WO2000034254A1 - Novel compounds - Google Patents

Novel compounds Download PDF

Info

Publication number
WO2000034254A1
WO2000034254A1 PCT/SE1999/002226 SE9902226W WO0034254A1 WO 2000034254 A1 WO2000034254 A1 WO 2000034254A1 SE 9902226 W SE9902226 W SE 9902226W WO 0034254 A1 WO0034254 A1 WO 0034254A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenoxy
oxoethyl
phenylpentylthio
methyl
acid
Prior art date
Application number
PCT/SE1999/002226
Other languages
French (fr)
Inventor
Stephen Connolly
Antonio Mete
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP99963777A priority Critical patent/EP1135377A1/en
Priority to JP2000586701A priority patent/JP2002531553A/en
Priority to AU20148/00A priority patent/AU2014800A/en
Publication of WO2000034254A1 publication Critical patent/WO2000034254A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2

Definitions

  • the present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing the compounds and the use of the compounds as pharmaceuticals. There are also provided chemical intermediates useful for the preparation of the compounds.
  • R represents hydrogen, Cl to 12 alkyl, phenyl or a 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S, which alkyl, phenyl or heterocyclic ring is optionally substituted by halogen, or which alkyl is optionally substituted by a group J, where J is phenyl or phenyl fused with one or two benzene rings, or biphenylyl, optionally ring substituted by 1 to 3 heteroatoms selected from O, N or S, each group J being optionally substituted by Cl to 6 alkyl, hydroxy, Cl to 6 alkoxy, nitro or halogen;
  • R represents hydrogen, Cl to 6 alkyl or R -B;
  • R represents hydrogen, Cl to 6 hydroxyalkyl, C3 to 9 alkenylcarboxyl or R -B, wherein R represents Cl to 6 alkyl and B represents COOH, PO3H2, OPO3H2,
  • R and R together represent a benzo ring or a six membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms, which benzo or heterocyclic
  • R 4 4 ring is optionally substituted by R , wherein R represents hydrogen, Cl to 6 alkoxy, Cl to 6 carboxyalkoxy, C3 to 9 alkenylcarboxyl, R -B or -(CH 2 ) p CO 2 PG, wherein R represents Cl to ⁇ lkyl and B represents COOH, PO3H2, OPO3H2,
  • R and R independently represent hydrogen, methyl, Cl to 6 alkyl, aryl or heteroaryl, or
  • R and R represent C3 to 6 cycloalkyl or a 3, 4, 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S;
  • Ar represents phenyl, or phenyl fused with one or two benzo rings, or biphenylyl optionally ring substituted with 1 to 3 heteroatoms selected from O, N or S, each Ar group being optionally substituted by Cl to 6 alkyl, hydroxy, Cl to 6 alkoxy, nitro or halogen;
  • X represents O, S, SO2, CH 2 or SO
  • Y represents O, NR or (CH2) a , where a represents an integer from 1 to 12 and R represents hydrogen or Cl to 6 alkyl
  • n represents an integer from 1 to 12; or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
  • Another aspect of the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.
  • the invention further provides a method of treating, or reducing the risk of, inflammatory disease in a patient suffering from, or at risk of, said disease, wherein the method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
  • R represents hydrogen, Cl to 12 alkyl, phenyl or a 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S, which alkyl, phenyl or heterocyclic ring is optionally substituted by halogen, or which alkyl is optionally substituted by a group J, where J is phenyl or phenyl fused with one or two benzene rings, or biphenylyl, optionally ring substituted by 1 to 3 heteroatoms selected from O, N or S, each group J being optionally substituted by Cl to 6 alkyl, hydroxy, Cl to 6 alkoxy, nitro or halogen.
  • R represents phenyl, dichlorophenyl (eg, 3,5- or 3,4-dichlorophenyl) or methyl. More preferably R represents phenyl or dichlorophenyl.
  • R represents hydrogen, methyl or -(CH2)4CO2H.
  • R when R is according to option (i), it represents hydrogen, -(CH2)2OH, -CO2H,
  • R represents hydrogen, OMe,
  • R 2 3 and p represents zero or an integer from 1 to 6. More preferably when R and R are
  • R represents hydrogen, OMe, -CO2H, -(CH2)2CO2H or
  • a represents an integer from 1 to 3.
  • Y represents O or CH2.
  • X represents O or S or SO2.
  • n 1, 5 or 9.
  • R represents hydrogen or methyl. More preferably R represents hydrogen.
  • R represents hydrogen, methyl, phenyl or isopropyl. More preferably R represents hydrogen.
  • Preferred compounds are those exemplified herein, both in free base form and as pharmaceutically acceptable salts.
  • R , R , R , R , X, Y and n are as defined above;
  • Z is as defined above or represents N-C(Ph3)
  • R represents hydrogen or Cl to 6 alkyl
  • R represents hydrogen, NH2 or halogen
  • L and LG each represents a leaving group
  • Ha represents halogen
  • A represents hydrogen or halogen
  • r represents zero or an integer from 1 to 6.
  • R 1 phenyl, 3,5-dichlorophenyl or 3,4-dichlorophenyl;
  • PG allyl, hydrogen or tert-butyl.
  • R hydrogen or methyl
  • reaction may for example be performed in the presence of BuLi.
  • Dess-Martin oxidation may for example be used.
  • oxidation may for example be performed using oxone.
  • Ha represents halogen (preferably Br) and L is as defined above.
  • the reaction may be performed in the presence of a base.
  • reaction may be performed in the presence of a base.
  • Compounds of formula XLI may be prepared by reaction of compounds of formula X with compounds of formula XI.
  • Compounds of formula X may be prepared by reaction of compounds of formula LX with an acyl halide in an alcohol, eg acetyl chloride in ethanol.
  • This reaction is performed in the presence of TEA (triethylamine).
  • Compounds of formula VLLI may be prepared by reaction of compounds of formula VLI, XIV or XV with Dibal-H (diisobutylaluminium hydride).
  • Ha represents halogen, preferably Br.
  • This reaction may be performed in the presence of a base.
  • Compounds of formula XV may be prepared from compounds of formula XIV.
  • the conditions for this reaction are firstly, hydrolysis of the ester to the acid. Then conversion of the acid to acid chloride. Then reaction of the acid chloride with N-methoxy-N- methylamine to give XV.
  • Compounds of formula XLV may be prepared by reacting compounds of formula XIII with compounds of formula LI. This reaction may be performed in the presence of base.
  • the thiazole intermediates of formula XLX may be prepared by reacting compounds of formula XVLL ⁇ with LiOH in a suitable solvent, eg THF-H2Q-
  • Compounds of formula XVLLI may be prepared by reacting compounds of formula XVLI with formamide in the presence of P2S5.
  • Compounds of formula XVII may be prepared by reacting compounds of formula XVI with Ha2 (where Ha represents halogen, preferably Br) in the presence of an alcohol, eg methanol.
  • a suitable solvent eg THF-H2O.
  • 7 alkyl may be prepared by reacting compounds of formula XXI, wherein R represents NH2 and R represents said alkyl with TMSHa, wherein TMS represents trimethylsilyl and Ha represents said halogen, in the presence of tert-butylONO.
  • Compounds of formula XX may be prepared by reacting compounds of formula XVI with TMSHa (preferably TMSBr) in DMSO.
  • Pharmaceutically acceptable derivatives of the compounds of formula I include esters, amides, salts and hydrates.
  • Salts of the compounds of formula I include metal ion salts, eg alkali metal and alkaline earth metal salts, and addition salts with suitable bases, eg suitable amines such as dicyclohexylamine and 1-adamantanamine.
  • Alkyl includes straight chain, branched, cyclic, saturated or unsaturated alkyl.
  • Hydrophilyl includes straight chain, branched, cyclic, saturated or unsaturated alkyl.
  • Hydrophilyl includes straight chain, branched, cyclic, saturated or unsaturated alkyl.
  • Carboxyl includes straight chain, branched, cyclic, saturated or unsaturated alkyl.
  • alkoxy includes straight chain, branched, cyclic, saturated or unsaturated alkyl.
  • the compounds of formula I may exist in enantiomeric forms, all enantiomers, racemates and mixtures thereof are included within the scope of the invention.
  • the various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, e.g. fractional crystallisation, or HPLC.
  • the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions which will not cause racemisation.
  • Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, racemates or mixtures.
  • the compounds of formula I and pharmaceutically acceptable salts, enantiomers and tautomers thereof, are useful because they possess pharmacological activity in animals.
  • the invention therefore provides a compound of formula (I) as defined herein as a therapeutic agent.
  • the compounds are useful as anti-inflammatory agents.
  • the compounds are indicated for use in the treatment or prophylaxis of inflammatory conditions in mammals including man.
  • Conditions that may be specifically mentioned are: osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, inflamed joints; eczema, psoriasis, dermatitis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including uveitis and conjunctivitis; lung disorders in which inflammation is involved, eg asthma, bronchitis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, bacteraemia, endotoxaemia (septic shock) and pancreatitis; conditions of the gastrointestinal tract including aphthous ulcers, gingivitis, Crohn's disease (a condition of the small and sometimes also of the large intestine), atrophic gastritis and gastritis varialoforme (conditions of the stomach), ulcerative colitis (a condition of the large and sometimes of the small intestine), coelia
  • doses administered will, of course, vary with compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compound is administered at a daily dosage of from about 0.1 mg to about 20 mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form.
  • the total daily dose is in the range of from 7.0 mg to 1400 mg and unit dosage forms suitable for oral administration comprise from 2.0 mg to 1400 mg of the compound admixed with a solid or liquid pharmaceutical diluent or carrier.
  • Topical administration of the compounds of invention or their pharmaceutically acceptable salts, enantiomers or tautomers is also contemplated.
  • the compounds of formula I may be used on their own or in the form of appropriate medicinal preparations for enteral, parenteral or topical administration.
  • composition comprising a compound of formula I, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the composition comprises preferably less than 80% and more preferably less than 50% by weight of the compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
  • adjuvants for tablets and dragees - lactose, starch, talc, stearic acid; for capsules - tartaric acid or lactose; for injectable solutions - water, alcohols, glycerin, vegetable oils; for suppositories - natural or hardened oils or waxes.
  • compositions in a form suitable for oesophageal administration include tablets, capsules and dragees; compositions in a form suitable for administration to the lung include aerosols, particularly pressurised aerosols; compositions in a form suitable for administration to the skin include creams, eg oil-in-water emulsions or water-in-oil emulsions; compositions in a form suitable for administration to the eye include drops and ointments.
  • the invention provides a method of treatment of the above disorders which comprises administering to the patient a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
  • the invention provides the use of a compound of formula (I) as defined herein in the manufacture of a medicament for the treatment of the above disorders.
  • Ethanol (3.0g) in chloroform (25 ml) was cooled to 0°C and stirred under an atmosphere of nitrogen gas.
  • Acetyl chloride (4. Ig) was added and the mixture stirred at 0°C for 0.5 hr.
  • (3-[4-(5-phenylpentylthio)phenoxy]-2-hydroxypropionitrile (0.94g) was added and the mixture was allowed to warm to 25°C over 1 hr and stirred at this temperature for a further 18 hrs.
  • the solvent was evaporated to give the required product as a white solid (1). This was used directly in the next step.
