WO2005097113A2 - Antagonistes du recepteur de la 5-ht2b - Google Patents

Antagonistes du recepteur de la 5-ht2b Download PDF

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WO2005097113A2
WO2005097113A2 PCT/GB2005/001378 GB2005001378W WO2005097113A2 WO 2005097113 A2 WO2005097113 A2 WO 2005097113A2 GB 2005001378 W GB2005001378 W GB 2005001378W WO 2005097113 A2 WO2005097113 A2 WO 2005097113A2
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alkyl
group
optionally substituted
cycloalkyl
aryl group
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PCT/GB2005/001378
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WO2005097113A3 (fr
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Richard Anthony Borman
Robert Alexander Coleman
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Pharmagene Laboratories Limited
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Priority claimed from GB0408064A external-priority patent/GB0408064D0/en
Priority claimed from GB0408062A external-priority patent/GB0408062D0/en
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Publication of WO2005097113A2 publication Critical patent/WO2005097113A2/fr
Publication of WO2005097113A3 publication Critical patent/WO2005097113A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • This invention relates to the use of 5-HT 2B receptor antagonists.
  • Serotonin also referred to as 5-hydroxytryptamine (5-HT)
  • 5-HT 5-hydroxytryptamine
  • 5-HT acts via a number of discrete 5-HT receptors.
  • ⁇ -HT ⁇ , 5-HT 2B and 5-HT 2C subtypes are known to exist.
  • the nomenclature and classification of 5-HT receptors has been reviewed by Martin and Humphrey, Neuropharm., 33, 261-273 (1994) and Hoyer, et al., Pharm. Rev., 46, 157-203 (1994).
  • 5-HT 2B receptor antagonists are likely to have a beneficial effect on patients suffering these disorders.
  • 5-HT 2B receptor antagonists are used in treating disorders of the Gl tract, and especially disorders involving altered motility (for example, irritable bowel syndrome (WO 01/08668)).
  • Functional bowel disorders such as irritable bowel syndrome (IBS) are characterised by disturbed motility, including constipation, diarrhoea or intermittent constipation and diarrhoea (Mayer E.A., et al., Dig. Dis., 19(3), 212-8 (2001)), and increased visceral sensitivity resulting in the perception of increased visceral pain (Verne G.N., et al., Pain, 105(1-2), 223-30 (2003). To achieve a complete treatment of such functional bowel disorders often requires treatment of both these classes of symptoms.
  • IBS irritable bowel syndrome
  • 5-HT 2B receptor antagonists Some of the recent disclosures relating to 5-HT 2B receptor antagonists, WO 97/44326 and US 5,958,934, mention the possible application of such compounds in treating pain and in particular for treating or preventing migraines.
  • WO 03/068226 US 10/364,672 and US 10/ 640,476, which are hereby incorporated by reference, aryl-2-amino-oxazoles were disclosed as being 5-HT 2B receptor antagonists. The use of these compounds in treating disorders of the Gl tract was discussed, and examples showing the effect of the disclosed compounds in a functional assay relating to gut motility were described.
  • aryl-2-amino-thiazoles were disclosed as being 5-HT 2B receptor antagonists.
  • WO 2005/012263 which claims priority from US 60/490,286 and GB 0317346.5, N 4 -aryl-pyrimidine-2,4-diamines, 6- aryloxy-pyrimidin-2-ylamines, 4-aryl-1 H-imidazol-2-ylamines, biaryl-2-amino-oxazoles, and N-aryl-triazole-diamines were disclosed as being 5-HT 2B receptor antagonists.
  • a first aspect of the present invention provides a the use of a compound selected from: (a) formula I:
  • R 1 and R 4 are selected from the group consisting of H, and optionally substituted C f . ⁇ alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkyl-C ⁇ alkyl, and phenyl-C ⁇ alkyl; and the other of R 1 and R 4 is an optionally substituted C 9 . 14 aryl or bi-C 5 . 7 aryl group;
  • R 2 and R 3 are either:
  • X is O or NH
  • R 8 and R 9 are independently selected from the group consisting of H, and optionally substituted C ⁇ e alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkyl-C ⁇ alkyl, and phenyl-C ⁇ alkyl;
  • R 7 is an optionally substituted C 9 .- ⁇ 4 aryl group or an optionally substituted bi-C 5 . 7 aryl group;
  • R 2 and R 3 are as defined above;
  • R 10 is selected from the group consisting of H, and optionally substituted C ⁇ - 6 alkyl, C 3 . 7 cycloalkyl, C 3 . cycloalkyl-C ⁇ alkyl, and phenyl-C 1 - 4 alkyl;
  • R 2 , R 3 and R 7 are as defined above;
  • R 11 is selected rom the group consisting of H and optionally substituted C- ⁇ - 6 alkyl
  • R 2 , R 3 and R 7 are as defined above;
  • R 13 is selected from the group consisting of H, and optionally substituted C ⁇ - 6 alkyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl-C 1 _ alkyl, and phenyl-C ⁇ alkyl; R 2 and R 3 are as defined above;
  • R 12 is an optionally substituted C 9 - 1 aryl group; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of increased visceral sensitivity and/or visceral pain.
  • R 1 and R 4 are selected from the group consisting of H, and optionally substituted C ⁇ e alkyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl-C ⁇ alkyl, and phenyl-C- ⁇ - alkyl; and the other of R 1 and R 4 is an optionally substituted C 9 - 14 aryl group;
  • R 2 and R 3 are either:
  • a second aspect of the present invention provides a method of treating visceral sensitivity, which method comprises administering to a patient in need of treatment an effective amount of a compound of formula I, II, III, IVa, IVb or V, or a pharmaceutically acceptable salt thereof.
