.4 alkanoyloxy, NR 2R33, C0NR32R 3 and/or OH) or a naturally occuring amino acid substituent,
R35 is C4.7 cycloalkyl optionally substituted by one or more Cχ_4 alkyl, phenyl (optionally substituted by one or more (X)n,
Figure imgf000093_0001
alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl (optionally substituted by one or more (X)n» C1.4 alkanoyl, NHR32, CON(R3 )2, and/or OH)), C1.4 alkoxy(Cι_4 alkyl), phenyl(Cι. )alkyloxy(Cι.4)alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,
R35a,b,c and d are each independently H, C4.7 cycloalkyl optionally substituted by one or more Cj_4 alkyl, phenyl optionally substituted by one or more (X)n or Cι_6 alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl optionally substituted by one or more (X)n),
R 6 and R3 each independently represent H, C3-6 alkylalkenyl, C4.7 cycloalkyl, phenyl optionally substituted by one or more (X)n, or C\.β alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, or phenyl optionally substituted by one or more (X)n)>
R38 is C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl optionally substituted by one or more (X)n, or C\.β alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Ci .4 alkyl, or phenyl optionally substituted by one or more (X)n), R2 when taken alone is H or halogen;
or R and R2, when attached to adjacent carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Hetla;
Hetla is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (and is preferably an optionally benzo-fused 5- to 7- membered heterocyclic ring) and which group is optionally substituted by one or more substituents independently selected from OH, =0, halogen, Ci _4 alkyl, Cj_4 haloalkyl, Ci _4 alkoxy and Ci -4 haloalkoxy, which Cι _4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and C1.4 haloalkoxy groups can be optionally substituted by one or more C3.6 cycloalkyl, aryl(Cι _g)alkyl, which aryl group is optionally substituted by one or more halogen, C1.4 alkyl, C1 -4 haloalkyl, C 1.4 alkoxy and C 1.4 haloalkoxy, which latter Cι _4 alkyl, Cι _4 haloalkyl, C1.4 alkoxy and C1.4 haloalkoxy groups can be optionally substituted by one or more NR23R24; NR2 S(0)nR 4; NR23C(0)mR2 , and if a S atom is present in a ring, it can be present as part of a -S-, S(O)- or -S(0 )- group,
which R23 and R2 when taken alone independently represent H, C1.4 alkyl, or Cι _4 haloalkyl,
or R23 and R2 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, Ci .4 alkyl, Cj-4 haloalkyl, C1.4 alkoxy and/or C1.4 haloalkoxy groups,
R3 is H, CN, halogen, C .β alkoxy, C\.β alkoxycarbonyl, C2_6 alkanoyl, C2_6 alkanoyloxy, C3-8 cycloalkyl, C3.8 cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, N 12R13, CONR12R13, NY2WYl, Cι _6 alkyl, C2_ιo alkenyl, C2.10 alkynyl, (each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or more CN, halogen, OH, C\.β alkoxy, C\.β alkoxycarbonyl, C _6 alkyloxycarbonyloxy, C\.β alkanoyl, C\.β alkanoyloxy, C3.8 cycloalkyl, C3.8 cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13S C0NR12R13 and/or NY2WYl), R4 is Cι_ι o alkyl, C3.10 alkenyl or C3.10 alkynyl, each of which groups is linked to the N atom via a sp3 carbon, and which group is substituted by one or more substituents selected from:
C2_6 alkoxy [substituted by one or more groups selected from OH, NR25R26, CONR25R26, halogen, C .β alkoxy, C2_4 alkynyl, C2_4 alkenyl, heteroaryl 1, aryll, COCH2CN, CO(heteroaryll), CO(aryll), C02(heteroaryll), COCH2(aryll), COCH (heteroaryll), C02CH2(aryll),*C02CH2(heteroaryll), S(O)n(Cι _6 alkyl), S(O)n(aryll), S(O)n(heteroaryll), S02NR25R26 and cycloalkyll],