  • the silyl ether prepared in 3b (0.62g,) was dissolved in dry THF (5 ml) and treated with a IM solution of TBAF in THF (3.3 ml). The mixture was stirred at 25°C for 1 hr. Water (70 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4 ), evaporated and passed down a silica gel column eluted with ethyl acetate:hexane (1: 1, v/v). The appropriate fractions were evaporated to a solid, which crystallised from ethyl acetate/hexane (0.12g).
  • 6-Hydroxybenzothiazole (0.246g) was dissolved in dry DMF (20 ml) and treated with sodium hydride (60% oil suspension, 0.072g). The mixture was stirred at 25°C for 10 min, treated with methyl iodide (0.23g) and stirring continued for 18 hrs. The reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO ) and evaporated to give the product as an oil, (0.25g).
  • Benzothiazole-6-carboxylic acid (0.483g) was dissolved in dry THF (30 ml) and cooled to -78°C under a nitrogen atmosphere. A 1.6 M solution of butyl lithium in hexane (3.7 ml) was added dropwise and the reaction mixture was stirred at -70°C for 0.5 hr. A solution of the amide prepared in example 5c, (0.517g) in dry THF (10 ml) was added dropwise and the reaction was stirred for a further 0.75 hr. The cooling bath was removed, the reaction was allowed to warm to 0°C and treated with a saturated aqueous solution of ammonium chloride (50 ml).
  • Methyl 6-oxo-heptanoate (5.22g) in dry acetonitrile (50 ml) was treated with slow addition of TMSBr (5.05g) followed by slow addition of DMSO (2.58g). During the additions the reaction temperature was kept below 20°C by cooling in an ice-bath. The mixture was then stirred at ambient temperature for 18 hrs, poured into water and extracted with ether. The ether extract was washed with water, brine, dried (MgSO 4 ) and evaporated to an oil which was purified by a silica gel column eluted with hexane:ethyl acetate (5: 1, v/v). The appropriate fractions were evaporated to afford the product as a clear oil (4.0g).
  • Methyl 5-bromo-6-oxoheptanoate (1.16g) was dissolved in ethanol (50 ml) and treated with thiourea (0.373g). The mixture was heated at reflux for 4 hrs and the solvent was removed under reduced pressure to give the product as a white solid ( 1.44g).
  • Ci 8 H 13 Cl 2 NO 3 S requires: C 54.8 H 3.3 N 3.6 S 8.1 % found: C 54.9 H 3.3 N 3.8 S 7.9 %
  • 5-Oxo-hexanoic acid was subjected to the sequence of reactions described in example 10 to give the title compound as a white solid as the monohydrate.
  • PLA 2 is responsible for the release of arachidonic acid and lysophospholipid from cell membrane phospholipids.
  • Arachidonic acid and certain lysophospholipids are metabolised to substances which are important mediators of the inflammatory response.
  • the usefulness of the compounds according to the invention as anti-inflammatory agents was therefore tested in vitro by measuring their ability to inhibit arachidonic acid release from PLA 2 enzyme provided with a suitable substrate.
  • Cells of the human leukaemic line HL60 are differentiated to a Polymo ⁇ honuclear cell-like phenotype by treatment with 1.3% DMSO for 4 days. During the final 24 hours of differentiation, the cells are incubated with [ 3 H] arachidonic acid. After washing to remove uninco ⁇ orated [ 3 H]arachidonic acid, the cells (at 2.6x10 6 /ml) are incubated for 10 minutes at 37°C with the compound of interest at concentrations up to lO ⁇ M. Arachidonic acid release is then stimulated by the addition of the Ca 2+ ionophore A23187. Control cells are incubated with vehicle alone.

Abstract

Compounds of formula (I) are disclosed, processes for their preparation, pharmaceutical compositions containing the compounds and the use of the compounds as pharmaceuticals. There are also provided chemical intermediates useful for the preparation of the compounds. The compounds are useful as pharmaceuticals, especially for the treatment of inflammatory disease.

Description

NOVEL COMPOUNDS
The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing the compounds and the use of the compounds as pharmaceuticals. There are also provided chemical intermediates useful for the preparation of the compounds.
According to the invention, there is provided a compound of formula I
Figure imgf000003_0001
wherein :-
R represents hydrogen, Cl to 12 alkyl, phenyl or a 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S, which alkyl, phenyl or heterocyclic ring is optionally substituted by halogen, or which alkyl is optionally substituted by a group J, where J is phenyl or phenyl fused with one or two benzene rings, or biphenylyl, optionally ring substituted by 1 to 3 heteroatoms selected from O, N or S, each group J being optionally substituted by Cl to 6 alkyl, hydroxy, Cl to 6 alkoxy, nitro or halogen;
2 3 for R and R :-
2 10
(i) R represents hydrogen, Cl to 6 alkyl or R -B; and
3 10
R represents hydrogen, Cl to 6 hydroxyalkyl, C3 to 9 alkenylcarboxyl or R -B, wherein R represents Cl to 6 alkyl and B represents COOH, PO3H2, OPO3H2,
SO3H, OSO3H, tetrazolyl, CONR1 lOU or CONHSO2R1 R1 l representing hydrogen or Cl to 6 alkyl; or
2 3
(ii) R and R together represent a benzo ring or a six membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms, which benzo or heterocyclic
4 4 ring is optionally substituted by R , wherein R represents hydrogen, Cl to 6 alkoxy, Cl to 6 carboxyalkoxy, C3 to 9 alkenylcarboxyl, R -B or -(CH2)pCO2PG, wherein R represents Cl to β lkyl and B represents COOH, PO3H2, OPO3H2,
SO3H, OSO3H, tetrazolyl, CONR1 !OH or CONHSO2R1 R1 * representing hydrogen or Cl to 6 alkyl, and PG is allyl or tert-butyl and p represents zero or an integer from 1 to 6;
8 9
R and R independently represent hydrogen, methyl, Cl to 6 alkyl, aryl or heteroaryl, or
8 9 together R and R represent C3 to 6 cycloalkyl or a 3, 4, 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S;
Ar represents phenyl, or phenyl fused with one or two benzo rings, or biphenylyl optionally ring substituted with 1 to 3 heteroatoms selected from O, N or S, each Ar group being optionally substituted by Cl to 6 alkyl, hydroxy, Cl to 6 alkoxy, nitro or halogen;
X represents O, S, SO2, CH2 or SO; Y represents O, NR or (CH2)a, where a represents an integer from 1 to 12 and R represents hydrogen or Cl to 6 alkyl;
Z represents O, S, CH=CH, N=N, N=CH or NR , where R represents hydrogen or Cl to
6 alkyl; and n represents an integer from 1 to 12; or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
According to the invention, there is also provided a compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, for use as a pharmaceutical.
Another aspect of the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.
The invention further provides a method of treating, or reducing the risk of, inflammatory disease in a patient suffering from, or at risk of, said disease, wherein the method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
Suitably R represents hydrogen, Cl to 12 alkyl, phenyl or a 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S, which alkyl, phenyl or heterocyclic ring is optionally substituted by halogen, or which alkyl is optionally substituted by a group J, where J is phenyl or phenyl fused with one or two benzene rings, or biphenylyl, optionally ring substituted by 1 to 3 heteroatoms selected from O, N or S, each group J being optionally substituted by Cl to 6 alkyl, hydroxy, Cl to 6 alkoxy, nitro or halogen. Examples of suitable 5 or 6-membered heterocyclic rings include thiophene, furan, pyrrole, pyridyl and pyrimidine rings. Preferably, R represents phenyl, dichlorophenyl (eg, 3,5- or 3,4-dichlorophenyl) or methyl. More preferably R represents phenyl or dichlorophenyl.
2 Preferably, R represents hydrogen, methyl or -(CH2)4CO2H.
3 Preferably, when R is according to option (i), it represents hydrogen, -(CH2)2OH, -CO2H,
-(CH2)3CO2H, -(CH2)2CO2H or CH=CH-CO2H.
2 3 4
Preferably, when R and R are according to option (ii), R represents hydrogen, OMe,
-CO2H, -(CH2)2CO2H, -OCH2CO2H or -(CH2)pCO2PG, where PG is ally, or tert-butyl
2 3 and p represents zero or an integer from 1 to 6. More preferably when R and R are
4 according to option (ii), R represents hydrogen, OMe, -CO2H, -(CH2)2CO2H or
-OCH2CO2H.
Preferably, a represents an integer from 1 to 3.
Preferably, Y represents O or CH2.
Preferably, X represents O or S or SO2.
Preferably, Z represents O, S, CH=CH, NH or NMe.
Preferably, n represents 1, 5 or 9.
8 „
Preferably, R represents hydrogen or methyl. More preferably R represents hydrogen.
9 9 Preferably, R represents hydrogen, methyl, phenyl or isopropyl. More preferably R represents hydrogen.
Preferred compounds are those exemplified herein, both in free base form and as pharmaceutically acceptable salts.
Chemical intermediates of formulae LT to XXI are useful for producing compounds of formula I or pharmaceutically acceptable salts, enantiomers or tautomers thereof. Novel intermediates of formulae LI to XXI form a further aspect of the invention. Formulae II to XXI are as follows:-
II R1— (CH2)n— LG
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
XVIII
Figure imgf000008_0002
Figure imgf000008_0003
wherein
1 2 4 8 9 R , R , R , R , R , X, Y and n are as defined above;
Z is as defined above or represents N-C(Ph3);
R3 is as defined above, or represents -CH=CHCO2R6, -CHO or -(CH2)2OTBDMS, wherein TBDMS is dimethyl( 1 , 1 -dimethylethyl)silyl;
R represents hydrogen or Cl to 6 alkyl;
7 R represents hydrogen, NH2 or halogen;
L and LG each represents a leaving group;
Ha represents halogen; A represents hydrogen or halogen; and r represents zero or an integer from 1 to 6.
In preferred embodiments of formulae LI to VI:-
Figure imgf000009_0001
=tert- uty .
In preferred embodiments of formulae VLI toXLl:-
X = O or S;
Y = 0;
Z = O or NH;
R1 = phenyl, 3,5-dichlorophenyl or 3,4-dichlorophenyl;
R4 = H, OMe, OCH2C02PG or (CH2)pC02PG, where p=0 or 2; n = 1 or 5;
PG = allyl, hydrogen or tert-butyl.
In preferred embodiments of formulae XLLl to XV:- X = 0; Y = CH2; R1 = phenyl; n = 5.
In preferred embodiments of formulae XVI to XXI:- r = 0, 2 or 3;
R = hydrogen or methyl; and
7 R = hydrogen, Br or NH2.
The process mentioned above, for the preparation of compounds of formula I or their pharmaceutically acceptable salts, enantiomers or tautomers, comprises:-
(a) reacting a compound of formula TV, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, with a compound of formula V, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formulae IV and V are as defined above; or (b) reacting a compound of formula IV, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, with a compound of formula VI, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formulae TV and VI are as defined above; or
(c) oxidising a compound of formula XLI, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formula XLI is as defined above; or
(d) preparing a compound of formula I, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein X represents SO2, by oxidising a compound of formula I, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein X represents S.
In options (a) and (b), the reaction may for example be performed in the presence of BuLi.
In option (c), Dess-Martin oxidation may for example be used.
In option (d), oxidation may for example be performed using oxone.
Compounds of formula IV may be prepared by reaction of compounds of formula LLI with the following compound: -
O
XXII Ha>
wherein Ha represents halogen (preferably Br) and L is as defined above. The reaction may be performed in the presence of a base.