  • Visceral Sensitivity comprises administering to a patient in need of treatment an effective amount of a compound of formula I, II, III, IVa, IVb or V, or a pharmaceutically acceptable salt thereof.
  • visceral sensitivity pertains to sensitivity of the hollow organs (i.e. the gut, the bladder and the uterus). I n particular, an increase in visceral sensitivity can lead to increase in the pain felt by a patient from the viscera, even if that organ is performing normally.
  • the present application relates to the increase in visceral sensitivity and/or visceral pain of the gut. This is often associated with functional disorders of the gut, and more specifically, the bowel (for example, I rritable Bowel Syndrome (IBS)).
  • IBS I rritable Bowel Syndrome
  • visceral hypersensitivity An increase in visceral sensitivity may be referred to as "visceral hypersensitivity”.
  • C ⁇ - 6 alkyl group refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a non-cyclic hydrocarbon compound having from 1 to 6 carbon atoms, and which may be saturated or unsaturated.
  • saturated alkyl groups include methyl (C ⁇ ); ethyl (C 2 ); propyl (C 3 ), which may be linear (n-propyl) or branched (iso-propyl); butyl (C 4 ), which may be linear (n-butyl) or branched (iso-butyl, sec-butyl and tert-butyl); pentyl (C 5 ), which may be linear (n-pentyl, amyl) or branched (iso-pentyl, neo-pentyl); hexyl (C 6 ), which may be linear (n-hexyl) or branched.
  • C 3 - 7 Cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 ri ng atoms
  • saturated cycloalkyl groups include, but are not limited to, those derived from: cyclopropane (C 3 ), cyclobutane (C 4 ), cyclopentane (C 5 ), cyclohexane (C 6 ), and cycloheptane (C 7 ).
  • unsaturated cylcoalkyl groups include, but are not limited to, those derived from: cyclobutene (C 4 ), cyclopentene (C 5 ), cyclohexene (C 6 ), and cycloheptene (C 7 ).
  • C 3 . 7 cycloalkyl-C-i- alkyl The term "C 3 - 7 cycloalkyl-C ⁇ - 4 alkyl", as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a non- cyclic hydrocarbon compound having from 1 to 4 carbon atoms (C ⁇ alkyl), which may be saturated or unsaturated, which itself is substituted by a C 3 . 7 cycloalkyl group.
  • C 3 . 7 alkyl groups include, but are not limited to, those derived from: cyclohexylethane (C 6 -C 2 ) and cyclopentylpropene (C 5 -C 3 ).
  • Phenyl-C ⁇ alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a non-cyclic hydrocarbon compound having from 1 to 4 carbon atoms (C- ⁇ - alkyl), which may be saturated or unsaturated, which itself is substituted by a phenyl group (C 6 H 5 -).
  • phenyl-C 1 . 4 alkyl groups include, but are not limited to, benzyl (phenyl-CH 2 -) and those derived from: phenylethane (phenyl-C 2 ) and phenylpropene (phenyl-C 3 ).
  • C 5 - 7 Heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has rom 5 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a C 5 . 7 heterocyclic ring, at least one ring atom will be nitrogen.
  • C 5 - 7 heterocyclyl groups having at least one nitrogen atom include, but are not limited to, those derived from:
  • C 9 - 14 Aryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound with at least two fused rings, which moiety has from 9 to 14 ring atoms.
  • each ring has from 5 to 7 ring atoms.
  • the ring atoms may be all carbon atoms, as in "carboaryl groups” (e.g. C 9 . 14 carboaryl).
  • carboaryl groups include, but are not limited to, those derived from naphthalene (C 10 ), azulene (C ⁇ 0 ), anthracene (C 14 ) and phenanthrene (C 14 ).
  • aryl groups which comprise fused rings include, but are not limited to, groups derived from indene (C 9 ), isoindene (C 9 ) tetralin (C 10 ) and fluorene (C 13 ).
  • the ring atoms may include one or more heteroatoms, as in "heteroaryl groups” (e.g. C 9 . 14 heteroaryl).
  • heteroaryl groups include, but are not limited to: C 9 heteroaryl groups (with 2 fused rings) derived from benzofuran (O ⁇ ), isobenzofuran (O0, indole (NO, isoindole (NO, indolizine (N-i), indoline (N-i), isoindoline (N , purine (N ) (e.g.
  • the above described C 9 . 14 aryl group includes the radical formed by removal of a hydrogen atom from any of the possible aromatic ring atoms.
  • the groups formed by this removal can be described by the number of the ring atom from which the hydrogen is removed, if there is more than one possibility.
  • the carboaryl groups derived from, for example, naphthalene (C 10 ) can be either napth-1-yl or nath ⁇ -y ⁇ l; and from azulene (C 10 ) can be azul-1-yl, azul-2-yl, azul-4-yl, azul-5-yl and azul-6-yl.
  • the heteroaryl groups derived, for example, from isoquinoline can be isoquinol-x-yl (x- isoquinolyl), where x can be 1 , 3, 4, 5, 6, 7 or 8.
  • Bi-C 5 - 7 aryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound with two aromatic rings, where each ring has from 5 to 7 ring atoms, and the rings are linked by a single bond.
  • ring atoms of an aromatic ring are all carbon atoms, as in a "carboaryl ring", then that ring will be derived from benzene.
