Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems

Definitions

• the present invention relates to a class of dopamine agonists, more particularly a class of agonists that are selective for D3 over D2.
• These compounds are useful for the treatment and/or prevention of neuropsychiatric disorders, neurodegenerative disorders, pain and sexual dysfunction, for example female sexual dysfunction (FSD), in particular female sexual arousal disorder (FSAD), and male sexual dysfunction, in particular male erectile dysfunction (MED).
• Male sexual dysfunction as referred to herein includes ejaculatory disorders such as premature ejaculation, anorgasmia (inability to achieve orgasm) or desire disorders such as hypoactive sexual desire disorder (HSDD; lack of interest in sex).
• the present invention encompasses compounds which belong to the chemical class of chromans.
• Other examples of chroman species may be found in publications including WO 96/30333, European Journal of Medicinal Chemistry (1976), 11 (3), 251-6; Journal of Medicinal Chemistry (2004), 47(16), 3927-30; Bioorganic and Medicinal Chemistry (1999), 7(2), 335-341 ; Journal of Chromatography , A, (1995), 704(1 ), 83-7; Journal of Medicinal Chemistry (1994), 37(24), 4245-50; European Journal of Medicinal Chemistry (1991 ), 26(5), 497-504; Journal of Labelled Compounds and Radiopharmaceuticals (1998), 25(8), 833-54; European Journal of Medicinal Chemistry (1976), 11 (3), 257-62; WO 90/12795; Journal of Medicinal Chemistry (1972), 15(8), 863-5; and US 4,801 ,605.
• the present invention provides for compounds of formula (I)
• A is C-R 6 ;
• R 1 is selected from H, (CrC ⁇ Jalkyl and (C 3 -C 8 )cyclic alkyl
• R 2 is selected from (Ci-C 6 )alkyl and (C 3 -C 8 )cyclic alkyl, wherein said (C r C 6 )alkyl is optionally substituted by phenyl or Het;
• R 3 is selected from H or (C r C 6 )alkyl
• R 4 is selected from H, CN, O(C r C 6 )alkyl, C(O)NH 2 , Cl, F and (C r C 6 )alkyl, wherein said (C r C 6 )alkyl is optionally substituted by OH;
• R 5 is selected from H, OH, O(C r C 6 )alkyl, C(O)NH 2 , CN, NH 2 and Het;
• R 6 is selected from H, (C r C 6 )alkyl, C(O)NH 2 , CN 1 Cl, F, and Het, wherein said (C r C 6 )alkyl is optionally substituted by OH or NH 2 ;
• Het is a 5 or 6 membered aromatic heterocycle, containing 1 to 3 heteroatoms, each independently selected from N, O and S, wherein said heterocycle is optionally substituted by 1 to 3 (C 1 - C 6 )alkyl groups; wherein phenyl is optionally substituted by 1 to 5 groups independently selected from (C 1 -C 6 JaIkVl, 0(C 1 - C 6 )alkyl, Cl or F;
• R 4 , R 5 and R ⁇ cannot all simultaneously represent H; b) when R 3 , R 5 and R 6 are H then R 4 cannot be OCH 3 ; c) when R 3 , R 4 and R 6 are H then R 5 cannot be OCH 3 ; d) when R 3 , R 4 and R 5 are H then R 6 cannot be CH 3 ; e) when R 1 and R 2 are n-propyl, R 3 is H, R 4 is H and R 5 is H then R 6 cannot be C(O)NH 2 ; f) when R 1 and R 2 are n-propyl, R 3 is H, R 4 and R 5 are OCH 3 then R 6 cannot be H; g) when R 1 , R 3 and R 5 are H, R 2 and R 4 are CH 3 then R 6 cannot be CH 3 ; h) when R 1 and R 2 are n-propyl, R 3 is H, R
• alkyl groups containing the requisite number of carbon atoms, can be unbranched or branched.
• alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl and t-butyl.
• cyclic alkyl groups include cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• the pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
• a pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate.
• the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
• Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
• Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
• Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
• the pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
• a compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms.
• Diastereoisomers of the present invention include compounds of formula (Ia) and (Ib):
• references in this document to compounds of formula (I) also encompass the compounds of formula (Ia) and (Ib).
• One embodiment of the present invention comprises compounds of formula (Ia) and (Ib). In an alternative embodiment, the present invention comprises compounds of formula (Ia). In a further alternative embodiment, the present invention comprises compounds of formula (Ib).
• R 1 is selected from H and (C 1 -C 6 JaIkVl.
• R 1 is selected from H, methyl, ethyl and propyl.
• R 1 is selected from H, ethyl and n-propyl.
• R 1 is H.
• R 2 is selected from (CrCeJalkyl and (C 3 -C 8 )cyclic alkyl, wherein said (C r C 6 )alkyl is optionally substituted by phenyl.
• R 2 is (C ⁇ C 6 )alkyl, wherein said (Ci-C 6 )alkyl is optionally substituted by phenyl.
• R 2 is (C 1 -C 3 )BlKyI, wherein said (C r C 3 )alkyl is optionally substituted by phenyl.
• R 2 is (Ci-C 3 )alKyl. In a fifth alternative embodiment R 2 is n-propyl.
• R 3 is selected from H, methyl or ethyl. In a second alternative embodiment R 3 is H.
• R 4 is selected from H, CN, O(C 1 -C 6 )alkyl, C(O)NH 2 , Cl, and F.
• R 4 is selected from H, CN, OCH 3 , C(O)NH 2 , Cl, F.
• R 4 is selected from H, CN, Cl and F.
• R 4 is selected from H, Cl and F.
• R 4 is selected from H and F. In a sixth alternative embodiment R 4 is H.
• R 5 is selected from H, OH, O(C r C 6 )alkyl, C(O)NH 2 , CN, and NH 2 .
• R 5 is selected from H, OH, C(O)NH 2 , CN, and NH 2 .
• R 5 is selected from H, OH, C(O)NH 2 and CN.
• R 5 is selected from H, OH and C(O)NH 2 .
• R 5 is selected from H and OH.
• R 5 is OH.
• R 6 is selected from H, (C r C 6 )alkyl, C(O)NH 2 , CN, Cl, F, and Het,- wherein said (C r C 6 )alkyl is optionally substituted by OH.
• R 6 is selected from H, C(O)NH 2 , CN, F, and Het.
• R 6 is selected from H, C(O)NH 2 , CN and Het.
• R 6 is selected from H, C(O)NH 2 , and CN.
• R 6 is selected from H, C(O)NH 2 and CN. In a sixth alternative embodiment R 6 is selected from C(O)NH 2 and CN.
• R 6 is C(O)NH 2 .
• Het is a 5 membered aromatic heterocycle containing 1 to 3 heteroatoms, each independently selected from N, O and S, said heterocycle optionally substituted by (C r C 6 )alkyl.
• Het is a 5 to 6 membered aromatic heterocycle containing 1 to 2 heteroatoms, each independently selected from N and O, said heterocycle optionally substituted by (C 1 - C 6 )alkyl.
• Het is a 5 membered aromatic heterocycle containing 1 to 2 heteroatoms, each independently selected from N and O, said heterocycle optionally substituted by (C 1 - C 3 )alkyl.
• Het is a 5 membered aromatic heterocycle containing 2 heteroatoms, each independently selected from N and O, said heterocycle optionally substituted by methyl.
• Het is imidazolyl or 5-methyl-2-oxazolyl.