Compounds of formula LU may be prepared by reaction of compounds of formula LI with the following compound:-
XXIII
Figure imgf000010_0001
wherein X and Y are as defined above. The reaction may be performed in the presence of a base.
Compounds of formula XLI may be prepared by reaction of compounds of formula X with compounds of formula XI. Compounds of formula X may be prepared by reaction of compounds of formula LX with an acyl halide in an alcohol, eg acetyl chloride in ethanol.
Compounds of formula LX may be prepared by reaction of compounds of formula VLI with the following compound:-
XXIV H^ N
This reaction is performed in the presence of TEA (triethylamine).
Compounds of formula VLLI may be prepared by reaction of compounds of formula VLI, XIV or XV with Dibal-H (diisobutylaluminium hydride).
Compounds of formula VLI may be prepared by reaction of compounds of formula LLI with the following compound: -
Figure imgf000011_0001
wherein Ha represents halogen, preferably Br. This reaction may be performed in the presence of a base.
Compounds of formula XV may be prepared from compounds of formula XIV. The conditions for this reaction are firstly, hydrolysis of the ester to the acid. Then conversion of the acid to acid chloride. Then reaction of the acid chloride with N-methoxy-N- methylamine to give XV.
Compounds of formula XLV may be prepared by reacting compounds of formula XIII with compounds of formula LI. This reaction may be performed in the presence of base.
The thiazole intermediates of formula XLX may be prepared by reacting compounds of formula XVLLΪ with LiOH in a suitable solvent, eg THF-H2Q-
Compounds of formula XVLLI may be prepared by reacting compounds of formula XVLI with formamide in the presence of P2S5. Compounds of formula XVII may be prepared by reacting compounds of formula XVI with Ha2 (where Ha represents halogen, preferably Br) in the presence of an alcohol, eg methanol.
Figure imgf000012_0001
in a suitable solvent, eg THF-H2O.
Compounds of formula XXI, wherein R
Figure imgf000012_0002
represents said
7 alkyl may be prepared by reacting compounds of formula XXI, wherein R represents NH2 and R represents said alkyl with TMSHa, wherein TMS represents trimethylsilyl and Ha represents said halogen, in the presence of tert-butylONO.
Compounds of formula XXI, where said alkyl may
Figure imgf000012_0003
be prepared by reacting compounds o ormu a X, wherein R represents said alkyl and Ha represents halogen (preferably Br), with thiourea.
Compounds of formula XX may be prepared by reacting compounds of formula XVI with TMSHa (preferably TMSBr) in DMSO.
Compounds of formula LI, XHL, XVI and XXLI to XXV are known and or may be prepared by conventional methods.
Pharmaceutically acceptable derivatives of the compounds of formula I include esters, amides, salts and hydrates. Salts of the compounds of formula I include metal ion salts, eg alkali metal and alkaline earth metal salts, and addition salts with suitable bases, eg suitable amines such as dicyclohexylamine and 1-adamantanamine.
"Alkyl" includes straight chain, branched, cyclic, saturated or unsaturated alkyl. "Hydroxyalkyl", "carboxyl", "alkoxy" and "carboxyalkoxy" are interpreted similarly.
The compounds of formula I may exist in enantiomeric forms, all enantiomers, racemates and mixtures thereof are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, e.g. fractional crystallisation, or HPLC. Alternatively the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions which will not cause racemisation.
Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, racemates or mixtures.
The compounds of formula I, and pharmaceutically acceptable salts, enantiomers and tautomers thereof, are useful because they possess pharmacological activity in animals. The invention therefore provides a compound of formula (I) as defined herein as a therapeutic agent. In particular, the compounds are useful as anti-inflammatory agents. The compounds are indicated for use in the treatment or prophylaxis of inflammatory conditions in mammals including man.
Conditions that may be specifically mentioned are: osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, inflamed joints; eczema, psoriasis, dermatitis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including uveitis and conjunctivitis; lung disorders in which inflammation is involved, eg asthma, bronchitis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, bacteraemia, endotoxaemia (septic shock) and pancreatitis; conditions of the gastrointestinal tract including aphthous ulcers, gingivitis, Crohn's disease (a condition of the small and sometimes also of the large intestine), atrophic gastritis and gastritis varialoforme (conditions of the stomach), ulcerative colitis (a condition of the large and sometimes of the small intestine), coeliac disease (a condition of the small intestine), regional ileitis (a regional inflammatory condition of the terminal ileum), peptic ulceration (a condition of the stomach and duodenum) and irritable bowel syndrome; pyresis, pain; damage to the gastrointestinal tract resulting from infections by, eg Helicobacter pylori, or treatments with non-steroidal anti-inflammatory drugs; and other conditions associated with inflammation, particularly those in which phospholipid, lipoxygenase and cyclooxygenase products are a factor.
For the above mentioned therapeutic indications, doses administered will, of course, vary with compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compound is administered at a daily dosage of from about 0.1 mg to about 20 mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form. For man the total daily dose is in the range of from 7.0 mg to 1400 mg and unit dosage forms suitable for oral administration comprise from 2.0 mg to 1400 mg of the compound admixed with a solid or liquid pharmaceutical diluent or carrier.
Topical administration of the compounds of invention or their pharmaceutically acceptable salts, enantiomers or tautomers is also contemplated.
The compounds of formula I may be used on their own or in the form of appropriate medicinal preparations for enteral, parenteral or topical administration.
For example there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The composition comprises preferably less than 80% and more preferably less than 50% by weight of the compound of formula I or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
Examples of such adjuvants, diluents and carriers are: for tablets and dragees - lactose, starch, talc, stearic acid; for capsules - tartaric acid or lactose; for injectable solutions - water, alcohols, glycerin, vegetable oils; for suppositories - natural or hardened oils or waxes.
Compositions in a form suitable for oesophageal administration include tablets, capsules and dragees; compositions in a form suitable for administration to the lung include aerosols, particularly pressurised aerosols; compositions in a form suitable for administration to the skin include creams, eg oil-in-water emulsions or water-in-oil emulsions; compositions in a form suitable for administration to the eye include drops and ointments.
In a further aspect the invention provides a method of treatment of the above disorders which comprises administering to the patient a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, enantiomer or tautomer thereof. In a still further aspect the invention provides the use of a compound of formula (I) as defined herein in the manufacture of a medicament for the treatment of the above disorders.
The invention is illustrated by the following examples: EXAMPLE 1 2-r2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethyllbenzoxazole-5-carboxylic acid a) (l.l-Dimethyl)ethyl 3-nitro-4-hvdroxybenzoate
s A mixture of DCC (33.0g), ( 1 , 1 -dimethyl)ethyl alcohol (300 ml) and 3-nitro-4- hydroxybenzoic acid (27.50g) in THF (150 ml) was treated with DMAP (0.5g) and stirred at 25°C for 18 hrs. A solid formed (DCU) which was filtered off and discarded. The filtrate was dissolved in ethyl acetate and hexane added to precipitate out further DCU which was removed by filtration. The filtrate was concentrated to a gum which was passed down a o silica gel column eluted with hexane:ethyl acetate (9: 1, v/v). The product was isolated as a solid (3.65g).
Mass spectrum : m/e 239
1H NMR, CDC13, d: 1.61 (s, 9H), 1.19 (d, 1H,), 8.17-8.20 (dd, 1H), s 8.74 (d, 1H).
b) (l.l-Dimethyl)ethyl 3-amino-4-hvdroxybenzoate
A solution of the product from la (3.25g) in ethyl acetate (100 ml) was treated with 0 10%Pd/C (0.25g) and stirred under an atmosphere of hydrogen gas at 3 bar for 4 hrs. The reaction mixture was filtered through celite and evaporated to give the required product as a solid (2.84g).
Mass spectrum : m/e 209 5 1H NMR, DMSO-D6, d: 1.49 (s, 9H), 3.38 (bs, 2H), 4.73 (bs, 1H)
6.68 (d, 1H), 7.03-7.06 (dd, 1H), 7.17 (d, 1H).
c) 5-Phenylpentyl mesylate
0 5-Phenylpentanol (6.0g) and triethylamine (5.6 ml) were dissolved in dry THF (50 ml) and cooled to -5°C. A solution of methanesulphonic anhydride (6.7g) in dry THF (20 ml) was added dropwise. The reaction mixture was stirred at 25°C for 3 hrs and then evaporated. The residue was dissolved in ethyl acetate, washed with 2N hydrochloric acid, water, brine, dried (MgSO-i) and evaporated to give the product as an oil (7.3g). 5
Mass spectrum: m e 326 NMR: CDCI3 d: 1.45 (m, 2H), 1.67 (m, 4H), 1.78 (m, 2H),
2.63 (t, 2H), 2.98 (s, 3H), 4.24 (t, 2H), 7.18 (m, 3H), 7.29 (m, 2H).
d) 4-(5-Phenylpentylthio)pheπol
5-Phenylpentyl mesylate (35.3g), 4-hydroxythiophenol (18.9g), caesium carbonate (47.6g) in acetonitrile were heated at reflux for 8 hrs. The mixture was then poured into water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to give an oil. This was passed down a silica gel column eluted with hexane:ethyl acetate (5: 1) to afford the product as a white solid, (33g).
NMR: CDCI3 d: 1.43 (m, 2H), 1.60 (m, 2H), 2.59 (t, 2H),
2.8 (t, 2H), 4.83 (s, 1H), 7.17 (m, 3H), 7.27 (m, 2H).
e) 2-r4-(5-Phenylpentylthio)phenoxy1acetonitrile
4-(5-Phenylpentylthio)phenol (2.73g), bromoacetonitrile (1.44g) and caesium carbonate (4.8g) in acetonitrile (50 ml) were heated at reflux for 4 hrs, with stirring. The reaction mixture was allowed to cool to 25°C, poured into 2N hydrochloric acid (300 ml) and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give an oil. This was passed down a silica gel column eluted with hexane:dichloromethane (1:1, v/v). The appropriate fractions were collected and evaporated to give the required product as a clear colourless oil, (2.39g).
Mass spectrum m/e 311
1H NMR, CDCl3 , d: 1.40-1.48 (m, 2H), 1.57-1.67 (m, 4H), 2.59 (t, 2H),
2.84 (t, 2H), 4.73 (s, 2H), 6.91 (d, 2H), 7.16 (m, 3H), 7.30 (m, 2H), 7.35 (d, 2H).
f) 2-r4-(5-Phenylpentylthio)phenoxy1acetaldehvde A stirred solution of 2-[4-(5-phenylpentylthio)phenoxy]acetonitrile (2.0g) in dry toluene (10 ml) was cooled to -45°C under a nitrogen atmosphere. A 1M solution of Dibal-H in toluene (9.5 ml) was added dropwise and the resulting solution was allowed to warm to 0°C over 1 hr and stirred at this temperature for a further 1 hr. A saturated solution of ammonium chloride (15 ml) was added followed by diethyl ether (15 ml). A solution of concentrated sulphuric acid (6 ml) in water ( 24 ml) was then added and the mixture was stirred at 25°C for 18 hrs. The mixture was added to ethyl acetate (500 ml), the separated organic phase washed with water, brine, dried (MgSO4) and the solvent was evaporated to give the product as a yellow oil, (1.66g).