  • One or more of the ring atoms may be a heteroatom, as in a "heteroaryl ring".
  • heteroaryl rings include, but are not limited to: Nv pyrrole (azole) (C 5 ), pyridine (azine) (C 6 );
  • N 1 O 1 oxazole (C 5 ), isoxazole (C 5 ), isoxazine (C 6 );
  • N 2 0 1 oxadiazole (furazan) (C 5 ); N 3 O 1 : oxatriazole (C 5 );
  • the bi-C 5 . 7 aryl group includes the radical formed by removal of a hydrogen atom from any of the possible aromatic ring atoms of the 'first' aromatic ring, i.e. the ring from which the hydrogen atom is removed, and the 'second' aromatic ring, i.e. the ring from which the hydrogen atom is not removed, may be bonded to the first aromatic ring at any position in relation to the ring atom from which the hydrogen atom has been removed. For example, if both aromatic rings are unsubstituted benzene rings, then the following groups are possible:
  • C ⁇ - 20 alkyl group The term "C 1 . 20 alkyl", as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated.
  • alkyl includes the sub-classes alkenyl, alkynyl and cycloalkyl discussed below.
  • the prefixes denote the number of carbon atoms, or range of number of carbon atoms.
  • the term "C ⁇ - 4 alkyl,” as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include Ci- 4 alkyl ("lower alkyl”), C ⁇ alkyl, and C ⁇ o alkyl.
  • saturated alkyl groups include, but are not limited to, methyl (CO, ethyl (C 2 ), propyl (C 3 ), butyl (C 4 ), pentyl (C 5 ), hexyl (C 6 ), heptyl (C 7 ), octyl (C 8 ), nonyl (C 9 ), decyl (C 10 ), n-undecyl (C ⁇ ), dodecyl (C 12 ), tridecyl (C 13 ), tetradecyl (C 14 ), pentadecyl (C15), and eicodecyl (C 20 ).
  • saturated linear alkyl groups include, but are not limited to, methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C 5 ), n-hexyl (C 6 ), and n-heptyl (C 7 ).
  • saturated branched alkyl groups include iso-propyl (C 3 ), iso-butyl (C ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C 5 ), and neo-pentyl (C 5 ).
  • Cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 3 to 7 ring atoms.
  • saturated cycloalkyl groups include, but are not limited to, those derived from: cyclopropane (C 3 ), cyclobutane (C ), cyclopentane (C 5 ), cyclohexane (C 6 ), cycloheptane (C 7 ), norbornane (C 7 ), norpinane (C 7 ), norcarane (C 7 ), adamantane (C 1 > and decalin (decahydronaphthalene) (C 10 ).
  • saturated cycloalkyl groups which are also referred to herein as "alkyl- cycloalkyl" groups, include, but are not limited to, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, and dimethylcyclohexyl, menthane, thujane, carane, pinane, bornane, norcarane, and camphene.
  • alkyl-cycloalkenyl groups examples include, but are not limited to, methylcyclopropenyl, dimethylcyclopropenyl, methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl, methylcyclohexenyl, and dimethylcyclohexenyl.
  • cycloalkyl groups with one or more other rings fused to the parent cycloalkyl group, include, but are not limited to, those derived from: indene (C 9 ), indan (e.g., 2,3- dihydro-1 H-indene) (C 9 ), tetraline (1 ,2,3,4-tetrahydronaphthalene (C ⁇ 0 ), acenaphthene (C 12 ), fluorene (C 13 ), phenalene (C- ⁇ 3 ), acephenanthrene (C ⁇ 5 ), aceanthrene (C- ⁇ 6 ).
  • indene C 9
  • indan e.g., 2,3- dihydro-1 H-indene
  • tetraline (1 ,2,3,4-tetrahydronaphthalene
  • C ⁇ 0 acenaphthene
  • fluorene C 13
  • phenalene C- ⁇ 3
  • acephenanthrene C ⁇
  • alkenyl is a C 5 cycloalkyl group with a substituent (phenyl) fused thereto.
  • Alkenyl The term "alkenyl,” as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include Q> 2 - A alkenyl, C 2 . 7 alkenyl, C 2 - 2 o alkenyl.
  • Examples of unsaturated cyclic alkenyl groups include, but are not limited to, cyclopropenyl (C 3 ), cyclobutenyl (C ), cyclopentenyl (C 5 ), and cyclohexenyl (C 6 ).
  • Alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C 2 . 4 alkynyl, C 2 . 7 alkynyl, C 2 . 20 alkynyl.
  • unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, - C ⁇ CH) and 2-propynyl (propargyl, -CH 2 -C ⁇ CH).
  • C 3 - 20 heterocyclyl group pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms.
  • C 5 - 6 heterocyclyl refers to a heterocyclyl group having 5 or 6 ring atoms.
  • groups of heterocyclyl groups include C 3 - 20 heterocyclyl, C 3 - 7 heterocyclyl, C 5 - 7 heterocyclyl.