• Representative compounds of the invention include:
• the present invention encompasses compounds of formula (I) wherein:
• A is selected from C-R 6 and N;
• R 1 and R 2 are each independently selected from H, (C r C 6 )alkyl, said alkyl optionally substituted by Ph; and (C 3 -C 8 ) cyclic alkyl;
• R 3 is as previously defined above
• R 4 is selected from H and halo
• R 5 is selected from H, OH, O(C r C 6 )alkyl or in combination with R 6 may form a (C 2 -C 5 ) alkylene link, said link optionally incorporating an alkene group, said link optionally incorporating 1-2 heteroatoms each independently selected from N, O and S; and
• R 6 is selected from H, C(O)NH 2 , CO 2 H, C(O)O(C r C 6 )alkyl, NHSO 2 (C r C 6 )alkyl, NHC(O)(CrC 6 )alkyl, halo, a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms each independently selected from N, O and S; (C 1 -C 6 JaIk ⁇ , said alkyl optionally substituted by OH; or in combination with R 5 may form a (C 2 -C 5 ) alkylene link, said link optionally incorporating an alkene group, said link optionally incorporating 1-2 heteroatoms each independently selected from N, O and S; and pharmaceutically acceptable salts, solvates and prodrugs thereof; with the provisos that when:
• A is CR 6 , R 1 and R 2 are propyl, R 3 is H, R 4 is OH, R 5 is H then R 6 cannot be H;
• A is CR 6 , R 1 and R 2 are propyl, R 3 is H, R 4 is H, R 5 is H then R 6 cannot be Br, H, CO 2 H, C(O)NH 2 Or OMe;
• A is CR 6 , R 1 and R 2 are propyl, R 3 is H 1 R 4 is H, then R 5 and R 6 cannot be a -O-CH-CH- link;
• A is CR 6 , R 1 is H, R 2 is H or propyl, R 3 is H, R 5 is H r R 6 is H then R 4 cannot be Br;
• A is CR 6 , R 1 is n-propyl or methylcyclopropyl, R 2 is n-propyl, R 3 is H, R 5 is H, R 6 is H then R 4 cannot be
• Compounds of formula (II) can be obtained by analogy with the methods of van Niet et. al. (J. Med. Chem. 2000; 43; 3549), or Brisander et. al. (J. Org. Chem. 1998; 63; 5362) or Andersson et. al. (WO 9012795).
• PG represents a suitable N protecting group, typically benzyl or allyl, more typically benzyl.
• PG is a suitable N protecting group, as described in "Protecting Groups in Organic Synthesis" by T. W. Greene and P. Wutz.
• This reaction may be carried out by, stirring the starting materials at temperatures such as 20 0 C to 80 0 C for 1 to 72 hours in a suitable solvent such as dichloromethane or tetrahydrofuran or heating amine (II) with excess R 2 (O)H (or an excess of R 1 (O)H or a ketone of a (C 3 -C 8 ) cyclic alkyl) with a suitable Lewis acid catalyst such as titanium tetrachloride or titanium tetraisopropoxide at temperatures such as 5O 0 C to 100 0 C in a suitable solvent such as dichloroethane or ethanol for 1 to 18 hours, followed by reduction of the intermediate imine/iminium species with a suitable reducing agent, such as sodium borohydride, or hydrogenation over a suitable catalyst, such as platinum oxide or palladium on carbon.
• a suitable solvent such as dichloromethane or tetrahydrofuran or heating amine (II) with excess R 2 (O)H
• Typical conditions are: 1.4 to 20 molar equivalents (eq) R 2 (O)H (or R 1 (O)H or a ketone of a (C 3 -C 8 ) cyclic alkyl), 1.5 to 3.5 eq Na(OAc) 3 BH, optionally in the presence of 1eq AcOH in tetrahydrofuran (THF) at room temperature (rt) for between 5 and 72 hours (hrs).
• THF tetrahydrofuran
• Step (b)-Deprotection Deprotection of compound (III) to provide the compound of formula (IV) is undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis” by T. W. Greene and P. Wutz.
• PG is benzyl.
• Typical conditions for such a deprotection are:
• a suitable mild iodinating agent such as N- iodosuccinimide
• a catalyst such as trifluoromethanesulphonic (triflic) acid or trifluoroacetic acid
• a suitable solvent eg MeCN
• Step (d)-Cyanation reaction Cyanation of the iodide of formula (Vl), according to the method of Tschaen et. al. (Syn. Comm. 1994;
• Hydrolysis of the nitrile of formula (VII) may be achieved in the presence of acid or base, in a suitable solvent, optionally at elevated temperature to afford the amide of formula (I).
• a metal hydroxide eg Li, K or Cs
• alcoholic solvent eg 2-methyl-2-propanol
• Typical conditions are: Excess KOH, nitrile (VII) in 2-methyl-2-propanol at reflux for up to 72 hrs.
• step (a) Reaction of the compounds of formula (IX) with R 2 (O)H (or a ketone of a (C 3 -C 8 ) cyclic alkyl), as described previously in step (a) provides the compounds of formula (Vl).
• R 7 represents C 1 -C 6 alkyl or benzyl, typically C 1 -C 4 alkyl and more typically CH 3
• Step (f)-Carbonvlation Carbonylation of the iodide of formula (Vl) using a suitable transition metal catalyst (eg Pd or Ni) in the presence of R 7 OH, a suitable base, such as Et 3 N, under an atmosphere of CO, in a suitable solvent, such as DMF, at elevated temperature provides compounds of the formula (XIV).
• a suitable transition metal catalyst eg Pd or Ni
• Step (q)-Hvdrolvsis Hydrolysis of the ester of formula (XIV) can be achieved in the presence of acid or base, in a suitable solvent, optionally at elevated temperature to afford the acid (XV).
• the ester of formula (XIV) is treated with a metal hydroxide (Li, Na, K or Cs) in aqueous solvent (MeOH, EtOH, dioxan, THF) at between rt and the reflux temperature of the reaction.
• Acid chloride of acid (XV) (generated in-sit ⁇ ), an excess of ammonia, optionally with an excess of 3° amine such as Et 3 N, H ⁇ nig's base or N-methylmorpholine (NMM), in DCM or THF, without heating for 1 to 24 hrs,
• step (a) Reductive amination with an aldehyde of formula R 2 (O)H (or a ketone of a (C 3 -C 8 ) cyclic alkyl) according to the method described in step (a) above provides the compound of formula (XVII).
• step (b) Deprotection of the compound of formula (XVII) as described previously for step (b) provides the compound of formula (I).
• PG 2 represents a suitable O protecting group, typically a C 1 -C 4 alkyl group, more typically methyl.
• PG 3 represents a suitable O protecting group and is typically benzyl.
• Ketone (XVIII) is reacted with an amine PGNH 2 of in the presence of a reducing agent, such as sodium triacetoxyborohydride or sodium cyanoborohydride, and optionally in the presence of acetic acid, to give the compound of formula (XIX).
• PG is a suitable N protecting group, as described in "Protecting Groups in Organic Synthesis" by T. W. Greene and P. Wutz.
• PG is benzyl or allyl, more typically benzyl.
• This reaction may be carried out by, stirring the starting materials at temperatures such as 0 0 C to 8O 0 C for 1 to 72 hours in a suitable solvent such as dichloromethane or tetrahydrofuran or heating the ketone of formula (XVIII) with PGNH 2 with a suitable Lewis acid catalyst such titanium tetrachloride or titanium tetraisopropoxide at temperatures such as 5O 0 C to 100 0 C in a suitable solvent such as dichloroethane or ethanol for 1 to 18 hours, followed by reduction of the intermediate imine/iminium species with a suitable reducing agent, such as sodium borohydride, or hydrogenolysis over a suitable catalyst, such as platinum oxide or palladium on carbon.