Mass spectrum : m e 314
Η NMR, CDC13, d: 1.43-1.47 (m, 2H), 1.59-1.65 (m, 4H),
2.58 (t, 2H) 2.81 (t, 2H), 4.54 (s, 2H), 6.82 (d, 2H), 7.16 (m, 3H), 7.26 (m, 2H), 7.36 (d, 2H).
g) 3-r4-(5-Phenylpentylthio)phenoxy1-2-hvdroxypropionitrile
2-[4-(5-Phenylpentylthio)phenoxy]acetaldehyde (1.56g), acetone cyanohydrin (0.7 ml) and triethylamine (1 drop) in dichloromethane (20 ml) were stirred at 25°C for 18 hrs. The solvent was evaporated to afford a yellow solid. The solid was passed down a silica gel column eluted with dichloromethane:methanol (50: 1, v/v). The appropriate fractions were combined and evaporated to afford the required product as a white solid (0.95g).
1H NMR, CDC13, d: 1.41-1.48 (m, 2H), 1.58-1.65 (m, 4H), 2.59 (t, 2H), 2.83 (t, 2H), 3.00 (d, 1H), 4.18-4.25 (m, 2H),
4.79-4.84 (m, 1H), 6.87 (d, 2H), 7.14-7.19 (m, 3H), 7.25-7.30 (m, 2H), 7.33 (d, 2H).
h) 3-r4-(5-PhenylpentvIthio)phenoxy]-2-hvdroxy-l-ethoxy-l-inιinopropane hvdrochloride
Ethanol (3.0g) in chloroform (25 ml) was cooled to 0°C and stirred under an atmosphere of nitrogen gas. Acetyl chloride (4. Ig) was added and the mixture stirred at 0°C for 0.5 hr. (3-[4-(5-phenylpentylthio)phenoxy]-2-hydroxypropionitrile (0.94g) was added and the mixture was allowed to warm to 25°C over 1 hr and stirred at this temperature for a further 18 hrs. The solvent was evaporated to give the required product as a white solid (1). This was used directly in the next step.
i) (l,l-Dimethyl)ethyl 2-f2-(4-(5-phenylpentylthio)phenoxy)-l- hvdroxyethyllbenzoxazole-5-carboxyIate
The product from lh (1.26g) and the product from lb (0.85g) in acetonitrile (30 ml) were heated at reflux for 6 hrs. The reaction mixture was cooled to 25°C, poured into ethyl acetate (500 ml), washed with water, brine, dried (MgSO ) and evaporated to give a gum. This was passed down a silica gel column eluted with hexane:ethyl acetate (4:1, v/v) to give the product as an oil, (1.20g).
Η NMR, CDC13, d: 1.40-1.46 (m, 2H), 1.55-1.60 (m, 4H), 1.62 (s, 9H),
2.58 (t, 2H), 2.80 (t, 2H), 3.80 (d, 1H) 4.44-4.53 (m, 2H) 5.33-5.38 (m, 1H), 6.85 (d, 2H), 7.13-7.19 (m, 3H), 7.25-7.29 (m, 2H), 7.31 (d, 2H), 7.55 (d, 1H), 8.05-8.07 (dd, 1H), 8.39 (d, 1H).
i) (l.l-Dimethyl)ethyl 2-r2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethvnbenzoxazoIe- 5-carboxylate
The product from li (0.54g, 1 mmol) was dissolved in dichloromethane (25 ml), treated with Dess-Martin reagent (0.75g) and stirred at 25°C for 4 hrs. The reaction mixture was mixed with ethyl acetate (200 ml), washed with a 10% aqueous solution of sodium thiosulphate (3 x 200 ml), brine and dried (MgSO4). The solvent was evaporated to give a yellow gum. This was passed down a silica gel column eluted with hexane:ethyl acetate (9: 1) to give the product as a yellow solid, (0.23g).
Mass spectrum: m e 550 (M+NH4) Η NMR, CDC13 , d: 1.41-1.47 (m, 2H), 1.58-1.62 (m, 4H), 1.64 (s, 9H),
2.59 (t, 2H), 2.83 (t, 2H), 5.55 (s, 2H), 6.95 (d, 2H), 7.15-7.19 (m, 3H), 7.23-7.30 (m, 2H), 7.35 (d, 2H) 7.71 (d, 1H), 8.26 (dd, 1H), 8.57 (d, 1H).
k) 2-r2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethyll benzoxazoIe-5-carboxylic acid
A solution of the product from lj (0.2g) in formic acid (10 ml) and dichloromethane (5 ml) was stirred at 25°C for 3 hrs. Toluene (20 ml) was added and the mixture was evaporated. This procedure was repeated twice to afford a yellow solid which was recrystallised from acetonitrile to give the required product (0.09g).
Mass spectrum: m e 474 (M-H) M.p.: 148-149°C
C27H25NO5S requires: C 68.2 H 5.3 N 3.0 S 6.7 % found: C 68.1 H 5.4 N 3.1 S 6.7 %
EXAMPLE 2 l-Methyl-2-f2-r4-(5-phenylpentylthio)phenoxyl-l-oxoethvnbenzimidazole
a) Ethyl 2-r4-(5-phenylpentylthio)phenoxy1acetate
4-(5-Phenylpentylthio)phenol (2.0g) was dissolved in acetonitrile (60 ml) and ethyl 2- bromoacetate (1.23g) was added. The mixture was treated with caesium carbonate (3.58g) and stirred at 25°C for 18 hrs. Water (50 ml) was added and the mixture was extracted with ethyl acetate. The combined extract was washed with saturated sodium bicarbonate, water, brine, dried (MgSO4) and evaporated to give the product as a solid, (2.32g).
Η NMR, CDC13 , d: 1.30 (t, 3H), 1.38-1.48 (m, 2H), 1.56-1.66 (m, 4H), 2.59 (t,
2H), 2.81 (t, 2H), 4.27 (q, 2H), 4.60 (s, 2H), 6.84 (d, 2H), 7.14-7.20 (dd, 2H), 7.25 (m, 3H), 7.32 (d, 2H). b) l-Methyl-2-r2-r4-(5-Phenylpentylthio)phenoxy1-l-oxoethvnbenzimidazole
A stirred solution of 1-Methylbenzimidazole (0.223g) in dry THF (30 ml) was cooled to - 78°C under a nitrogen atmosphere. Butyl lithium ( 1.6M in hexane, 1.06 ml,) was added dropwise and the solution stirred at below -60°C for 15 mins. The ester prepared in 2a, (0.60g) in THF (10 ml) was added dropwise over 5 mins, and the reaction was stirred at below -60°C for 0.5 hr. Cooling was removed and the reaction was allowed to attain ambient temperature. Diethyl ether (100 ml) and 2N hydrochloric acid (50 ml) were added and the two layers separated. The aqueous layer was extracted with ether, the combined ether extract was washed with water, brine, dried (MgSO ) and evaporated to a colourless oil. The oil was passed down a silica gel column eluted with hexane:ethyl acetate (4:1, v/v). The appropriate fractions were combined and evaporated to give a white solid which was recrystallised from acetonitrile to afford the product, (0.35g).
Mass spectrum: m/e 445 (M+H) M.p.: 94-95°C
C27H28N2O2S requires: C 72.9 H 6.4 N 6.3 S 7.2 % found: C 73.0 H 6.1 N 6.4 S 7.2 %
EXAMPLE 3
5-(2-Hydroxyethyl)-4-methyl-2-r2-(4-(5-phenylpentvIthio)phenoxy)-l- oxoethyllthiazole
a) 5-(2-(Dimethyl(l.l-dimethylethyl)siIyloxy)ethyl)-4-methylthiazole
5-(2-Hydroxyethyl)-4-methylthiazole (15.0g) was dissolved in DMF (80 ml) and imidazole (7.15g) was added. The reaction was cooled to 0°C and t-butyldimethylsilylchloride (15.8g) in DMF (100 ml) was added dropwise over 1 hr. The reaction was stirred at 25°C for 18 hrs, water (100 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to give an oil. This was passed down a silica gel column eluted with hexane:ethyl acetate (3:2, v/v) to give the product as a colourless oil (23.74g).
1H NMR, CDC13 , d: 0.01 (s,6H), 0.87 (s, 9H), 2.39 (s, 3H), 2.94 (t, 2H), 3.76 (t, 2H), 8.55 (s, 1H). b 5-(2-(Dimethyl(Ll-dimethylethyl)silyloxy)ethyl)-4-methyl-2-r2-(4-(5- phenylpentylthio)phenoxy)-l-oxoethyllthiazole
Using the procedure described for example 2b but using the thiazole derivative prepared in example 3 a, in place of 1-methylbenzimidazole led to the preparation of the required compound as an oil in 79% yield.
Η NMR, CDC13 , d: 0.02 (s, 6H), 0.88 (s, 9H), 1.40-1.48 (m, 2H), 1.56-1.66 (m,
4H), 2.45 (s, 3H), 2.59 (t, 2H), 2.81 (t, 2H), 3.02 (t, 2H), 3.83 (t, 2H), 5.46 (s, 2H), 6.92 (d, 2H), 7.14-7.19 (dd, 2H), 7.26
(m, 3H), 7.31 (d, 2H).
c) 5-(2-Hvdroxyethyl)-4-methyl-2-f2-(4-(5-phenylpentylthio)phenoxy)-l- oxoethyll thiazole
The silyl ether prepared in 3b (0.62g,) was dissolved in dry THF (5 ml) and treated with a IM solution of TBAF in THF (3.3 ml). The mixture was stirred at 25°C for 1 hr. Water (70 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), evaporated and passed down a silica gel column eluted with ethyl acetate:hexane (1: 1, v/v). The appropriate fractions were evaporated to a solid, which crystallised from ethyl acetate/hexane (0.12g).
Mass spectrum: m/e 456 (M+H)
M.p.: 68-69°C
C25H29NO3S2 requires: C 65.9 H 6.4 N 3.1 S 14.1 % found: C 65.9 H 6.5 N 3.2 S 14.4 %
EXAMPLE 4 6-Methoxy-2-r2-r4-(5-phenylpentylthio)phenoxy1-l-oxoethvnbenzothiazole
a) 6-Methoxybenzothiazole
6-Hydroxybenzothiazole (0.246g) was dissolved in dry DMF (20 ml) and treated with sodium hydride (60% oil suspension, 0.072g). The mixture was stirred at 25°C for 10 min, treated with methyl iodide (0.23g) and stirring continued for 18 hrs. The reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO ) and evaporated to give the product as an oil, (0.25g).
Η NMR, CDC13 , d: 3.90 (s, 3H), 7.11-7.15 (dd, 1H), 7.40 (d, 1H), 8.01 (d, 1H), 8.83 (s, 1H).
b) 6-Methoxy-2-r2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethvnbenzothiazole
Using the procedure described for example 2b but using 6-methoxy-benzothiazole (4a) in place of 1-methylbenzimidazole led to the preparation of the required compound as a white solid in 48% yield.
Mass spectrum: m/e 478 (M+H) M.p.: 84-86°C C27H27NO3S2 requires: C 67.9 H 5.3 N 2.9 S 13.4 % found: C 67.6 H 5.6 N 3.0 S 12.9 %
EXAMPLE 5 l-Methyl-2-r2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethyl1imidazole
a) (l.l-Dimethyl)ethyl 2-r4-(phenylpentylthio)phenoxy1acetate
Using the procedure described for example 2a but using (l,l-dimethyl)ethyl 2- bromoacetate in place of ethyl 2-bromoacetate gave the required product as a colourless oil in quantitative yield.