S(0)nCι_6 alkyl [optionally substituted by one or more groups selected from OH, NR25R26, CONR25R26; halogen, C\.β alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl 1, aryl , COCH2CN, CO(heteroaryll), CO(aryll), C0 (heteroaryll), COCH2(aryll), COCH2(heteroaryll), C02CH2(aryll), C02CH2(heteroaryll), S(0)n(Cι_6 alkyl), S(0)n(aryll), S(0)n(heteroaryl ), S02NR25R26 and cycloalkyll],
aryl2,
C02CH2(heteroaryll),
C02CH2(aryll), cycloalkyll,
CO(heteroaryll),
CO(aryll),
OCO(aryll),
OCO(heteroaryll), OCO(Cι_6 alkyl),
OCOCH2CN,
C02(heteroaryll),
C02(aryll),
COCH2(heteroaryll), S(0)naryll,
S(0)nCH2aryll,
S(0)n(heteroaryll),
S(0)nCH2(heteroaryll),
NHS02aryll, NHSO2(Cι _6 alkyl), NHSO2(heteroaryll),
NHSO2CH2(heteroaryl 1),
NHSO CH2(aryll),
NHCOaryll, NHCO(Cι_6 alkyl),
NHCONHaryll,
NHCONH(Cι _6 alkyl),
NHCOheteroaryll,
NHCONHheteroaryl 1 , NHCO2(aryll),
NHCO2(Cι_6 alkyl),
NHC02(heteroaryll), aryloxy, heteroaryl loxy, C\.β alkoxycarbonyl substituted by C\.β alkyl, aryl, C\.β alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR 5R26,
C _6 alkanoyl substituted by C\.β alkyl, aryl, C\.β alkoxy, CH (aryll), C1.4 haloalkyl, halogen, OH, CN or NR^R2^
C2_6 alkanoyloxy substituted by Cι _g alkyl, aryl, C\.β alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR2 26, cycloalkyl loxy,
COcycloalkyll, heterocycle substituted by one or more substituent selected from C\.β alkyl(substituted by
OH), CONR 5R26 CH CONR25R26, NR25R26; NHCONR25R26; CO(Cι _6 alkyl), S02NR25R265 S02(CI.6 alkyl), C02(Cι_6 alkyl), CH2C02(Cι.6 alkyl), OCH2C02(Cι.6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl,
heterocyclyloxy substituted by one or more substituent selected from Ci _g alkyl(substituted by OH), CONR25R26J CH2CONR25R265 NR25R26 HCONR25R26, CO(Ci-6 alkyl), S02NR25R26, S02(CI_6 alkyl), C02(Cι_6 alkyl), CH2C02(Cι_6 alkyl), OCH2C02(Cι_6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl,
WHEREIN aryll is phenyl optionally fused to a C5.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C\.β alkyl(optionally substituted by OH, CN or halogen), C\.β haloalkoxy, OH, =O, NY2WYl, halogen, C\.β alkoxy, CO R25R265 CH2CONR25R26, NR25R26, NHCONR25R263 co(Ci-6 alkyl), COaryl, COheteroaryl, S02NR25R26, S(0)n(Cι _6 alkyl), S(0)n(aryl), S(O)n(heteroaryl), CO2(Ci.6 alkyl), C02(aryl), C02(heteroaryl), C02H, (CH2)ι_4C02(Cι_6 alkyl), (CH2)!_ 4CO2H, (CH2)ι.4C02(aryl), (CH2)1.4CO2(heteroaryl), 0(CH2)ι.4C02(Cι.6 alkyl), 0(CH2) i -4CO H, 0(CH ) i _4C02(aryl), 0(CH2) i _4C02(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, 0(CH2)I_4CONR25R26 and C3.7 cycloalkyl,
aryl2 is phenyl optionally fused to a C5.7 carbocyclic ring, which group is substituted by one or more substituent selected from C .β alkyl(substituted by OH), CON 25R26, CH2CONR25R26; R25R 6, NHCONR25R26, CO(CI_6 alkyl), COaryl, COheteroaryl, S02NR25R26, S(0)n(Cι_6 alkyl), S(0)n(aryl), S(0)n(heteroaryl), C02(Cι _6 alkyl), CO2(aryl), CO2(heteroaryl), C02H, (CH2)ι _4C02(Cι_6 alkyl), (CH2)ι.4C02H, (CH2)ι_ CO2(aryl), (CH2)ι_4C02(heteroaryl), 0(CH2)ι.4C02(Cι.6 alkyl), 0(CH2)l-4C02H, O(CH2)i_4C02(aryl), 0(CH2)i-4C02(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, 0(CH2)I_4CONR25R26 and C3.7 cycloalkyl,