  • monocyclic heterocyclyl groups include, but are not limited to, those derived from: N ⁇ aziridine (C 3 ), azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C 5 ), pyrroline (e.g.,
  • Oi oxirane (C 3 ), oxetane (C ), oxolane (tetrahydrofuran) (C 5 ), oxole (dihydrofuran) (C 5 ), oxane (tetrahyd ropy ran) (C 6 ), dihydropyran (C 6 ), pyran (C 6 ), oxepin (C 7 );
  • trioxane C 6
  • N 2 imidazolidine (C 5 ), pyrazolidine (diazolidine) (C 5 ), imidazoline (C 5 ), pyrazoline
  • NiO-i tetrahyd rooxazole (C 5 ), dihydrooxazole (C 5 ), tetrahyd roisoxazole (C 5 ), dihydroisoxazole (C 5 ), morpholine (C 6 ), tetrahyd rooxazine (C 6 ), dihydrooxazine (C 6 ), oxazine (C 6 ); thiazoline (C 5 ), thiazolidine (C 5 ), thiomorpholine (C 6 );
  • Halo -F, -CI, -Br, and -I.
  • Ether -OR, wherein R is an ether substituent, for example, a C ⁇ alkyl group (also referred to as a C- ⁇ - 7 alkoxy group, discussed below), a C 3 - 20 heterocyclyl group (also referred to as a C 3 - 20 heterocyclyloxy group), or a C 5 - 20 aryl group (also referred to as a C 5 . 2 o aryloxy group), preferably a C ⁇ alkyl group.
  • R is an ether substituent, for example, a C ⁇ alkyl group (also referred to as a C- ⁇ - 7 alkoxy group, discussed below), a C 3 - 20 heterocyclyl group (also referred to as a C 3 - 20 heterocyclyloxy group), or a C 5 - 20 aryl group (also referred to as a C 5 . 2 o aryloxy group), preferably a C ⁇ alkyl group.
  • C ⁇ - 7 alkoxy -OR, wherein R is a C- ⁇ - 7 alkyl group.
  • Examples of C- ⁇ - 7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr)
  • R is an acyl substituent, for example, a C ⁇ - 7 alkyl group (also referred to as C ⁇ alkylacyl or C ⁇ alkanoyl), a C 3 - 2 o heterocyclyl group (also referred to as C3- 20 heterocyclylacyl), or a C 5 - 2 - aryl group (also referred to as C 5 - 2 o arylacyl), preferably a C ⁇ - 7 alkyl group.
  • R is an acyl substituent, for example, a C ⁇ - 7 alkyl group (also referred to as C ⁇ alkylacyl or C ⁇ alkanoyl), a C 3 - 2 o heterocyclyl group (also referred to as C3- 20 heterocyclylacyl), or a C 5 - 2 - aryl group (also referred to as C 5 - 2 o arylacyl), preferably a C ⁇ - 7 alkyl group.
  • Carboxy (carboxylic acid): -C( 0)OH.
  • R is an acyloxy substituent, for example, a C ⁇ - 7 alkyl group, a C 3 - 2 o heterocyclyl group, or a C 5 - 2 o aryl group, preferably a C 1 - 7 alkyl group.
  • Oxycarboyloxy: -OC( 0)OR, wherein R is an ester substituent, for example, a Ci_ 7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 - 2 oaryl group, preferably a C ⁇ alkyl group.
  • Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C( 0)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • Acylamido (acylamino): -NR 1 C( 0)R 2 , wherein R 1 is an amide substituent, for example, hydrogen, a C- ⁇ - 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably hydrogen or a C ⁇ alkyl group, and R 2 is an acyl substituent, for example, a d- 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably hydrogen or a C ⁇ alkyl group.
  • R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:
  • Thioamido (thio carbamyl): -C( S)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 2 and R 3 are independently amino substituents, as defined for amino groups, and R 1 is a ureido substituent, for example, hydrogen, a C ⁇ alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 20 aryl group, preferably hydrogen or a C,- 7 alkyl group.
  • ureido groups include, but are not limited to, -NHCONH 2 , - NHCONHMe, -NHCONHEt, -NHCONMe 2 , -NHCONEt 2 , -NMeCONH 2 , -NMeCONHMe, -NMeCONHEt, -NMeCONMe 2 , and -NMeCONEt 2 .
  • Tetrazolyl a five membered aromatic ring having four nitrogen atoms and one carbon atom
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a C ⁇ - alkyl group (also referred to as C ⁇ - alkylamino or di-C 1 - 7 alkylamino), a C 3 - 2 o heterocyclyl group, or a C 5 - 2 o aryl group, preferably H or a C ⁇ - alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a C ⁇ - alkyl group (also referred to as C ⁇ - alkylamino or di-C 1 - 7 alkylamino), a C 3 - 2 o heterocyclyl group, or a C 5 - 2 o aryl group, preferably H or a C ⁇ - alkyl group, or,
  • Amino groups may be primary (-NH 2 ), secondary (-NHR 1 ), or tertiary (-NHR 1 R 2 ), and in cationic form, may be quaternary (- + NR 1 R 2 R 3 ).
  • Examples of amino groups include, but are not limited to, -NH 2 , -NHCHs, -NHC(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , and -NHPh.
  • Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.
  • Examples of d- 7 alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3 .
  • Disulfide -SS-R, wherein R is a disulfide substituent, for example, a d_ 7 alkyl group, a C 3 -2o heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ - 7 alkyl group (also referred to herein as d_ 7 alkyl disulfide).
  • R is a disulfide substituent, for example, a d_ 7 alkyl group, a C 3 -2o heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ - 7 alkyl group (also referred to herein as d_ 7 alkyl disulfide).
  • d- 7 alkyl disulfide groups include, but are not limited to, -SSCH 3 and -SSCH 2 CH 3 .
  • Sulfine (sulfinyl, sulfoxide): -S( 0)R, wherein R is a sulfine substituent, for example, a d- 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ y alkyl group.
  • R is a sulfine substituent, for example, a d- 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ y alkyl group.