Η NMR, CDC13 , d: 1.48 (s, 9H), 1.38-1.51 (m, 2H), 1.56-1.66 (m, 4H), 2.59 (t,
2H), 2.81 (t, 2H), 4.49 (5, 2H), 6.80-6.85 (d, 2H), 7.15-7.20 (m, 3H), 7.24-7.28 (m, 2H), 7.29-7.33 (d, 2H).
b) 2-f4-(Phenylpentylthio)phenoxyTacetic acid
The ester prepared in example 5a (5.33g) was dissolved in a mixture of formic acid (20 ml) and dichloromethane (80 ml) and stirred at 25°C for 24 hrs. The dichloromethane was evaporated under reduced pressure and the residue treated with water (30 ml). A white precipitate formed which was collected by filtration, washed with water and dried in a vacuum desiccator to give the product as a white solid (4.08g).
Η NMR, CDC13 , d: 1.38-1.48 (m, 2H), 1.49-1.67 (m, 4H), 2.56-2.62 (t, 2H), 2.80-2.85 (s, 2H), 4.66 (t, 2H), 6.83-6.88 (dd, 2H), 7.14-7.20
(m, 3H), 7.25-7.30 (m, 2H), 7.30-7.35 (d, 2H).
c) N-r2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethyl1pyrrolidine
2-[4-(Phenylpentylthio)phenoxy]acetic acid (4.08g) was dissolved in THF (50 ml) and cooled to 0°C. l,l '-carbonyldiimidazole (2.20g) was added and the solution stirred at 0°C for 1.5 hrs. Pyrrolidine (0.97g) in THF (10 ml) was added dropwise while keeping the reaction temperature below 5°C. The ice-bath was then removed and the reaction was stirred at 25°C for 1.5 hrs. Ethyl acetate (200 ml) was added and the mixture was washed with 2N hydrochloric acid, water, saturated sodium bicarbonate, brine, dried (MgSO4) and evaporated to a gum. The gum was passed down a silica gel column eluted with ethyl acetate :hexane (4: 1, v/v) to afford the product as a colourless oil (4.06g, 86%).
Mass spectrum: m e 384 (M+H) C23H29NO2S requires: C 72.0 H 7.6 N 3.7 S 8.3 % found: C 71.7 H 7.6 N 3.7 S 8.2 %
d) l-Methyl-2-r2-(4-(5-phenylpentylthio)phenoχy)-l-oxoethvnimidazole
A stirred solution of 1-methylimidazole (0.12g) in dry THF (10 ml) was cooled to -78°C under a nitrogen atmosphere. Butyl lithium (1.6M in hexane, 0.93 ml) was added dropwise and the solution stirred at below -60°C for 15 mins. The amide prepared in 5c, (0.515g) in THF (10 ml) was added dropwise over 5 mins, keeping the temperature below -60°C. The reaction was allowed to attain ambient temperature and stirred at 25°C for 0.5 hr. Diethyl ether (20 ml) and 2N hydrochloric acid (50 ml) were added and the two layers separated. The aqueous layer was extracted with ether (2 x 30 ml) and the combined ether extract was washed with water, dried (MgSO4) and evaporated to a colourless oil which solidified on standing (0.46g). The solid re-crystallised from ethyl acetate/hexane.
Mass spectrum: m/e 395 (M+H) M.p.: 76-77°C C23H26N2O2S requires: C 70.0 H 6.6 N 7.1 S 8.1 % found: C 69.7 H 6.7 N 7.0 S 7.8 %
EXAMPLE 6 2-r2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethvnbenzothiazole
Using the procedure described for example 5d but using benzothiazole in place of 1- methylimidazole led to the preparation of the required compound as a white solid in 43% yield.
Mass spectrum: m/e 448 (M+H) M.p.: 91-92°C
C26H25NO2S2 requires: C 69.8 H 5.6 N 3.1 S 14.3 % found: C 69.6 H 5.7 N 3.3 S 14.3 %
EXAMPLE 7 2-f2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethvnthiazole
Using the procedure described for example 5d but using 2-bromothiazole in place of 1- methylimidazole led to the preparation of the required compound as a white solid in 34% yield.
Mass spectrum: m/e 398 (M+H) M.p.: 74-75°C
C22H23NO2S2 requires: C 66.5 H 5.8 N 3.5 S 16.1 % found: C 66.8 H 5.9 N 3.7 S 16.0 %
EXAMPLE 8 2-r2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethvnbenzothiazole-6-carboxylic acid
Benzothiazole-6-carboxylic acid (0.483g) was dissolved in dry THF (30 ml) and cooled to -78°C under a nitrogen atmosphere. A 1.6 M solution of butyl lithium in hexane (3.7 ml) was added dropwise and the reaction mixture was stirred at -70°C for 0.5 hr. A solution of the amide prepared in example 5c, (0.517g) in dry THF (10 ml) was added dropwise and the reaction was stirred for a further 0.75 hr. The cooling bath was removed, the reaction was allowed to warm to 0°C and treated with a saturated aqueous solution of ammonium chloride (50 ml). The mixture was extracted with ethyl acetate and the extract was washed with water, brine, dried (MgSO ) and evaporated to give the crude product as a solid. This was passed down a silica gel column eluted with hexane:ethyl acetate (1 : 1, v/v) to give the product as a yellow solid, (0.15g).
Mass spectrum: m/e 492 (M+l)
M.p.: 107-171°C
C27H25NO4S requires: C 66.0; H 5.1 ; N 2.9; SI 3.0% found: C 66.2; H 5.2; N 3.0; S 12.9 %
EXAMPLE 9
4-Methyl-2-r2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethynthiazole-5-carboxylic acid
a) Ethyl 2-bromo-4-methylthiazole-5-carboxylate
A solution of (l,l-dimethyl)ethane-2-nitrite (2.5 ml) in acetonitrile (100 ml) was cooled in an ice-bath and treated with the dropwise addition of trimethylsilyl bromide (2.8 ml). After addition was complete the mixture was stirred at 0°C for 20 mins. Ethyl 2-amino-4- methylthiazole-5-carboxylate (2.0 g), dissolved in a mixture of acetonitrile (75 ml) and ethyl acetate (25 ml), was added dropwise, over 40 min while maintaining the temperature at 0°C. The cooling bath was removed and the mixture was stirred at 25°C for 18 hrs. The solvent was removed under reduced pressure and the residue was passed down a silica gel column eluted with ethyl acetate:hexane (2: 1) to afford the product as an orange-red oil (1.88g).
Mass spectrum: m/e 250 / 252 (M+l)
Η NMR, CDC13 , d: 1.36 (t, 3H), 2.71 (s, 3H), 4.33 (q, 2H).
b) 2-Bromo-4-methylthiazole-5-carboxyIic acid
The thiazole prepared in 9a (1.88g,) was dissolved in a mixture of THF (40 ml) and water (10 ml). Lithium hydroxide monohydrate (1.58g,) was added and the mixture was stirred at 25°C for 18hrs. The reaction mixture was then poured into 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO4) and evaporated to afford the product as a white solid, (1.64g). Mass spectrum: m/e 293 / 295 (TMS -ester) Η NMR, DMSOlD6 , d: 2.60 (s, 3H).
c) 4-Methyl-2-r2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethyllthiazole-5-carboxylic acid
Using the procedure described for example 8 but using 2-bromo-4-methyl-thiazole-5- carboxylic acid in place of benzothiazole-6-carboxylic acid led to the preparation of the required compound as a white solid in 71% yield.
Mass spectrum: m/e 456 (M+l)
M.p.: 142-3°C
C24H25NO4S2 requires: C 63.3 H 5.5 N 3.1 S 14.1 % found: C 63.0 H 5.4 N 3.2 S 13.8 %
EXAMPLE 10
4.[2-(2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethyl)-4-methylthiazol-5-yllbutanoic acid
a) Methyl 5-bromo-6-oxo-heptanoate
Methyl 6-oxo-heptanoate (5.22g) in dry acetonitrile (50 ml) was treated with slow addition of TMSBr (5.05g) followed by slow addition of DMSO (2.58g). During the additions the reaction temperature was kept below 20°C by cooling in an ice-bath. The mixture was then stirred at ambient temperature for 18 hrs, poured into water and extracted with ether. The ether extract was washed with water, brine, dried (MgSO4) and evaporated to an oil which was purified by a silica gel column eluted with hexane:ethyl acetate (5: 1, v/v). The appropriate fractions were evaporated to afford the product as a clear oil (4.0g).
Mass spectrum : m/e 236 / 238
1H NMR, CDC13, d: 1.6-2.2 (m, 4H), 2.36 (s, 3H,), 2.38(t, 2H),
3.7 (s, 3H) 4.24 (dd, 1H). b) Methyl 4-(2-amino-4-methylthiazol-5-yl)butanoate hvdrobromide
Methyl 5-bromo-6-oxoheptanoate (1.16g) was dissolved in ethanol (50 ml) and treated with thiourea (0.373g).The mixture was heated at reflux for 4 hrs and the solvent was removed under reduced pressure to give the product as a white solid ( 1.44g).
Mass spectrum : m/e 214
Η NMR, CDC13, d: 1.81 - 1.91 (m, 2H), 2.20 (s, 3H), 2.36 (t, 2H), 2.60 (t, 2H),
3.69 (s, 3H), 8.80 (bs, 3H).
c) Methyl 4-(2-bromo-4-methylthiazol-5-yl)butanoate
Using the procedure described in 9a, with the 2-aminothiazole derivative prepared in 10b, led to the required product as an orange-red oil in 33% yield.
Mass spectrum : m/e 277 / 279
1H NMR, CDC13, d: 1 1..81 7-1.98 (m, 2H), 2.31 (s, 3H), 2.36 (t, 2H), 2.75 (t, 2H), 3.67 (s, 3H).
d) 4-(2-Bromo-4-methylthiazol-5-yl)butanoic acid
Using the procedure described in 9b, with the 2-bromothiazole derivative prepared in 10c, led to the required product as a white solid in 73% yield.
Mass spectrum : m e 264 / 266 (M+l)
1H NMR, CDC13, d: 1.88- 1.98 (m, 2H), 2.32 (s, 3H), 2.42 (t, 2H), 2.78 (t,
2H).
e) 4-r2-(2-(4-(5-Phenylpentylthio)phenoχy)-l-oxoethyl)-4-methylthiazol-5-yllbutanoic acid
Using the procedure described for example 8 but using 4-(2-bromo-4-methylthiazol-5- yl)butanoic acid in place of benzothiazole-6-carboxylic acid led to the preparation of the required compound as a white solid in 33% yield.
Mass spectrum: τn/e 498 (M+ 1 ) M.p.: 97-98°C
C27H31NO4S2 requires: C 65.2 H 6.3 N 2.8 S 12.9 % found: C 65.2 H 6.4 N 2.8 S 12.7 %
EXAMPLE 11
2-r2-(4-(3,5-DichlorobenzvIoxy)phenoxy)-l-oxoethvπthiazole
a) 4-r3,5-Dichlorobenzyloxylphenol
Quinol (4.9g) was dissolved in dry DMF (100 ml) and treated with caesium carbonate (14.6g). 3,5-Dichlorobenzylchloride (2.9g) was added and the mixture was stirred at 25°C for 72 hrs. The mixture was poured into 2N hydrochloric acid (250 ml) and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO4), evaporated and the residue passed down a silica gel column eluted with hexane:ethyl acetate (5:1, v/v). The appropriate fractions were combined and evaporated to give the product as a white solid, (2.41g).