heteroaryl is heteroaryl optionally fused to a 05.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C\.β alkyl(optionally substituted by OH, CN or halogen), C\.β haloalkoxy, OH, =0, NY2WYl, halogen, Cι_6 alkoxy, CONR25R26; CH2CONR25R26, NR25R26, NHCONR25R26, CO(Cι_6 alkyl), COaryl, COheteroaryl, S02NR25R26, S(0)n(Cι_6 alkyl), S(0)n(aryl), S(0)n(heteroaryl), CO2(Cι_6 alkyl), C02(aryl), C02(heteroaryl), C02H, (CH2)ι.4C02(Cι_6 alkyl), (CH2)ι_ 4CO2H, (CH2)i-4C02(aryl), (CH2)ι.4CO2(heteroaryl), 0(CH2)1.4C02(Cι.6 alkyl), 0(CH2)ι_4CO H, 0(CH2)1.4C02(aryl), 0(CH2)i.4C02(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, 0(CH2)i-4C0NR 5R26 and C3.7 cycloalkyl,
cycloalkyll is a C3.10 carbocyclic system with one or two rings and which is substituted by Cι_6 alkyl, aryl, C\.β alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR25R26>
WITH THE PROVISO THAT THERE ARE NO N-R4 GROUPS WHEREIN THERE IS A HETERO-ATOM LINKED TO ANOTHER HETEROATOM VIA ONE SP3 CARBON
Z is a direct bond, CO or S(0)n group,
B is (CH2)p, R 2 and Rl3 each independently represent H or C1.4 alkyl,
or Rl and Rl3 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from N 16, O and/or S, and which is optionally substituted by one or more Cj_4 alkyl,
Rl4 and Rl5 each independently represent H, Cι_ιo alkyl, C3. Q alkenyl, 03.1 rj alkynyl, C3-8 cycloalkyl, aryl or heteroaryl,
or R and Rl 5 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR16, O and/or S, and which is optionally substituted by one or more Ci ..4 alkyl,
Rl6 is H, C\.β alkyl, C3.8 cycloalkyl, (C\.β alkylene)(C3_8 cycloalkyl) or (C\.β alkylene)aryl,
R5 and R when taken separately are each independently H, C\.β alkyl,
R5 and Εβ can be taken together with the carbon atoms to which they are joined to form a C3_8 cycloalkyl ring,
R6, R7; R9 and RlO when taken separately are H,
R5 and R6 or R can be taken together with the carbon atoms to which they are joined to form a C3.8 cycloalkyl ring,
X is halogen, C1.4 alkyl, Cι _4 alkoxy, Cι_4 haloalkyl or C 1.4 haloalkoxy,
m is 1 or 2;
n is 0, 1 or 2;
p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
q is O or l; "Naturally occuring amino acid substituent" means the α-substituent that occurs in any one of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline;
"Heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if a S atom is present in the ring, it can be present as part of a - S-, S(O)- or -S(0)2- group, and which may be joined to the remainder of the compound via any available atom(s);
"Heterocycle" is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms;
"Aryl", including in the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.);
"Alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbon atoms allows;
"Cycloalkyl" groups can be polycyclic if the number of carbon atoms allows;
or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.
2. A substance according to claim 1 wherein the "Ar" ring represents phenyl or pyridyl.
3. A substance according to any preceding claim wherein Rl when taken alone is OH, CN, halogen, N02, NH2, NY2WYl or Hetl .
4. A substance according to any preceding claim wherein R2 when taken alone is H.
5. A substance according to claim 1 or 2 wherein Rl and R2 are taken together with the carbon atoms to which they are attached and represent an optionally benzo-fused 5- to 7- membered heteroaryl ring optionally substituted by C 1.4 alkyl or C .4 haloalkyl.
6. A substance according to any preceding claim wherein X is CI.
7. A substance according to any preceding claim wherein n is 0 and q is 0.
8. A substance according to any preceding claim wherein R is H, CN, or C\.β alkyl (optionally substituted by one or more halogen, OH, C\.β alkoxy, C\.β alkoxycarbonyl, C2_ β alkanoyl, C2-6 alkanoyloxy, C2.β alkyloxycarbonyloxy, NR1 R13, CONR12R13 and/or NY2WYl).