• a suitable solvent such as dichloromethane or tetrahydrofuran
• a suitable Lewis acid catalyst such titanium tetrachloride or titanium tetraisopropoxide
• a suitable reducing agent such as sodium borohydride
• hydrogenolysis
• Step (b)-Deprotection Deprotection of the compound of formula (XX) to provide the compound of formula (XXI) is undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis” by T.W. Greene and P. Wutz.
• PG 2 is methyl.
• the typical conditions for such a deprotection are: 48% hydrobromic acid at about 80 0 C for between 1 and 48 hours.
• Compounds of formula (XXVIII) may be prepared from compounds of formula (XXVII) by analogy with the methods previously described for step (b).
• Compounds of formula (XXIX) may be prepared from compounds of formula (XXVIII) by analogy with the methods previously described for step (c).
• Step (k) - Triflate formation Conversion of compound (XXI) into its triflate (XXXIV) may be accomplished by reaction with a triflating reagent such as N-phenylbis(trifluoromethanesulphonimide) or trifluoromethanesulfonic anhydride in the presence of a suitable base such as Et 3 N or N-ethyldiisopropylamine in a suitable solvent such as DCM or THF.
• a triflating reagent such as N-phenylbis(trifluoromethanesulphonimide) or trifluoromethanesulfonic anhydride
• a suitable base such as Et 3 N or N-ethyldiisopropylamine
• a suitable solvent such as DCM or THF.
• Typical conditions for this transformation are 1.05 eq N-phenylbis(trifluoromethanesulphonimide) and 1.1 eq Et 3 N in DCM at room temperature for 18 hrs.
• the carboxamide of formula (XXXVl) may be prepared from the nitrile of formula (XXXV) by hydrolysis as previously described for step (e).
• the amine of formula (I) may be prepared from the carboxamide of formula (XXXV) by a deprotection reaction as previously described for step (b).
• the compounds of formula (I), wherein R 1 does not represent H, may be prepared by reductive amination as previously described in step (a).
• Step (n)-Rinq Opening The compound of formula (XXXIX) may be prepared by reaction of the epoxide of formula (XXXVIII) with the amine of formula R 2 NH 2 in a suitable solvent (eg MeOH, EtOH) at elevated temperature for up to 18 hrs.
• a suitable solvent eg MeOH, EtOH
• the aziridine of formula (XL) may be prepared by reaction of the compound of formula (XXXIX), under standard Mitsunobu conditions, as described in J. Org. Chem. 2003; 68(13); 5160.
• the compound of formula (I), wherein R 6 is H, are prepared by hydrogenation of the compound of formula (XL). Typically this may be achieved by catalytic hydrogenation in the presence of a suitable catalyst e.g. Pd/C, in a suitable alcoholic solvent, e.g. H 2 O, MeOH, or EtOH at between rt and about
• a suitable catalyst e.g. Pd/C
• a suitable alcoholic solvent e.g. H 2 O, MeOH, or EtOH at between rt and about
• Compounds of formula (I) may also be converted to alternative compounds of formula (I) using standard chemical reactions and transformations.
• R 2 is also a protecting group, typically benzyl
• removal of this protecting group affords compounds of formula (I) where R 1 represents H, as described previously in step (b). This is exemplified in examples 3 and 7 to 10
• compounds of formula (I) may be obtained from compounds of formula (I), where R 1 is H, by a reductive amination reaction with the aldehyde R 1 C(O)H, as previously described in step (a). This is exemplified by example 4.
• compounds of formula (I) may be prepared from compounds of formula (I) where R 6 represents CN, by hydrolysis. This may be achieved under acidic (eg cone. H 2 SO 4 , AcOH/BF 3 ) or basic conditions (eg KOH in t-butanol). Typically, the nitrile compound is treated with 6 eq KOH in t- butanol, at the reflux temperature of the reaction for about 18 hrs. This is exemplified by example 11.
• the compounds of the present invention have utility as selective D3 agonists in the treatment of disease states.
• D2 and D3 agonists There are a number of prior art compounds with activity as both D2 and D3 agonists; however the use of such compounds is associated with a large number of side effects including nausea, emesis, syncope, hypotension and bradycardia, some of which are a cause for serious concern.
• the present invention provides a class of selective D3 agonists. These have been found to be efficacious, whilst reducing the side effects associated with unselective prior art compounds. Accordingly a further aspect of the invention provides a compound of formula (I) for use as a medicament.
• references to compounds of formula (I) include the said compounds with or without provisos a) to j) defined hereinabove.
• Compounds of the present invention are particularly useful in treating sexual dysfunction, female sexual dysfunction, including hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder; male erectile dysfunction, hypertension, neurodegeneration, depression, pain and psychiatric disorders.
• the present invention provides for the use of a compound of formula (I), in the preparation of a medicament for the treatment or prevention of sexual dysfunction.
• the compounds of the present invention are useful in male sexual dysfunction, including male erectile dysfunction.
• Male erectile dysfunction otherwise known as male erectile disorder, is defined as:
• MED elman et al 1999, J. Urology, 161, p5-11.
• the condition has a significant negative impact on the quality of life of the individual and their partner, often resulting in increased anxiety and tension which leads to depression and low self-esteem.
• MED was primarily considered to be a psychological disorder (Benet et al 1994 Comp. Ther., 20: 669-673), it is now known that for the majority of individuals there is. an underlying organic cause. As a result, much progress has been made in identifying the mechanism of normal penile erection and the pathophysiologies of MED.
• Penile erection is a haemodynamic event which is dependent upon the balance of contraction and relaxation of the corpus cavernosal smooth muscle and vasculature of the penis (Lerner et al 1993, J. Urology, 149, 1256-1255).
• Corpus cavernosal smooth muscle is also referred to herein as corporal smooth muscle or in the plural sense corpus cavernosa. Relaxation of the corpus cavernosal smooth muscle leads to an increased blood flow into the trabecular spaces of the corpus cavernosa, causing them to expand against the surrounding tunica and compress the draining veins. This produces a vast elevation in blood pressure which results in an erection (Naylor, 1998, J. Urology, 81, 424-431).
• NANC neurotransmitters found in the penis, other than NO, such as calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP).
• CGRP calcitonin gene related peptide
• VIP vasoactive intestinal peptide
• NO nitric oxide
• NOS nitric oxide synthase
• sGC soluble guanylate cyclase
• cGMP intracellular cyclic guanosine 3',5'-monophosphate
• Dopamine D3 receptors are expressed almost exclusively in the limbic area of the brain, regions involved in the reward, emotional and cognitive processes.
• agonism of the D3 receptor initiates of sexual behaviour.
• the present invention provides for the use of a compound of formula (I), in the preparation of a medicament for the treatment or prevention of male sexual dysfunction, particularly, but not limited to, male erectile dysfunction.
• MED patient groups should benefit from treatment with a selective D3 agonist and a PDE5i and/or a NEPi (or other combination set out hereinafter). These patient groups, which are described in more detail in Clinical Andrology vol. 23, no.4, p773-782 and chapter 3 of the book by I. Eardley and K. Sethia "Erectile Dysfunction-Current Investigation and
• the present invention provides for the use of a compound of formula (I), in the preparation of a medicament in combination with a PDE5 inhibitor; particularly for, but not limited to, the treatment of erectile dysfunction
• Suitable PDE5 inhibitors are described herein.
• the compounds of the present invention are useful in the treatment or prevention of female sexual dysfunction (FSD), including FSAD.
• FSD female sexual dysfunction
• FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression.
• FSD is a collective term for several diverse female sexual disorders
• Desire or libido is the drive for sexual expression. Its manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli.
• Arousal is the vascular response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal lubrication, elongation of the vagina and increased genital sensation/sensitivity.
• Orgasm is the release of sexual tension that has culminated during arousal.
• FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm.
• FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders.