Mass spectrum : m/e 268 / 270 / 272
Η NMR, CDC13, d: 4.55 (s, 1H), 4.95 (s, 2H), 6.75-6.85 (m, 4H) 7.31 (s, 3H).
b) Ethyl 2-r4-(3.5-dichlorobenzyloxy)phenoxy]acetate
The procedure described in example 2a was used with ethyl 2-bromoacetate and 4-(3,5- dichlorobenzyloxy)phenol to give the product as a white solid in 98% yield.
Mass spectrum : m e 354 / 356 / 358
Η NMR, CDC13, d: 1.30 (t, 3H), 4.3 (q, 2H), 4.58 (s, 2H), 4.96 (s, 2H)
6.89 (s, 4H), 7.31 (s, 3H).
c) 2-r2-(4-(3.5-Pichlorobenzyloxy)phenoxy)-l-oxoethvnthiazole
The procedure described in example 2b was used with 2-bromothiazole and ethyl 2-[4- (3, 5-dichlorobenzyloxy)phenoxy] acetate to give the product as a white solid in 32% yield.
Mass spectrum: m/e 394 / 396 / 398 (M+l) M.p.: 116-118°C
Ci8H13Cl2NO3S requires: C 54.8 H 3.3 N 3.6 S 8.1 % found: C 54.9 H 3.3 N 3.8 S 7.9 %
EXAMPLE 12
5-(2-Hydroxyethyl)-4-methyl-2-r2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l- oxoethyllthiazole
a) 5-(2-(Di ethyl(lJ-dimethylethyl)silyloxy)ethyl)-4-methyl-2-r2-(4-(3.5- dichlorobenzyloxy)phenoxy)-l-oxoethyl1thiazole
The procedure described in example 2b was used with the thiazole prepared in 3 a and ethyl 2-[4-(3,5-dichlorobenzyloxy)phenoxy]acetate to give the product as a yellow gum in 32% yield.
Mass spectrum: m/e 566 / 568 / 570 (M+l)
1H NMR, CDC13, d: 0.02 (s, 6H), 0.88 (s, 9H), 2.44 (s, 3H), 3.02 (t, 2H),
3.82 (t, 2H), 4.95 (s, 2H), 5.43 (s, 2H),
6.8-7.0 (m, 4H), 7.31 (s, 3H).
b) 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(3,5-dichlorobenzyloχy)phenoxy)-l- oxoethyll thiazole
The product from 12a (0.36g) was dissolved in ethanol (10 ml), treated with pyridinium p- toluenesulfonate (0.08g) and water (0.25 ml) and the reaction was heated at 60°C for 8 hrs. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (100 ml), washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by passing down a silica gel column eluted with ethyl acetate:hexane (1:1, v/v) to give the product as a white solid which crystallised from ethyl acetate/hexane (0.18g).
Mass spectrum: m/e 452 / 454 / 456 (M+l) M.p.: 115-116°C
1H NMR, CDC13, d: 1.64 (bs, 1H), 2.45 (s, 3H), 3.08 (t, 2H), 3.91 (m, 2H), 4.96 (s, 2H), 5.43 (s, 2H),
6.8-7.0 (m, 4H), 7.31 (s, 3H). EXAMPLE 13
5-(2-Hvdroxyethyl)-4-nιethvI-2-r2-(4-(decylsulfonyl)phenoxy)-l-oxoethyllthiazole
a) 4-(Decylthio)phenol
A solution of decyl bromide (11.5 ml) and 4-hydroxythiophenol (7g) in acetonitrile (100 ml) was treated with caesium carbonate (18g) and stirred at 25°C for 18 hrs. The reaction was poured into 2N hydrochloric acid (500 ml) and the product was extracted into ethyl acetate. The extract was washed with water, brine, dried (MgSO ) and evaporated under reduced pressure to give the product as a solid (12.5g).
Mass spectrum: m/e 266 M.p.: 81-82°C C16H26OS requires: C 72.1 H 9.8 N 12.0 % found: C 72.2 H 9.9 N 12.1 %
b 4-(PecylsuIfonyl phenol
4-(Decylthio)phenol (5.3 lg) was dissolved in acetone (500 ml). Water (100 ml) was added and the solution was cooled in an ice-bath. Oxone (15g) was added, the ice-bath was removed and the mixture was stirred at 25°C for 18 hrs. A 10% aqueous solution of sodium metabisulphite (1 It) was added and the mixture was stirred for a further lhr. The mixture was extracted with ethyl acetate and the extract was washed with water, brine, dried (MgSO4) and evaporated to give a clear oil, (5.65g).
Mass spectrum: m/e 297 (M-l)
1H NMR, CDC13, d: 0.87 (t, 3H), 1.2-1.3 (m, 12H), 1.35 (m, 2H),
1.67 (m, 2H), 3.06 (m, 2H), 6.56 (bs, 1H), 6.96 (d, 2H), 7.75 (d, 2H).
c) Ethyl 2-f 4-(decylsulf on vDphenoxyl acetate
The procedure described in example 2a was used with ethyl 2-bromoacetate and 4- (decylsulfonyl)phenol to give the required product as a white solid in 78% yield. Mass spectrum : m/e 385 (M+l)
1H NMR, CDC13, d: 0.87 (t, 3H), 1.23 (m, 14H), 1.31 (t, 3H), 1.64-1.74 (m, 2H),
3.02-3.07 (m, 2H), 4.29 (q, 2H), 4.70 (s, 2H), 7.00-7.04 (d, 2H), 7.82-7.86 (d, 2H).
d) 5-(2-(Dimethyl(l.l-dimethylethvnsilyloxy)ethyl)-4-methyl-2-r2-(4- (decylsulfonyl)phenoxy)-l-oxoethyl1thiazole
The procedure described in example 2b was used with the thiazole prepared in 3a and ethyl 2-[4-(decylsulfonyl)phenoxy]acetate to give the product as a colourless gum in 20% yield.
Η NMR, CDC13, d: 0.02 (s, 6H), 0.87 (s, 12H), 1.2-1.3 (m, 12H),
1.35 (m, 2H), 1.69 (m, 2H), 2.46 (s, 3H), 3.05 (m, 4H), 3.84 (t, 2H), 5.57 (s, 2H),
7.07 (d, 2H), 7.83 (d, 2H).
e) 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(decylsulfonyl)phenoxy)-l-oxoethvnthiazole
The procedure described in example 12b was used with the product of 13d to give the product as white solid, which analysed as a monohydrate.
Mass spectrum: m/e 482 (M+l) M.p.: 53-55°C C24H35NO5S2.H2O requires: C 57.7 H 7.5 N 2.8 S 12.8 % found: C 57.9 H 7.4 N 2.8 S 12.7 %
EXAMPLE 14 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(benzyloxy)phenoxy)-l-oxoethvnthiazoIe
a) Ethyl 2-r4-(benzyloχy)phenoxy1acetate
The procedure described in example 2a was used with ethyl 2-bromoacetate and 4- (benzyloxy)phenol to give the required product as a white solid in 78% yield.
Mass spectrum : m/e 286 1H NMR, CDC13, d: 1.29 (t, 3H), 4.26 (q, 2H)), 4.56 (s, 2H), 5.01 (s, 2H)., 6.84-
6.92 (m, 4H), 7.29-7.44 (m, 5H).
b) 5-(2-(Dimethyl(Ll-dimethylethyl)silyloxy)ethyl)-4-methyl-2-r2-(4- (benzyloxy)phenoxy)-l-oxoethyllthiazole
The procedure described in example 2b was used with the thiazole prepared in 3 a and ethyl 2- [4-(benzyloxy)phenoxy] acetate to give the product as a pale yellow gum in 67% yield.
1H NMR, CDC13, d: 0.02 (s, 6H), 0.87 (s, 9H), 2.44 (s, 3H),
3.01 (t, 2H), 3.82 (t, 2H), 5.01 (s, 2H), 5.42 (s, 2H), 6.8-7.0 (m, 4H), 7.3-7.5 (m, 5H).
c) 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(benzyloxy)phenoxy)-l-oxoethyllthiazole
The procedure described in example 12b was used with the product of 14b to give the product as white solid in 64% yield.
Mass spectrum: m e 384 (M+l) M.p.: 109-110°C
C21H21NO4S requires: C 65.8 H 5.5 N 3.7 S 8.4 % found: C 66.2 H 5.6 N 3.8 S 8.4 %
EXAMPLE 15 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(benzylthio)phenoxy)-l-oxoethyllthiazole
a) 4-(Benzylthio)phenol
The procedure described in example 13a was used with 4-hydroxythiophenol and benzyl chloride to give the required product as a white solid in 48% yield.
Mass spectrum : m/e 215 (M-l)
1HNMR, CDC13, d: 3.97 (s, 2H), 4.92 (s, 1H), 6.73 (d, 2H), 7.25 (m, 7H).
b) Ethyl 2-f4-(benzylthio)phenoxy1acetate The procedure described in example 2a was used with ethyl 2-bromoacetate and 4- (benzylthio)phenol to give the required product as a white solid in 90% yield.
Mass spectrum : m/e 302 (M+) Η NMR, CDC13, d: 1.29 (t, 3H), 3.99 (s, 2H), 4.26 (q, 2H), 4.58 (s, 2H),
6.8 (d, 2H), 7.25 (m, 7H).
c) 5-(2-(Dimethyl(l.l-dimethylethyl)silvIoxy ethyl)-4-methyl-2-r2-(4- (benzvIthio)phenoxy)-l-oxoethvHthiazole
The procedure described in example 2b was used with the thiazole prepared in 3a and ethyl 2-[4-(benzylthio)phenoxy]acetate to give the product as an yellow-orange gum 95% yield.
Mass spectrum : m/e 514 (M+) Η NMR, CDC13, d: 0.05 (s, 6H), 0.88 (s, 9H), 2.45 (s, 3H), 3.0 (t, 2H),
3.83 (t, 2H), 3.99 (s, 2H), 5.44 (s, 2H), 6.88 (d, 2H), 7.27 (m, 7H).
d) 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(benzylthio)phenoxy)-l-oxoethyl)thiazole
The procedure described in example 12b was used with the product of 15c to give the product as white solid in 45% yield.
Mass spectrum: m/e 400 (M+l) M.p.: 103-4°C
C21H21NO3S2 requires: C 63.1 H 5.3 N 3.5 S 16.1 % found: C 62.8 H 5.2 N 3.6 S 16.2%
EXAMPLE 16
5-(2-Hvdroxyethyl)-4-methyl-2-f2-(4-(3,5-dichlorobenzylthio)phenoxy)-l- oxoethyllthiazole
a) 4-r3,5-Dichloro(benzylthio)1phenol
The procedure described in example 13a was used with 4-thiophenol and 3,5- dichlorobenzylchloride to give the required product as a colourless oil in 97% yield.
Mass spectrum : m/e 283 / 285 / 287 (M-l) lH NMR, CDC13, d: 2.05 (s, 1H), 3.86 (s, 2H), 6.75 (d, 2H), 6.91 (d, 2H),
7.20 (m, 3H).
b Ethyl 2-r4-(3,5-dichlorobenzylthio)phenoxylacetate
The procedure described in example 2a was used with ethyl 2-bromoacetate and 4-[3,5- Dichloro(benzylthio)]phenol to give the required product as a colourless oil in 78% yield.