9. A substance according to any preceding claim wherein R is Cι_ιo alkyl substituted by one or more substituents selected from:
C2_g alkoxy [substituted by one or more groups selected from OH, R2^R26, CONR ^R26, halogen, C\.β alkoxy, C2_4 alkynyl, C2_4 alkenyl, heteroaryl 1, aryll, COCH2CN, CO(heteroaryll), CO(aryll), C02(heteroaryll), COCH2(aryll), COCH2(heteroaryll), C02CH2(aryll), C02CH2(heteroaryll), S(0)n(Cι.6 alkyl), S(O)n(aryll), S(0)n(heteroaryll), S02NR25R26 and cycloalkyll],
S(0)nCι_6 alkyl [optionally substituted by one or more groups selected from OH, NR25R26, CONR25R26 halogen, C\.β alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryll, aryll, COCH2CN, CO(heteroaryll), CO(aryll), Cθ2(heteroaryll), COCH2(aryll),
COCH2(heteroaryll), CO2CH2(aryll), CO2CH2(heteroaryll), S(O)n(Cι.6 alkyl), S(O)n(aryll), S(O)n(heteroaryll), S02NR25R26 and cycloalkyll],
aryl2, C0 CH2(heteroaryll),
C02CH2(aryll), cycloalkyll,
COheteroaryl1),
CO(aryll), OCO(aryll), OCO(heteroaryll),
OCO(Cι_6 alkyl),
OCOCH2CN,
C0 (heteroaryll), C02(aryll),
COCH (heteroaryll),
S(0)naryll,
S(0)nCH2aryll,*
S(0)n(heteroaryll), S(0)nCH2(heteroaryll),
NHS02aryll,
NHS02(Cι_6 alkyl),
NHS02(heteroaryll),
NHS02CH2(heteroaryl 1 ), NHSθ2CH2(aryll),
NHCOaryll,
NHCO(Cι _6 alkyl),
NHCONHaryll,
NHCONH(Cι_6 alkyl), NHCOheteroaryll,
NHCONHheteroaryl 1 ,
NHC02(aryll),
NHC02(Cι.6 alkyl),
NHC02(heteroaryll), aryl2oxy, heteroaryl loxy,
Cι_6 alkoxycarbonyl substituted by C\.β alkyl, aryl, C\.β alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR25R26,
C2_6 alkanoyl substituted by C\.β alkyl, aryl, C\.β alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR2 26,
C2_6 alkanoyloxy substituted by Ci _g alkyl, aryl, Cι_6 alkoxy, CH2(aryll), Cι _4 haloalkyl, halogen, OH, CN or NR25R26, cycloalkyl loxy,
COcycloalkyll, heterocycle substituted by one or more substituent selected from Ci .β alkyl(substituted by OH), C0NR25R26 CH CONR25R26, NR25R26S NHCONR25R26; CO(CI_6 alkyl), SO2NR25R26; S02(C1_6 alkyl), CO (Cι.6 alkyl), CH2C02(Ci _6 alkyl), OCH2C02(Cι_6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl,
heterocyclyloxy substituted by one or more substituent selected from Ci _g alkyl(substituted by OH), CONR25R26) CH2CONR25R26, N 25R26, NHCONR25R 6, CO(Cι _g alkyl), SO2NR25R26; S02(Cι _6 alkyl), C02(Cι _6 alkyl), CH2C02(Cι.6 alkyl), OCH2C02(C1.6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl,
10. A substance according to any preceding claim wherein R^, Rδ, R7, R8 R9 an(j R10 are each taken separately and are all H.
11. A substance according to any preceding claim wherein the " Ar" ring represents a group of formula:
Figure imgf000102_0001
12. A substance according to any preceding claim wherein R3 is H, CH3, C2H5, i-C3H7, n- C3H7 or CH2OCH3.
13. A substance according to any preceding claim except claim 5 wherein Rl is OH, CN, I, CI, NH2, NO2, optionally benzo-fused heteroaryl, NHS02γl, NHCOγl or NHC02γl.
14. A substance according to any preceding claim wherein R4 is C\.\Q alkyl substituted by cycloalkyll.
15. A substance according to any preceding claim except claims 3, 4 and 13 wherein R and R2 are taken together with the carbon atoms to which they are attached are a 5-membered heteroaryl moiety optionally substituted by Ci .4 alkyl or Ci .4 haloalkyl.
16. A substance according to any preceding claim wherein R3 is CH3 or C Hf.
17. A substance according to any preceding claim except claims 5 and 15 wherein Rl when taken alone is OH, CN, I, CI, NH2, Nθ2,l,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHS02(Cι_6 alkyl), NHSO2(Cι_ β alkyl substituted by methoxy, CONH2, OH, C02(C2-6 alkyl), phthalimido, NH2 or halogen), NHS02NH2, NHS02NH(Cι _6 alkyl), NHS02N(Cι_6 alkyl)2, NHS02Hetιa, NHCO(Cι_6 alkyl) or NHC02(Cι_6 alkyl).