• the compounds of the invention will improve the genital response to sexual stimulation (as in female sexual arousal disorder), in doing so it may also improve the associated pain, distress and discomfort associated with intercourse and so treat other female sexual disorders.
• Hypoactive sexual desire disorder is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies.
• This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety.
• FSAD sexual arousal disorder
• vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded.
• Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and atherosclerosis.
• Other causes result from treatment with diuretics, antihistamines, antidepressants e.g. selective serotonin re- uptake inhibitors (SSRIs) or antihypertensive agents.
• SSRIs serotonin re- uptake inhibitors
• Sexual pain disorders (includes dyspareunia and vaginismus) is characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
• D3 is thought to be an initiator of sexual behaviour.
• the clitoris is considered to be a homologue of the penis (Levin, R.J. (1991 ), Exp. CHn. Endocrinol., 98, 61-69); the same mechanism that provides an erectile response in the male produces an increase in genital blood flow in the female with an associated effect upon FSD.
• proceptivity and receptivity are changes in proceptivity and receptivity.
• a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder or sexual pain disorder.
• the compounds of formula (I) are useful in the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder, and hypoactive sexual desire disorder, and in a further embodiment, in the treatment or prophylaxis of sexual arousal disorder.
• the compounds of formula (I) are useful in the treatment of a subject with female sexual arousal disorder and concomitant hypoactive sexual desire disorder.
• DSM Diagnostic and Statistical Manual
• FSAD Female Sexual Arousal Disorder
• FSAD vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia.
• the disturbance causes marked distress and/or interpersonal difficulty.
• FSAD is a highly prevalent sexual disorder affecting pre-, peri- and post-menopausal ( ⁇ hormone replacement therapy (HRT)) women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and urogenital (UG) disorders.
• FSAD FSAD-induced sexual desire
• Drug candidates for treating FSAD which are under investigation for efficacy, are primarily erectile dysfunction therapies that promote circulation to male genitalia. .
• the compounds of the present invention are advantageous by providing a means for restoring a normal sexual arousal response - namely increased genital blood flow leading to vaginal, clitoral and labial engorgement. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital sensitivity.
• the present invention provides a means to restore, or potentiate, the normal sexual arousal response.
• a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual arousal disorder.
• the genital organs consist of an internal and external group.
• the internal organs are situated within the pelvis and consist of ovaries, the uterine tubes, uterus and the vagina.
• the external organs are superficial to the urogenital diaphragm and below the pelvic arch. They comprise the mons pubis, the labia majora and minora pudendi, the clitoris, the vestibule, the bulb of the vestibule, and the greater vestibular glands" (Gray's Anatomy, CD. Clemente, 13 th American Edition).
• the compounds of the invention find application in the following sub-populations of patients with FSD: the young, the elderly, pre-menopausal, peri-menopausal, post-menopausal women with or without hormone replacement therapy.
• the compounds of the invention find application in patients with FSD arising from:- i) Vasculogenic etiologies e.g. cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the iliohypogastric pudendal vascular system. ii) Neurogenic etiologies such as spinal cord injuries or diseases of the central nervous system including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular accidents, peripheral neuropathies, trauma or radical pelvic surgery.
• Hormonal/endocrine etiologies such as dysfunction of the hypothalamic/pituitary/gonadal axis, or dysfunction of the ovaries, dysfunction of the pancreas, surgical or medical castration, androgen deficiency, high circulating levels of prolactin e.g. hyperprolactinemia, natural menopause, premature ovarian failure, hyper and hypothyroidism.
• prolactin e.g. hyperprolactinemia, natural menopause, premature ovarian failure, hyper and hypothyroidism.
• Psychogenic etiologies such as depression, obsessive compulsive disorder, anxiety disorder, postnatal depression/"Baby Blues", emotional and relational issues, performance anxiety, marital discord, dysfunctional attitudes, sexual phobias, religious inhibition or a traumatic past experiences.
• the Compounds of the present invention are also useful in the treatment of depression.
• Dopamine D3 receptors are expressed almost exclusively in the limbic area of the brain, regions involved in reward, emotional and cognitive processes.
• Chronic treatment with several classes of antidepressants are known to increase the expression of D3 in the limbic area, and antidepressant effects of desipramine can be blocked by sulpride (D2/D3 antagonist) when injected to nucleus accumbens (area rich in D3) but not caudate-putamen (area rich in dopamine D2 receptors).
• sulpride D2/D3 antagonist
• antidepressant effects were observed preclinical models of depression and in patients treated with pramipexole, a D3-preferring agonist.
• D3 receptors mediate the anti-depressant activity and that selective D3 receptor agonists represent a new class of antidepressant drugs. Since antidepressants are known to be effective in other psychiatric disorders, D3 agonists would have the potential to treat psychiatric diseases.
• Suitable conditions include depression (e.g. depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, paediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression and grumpy old man syndrome), generalized anxiety disorder, phobias (e.g. agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, eating disorders (e.g. anorexia nervosa and bulimia nervosa), chemical dependencies (e.g.
• addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g. dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g. dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g. hyperprolactinaemia), negative symptoms of schizophrenia, Tourette's syndrome, trichotillomania, kleptomania, attention deficit hyperactivity disorder (ADHD), emotional lability, pathological crying, sleeping disorder (cataplexy) and shock.
• ADHD attention deficit hyperactivity disorder
• the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment of depression or psychiatric disorders.
• Suitable depressive conditions and psychiatric disorders are described above.
• the compounds of the present invention also have utility in the treatment of neurodegeneration; sources of neurodegeneration include neurotoxin poisoning; vision loss caused by neurodegeneration of the visual pathway, such as by a stroke in the visual pathway eg in retina, optic nerve and/or occipital lobe; epileptic seizures; and from impairment of glucose and/or oxygen supply to the brain.
• sources of neurodegeneration include neurotoxin poisoning; vision loss caused by neurodegeneration of the visual pathway, such as by a stroke in the visual pathway eg in retina, optic nerve and/or occipital lobe; epileptic seizures; and from impairment of glucose and/or oxygen supply to the brain.
• the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of neurodegeneration.
• the compounds of the present invention also have utility in the treatment of pain, particularly, but not limited to, chronic nociceptive pain.
• Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
• the system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review).
• These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
• nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
• A-delta fibres myelinated
• C fibres non-myelinated.
• the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
• Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
• neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
• carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
• back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
• Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
• Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the ' spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
• Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
• Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
• Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
• Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
• neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
• the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
• Arthritic pain is the most common inflammatory pain.
• Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
• Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
• Gl gastrointestinal
• FBD functional bowel disorder
• IBD inflammatory bowel disease
• Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro ⁇ esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
• Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.
• musculoskeletal disorders including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis; heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia; head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and
• orofacial pain including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
• the present invention provides for the use of a compound of formula (I), in the preparation of a medicament for the treatment or prevention of pain.
• the present invention provides for the use of a compound of formula (I), in the preparation of a medicament for the treatment or prevention of chronic nociceptive pain.
• the compounds of the present invention are likely to be efficacious in a number of additional indications. Accordingly, the present invention provides for the use of compounds of formula (I) in the preparation of a medicament for the treatment of hypertension, premature ejaculation, obesity, cluster headache, migraine, pain, endocrine disorders (e.g. hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), premenstrual syndrome, fibromyalgia syndrome, stress incontinence, chronic paroxysmal hemicrania, and headache (associated with vascular disorders).