Mass spectrum : m/e 370 / 372 / 374 (M+)
1H NMR, CDC13, d: 1.29 (t, 3H), 3.88 (s, 2H), 4.27 (q, 2H), 4.59 (s, 2H),
6.82 (d, 2H), 7.03 (d, 2H), 7.22 (m, 3H). c) 5-(2-(Dimethyl(l.l-dimethylethyl)silyloχy)ethyl)-4-methyl-2-r2-(4-(3.5- dichlorobenzylthio)phenoxy)-l-oxoethvnthiazole
The procedure described in example 2b was used with the thiazole prepared in 3a and ethyl 2-[4-(3,5-dicholrobenzylthio)phenoxy]acetate to give the product as a pale yellow oil in 99% yield.
Mass spectrum : m/e 582 / 584 / 586 (M+l)
Η NMR, CDC13, d: 0.04 (s, 6H), 0.88 (s, 9H), 2.45 (s, 3H), 3.02 (t, 2H), 3.82 (t, 2H), 3.88 (s, 2H), 5.46 (s, 2H), 6.9 (d, 2H),
7.25 (m, 7H).
d) 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(3,5-dichlorobenzylthio)phenoxy)-l- oxoethvDthiazole
The procedure described in example 12b was used with the product of 16c to give the product as white solid in 57% yield. This analysed as the hemi-hydrade.
Mass spectrum: m/e 468 / 470 / 472 (M+ 1 ) M.p.: 99-100°C
C2iHI9Cl2NO3S2 • 1/2H2O requires: C 52.8 H 4.1 N 2.9 S 13.4% found: C 52.9 H 4.0 N 2.9 S 13.0 %
EXAMPLE 17 l-Methyl-2-r2-(4-(5-phenylpentylsulfonyl)phenoxy)-l-oxoethyllbenzimidazole
1 -Methyl-2-[2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyljbenzimidazole (0.075g) was dissolved in a mixture of acetone (5 ml) and water (1 ml). Oxone (0.15g) was added and the mixture was stirred at 25°C for 18 hrs. A 10% aqueous solution of sodium thiosulphate (50 ml) was added and the mixture was stirred for a further 0.5 hr. The mixture was extracted with ethyl acetate and the extract was washed with 10% sodium thiosulphate solution, water, brine, dried (MgSO ) and evaporated to give a white solid (0.058g) which recrystallised from acetonitrile.
Mass spectrum: m/e 477 (M+l) M.p.: 149-150 °C Η NMR, CDC13, d: 1.4 (m, 2H), 1.5-1.8 (m, 4H), 2.58 (t, 2H),
3.04 (m, 2H), 4.18 (s, 3H), 5.77 (s, 2H), 7.1-7.3 (m, 7H), 7.4-7.6 (m, 3H), 7.8-8.0 (m, 3H).
EXAMPLE 18
2-r2-(4-(5-Phenylpentylsulfonyl)phenoxy)-l-oxoethvnbenzothiazole
The procedure described in example 17 was used with 2-[2-(4-
(phenylpentylthio)phenoxy)-l-oxoethyl]benzothiazole to give the product as a white solid in 65% yield.
Mass spectrum: m/e 480 (M+l) M.p.: 127-8°C
C27H28N2O4S requires: C 65.1 H 5.3 N 2.9 S 13.4 % found: C 64.9 H 5.1 N 2.9 S 13.0 %
EXAMPLE 19 2-f2-(4-(5-PhenylpentylsulfonvI)phenoxy)-l-oxoethyll-6-methoxybenzothiazole
The procedure described in example 17 was used with 2-[2-(4-
(phenylpentylthio)phenoxy)-l-oxoethyl]-6-methoxybenzothiazole to give the product as a solid in 60% yield.
Mass spectrum: m/e 510 (M+l) M.p.: 109-110°C
C26H25NO4S2 requires: C 63.6 H 5.3 N 2.8 S 12.6 % found: C 64.6 H 5.5 N 2.9 S 12.7 %
EXAMPLE 20 5-(2-Hvdroxyethyl)-4-methyl-2-r2-(4-(3.5-dichlorobenzylsulfonyl)phenoxy)-l- oxoethyllthiazole
The procedure described in example 17 was used with 5-(2-hydroxyethyl)-4-methyl-2-[2- (4-(3,5-dichlorobenzylthio)phenoxy)-l-oxoethyl]thiazole to give the product as a solid in 69% yield. Mass spectrum: m/e 500 / 502 / 504 (M+ 1 ) M.p.: 116-7°C
C2iH19Cl2NO5S2 requires: C 50.4 H 3.8 N 2.8 S 12.8 % found: C 49.9 H 3.7 N 2.7 S 13.2%
EXAMPLE 21
2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-oxoethvnbenzoxazole
a) 4-(3.4-DichlorobenzvIthio)phenol
The procedure described in example 13a was used with 4-thiophenol and 3,4- dichlorobenzylchloride to give the required product as a yellow solid in quantitative yield.
Mass spectrum: m/e 283 / 285 / 287
NMR: CDC13 d: 3.87 (s, 2H), 4.91 (s, 1H), 6.74 (d, 2H), 6.96 (dd,
1H), 7.19 (d, 2H), 7.2-7.5 (m, 2H).
b) 2-r4-(3.4-Dichlorobenzylthio)phenoxylacetonitrile
The procedure described in example le was used with 2-bromoacetonitrile and 4-(3,4- dichlorobenzylthio)phenol to give the required product as a yellow oil in 71% yield.
Mass spectrum: m/e 323 / 325 / 327 NMR: CDCI3 d: 3.94 (s, 2H), 4.76 (s, 2H), 6.90 (d, 2H), 7.02 (d,
1H), 7.27-7.35 (m, 4H).
c) 2-r4-(3.4-Dichlorobenzylthio)phenoxy1acetaldehvde
The procedure described in example If was used with the product of 21b to give the required product as a colourless oil in 50% yield. This was used directly in the next step.
NMR: CDCI3 d: 3.90 (s, 2H), 4.56 (s, 2H), 7.2-7.35 (m, 7H),
9.85 (s, 1H).
d) 3-r4-(3,4-Dichlorobenzylthio)phenoxy1-2-hvdroχypropionitrile The procedure described in example lg was used with the product from 21c to give the required product as a colourless oil in 74% yield.
NMR: CDC13 d: 3.04 (d, IH), 3.91 (s, 2H), 4.4-4.5 (m,2H), 4.82 (m, IH),
6.84 (d, 2H), 6.99 (dd, IH), 7.23-7.28 (m, 3H), 7.32 (d, IH).
e) 3-f4-(3<4-Dichlorobenzylthio)phenoxy]-2-hydroxy-l-ethoxy-l-iminopropane hvdrochloride
The procedure described in example lh was used with the product from 2 Id to give the required product as a white solid in 93% yield. This was used directly in the next step.
NMR: DMSOD6 d: 1.29 (t, 3H), 4.12 (s, 2H), 4.21 (d, 2H),
4.47(m, 2H), 4.81 (s, IH), 6.88 (d, 2H), 7.2-7.3 (m,3H), 7.46 (d, IH), 7.53 (d, IH).
f) 2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-hydroxyethvnbenzoxazole
The procedure described in example li was used with the product from 21e and 2- aminophenol to give the required product as a yellow solid in 64% yield.
Mass spectrum: m/e 446 / 448 / 450 (M+l) NMR: CDCI3 d: 3.41 (d, IH), 3.88 (s, 2H), 4.47 (m, 2H), 5.35 (m, IH),
6.84 (d, 2H), 6.94 (dd, IH), 7.18-7.32 (m, 6H), 7.75 (m, IH), 8.57 (m, IH).
g) 2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-oxoethvn benzoxazole
The procedure described in example lj was used with the product from 21h to give the required product as a yellow solid in 80% yield.
Mass spectrum: m/e 444 / 446 / 448 (M+l ) M.p.: 122-123°C
C22H15CI2NO3S requires: C 59.5 H 3.4 N 3.2 S 7.2 % found: C 59.4 H 3.4 N 3.4 S 7.4 %
EXAMPLE 22 2-f2-(4-(3,4-Dichlorobenzylthio)phenoxy)-l-oxoethvn benzimidazole
a) 2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-hvdroxyethyl1benzimidazole
The procedure described in example li was used with the product from 21e and 2,3- diaminobenzene to give the required product as a yellow solid in 65% yield.
Mass spectrum: m/e 445 / 447 / 449 (M+ 1 )
NMR: CDC13 d: 3.89 (s, 2H), 4.26 (dd, IH), 4.57 (dd, IH), 5.42 (q, IH), 6.88
(d, 2H), 6.97 (dd, IH), 7.20-7.31 (m, 8H), 7.61 (m, 2H).
b) 2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-oxoethyllbenzimidazole
The procedure described in example lj was used with the product from 22a to give the required product as a white solid in 56% yield which analysed as a hemihydrate.
Mass spectrum : m/e 443 / 445 / 447 (M+l) M.p.: 141-142°C
C22H16CI2N2O2S • 0.5H2O requires: C 58.4 H 3.8 N 6.2 S 7.1 % found: C 58.8 H 3.7 N 6.2 S 7.1 %
EXAMPLE 23
2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-oxoethyll-6-methoxy benzoxazole
a) 2-f2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-hvdroxyethvn-6-methoxybenzoxazole
The procedure described in example li was used with the product from 21e and 2-amino- 5-methoxyphenol to give the required product as a yellow solid in 57% yield.
Mass spectrum: m/e 476 / 478 / 480 (M+l) M.p.: 87-88°C C23H19NCI2O4S requires: C 58.0 H 4.0 N 2.9 S 6.7 % found: C 58.1 H 4.0 N 3.0 S 6.9 % b) 2-r2-(4-(3,4-Dichlorobenzylthio phenoxy)-l-oxoethyl]-6-methoxybenzoxazoIe
The procedure described in example lj was used with the product from 23 a to give the required product as a yellow solid in 84% yield.
Mass spectrum: m/e 474 / 476 / 478 (M+l ) M.p.: 136-137 °C
C23H17NCl2O4S requires: C 58.2 H 3.6 N 3.0 S 6.8 % found: C 57.9 H 3.6 N 3.2 S 6.7 %
EXAMPLE 24 2-r2-(4-(3>4-Dichlorobenzylthio)phenoxy)-l-oxoethvnbenzoxazole-5-carboxylic acid
a) (l -Dimethyl ethyl 2-r2-(4-(3.4-dichlorobenzylthio)phenoxy)-l- hydroxyethyllbenzoxazole-5-carboxylate.
The procedure described in example li was used with the product from 21e and product from lb to give the required product as a yellow solid in 61% yield.
NMR: CDC13 d: 1.62 (s, 9H), 3.32 (d, IH), 3.88 (s, 2H)
4.49 (m, 2H), 5.36 (m, IH), 6.84 (d, 2H), 6.97 (dd, IH), 7.2-7.31 (m, 4H), 7.56 (d, IH), 8.08 (dd, IH), 8.39 (d, IH).
b) (l.l-Dimethvnethyl 2-r2-(4-(3.4-dichlorobenzylthio)phenoxy)-l- oxoethvHbenzoxazole-5-carboxylate.
The procedure described in example lj was used with the product from 24a to give the required product as a yellow solid in 66% yield.
NMR: CDCI3 d: 1.60 (s, 9H), 3.91 (s, 2H), 5.55 (s, 2H),
6.92 (d, 2H), 6.98 (dd, IH), 7.23-7.32 (m, 4H), 7.72 (d, IH), 8.26 (dd, IH), 8.57 (d, IH). c) 2-r2-(4-(3,4-Dichlorobenzylthio)phenoxy)-l -oxoethyllbenzoxazole-5-carboxylic acid
The procedure described in example Ik was used with the product from 24b to give the required product as a white solid in 56% yield which analysed as a monohydrate.