18. A substance according to claim 17 wherein Rl is OH, NHS0 CH3, NHS02C2H5, NHS02(n-C3H7), NHS02(i-C H7), NHS02(n-C4H7), NHS02NH(i-C3H7), NHS02(N- methylimidazol-4-yl), NHS02(CH2)2OCH3, NHS02(CH )20H, 1,2,4-triazolyl or imidazol- 2-yl.
19. A substance according to claim 18 wherein R is OH, NHS02CH3, NHSO2C2H5 or imidazol-2-yl.
20. A substance according to claim 15 wherein Rl and R2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2-substituted by CF3.
21. A substance according to any preceding claim wherein R4 is C _4 alkyl substituted by cycloalkyll.
22. A substance according to any preceding claim wherein R4 is propyl substituted by cycloalkyll.
23. A substance according to any preceding claim wherein R4 is propyl substituted by a C3. 10 carbocyclic system with one or two rings and which is substituted by OH.
24. A substance according to any preceding claim wherein R4 is propyl substituted by (cyclohexyl substituted by OH).
25. A substance according to any preceding claim wherein R4 is (l-hydroxycyclohexyl)prop- 3-yl.
26. A substance according to claim 1 which has the following relative stereochemistry:
Figure imgf000104_0001
27. A substance according to claim 1 which is selected from the compounds of the Examples as described herein, and the salts and prodrugs thereof.
28. A pharmaceutical or veterinary composition comprising a substance according to any one of the preceding claims, and a pharmacutically or veterinarily acceptable carrier.
29. A substance according to any of claims 1 to 26 for use in medicine.
30. A substance according to any of claims 1 to 26 for use as a medicament useful for the treatment of an opiate-mediated disease or condition.
31. The use of a substance according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of a disease or condition mediated by opiate receptors.
32. A method of treatment of a condition mediated by an opiate receptor or receptors comprising administration of a therapeutically active amount of a substance according to any one of claims 1 to 26.
33. A process for the preparation of a substance according to claim 1 which comprises: (a) for compounds of formula I in which q is 0 and Rl represents Nγ2wγl, reacting a compound of formula II,
Figure imgf000105_0001
II with a compound of formula III,
Figure imgf000105_0002
wherein l is a suitable leaving group, such as halogen or γlS020- ;
(b) for compounds of formula I in which q is 0 and Rδ and R7 both represent H, reduction of a compound of formula IV,
Figure imgf000105_0003
IV using a suitable reducing agent;
(c) for compounds of formula I in which q is 0 and R and RlO both represent H, reduction of a compound of formula V,
Figure imgf000106_0001
V using a suitable reducing agent;
(d) for compounds of formula I in which q is 0 and Rl and R2 are attached to adjacent carbon atoms and are taken together with the carbon atoms to which they are attached to represent Hefla, m which Hetl represents an imidazolo unit, reaction of a corresponding compound of formula VI,
Figure imgf000106_0002
VI with a compound of formula VII,
RYC0 H VII wherein RY represents H or any of the optional substituents on Hetla (as defined above), preferably H, C1.4 alkyl or C 1.4 haloalkyl;
(e) where q is 0, reacting a compound of formula VIII,
Figure imgf000107_0001
Nπi with a compound of formula IX,
R4-Lg IX wherein Lg is a leaving group; (f) for compounds of formula I in which q is 0 and R6, R7, R9 and RlO are all H, reduction of a compound of formula X,
Figure imgf000107_0002
X
with a suitable reducing agent;
(g) for compounds of formula I in which q is 0 and R represents OH, reacting a compound of formula II, where γ2 is H, as defined above, with fluoroboric acid and isoamyl nitrite;
(h) for compounds of formula I in which q is 0 and Rl represents CI, reacting a compound of formula II, where γ2 is H, as defined above, with sodium nitrite in the presence of dilute acid, followed by reaction with copper (I) chloride in the presence of concentrated acid;
(i) for compounds of formula I in which q is 1 , reacting a compound of formula I where q is 0 with a suitable oxidising agent such as aqueous hydrogen peroxide; or
(j) for compounds of formula I where q is 0, by reduction of a corresponding compound of formula XXXI,
Figure imgf000108_0001
XXXI
where R4aCH2 takes the same meaning as R4 as defined above,
(K) for compounds of formula (I) where q is 0, reductive amination reaction of the amine of formula VIII above with an aldehyde of formula R4a-CHO wherein R4aCH2 takes the same meaning as R4 as defined above,
and where desired or necessary converting the resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa.
34. A compound of formula II, IV, V, VI, X, xa χι, χπs χχι, χχιι, χχiπ, χχιv, XXIX, XXIXa, XXX, or XXXI, or salt thereof, as described herein.
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