• endocrine disorders e.g. hyperprolactinaemia
• vasospasm particularly in the cerebral vasculature
• cerebellar ataxia e.g. gastrointestinal tract disorders (involving changes in motility and secretion)
• premenstrual syndrome fibromyalgia syndrome
• stress incontinence
• the present invention provides a method for treating or preventing the conditions, diseases or disorders mentioned herein above, which comprises administering to a mammalian subject, including a human, in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
• D3/D2 AGONIST BINDING ASSAY Gonazalez et al discloses an assay for determining the binding capability of a compound at D3 and/or D2 dopamine receptors and thus the binding selectivity of such compounds. This assay is, thus, herein referred to as a binding assay.
• the compounds of the present invention all exhibit a functional potency at D3 receptor expressed as an EC50, lower than 100OnM and a 10 fold selectivity for D3 over D2.
• the compound of example 5 has a functional potency at D3 receptor expressed as an EC50, of 83nM and 120 fold selectivity for D3 over D2.
• the compound of example 14 has a functional potency at D3 receptor expressed as an EC50, of 27nM and 370 fold selectivity for D3 over D2.
• the compound of example 16 has a functional potency at D3 receptor expressed as an EC50, of 1OnM and 118 fold selectivity for D3 over D2.
• the compound of example 23 has a functional potency at D3 receptor expressed as an EC50, of 33nM and 303 fold selectivity for D3 over D2. Selectivity is calculated as the D2 EC50 value divided by the D3 EC50 value. Where the value of the D2 EC50 was >10000, a figure of 10000 was used in the calculation.
• the activity of a compound in the treatment of neuropathic pain may be measured according to the following test protocol.
• CCI Chronic constriction injury
• YK A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain:33:87-107, 1988).
• Animals were anaesthetised with a 2% isofluorane/O2 mixture.
• the right hind thigh was shaved and swabbed with 1 % iodine.
• Animals were then transferred to a homeothermic blanket for the duration of the procedure and anaesthesia maintained during surgery via a nose cone.
• the skin was cut along the line of the thighbone.
• the common sciatic nerve was exposed at the middle of the thigh by blunt dissection through biceps femoris.
• Streptozocin (STZ)-induced diabetes neuropathy in the rat Diabetes was induced by a single intraperitoneal injection of streptozotocin (50mg/kg) freshly dissolved in 0.9% sterile saline. Streptozotocin injection induces a reproducible mechanical allodynia within 3 weeks, lasting for at least 7 weeks (Chen and Pan, (Chen SR and Pan HL. Hypersensitivity of Spinothalamic Tract Neurons Associated With Diabetic Neuropathic Pain in Rats. J Neurophysiol 87: 2726-2733, 2002).
• paw withdrawal threshold PWT
• Static allodynia was defined as present if animals responded to a stimulus of, or less than, 4g, which is innocuous in naive rats (Field MJ, Bramwell S, Hughes J, Singh L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones? Pain,1999;83:303-11 ).
• Dynamic allodynia was assessed by lightly stroking the plantar surface of the hind paw with a cotton bud. To avoid recording general motor activity, care was taken to perform this procedure in fully habituated rats that were not active. At least two measurements were taken at each time point, the mean of which represented the paw withdrawal latency (PWL). If no reaction was exhibited within 15 sec the procedure was terminated and animals were assigned this withdrawal time. A pain withdrawal response was often accompanied with repeated flinching or licking of the paw. Dynamic allodynia was considered to be present if animals responded to the cotton stimulus within 8 sec of commencing stroking (Field et al, 1999).
• the activity of a compound in the treatment of nociceptive pain may be measured according to the following test protocols.
• mice Male Sprague Dawley rats are placed on a hot plate (Ugo Basile, Italy) maintained at 55 ⁇ 5 0 C. The time between placement of the animal on the hot plate and occurrence of either licking of fore or hind paw, shaking or jumping off the surface is measured. Baseline measurements will be made and animals reassessed following drug administration. The cut off time for hot plate latencies is set at 20 seconds to prevent tissue damage.
• Ovariohysterectomy (OVX)
• mice Female Sprague Dawley rats are placed into an anaesthetic chamber and anaesthetised with a 2% isofluorane / O 2 mixture. During surgery, anaesthesia is maintained via a nose cone. OVX is performed via a midline incision (2cm in length) in the linea alba, whilst the animal is on a heat blanket. The ovarian ligaments and cervix are ligated with 5-0 silk, using a single clamp technique. The ovaries and uterus are then removed. The abdominal wall is closed using 4 simple interrupted sutures and the skin closed using 4 wound clips. Immediately after surgery animals are placed in individual plexiglass chambers.
• Postures scored are humpback position, contraction of the muscle of the abdomen associated with inward movements of the hind limb, stretching of the body and squashing of the lower abdomen against the floor. Each of these behaviours is scored as one posture.
• mice were housed in accordance with National Institutes of Health guidelines in a vivarium maintained at 22 0 C with a 12-hour alternating light-dark cycle, and were given food and water ad libitum.
• the sarcoma injection protocol used has been described. After induction of general anesthesia with an inhalation of isofluran (2%), a superficial incision was made in the skin overlying the patella, using Mora scissors. The patellar ligament was then cut, exposing the condyles of the distal femur.
• a 30-gauge needle was inserted at the level of the intercondylar notch and into the medullary canai to create an initial core pathway. After the initial core was made, a 29-gauge needle was used to make the final pathway into the bone. A 0.5-mm depression was then made using a half-round bur in a pneumatic dental high speed handpiece, to serve as mechanical retention for the dental resin plug. Then, 20 ⁇ l ⁇ -minimum essential media (Sigma; sham injection) or 20 ⁇ l media containing 1 X10 5 2472 osteolytic sarcoma cells (American Type Culture
• the activity of compound in the treatment of inflammatory pain may be measured according to the following test protocol.
• CFA 300 ⁇ g of Mycobacterium Tuberculosis H37 RA (Difco Laboratories) in 100 ⁇ L of liquid paraffin (Wako)
• Wako liquid paraffin
• Incapacitance tester Linton Instrumentation, UK.
• the test compound suspended in 0.1% MC (Wako) is administered orally in a volume of 1 mL per 100 g body weight.
• Each animal is placed in the apparatus and the weight load exerted by the hind paws is measured before, 1 , 2 and 4 hours after drug administration.
• Hyperalgesia is induced by intraplantar injection of Lambda ⁇ -carrageenin (0.1 ml of 1% w/v solution in saline, Zushikagaku).
• the test compound (1ml of 0.1 % methylcellulose/100g body weight) is given orally at 5.5 hours after the carrageenin injection.
• the paw withdrawal threshold (gram) is measured by analgesimeter (Ugo Basile) at 3.5, 4.5, 6.5 and 7.5 hours after the carrageenin injection.
• Carra ⁇ eenan-lnduced Thermal Hyperalgesia (CITH) in the Rat Thermal hyperalgesia was assessed using the rat plantar test (Ugo Basile, Comerio, Italy), according to a method modified by Hargreaves et al. (1988). Briefly, rats were habituated to the apparatus that consisted of three individual Perspex boxes on a glass table. A mobile radiant heat source was located under the table and focused onto the desired paw. Paw withdrawal latencies (PWLs) were recorded three times for both hind paws of each animal, the mean of which represented baseline for left and right hind paws. The apparatus was calibrated to give a PWL of approximately 10 s in na ⁇ ve rats.
• Lambda carrageenan was injected intraplantarly (100 ⁇ l, 20 mg/ml) the right hind paw and baseline recordings of PWT were taken 2 hr post administration.
• the activity of a compound in the treatment of visceral pain may be measured according to the following test protocols.