  • R is a sulfinate substituent, for example, a d-7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 . 2 o aryl group, preferably a Ci- 7 alkyl group.
  • R is a sulfonate substituent, for example, a d- 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 0 aryl group, preferably a Ci- 7 alkyl group.
  • R is a sulfinyloxy substituent, for example, a d- 7 alkyl group, a C 3 . 20 heterocyclyl group, or a C 5 . 20 aryl group, preferably a d- 7 alkyl group.
  • R is a sulfonyloxy substituent, for example, a d- 7 alkyl group, a C 3 . 2 o heterocyclyl group, or a C 5 - 20 aryl group, preferably a Ci- 7 alkyl group.
  • R is a sulfate substituent, for example, a d- 7 alkyl group, a C 3 - 2 o heterocyclyl group, or a C 5 - 2 o aryl group, preferably a C ⁇ - 7 alkyl group.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfonamino substituent, for example, a C 1 -7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a C 1 - 7 alkyl group.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfinamino substituent, for example, a C 1 -7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a d- 7 alkyl group.
  • a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO " ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 " ), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal- forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., d- 7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
  • keto enol enolate Tautomeric forms of particular relevance to the present invention include those of formula III, as illustrated below:
  • H may be in any isotopic form, including 1 H, H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 3 C, and 14 C; O may be in any isotopic form, including 16 0 and 1 ⁇ O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
  • a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below.
  • a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
  • a pharmaceutically-acceptable salt examples are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977), which is herein incorporated by reference.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • ether -OR
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2- trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc),
  • a carboxylic acid group may be protected as an ester for example, as: an C 1 -7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a d- 7 haloalkyl ester (e.g., a C 1 - 7 trihaloalkyl ester); a trid- 7 alkylsilyl-C ⁇ - 7 alkyl ester; or a C 5 - 2 o aryl-C ⁇ - 7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an C 1 -7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a d- 7 haloalkyl ester e.g., a C 1 - 7 trihaloalkyl ester
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis is also included.
  • terapéuticaally-effective amount pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen. Suitable dose ranges will typically be in the range of from 0.01 to 20 mg/kg/day, preferably from 0.1 to 10 mg/kg/day.
  • compositions and their administration are provided.
  • compositions may be formulated for any suitable route and means of administration.
  • Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like may be used.
  • the active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, acetylated triglycerides and the like, as the carrier.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc, an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like
  • the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • composition or formulation to be administered will, in any event, contain a quantity of the active compound(s) in an amount effective to alleviate the symptoms of the subject being treated.
  • Dosage forms or compositions containing active ingredient in the range of 0.25 to 95% with the balance made up from non-toxic carrier may be prepared.
  • a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, sodium crosscarmellose, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like.
  • excipients such as, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, sodium crosscarmellose, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like.
  • Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
  • Such compositions may contain 1 %-95% active ingredient, more preferably 2-50%, most preferably 5-8%.
  • Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, triethanolamine sodium acetate, etc.
  • the percentage of active compound contained in such parental compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.1% to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages.
  • the composition will comprise 0.2-2% of the active agent in solution.
  • Aryl represents the optionally substituted C 9 . 14 aryl group
  • R represents a group selected from H, and optionally substituted C 1 - 6 alkyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl- d- 4 alkyl, and phenyl-d- 4 alkyl.
  • the 2-amino oxazole is produced by the condensation of the appropriate ⁇ - hydroxy ketone with cyanamide or alkylcyanamide, which reaction can be carried out in aqueous solution or in the presence of a mineral acid or a base catalyst.
  • the product of the reaction may be either the 2-amino-4-aryl- oxazole, the 2-amino-5-aryl-oxazole, or a mixture of the two, with the 2-amino-5-aryl oxazole being favoured. It is thought that carrying out the reaction under milder conditions may favour production of the 2-amino-4-aryl oxazole.
  • the product of the method is a mixture of compounds of formula I these may be separated by column chromatography.
  • the 2-amino-5-aryl-oxazole product results from the reaction of the tautomeric form of the starting material:
  • the starting ⁇ -hydroxyketones can be synthesised via ⁇ -bromo and ⁇ -acetoxy intermediates, some of which are commercially available, from the parent ketones.
  • substitution on the 2-amino group can be introduced using a substituent on the cyanamide, or may be introduced later in the reaction scheme, again with, if necessary, protection of other functional groups in the molecule.
  • R 1 is the optionally substituted C 9 - ⁇ 4 aryl group, and where R 4 is hydrogen and R 2 and R 3 are hydrogen or an alkyl group
  • R 4 is hydrogen and R 2 and R 3 are hydrogen or an alkyl group
  • a stereoselective method described by van Leusen, et al., J. Org. Chem., 46, 2069-2072 (1981), which is incorporated herein by reference, that employs the reaction of an N-tosylmethylcarbodiimide with an aromatic aldehyde in a solvent, such as methylene chloride, in the presence of a base (e.g. aqueous sodium hydroxide) and a phase transfer catalyst (e.g. tetrabutylammonium bromide), as shown below.
  • a base e.g. aqueous sodium hydroxide
  • a phase transfer catalyst e.g. tetrabutylammonium bromide
  • the 2-amino oxazole is produced by the condensation of the appropriate ⁇ - bromo ketone with 1 ,1-dialkyl urea, which reaction is carried out in an organic solvent.
  • the 5-substituent on the oxazole ring is present in the starting material as the alkyl chain of the ⁇ -bromo alkylarylketone, which can be obtained from the parent alkylarylketone if necessary.