• TNBS trinitrobenzenesulfonic acid
• mice Male Sprague-Dawley rats are used. The animals are housed 3 per cage in a regulated environment (20 ⁇ 1°C, 50 ⁇ 5 % humidity, with light 8:00 am to 8:00 pm). At day 0, under anesthesia (ketamine 80 mg/kg Lp.; acepromazine 12 mg/kg Lp.), the injection of TNBS (50 mg/kg in ethanol 30 %), or saline (1.5 ml/kg) for control rats, is performed into the proximal colon wall (1 cm from the cecum). After the surgery, animals are individually housed in polypropylene cages and kept in a regulated environment (20 ⁇ 1°C, 50 ⁇ 5 % humidity, with light 8:00 a.m.
• a balloon (5-6 cm length) is inserted by anus, and kept in position (tip of balloon 5 cm from the anus) by taping the catheter to the base of the tail.
• Oral administration of the test compound is performed 1 h before the colonic distension cycle: the balloon is progressively inflated by steps of 5 mm Hg (0.667 kPa), from 0 to 75 mm Hg, each step of inflation lasting 30 s.
• Each cycle of colonic distension is controlled by a standard barostat.
• the threshold (mm Hg) corresponds to the pressure which produced the first abdominal contraction, and the cycle of distension is then discontinued.
• the colonic threshold is determined after performance of four cycles of distension on the same animal.
• LPS lipo-polysaccharide
• Animals are surgically prepared for electromyography: rats are anaesthetized by intraperitoneal injection of acepromazine (0.6 mg/kg) and ketamine (120 mg/kg). Three groups of three electrodes are implanted in the abdominal external oblique musculature, just superior to the inguinal ligament. Electrodes are exteriorized on the back of the neck and protected by a glass tube attached to the skin. Animals are individually housed in polypropylene cages and kept in a temperature-controlled room (21 0 C). Food (UAR pellets, Epinay, France) and water are provided ad libitum.
• Rats are placed in plastic tunnels (6 cm diameter x 25 cm long), where they cannot move, escape, or turn around, in order to prevent damage to the balloon. Animals are accustomed to this procedure for four days before rectal distension in order to minimize stress reactions during experiments.
• the balloon used for distension is an arterial embolectomy catheter (Fogarty,
• Rectal distension is performed by insertion of the balloon (2 mm diameter x 2 cm long) into the rectum, at 1 cm from the anus, and catheter is fixed at the base of the tail. It is inflated progressively with tepid water by steps of 0.4 ml, from 0 to 1.2 ml, each step of inflation lasting 5 min. To detect possible leakage, the volume of water introduced in the balloon is checked by complete removal with a syringe at the end of the distension period.
• Suitable auxiliary active agents for use in combination with the compounds of the present invention include:
• prostaglandins for use herein include compounds such as alprostadil, prostaglandin E 1 prostaglandin E 0 , 13, 14 - dihydroprosta glandin E 1 , prostaglandin E 2 , eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in WO-00033825 and/or US 6,037,346 issued on 14th March 2000 all incorporated herein by reference, PGE 0 , PGE 1 , PGA 1 ,
• ⁇ - adrenergic receptor antagonist compounds also known as ⁇ - adrenoceptors or ⁇ -receptors or ⁇ -blockers.
• Suitable compounds for use herein include: the ⁇ -adrenergic receptor blockers as described in PCT application WO99/30697 published on 14th June 1998, the disclosures of which relating to ⁇ -adrenergic receptors are incorporated herein by reference and include, selective o ⁇ -adrenoceptor or ⁇ 2 -adrenoceptor blockers and non-selective adrenoceptor blockers, suitable ⁇ 1 -adrenoceptor blockers include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohim
• ⁇ 2 -blocker blockers from US 6,037,346 [14th March 2000] dibenarnine, tolazoline, trimazosin and dibenarnine; ⁇ -adrenergic receptors as described in US patents: 4,188,390; 4,026,894; 3,511 ,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381 ,009; 4,252,721 and 2,599,000 each of which is incorporated herein by reference; ⁇ 2 -Adrenoceptor blockers include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine;
• NO-donor compounds for use herein include organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl trinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3- morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine (SNAP) S-nitroso-N- glutathione (SNO-GLU), N-hydroxy - L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1 ) S-nitroso - N-cysteine, diazenium diolates,
• organic nitrates such as mono- di or
• potassium channel openers or modulators include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCI 2 ;
• Vasodilator agents include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, , Rec 15/2739, trazodone;
• March 2000 and include acetergamine, brazergoiine, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride;
• Atrial naturetic factor also known as atrial naturetic peptide
• B type and C type naturetic factors such as inhibitors or neutral endopeptidase
• Angiotensin receptor antagonists such as losartan
• Substrates for NO-synthase such as L-arginine
• Calcium channel blockers such as amlodipine
• Antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme are antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme
• Cholesterol lowering agents such as statins (e.g. atorvastatin/ Lipitor- trade mark) and fibrates;
• Antiplatelet and antithrombotic agents e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors;
• Insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide;
• Acetylcholinesterase inhibitors such as donezipil
• Estrogen receptor modulators and/or estrogen agonists and/or estrogen antagonists for example raloxifene or lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 5,6,7,8-tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof the preparation of which is detailed in WO 96/21656;
• a PDE inhibitor more particularly a PDE 2, 3, 4, 5, 7 or 8 inhibitor, typically a PDE2 or PDE5 inhibitor and most typically a PDE5 inhibitor (see hereinafter), said inhibitors preferably having an IC50 against the respective enzyme of less than 10OnM (with the proviso that PDE 3 and 4 inhibitors are only administered topically or by injection to the penis); 22) Vasoactive intestinal protein (VIP), VIP mimetic, VIP analogue, more particularly mediated by one or more of the VIP receptor subtypes VPAC1.VPAC or PACAP (pituitory adenylate cyclase activating peptide), one or more of a VIP receptor agonist or a VIP analogue (e.g. Ro-125-1553) or a VIP fragment, one or more of a ⁇ -adrenoceptor antagonist with VIP combination (e.g.
• a melanocortin receptor (particularly of the MC3 or MC4 subtype) agonist or modulator or melanocortin enhance, such as melanotan II, PT-14, PT-141 or compounds claimed in WO- 09964002, WO-00074679, WO-09955679, WO-00105401 , WO-00058361 , WO-00114879, WO-
• a serotonin receptor agonist, antagonist or modulator more particularly agonists, antagonists or modulators for 5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993;
• a testosterone replacement agent including dehydroandrostendione), testosternone (Tostrelle), dihydrotestosterone or a testosterone implant;
• Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate i.e. as a combination
• estrogen and methyl testosterone hormone replacement therapy agent e.g. HRT especially Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone);
• a purinergic receptor agonist and/or modulator A purinergic receptor agonist and/or modulator
• a neurokinin (NK) receptor antagonist including those described in WO-09964008;
• An opioid receptor agonist, antagonist or modulator preferably agonists for the ORL-1 receptor
• An agonist, antagonist or modulator for oxytocin receptors preferably a selective oxytocin agonist or modulator
• a SEP inhibitor for instance a SEPi having an IC 50 at less than 100 nanomolar, more preferably, at less than 50 nanomolar.
• the SEP inhibitors according to the present invention have greater than 30-fold, more preferably greater than 50-fold selectivity for SEP over neutral endopeptidase NEP EC 3.4.24.11 and angiotensin converting enzyme (ACE).
• ACE angiotensin converting enzyme
• the SEPi also has a greater than 100-fold selectivity over endothelin converting enzyme (ECE).
• PDE5 Inhibitor Suitable PDE5 inhibitors include:
• a selective dopamine D4 receptor agonist such as 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H- benzimidazole (ABT724).