  • This route can be used for compounds of formula la where R 4 is an optionally substituted Cg. ⁇ aryl group and at least one of R 2 and R 3 are hydrogen, but is less preferred for these compounds.
  • the starting ketones for both routes are either commercially available or accessible by, for example, Grignard reactions on the corresponding nitriles or Friedal Crafts reaction of substituted aryls.
  • 1 aryl group is by a palladium catalysed coupling reaction of a 2-amino-4- substituted oxazole with an aryl boronic acid, or derivative thereof.
  • the 4-substituent on the oxazole ring may typically be a halogen, such as bromo, iodo or chloro, or a group such as trifluoromethanesulfonate or a phophate ester.
  • the aryl boronic acid may also be replaced by certain magnesium, tin or zinc containing organometallic reagents.
  • a 2-amino-4-bromo-oxazole may be reacted with an aryl boronic acid derivative in an aqueous solvent, for example a mixture of ethanol, water and dimethoxyethane, containing a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and an inorganic base such as sodium carbonate.
  • an aqueous solvent for example a mixture of ethanol, water and dimethoxyethane
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • an inorganic base such as sodium carbonate
  • the boronic acid residue, or equivalent may be on the 4-position of the oxazole ring and the halogen, or equivalent, on the aryl group.
  • This route is equally applicable to compounds of formula la where R 1 is an optionally substituted C 9 . 1 aryl group, where the 2-amino-4-bromo-oxazole is replaced with a 2- amino-5-bromo-oxazole:
  • This route may be varied in the same way as described above.
  • Compounds of formula la may also be prepared by nucleophilic displacement of the intermediate chloro compounds with ammonia or amines as described, for example, by Marchetti, E., et al., J. Med. Chem., 11, 1092-1093 (1968), which are incorporated herein by reference.
  • any substitution on the C 9 . 14 aryl group is preferably present in the relevant starting material, but could be introduced later in the reaction scheme, with, if necessary, appropriate protection of other functional groups present in the molecule.
  • R 1 /R 4 group which is not the C 9 . 14 aryl group may be the subject of further reactions to provide alternative substituent patterns.
  • R 1 , R 2 , R 3 and R 4 are preferably independently selected from halo, hydroxy, alkoxy (more preferably d- alkoxy), amino (more preferably NH 2 , C-u alkyl amino, d- 4 dialkyl amino), and amido (more preferably CONH 2 , d- 4 alkyl amido, C M dialkyl amido) ln some embodiments it is preferred that both R 2 and R 3 are substituted, and in other embodiments that only one or neither of R 2 and R 3 are substituted.
  • R 2 and R 3 are preferably independently selected from H, R, R', where R and R' are as defined above, and more preferably selected from H and R.
  • R is preferably an optionally substituted C-M alkyl group.
  • the preferred substituents for R and R' include halo, hydroxy, amino and acetyl. In some embodiments it is preferred that R is unsubstituted.
  • R 2 and R 3 together with the nitrogen atom to which they are attached, form an optionally substituted C 5 - 7 heterocylic group, then this is preferably selected from pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperazine and azepine and more preferably selected from pyrrolidine, piperidine, piperazine, homopiperazine and azepine.
  • R 1 is the optionally substituted C 9 - ⁇ 4 aryl group.
  • R 1 and R 4 is preferably selected from H and optionally substituted d- 6 alkyl and C 3 - 7 cycloalkyl, more preferably H and optionally substituted C ⁇ - 6 alkyl. Especially preferred are H, and C ⁇ - 4 alkyl (e.g. methyl, /so-propyl). In some embodiments the group may be unsubstituted, but when the group is substituted, preferred substituent groups include halo, hydroxy, and amino. Most preferably, one of R 1 and R 4 is H or methyl.
  • the other of R 1 and R 4 is preferably an optionally substituted C 9 .
  • 14 carboaryl group for example, naphth-1-yl, naphth-2-yl, anthracen-1-yl, anthracen-2-yl, anthracen-9-yl, phenanthren-1 -yl, phenanthren-2-yl, phenanthren-3-yl and phenanthren- 4-yl, phenanthren-9-yl.
  • napth-1-yl and napth-2-yl are preferred, with napthy-1-yl being most preferred.
  • Other preferred R 4 groups include benzo[b]thiophen-2-yl, benzo[b]thiophen-4-yl and benzo[1 ,4]dioxin-5-yl.
  • aryl group include halo, hydroxy, d- 4 alkoxy, cyano, amino, amido and C- 1 - 4 alkyl, of which hydroxy, C ⁇ - alkyl and C ⁇ - 4 alkoxy are more preferred. It is also preferred that the C 9 - aryl group bears no oxo substituents.
  • C 9 - 14 aryl group is a naphth-1-yl group
  • preferred substituent positions are 2, 4 and 7, with 2 being most preferred.
  • the preferred substituents at the 2-position are hydroxy, d- 4 alkyl (e.g. methyl) and C 1 - 4 alkoxy, with C alkyl (e.g. methyl) being most preferred.
  • a particularly preferred compound is 2-amino-5-(2'-methylnaphth-1-yl)oxazole (2) and its salts, especially its methane sulphonic acid salt (3).
  • the other of R 1 and R 4 is preferably is preferably an optionally substituted bi-C 6 aryl group and is more preferably a bi-phenyl group.
  • the group is a 3-phenyl-phenyl group or a 2-phenyl-phenyI group.
  • the phenyl groups are preferably either unsubstituted or substituted with an alkoxy (preferably methoxy), halo (preferably chloro), d- 4 alkyl (preferably methyl or iso-propyl) or hydroxy. It is preferred that the subtituent is on the distal phenyl ring, preferably at the 2-position.
  • R 8 R 8 is preferably selected from H, optionally substituted d-e alkyl and optionally substituted C 3 . 7 cycloalkyl, more preferably from H and unsubstituted C 1 - 6 alkyl (preferably methyl) and is most preferably H.
  • R 9 R 9 is preferably selected from H, optionally substituted d- 6 alkyl and optionally substituted C 3 - 7 cycloalkyl (especially when X is NH), more preferably from H and optionally substituted d- 6 alkyl (preferably methyl and ethyl) and is most preferably methyl.
  • X is preferably NH.
  • R 7 is preferably an optionally substituted C 9 - ⁇ aryl group (more preferably naphthyl) or an optionally substituted bi-C 5 - 7 aryl group (more preferably bi-C 6 aryl, most preferably bi- phenyl).
  • This preference for R 1 is especially preferred when R N1 , R N2 and R 2 are H, R 3 is methyl and X is NH.
  • R 7 is an optionally substituted C 5 . 7 aryl group (preferably phenyl), then it preferably bears an halo group at the meta position, and may be further substituted, in particular with halo groups. If R 7 is an optionally substituted C 5 . 7 aryl group, then it is preferred that is is not substituted by a carbonyl based group, for example amido. It is also preferred that the sole substituent is not in the ortho position.
  • R 7 is a C 9 . 14 aryl group or a bi-C 5 . 7 aryl group, where the second aryl group is meta to the first.
  • R 7 is an optionally substituted bi-C 5 - 7 aryl group
  • preferred substituents include, but are not limited to, d- 4 alkyl (preferably methyl), hydroxy, d- 4 alkoxy (preferably methoxy) and NH 2 . It is preferred that the substituent is not acylamido or a sulfur based group (e.g. sulfonyl).
  • R 7 is an optionally substituted bi-C 5 . 7 aryl group, then it is preferably a bi-C 6 aryl group and is more preferably a bi-phenyl group. Most preferably R 1 is a 3-phenyl-phenyl group. It is preferred that any subtituent is on the distal phenyl ring, preferably at the 2-position.
  • R 7 is an optionally substituted C 8 - ⁇ aryl group
  • preferred substituent groups for the C 9 - 1 aryl group include halo, hydroxy, d- 4 alkoxy, cyano, amino, amido and d- 4 alkyl, of which hydroxy, and C ⁇ - 4 alkoxy are more preferred. It is also preferred that the C 9 - 14 aryl group bears no oxo substituents.
  • C 9 - 4 aryl group is a naphth-1-yl group
  • preferred substituent positions are 2, 4 and 7, with 2 being most preferred.
  • the preferred substituents at the 2-position are hydroxy, C ⁇ - 4 alkyl and d- 4 alkoxy, with d- alkoxy (e.g. methoxy and ethoxy) being most preferred.
  • R 10 is preferably selected from H, optionally substituted d- 6 alkyl and optionally substituted C 3 - 7 cycloalkyl, more preferably from H and unsubstituted C ⁇ - 6 alkyl (preferably methyl, and -C(CH 3 ) 2 ) and is most preferably H.
  • R 5 is an optionally substituted C-
  • d- 6 alkyl especially d- 3 alkyl (e.g. methyl, iso-propyl)
  • R 4 is an unsubstituted naph
  • R 11 is preferably selected from H, and d- 4 alkyl (e.g. methyl, /so-propyl) and more preferably d- alkyl.
  • the group may be unsubstituted, but when the group is substituted, preferred substituent groups include halo, hydroxy, and amino. Most preferably, R 11 is methyl.
  • R 7 is preferably an optionally substituted bi-C 6 aryl group and is more preferably a bi- phenyl group. Most preferably R 7 is a 3-phenyl-phenyl group.
  • the phenyl groups are preferably either unsubstituted or substituted with an alkoxy (preferably methoxy), halo (preferably chloro), C ⁇ - alkyl (preferably methyl or iso-propyl) or hydroxy. It is preferred that the subtituent is on the distal phenyl ring, preferably at the 2-position.
  • R 13 is preferably selected from H and optionally substituted C- ⁇ - 6 alkyl and C 3 - 7 cycloalkyl, more preferably H and optionally substituted C ⁇ - 6 alkyl. Especially preferred are H, and d- 4 alkyl (e.g. methyl, /so-propyl).
  • R 1 may be unsubstituted, but when R 1 is substituted, preferred substituent groups include halo, hydroxy, and amino.
  • all of the fused rings in R 4 are aromatic or only contain only carbon rings atoms (i.e. a carboaryl group).
  • R 12 is preferably an optionally substituted C 9 .
  • 1 carboaryl group for example, naphth-1-yl, naphth-2-yl, anthracen-1-yl, anthracen-2-yl, anthracen-9-yl, phenanthren-1-yl, phenanthren-2-yl, phenanthren-3-yl and phenanthren-4-yl, phenanthren-9-yl. Of these napth-1-yl and napth-2-yl are preferred, with napthy-1-yl being most preferred.
  • Preferred substituent groups for R 4 include halo, hydroxy, amino, amido and d- alkyl.
  • Fig. 1 shows the effect of salt 3 on abdominal contractions caused by colorectal distention in acetic acid-treated rats.