• SSRIs selective serotonin reuptake inhibitors
• SSRIs selective serotonin reuptake inhibitors
• WO 0172687 3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy] benzenesulfonamide
• ⁇ /-methyl- ⁇ /-( ⁇ 3-[3-methyl-4- (methylsulfanyl)phenoxy]-4-pyridinyl ⁇ methyl)amine Example 38, PCT Application no PCTVI B02/01032.
• NEP inhibitors preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC 3.4.24.11 , more preferably a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11 , which has an IC 50 of less than 10OnM (e.g. ompatrilat, sampatrilat) suitable NEP inhibitor compounds are described in EP-A-1097719; IC50 values against NEP and ACE may be determined using methods described in published patent application EP1097719-A1 , paragraphs [0368] to [0376];
• 10OnM e.g. ompatrilat, sampatrilat
• Melanocortin receptor agonists e.g. Melanotan Il and PT141
• selective MC3 and MC4 agonists e.g.THIQ
• NRIs Noradrenaline Re-uptake Inhibitors
• a combination of active agents may be administered simultaneously, separately or sequentially.
• the compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
• composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.
• the compounds of the formula (I) can be administered orally, buccally or sublingually in the form of tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
• Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
• excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
• disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch
• Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
• the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
• Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
• the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
• Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent.
• Some components of the formulation may perform more than one function.
• the compound of formula (I) may be water-soluble or insoluble.
• a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
• the compound of formula (I) may be in the form of multiparticulate beads.
• the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
• Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
• the compounds of the formula (I) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneal Iy, intrathecal ⁇ , intraventricular ⁇ , intraurethrally, intrasternally, intracranial ⁇ , intramuscularly or subcutaneously, or they may be administered by infusion techniques.
• parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
• the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
• the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
• the compounds of formula (I) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops.
• the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
• the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
• a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
• the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
• comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
• Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
• blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I- leucine, mannitol, or magnesium stearate.
• the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
• Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
• a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
• a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
• Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
• Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
• Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
• Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
• Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the compounds may also be administered by the ocular route.
• the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
• they may be formulated in an ointment such as petrolatum.
• the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• the compounds of the formula (I) may also be used in combination with a cyclodextrin.
• Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug- cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
• the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
• Alpha-, beta- and gamma- cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-
• compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
• the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
• a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
• the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
• the kit typically comprises directions for administration and may be provided with a so-called memory aid.
• TLC thin layer chromatography
• Acetaldehyde (0.41ml, 7.26mmol) was added to a solution of the amine from example 3 (80mg, 0.36mmol) in tetrahydrofuran (15ml) and the solution stirred for 10 minutes.
• Acetic acid 22mg, 0.36mmol
• sodium triacetoxyborohydride 115mg, 0.55mmol
• the reaction was quenched by the addition of 1N sodium hydroxide solution (15ml) and the mixture extracted with ethyl acetate (2x15ml). The combined organic extracts were dried (MgSO 4 ) and evaporated under reduced pressure.
• Cyclobutanone (69mg, 0.99mmol) was added to a solution of the amine from example 3 (67mg, 0.30mmol) in tetrahydrofuran (15ml) and the solution stirred for 10 minutes.
• Acetic acid (18mg, 0.30mmol) and sodium triacetoxyborohydride (96mg, 0.46mmol) were added and the reaction stirred at room temperature for 18 hours.
• TLC analysis showed starting material remaining, so the reaction was filtered and the filtrate concentrated under reduced pressure. The residue was suspended in cyclobutanone (1ml) and stirred at room temperature for 72 hours.
• Sodium triacetoxyborohydride (96mg, 0.46mmol) was added and the reaction stirred for a further 18 hours.
• Ammonium formate (41 mg, 0.66mmol) was added to a solution of the compound from example 2 (43mg, 0.13mmol) and 10% Pd/C (21mg) in methanol (5ml) and the mixture heated under reflux for 2 hours. The cooled mixture was filtered through Arbocei®, washing through with additional methanol. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to give the title compound as a colourless oil, 25mg.
• the title compound was obtained as an off-white foam, from the compound from preparation 20, following a similar procedure to that described in example 7, except the product was not purified by column chromatography on silica gel.
• Acetaldehyde (0.1ml, 1.73mmol) was added to an ice-cold solution of the amine from preparation 17 (35mg, 0.17mmol) in tetrahydrofuran (5ml), the solution stoppered and stirred for 30 minutes.
• Sodium triacetoxyborohydride (13mg, 0.2mmol) was added and the reaction stirred at room temperature for 3 hours. TLC analysis showed starting material remaining, so additional acetaldehyde (0.1ml, 1.73mmol) was added and the reaction stirred for a further hour at O 0 C.
• the reaction mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate (75ml) and washed with brine (50ml).
• Propionaldehyde (52 ⁇ l, 0.72mmol) was added to a solution of the amine from preparation 18 (130mg, 0.60mmol) in tetrahydrofuran (5ml) and the solution stirred at room temperature for 1.5 hours.
• Sodium triacetoxyborohydride (178mg, 0.84mmol) was added and the reaction stirred at room temperature for 18 hours.
• the reaction was diluted with ethyl acetate (100ml), the mixture washed with saturated sodium bicarbonate solution (50ml), brine (50ml) and dried (MgSO 4 ) and evaporated under reduced pressure.
• a mixture of ⁇ /-benzyl- ⁇ /-(6-carboxamide-7-benzyloxy-3,4-dihydro-2/-/-chromen-3-yl)- ⁇ /-propylamine from preparation 30 (60mg, 0.14mmol), ammonium formate (150mg, 2.3mmol) and 10% palladium on charcoal (50mg) in methanol (5ml) was heated at 80 0 C for 15 minutes. The cooled mixture was filtered through Arbocel®, washing through with methanol then dichloromethane.
• example 16A as a pale yellow powder 99mg (contaminated with 0.43 eq diethylamine) and example 16B as an off-white solid 131mg (contaminated with 0.79 eq diethylamine).
• Example 16A 1 H NMR (CD 3 OD, 400MHz) ⁇ : 0.98 (t, 3H), 1.60 (m, 2H), 2.70 (dd, 1 H), 2.81 (t, 2H), 3.08 (dd, 1 H), 3.37 (br, m, 1 H), 4.06 (m, 1 H), 4.23 (d, 1 H), 6.28 (s, 1 H), 7.57 (s, 1 H).
• Example 16B 1 H NMR (CD 3 OD, 400MHz) ⁇ : 0.98 (t, 3H), 1.61 (m, 2H), 2.75 (dd, 1 H), 2.87 (t, 2H), 3.13 (dd, 1 H), 3.43 (br, m, 1 H), 4.14 (dd, 1 H), 4.23 (d, 1 H), 6.30 (s, 1 H), 7.57 (s, 1 H).
• example 16A was obtained directly as a single enantiomer from the compound from preparation 53 (2.95g, 6.86mmol), by reaction with ammonium formate (4.32g, 68.6mmol) and 10% palladium on charcoal (300mg) in methanol (100ml) at 80 0 C for 3h. The cooled mixture was filtered through Arbocel®, washing through with methanol. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography on silica eiuting with 10% MeOH/EtOAc followed by EtOAc:methanol:ammonia hydroxide 90:10:1 to afford the title compound as a pale yellow solid 1.7Og.
• Acetaldehyde (0.10ml, 1.80mmol) was added to a solution of 7-hydroxy-3-(propylamino)chromane-6- carboxamide from example 16 (30mg, 0.12mmol) in tetrahydrofuran (5ml) and then acetic acid (7mg, 0.12mmol) followed by Sodium triacetoxyborohydride (38mg, 0.1 ⁇ mmol) was added and the reaction stirred at room temperature for 18 hours. Water (10ml) was added then ammonia solution (1ml), and the mixture extracted with ethyl acetate (2x20ml).