  • each animal was quietly placed into a clear plastic syringe (ID: 6 cm; length: 10-17 cm), and a 5 cm long balloon made from the tip of a condom was inserted through the anal canal and advanced 7 cm into the rectum.
  • the force-transducer was connected to a polygraph system (WindGraf 980, Gould Inc.) and distention pressure was constantly monitored by a pressure gauge.
  • the colorectal distention procedure (30 mmHg for 10 min) was conducted once before the acetic acid-treatment.
  • Acetic acid solution (0.8%, 2 mL) was applied to the colorectal region through a silicone catheter inserted 7 cm in from the anal verge.
  • the animals displayed a hypersensitive response to colorectal distention.
  • the most appropriate distention pressure i.e., one that produced more than 10 contractions/10 minutes was selected by increasing in 5 mmHg steps from 30 mmHg. Any animal that did not exhibit an adequate response after the pressure had been increased to 45 mmHg was excluded from the study.

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Abstract

Cette invention concerne l'utilisation d'un composé représenté par la formule (Ia) ou d'un sel pharmaceutiquement acceptable de celui-ci dans la fabrication d'un médicament servant au traitement d'une sensibilité viscérale accrue ou d'une douleur viscérale. Dans cette formule, R1 ou R4 est sélectionné dans un groupe comprenant H et C1-6 alkyle, C3-7 cycloalkyle, C3-7 cycloalkyle-C1-4 alkyle et phényle-C1-4 alkyle éventuellement substitués, tandis que le R1 ou R4 restant désigne un groupe C9-14 aryle éventuellement substitué; R2 et R3 soit (i) sont sélectionnés indépendamment parmi H, R, R', SO2R, C(=O)R, (CH2)nNR5R6, n étant compris entre 1 et 4, et R5 et R6 étant sélectionnés indépendamment parmi H et R, R désignant C1-4 alkyle éventuellement substitué et R' désignant phényle-C1-4 alkyle éventuellement substitué; soit (ii) forment, avec l'atome d'azote auquel ils sont liés, un groupe hétérocyclique C5-7 éventuellement substitué.
PCT/GB2005/001378 2004-04-08 2005-04-08 Antagonistes du recepteur de la 5-ht2b WO2005097113A2 (fr)

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GB0408064A GB0408064D0 (en) 2004-04-08 2004-04-08 5-HT2B receptor antagonists
GB0408062.8 2004-04-08
GB0408062A GB0408062D0 (en) 2004-04-08 2004-04-08 5-HT2B receptor antagonists
GB0408064.4 2004-04-08

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WO2005097113A2 true WO2005097113A2 (fr) 2005-10-20
WO2005097113A3 WO2005097113A3 (fr) 2006-10-12

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001008668A2 (fr) * 1999-07-30 2001-02-08 Pharmagene Laboratories Ltd Utilisation de 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine pour le traitement des troubles gastro-intestinaux
WO2001014372A2 (fr) * 1999-08-25 2001-03-01 Takeda Chemical Industries, Ltd. Agent promoteur de la production/secretion de neurotrophine
WO2003068227A1 (fr) * 2002-02-13 2003-08-21 Pharmagene Laboratories Limited Antagonistes du recepteur 5-ht2b
WO2003068226A1 (fr) * 2002-02-13 2003-08-21 Pharmagene Laboratories Limited 2-oxazolamines et leur utilisation comme antagonistes du recepteur 5-ht2b
WO2004009016A2 (fr) * 2002-07-18 2004-01-29 Bristol-Myers Squibb Company Compositions et procedes impliquant le site ii des recepteurs nucleaires d'hormones (nhr)
WO2004009017A2 (fr) * 2002-07-18 2004-01-29 Bristol-Myers Squibb Company Modulateurs de recepteurs de glucocorticoides et procede associe
WO2004094395A2 (fr) * 2003-04-18 2004-11-04 Merck & Co., Inc. Thiazoles, oxazoles et imidazoles a substitution biaryle utilises comme bloqueurs du canal sodique
WO2005012263A1 (fr) * 2003-07-24 2005-02-10 Pharmagene Laboratories Limited Antagonistes du recepteur 5-ht2b

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001008668A2 (fr) * 1999-07-30 2001-02-08 Pharmagene Laboratories Ltd Utilisation de 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine pour le traitement des troubles gastro-intestinaux
WO2001014372A2 (fr) * 1999-08-25 2001-03-01 Takeda Chemical Industries, Ltd. Agent promoteur de la production/secretion de neurotrophine
WO2003068227A1 (fr) * 2002-02-13 2003-08-21 Pharmagene Laboratories Limited Antagonistes du recepteur 5-ht2b
WO2003068226A1 (fr) * 2002-02-13 2003-08-21 Pharmagene Laboratories Limited 2-oxazolamines et leur utilisation comme antagonistes du recepteur 5-ht2b
WO2004009016A2 (fr) * 2002-07-18 2004-01-29 Bristol-Myers Squibb Company Compositions et procedes impliquant le site ii des recepteurs nucleaires d'hormones (nhr)
WO2004009017A2 (fr) * 2002-07-18 2004-01-29 Bristol-Myers Squibb Company Modulateurs de recepteurs de glucocorticoides et procede associe
WO2004094395A2 (fr) * 2003-04-18 2004-11-04 Merck & Co., Inc. Thiazoles, oxazoles et imidazoles a substitution biaryle utilises comme bloqueurs du canal sodique
WO2005012263A1 (fr) * 2003-07-24 2005-02-10 Pharmagene Laboratories Limited Antagonistes du recepteur 5-ht2b

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