• Propionaldehyde (8mg, 0.132mmol) was added to a solution of 7-hydroxy-3-(propylamino)chromane-6- carboxamide from example 16 (30mg, 0.12mmol) in tetrahydrofuran (5ml) and then acetic acid (7mg, 0.12mmol) followed by Sodium triacetoxyborohydride (38mg, 0.18mmoi) was added and the reaction stirred at room temperature for 18 hours. Water (10ml) was added then ammonia solution (1ml), and the mixture extracted with ethyl acetate (2x20mI).
• the crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford a white solid, 100mg.
• Ammonium formate (424mg, 6.7mmol) was added portionwise to a mixture of the compound from preparation 26 (200mg, 0.67mmol) and 10% palladium on charcoal (20mg) in ethanol (10ml) and the mixture heated under nitrogen at 100 0 C for 3 hours. The cooled mixture was filtered through a pad of Arbocel® and the filtrate evaporated under reduced pressure. The crude product was purified by column chromatography using Dowex® 50W8-X200 ion exchange resin and an elution gradient of water:0.88 ammonia (100:0 to 95:5) to afford the title compound as a clear gum.
• Formaldehyde (3.8ml, 37% aq, 44.5mmol) was added to a solution of the amine from preparation 3 (1 Jg, 8.9mmol) in tetrahydrofuran (50ml) and the solution stirred at room temperature for 1 hour.
• Sodium triacetoxyborohydride (4.7g, 22mmol) was added and the reaction stirred at room temperature for 18 hours.
• Saturated sodium bicarbonate solution 300ml was added, and the mixture extracted with ethyl acetate (2x200ml). The combined organic solutions were dried (MgSO 4 ) and evaporated under reduced pressure to afford the title compound as a colourless oil, 1.76g.
• Propionaldehyde (0.83ml, 11.5mmol) was added to a solution of the amine from preparation 5 (3g, 8.2mmol) in tetrahydrofuran (100ml), and the solution stirred at room temperature for 2 hours.
• Acetic acid (0.47ml, 8.2mmol) and sodium triacetoxyborohydride (4.8g, 23mmol) were added and the reaction stirred at room temperature for 18 hours.
• the mixture was diluted with ethyl acetate (200ml), washed with sodium bicarbonate solution (200ml) and brine (150ml) then dried (MgSO 4 ) and evaporated under reduced pressure, to give the title compound as a colourless oil, 3.15g.
• Tetrakis(triphenylphosphine)palladium (505mg, 0.44mmol), followed by zinc cyanide (456mg, 3.9mmol) were added to a solution of the iodide from preparation 5 (2.9g, ⁇ .Ommol) in N,N-dimethylformamide (20ml) and the reaction stirred at 9O 0 C for 4 hours.
• the cooled reaction mixture was partitioned between ethyl acetate (250ml) and water (250ml) and the layers separated. The aqueous phase was extracted with additional ethyl acetate (200ml) and the combined organic solutions were dried (MgSO 4 ) and evaporated under reduced pressure.
• Tetrakis(triphenylphosphine)palladium (460mg, 0.39mmol), followed by zinc cyanide (655mg, 5.6mmol) were added to a solution of the iodide from preparation 7 (2.64g, 7.97mmol) in N,N-dimethylformamide (25ml) and the reaction stirred at 100°C for 18 hours.
• the cooled reaction mixture was partitioned between ethyl acetate (250ml) and water (200ml) and the layers separated. The organic phase was washed with brine (200ml), dried (MgSO 4 ) and evaporated under reduced pressure.
• Butyraldehyde (0.09ml, 1.Ommol) followed by acetic acid (0.04ml, 0.71 mmol) and sodium triacetoxyborohydride (420mg, 1.9mmol) were added to a solution of the amine from preparation 19 (200mg, 0.71 mmol) in tetrahydrofuran (10ml) and the reaction stirred at room temperature for 18 hours.
• the mixture was partitioned between ethyl acetate (100ml) and sodium bicarbonate solution (75ml) and the layers separated.
• the organic phase was dried (MgSO 4 ) and evaporated under reduced pressure to give the title compound as a colourless oil, 252mg.
• the titile compound was obtained as a colourless oil, from the amine from preparation 19 and valeraldehyde, following the procedure described in preparation 20.
• Phenylacetaldehyde (0.10ml, 0.89mmol) was added to a solution of the amine from preparation 19 (180mg, 0.64mmol) in tetrahydrofuran (10ml) and the solution stirred for 1 hour.
• Acetic acid 36 ⁇ l, 0.64mmol
• sodium triacetoxyborohydride 378mg, 1.78mmol
• TLC analysis showed starting material remaining, so additional phenylacetaldehyde (0.10ml, 0.89mmol) followed by sodium triacetoxyborohydride (189mg, 0.89mmol) were added and the reaction stirred for a further 18 hours.
• Phenylpropionaldehyde (0.085ml, 0.65mmol) was added to a solution of the amine from preparation 19 (130mg, 0.46mmol) in tetrahydrofuran (10ml) and the solution stirred for 2 hours.
• Acetic acid (26 ⁇ l, 0.46mmol) and sodium triacetoxyborohydride (273mg, 1.3mmol) were added and the reaction stirred at room temperature for 18 hours.
• the mixture was partitioned between ethyl acetate (100ml) and saturated sodium bicarbonate solution (100ml) and the layers separated.
• the organic phase was dried (MgSO 4 ) and evaporated under reduced pressure.
• Benzyl amine (4.06ml, 37.1 mmol) was added dropwise to a solution of 7-methoxy-2/-/-chromen-3(4H)- one (J. Am. Chem. Soc. (1993), 115(20), 9327-8) (6.02g, 33.8mmol) in tetrahydrofuran (100ml). Then acetic acid (1.93ml, 33.8mmol) and sodium triacetoxyborohydride (10.73g, 50.63mmol) were added and the reaction stirred at room temperature for 20 hours under nitrogen. The reaction was quenched by the addition of sodium bicarbonate solution (40ml) and the mixture extracted with ethyl acetate (2x80ml).
• Tetrakis(triphenylphosphine)palladium (50mg, 0.04mmol) and zinc cyanide (30mg, 0.26mmol) were added to a solution of ⁇ /-benzyl- ⁇ /-(6-iodo-7-benzyloxy-3,4-dihydro-2H-chromen-3-yl)-/V-propylamine from preparation 28 (224mg, 0.44mmol) in N,N-dimethylformamide (5ml) and the reaction stirred at 90 0 C for 0.5h.
• the crude product was pre-adsorbed onto silica gel and purified by column chromatography on silica gel using an elution gradient of dichloromethane:pentane (30:70 to 50:50) to afford the title compound as a brown crystalline solid, 730mg.
• N-lodosuccinimide (1.04g, 4.6mmol) was added portionwise to solution of the compound from example 22 (970mg, 4.6mmol) in tetrahydrofuran (15ml) at O 0 C. The reaction was allowed to warm to room temperature and stirred for a further 18 hours. The reaction was carefully poured onto ice, the mixture basified using potassium carbonate then extracted with ethyl acetate (2x200ml). The combined organic extracts were dried (MgSO 4 ) and evaporated under reduced pressure to provide the title compound as a brown oil in quantitative yield.
• Ammonium formate (1.36g, 21.6mmol) was added portionwise to a mixture of the compound from preparation 33 (700mg, 2.16mmol) and 10% palladium on charcoal (70mg) in ethanol (30ml) and the mixture heated under nitrogen at 100 0 C for 3 hours. Further ammonium formate (500mg, 7.94mmol) was added and the reaction continued for a further hour. The cooled mixture was filtered through a pad of Celite® and Arbocel® and the filtrate evaporated under reduced pressure.

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