Mass spectrum: m/e 488 / 490 / 492 (M+l) M.p.: 174-175°C
C23H15NCl2O5S.H2O requires: C 54.6 H 3.4 N 2.8 S 6.3 % found: C 54.2 H 3.2 N 2.9 S 6.1 %
EXAMPLE 25 2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-oxoethyllbenzoxazole-6-carboxylic acid
a) Propen-3-yl 3-hvdroxy-4-aminobenzoate
3-Hydroxy-4-aminobenzoic acid (l.Og) was suspended in propen-3-ol (20 ml) and trimethylsilyl chloride (3.3 ml) was added dropwise. The reaction mixture was heated at 65 °C for 18 hrs, the reaction was allowed to cool to room temperature and poured into 2N hydrochloric acid. The mixture was extracted with ethyl acetate and the extract evaporated to give a brown oil. This was passed down a silica gel column eluted with ethyl acetate:hexane (4: 1) to afford the product as a yellow solid (0.62g).
lH NMR: CDC13 d: 4.20 (bs, 2H), 4.77 (m, 2H),
5.27 (dd, IH), 5.39 (dd, IH), 5.89 (bs, IH), 6.03 (m, IH), 6.68 (d, IH), 7.56 (m, 2H).
b) Propen-3-yl 2-r2-(4-(3,4-dichlorobenzylthio)phenoxy)-l -hvdroxyethyllbenzoxazole- 6-carboxylate.
The procedure described in example li was used with the product from 21e and the product from 25a to give the required product as a yellow solid in 14% yield.
lU NMR: CDCI3 d: 3.28 (d, IH), 3.88 (s, 2H) 4.49 (m, 2H),
4.87 (d, 2H), 5.3-5.47 (m, 3H), 6.06 (m, IH), 6.84 (d, 2H), 6.97 (dd,lH), 7.2-7.31 (m, 4H),
7.78 (d, IH), 8.14 (dd, IH), 8.28 (s, IH). c Propen-3-yl 2-r2-(4-(3.4-dichlorobenzylthio)phenoxy)-l-oxoethyllbenzoxazole-6- carboxylate.
The procedure described in example lj was used with the product from 25b to give the required product as a yellow solid in 56% yield.
H NMR: CDC13 d: 3.89 (s, 2H), 4.89 (m, 2H), 5.35 (dd, IH), 5.45 (dd,
IH), 5.55 (s,2H), 6.07 (m, IH), 6.92 (d, 2H), 6.98 (dd,lH), 7.23-7.28 (m, 3H), 7.31 (d,lH), 7.97 (m, 2H), 8.41 (s, IH).
d) 2-r2-(4-(3.4-Dichlorobenzylthio)phenoxy)-l-oxoethvnbenzoxazole-6-carboxylic acid
Dry nitrogen was bubbled through dry THF (10 ml) for 0.5hrs. The product from 25c (0.14g) was added followed by tetrakis(triphenylphosphine)palladium (0.02g) and acetic acid (0.3 ml). The reaction was stirred at 25°C, under nitrogen for 2 hrs. The reaction was evaporated and the residue passed down a silica gel column eluted with 5% methanol in dichloromethane to give the product as a pale yellow solid (0.092g).
Mass spectrum: m/e 488 / 490 / 492 (M+ 1 ) M.p.: 179-180°C
EXAMPLE 26
2-r2-(4-(3.5-Dichlorobenzyloxy)phenoxy)-l-oxoethyllbenzoxazole-5-carboxylic acid
a) 2-f4-(3.5-Dichlorobenzyloxy)phenoxy1acetonitrile
The procedure described in example le was used with 2-bromoacetonitrile and 4-(3,5- dichlorobenzyk>xy)phenol to give the required product as a yellow oil in 82% yield.
H NMR: CDCI3 d: 4.72 (s, 2H), 4.98 (s, 2H), 6.94 (m, 4H), 7.32 (s, 3H). b) 2-r4-(3,5-Dichlorobenzyloxy)phenoxylacetaldehyde
The procedure described in example If was used with the product of 26a to give the required product as a yellow oil in 84% yield. The product was used directly in the next step.
c) 3-r4-(3,5-dichlorobenzyloxy)phenoxyl-2-hvdroxypropionitrile
The procedure described in example lg was used with the product from 26b to give the required product as a white solid in 78% yield.
M.p.: 89-90°C
!H NMR: CDC13 d: 3.02 (s, IH), 4.20 (m, 2H), 4.79 (m, IH), 4.97 (s, 2H), 6.90 (s, 4H),
7.31 (s, 3H).
d) 3-r4-(3.5-dichlorobenzyloxy)phenoxy1-2-h vdroxy-1 -ethoxy-1 -iminopropane hvdrochloride
The procedure described in example lh was used with the product from 26c to give the required product as a white solid in 71% yield. This was used directly in the next step.
!H NMR: DMSOd6 d: 1.30 (t,3H), 4.17 (d, 2H), 4.44 (m, 2H), 4.78 (s, IH),
5.09 (s, 2H), 5.92 (m, 4H), 7.49 (s, 2H), 7.57 (s, IH).
e) (l.l-Dimethyl)ethyl 2-r2-(4-(3.5-dichlorobenzyloxy)phenoxy)-l- hvdroxyethyllbenzoxazole-5-carboxylate
The procedure described in example li was used with the product from 26d and the product from example lb to give the required product as an orange oil in 93% yield.
Mass spectrum: m/e 530 / 532 / 534 (M+l )
!H NMR: CDCI3 d: 1.62 (s, 9H), 3.31( d, IH), 4.47 (m, 2H), 4.95 (s, 2H), 5.34
(m, IH), 6.87 (d, 4H), 7.30 (s, 3H), 7.56 (d, IH), 8.07 (dd,
IH), 8.39 (d, IH). f) (l.l-Dimethyl)ethyl 2-r2-(4-(3.5-dichlorobenzyloxy)phenoxy)-l- oxoethvπbenzoxazole-5-carboxylate.
The procedure described for example lj was used with the product from example 26e to give the product as an off-white solid in 94% yield.
Mass spectrum: m/e 528 / 530 / 532 (M+l)
JH NMR: CDC13 d: 1.64 (s, 9H), 4.97 (s, 2H), 5.52 (s, 2H), 6.94 (q, 4H), 7.31 (s,
3H), 7.71 (d, IH), 8.25 (d, 1H),8.56 (d, IH).
g) 2-r2-(4-(3.5-Dichlorobenzyloxy)phenoxy)-l -oxoethvnbenzoxazole-5-carboxylic acid
The procedure described in example Ik was used with the product from 26f to give the required product as a white solid in 62% yield.
Mass spectrum: m/e 472 / 474 / 476 (M+l) M.p.: 169-170°C
C23Hι5NCl2O6 requires: C 58.4 H 3.2 N 3.0 % found: C 57.5 H 3.0 N 3.0 %
EXAMPLE 27 2-r2-(4-(3.5-Dichlorobenzyloxy)phenoxy)-l-oxoethyllbenzimidazole-5-carboxyIic acid
a) Propen-3-yl 3.4-diaminobenzoate
The procedure described for example 25a was used with 3,4-diaminobenzoic acid to afford the product as a brown solid in 43% yield.
*H NMR: CDCI3 d: 4.77 (m, 2H), 5.26 (dd, IH), 5.35 (dd, IH), 6.02 (m, IH), 6.65 (d, IH), 7.43 (d, IH), 7.51 (dd, IH).
b) Propen-3-yl 2-r2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l -hvdroxyethyl]-5- benzimidazole carboxylate.
The procedure described in example 1 i was used with the product from 26d and product from 27a to give the required product as a light brown oil in 61% yield. Mass spectrum: m/e 513 / 515 / 517 (M+l)
c) Propen-3-yl 2-r2-(4-(3.5-dichlorobenzyloxy)phenoxy)-l -oxoethyll-5-benzimidazole carboxylate.
The procedure described in example lj was used with the product from 27b to give the required product as a yellow solid in 78% yield.
Mass spectrum: m/e 51 1 / 513 / 515 (M+l) lH NMR: DMSOD6 d: 4.85 (d, 2H), 5.08 (s, 2H), 5.31-5.46 (m, 2H),
5.66 (s, 2H) 6.09 (m, IH), 6.96 (m, 4H), 7.50 (s, 2H), 7.57 (m, IH), 7.70 (d, IH), 8.02 (dd, IH) 8.230 (d, IH).
d) 2-r2-(4-(3.5-DichlorobenzvIoxy)phenoxy)-l-oxoethvnbenzimidazole-6-carboxylic acid
The procedure used in example 25d was used with the product from 26c to give the product as a pale yellow solid in 38 % yield, as the hydrate.
Mass spectrum: m/e 471 / 473 / 475 (M+ 1 ) M.p.: >300°C
C23H16N2CI2O5.H2O requires: C 56.5 H 3.7 N 5.7 % found: C 56.8 H 3.6 N 5.5 %
EXAMPLE 28
3-r2-(2-(4-(3.5-Dichlorobenzyloxy)phenoxy)-l-oxoethyl)benzoxazol-5-vnpropionic acid
a) Propen-3-yl 3-(3-hvdroxy-4-aminophenyl)propionate
The procedure described for example 25a was used with 3-(3-hydroxy-4- aminophenyl)propionic acid to afford the product as a brown solid in 41% yield.
iH NMR: CDCI3 d: 2.60 (t, 2H), 2.82 (t, 2H), 4.58 (m, 2H), 5.27 (dd, IH), 5.31
(dd, IH), 5.90 (m, IH), 6.5-6.8 (m, 3H). b) Propen-3-yl 3 2-(2-(4-(3.5-dichlorobenzyloxy)phenoxy)-l- hvdroxyethyl)benzoxazol-5-yllpropionate.
The procedure described in example 1 i was used with the product from 28a and the product from example 27d to give the required product as a light brown solid in 78% yield.
lK NMR: CDC1 d: 2.70 (t, 2H), 3.08 (t, 2H), 3.30 (d, IH), 4.43 (m, 2H), 4.58
(m, 2H), 4.95 (s, 2H), 5.20-5.33 (m, 3H), 5.88 (m, IH), 6.87 (m, 4H), 7.21 (dd, IH), 7.30 (s, 3H), 7.45 (d, IH), 7.56 (d,
IH).
c Propen-3-yl 3-r2-(2-(4-(3.5-dichlorobenzyloxy)phenoxy)-l-oxoethyl benzoxazol-5- vnpropionate.
The procedure described for example lj was used with the product from example 28b to give the product as an yellow solid in 94% yield.
Mass spectrum: m/e 540 / 542 / 544 (M+ 1 ) lH NMR: CDCI3 d: 2.74 (t, 2H), 3.14 (t, 2H), 4.58 (m, 2H), 4.97 (s, 2H), 5.21-
5.26 (m, 2H), 5.50 (s, 2H), 5.88 (m, IH), 6.88-6.99 (q, 4H), 7.26 (s, 2H), 7.31 (s, IH), 7.42 (dd, IH), 7.61 (d, IH), 7.73 (s, IH).
d) 2-f2-(4-(3,5-Dichlorobenzyloxy)phenoxy)-l-oxoethvnbenzoxazoIe-5-yllpropionic acid
The procedure described in example 25d was used with the product from 28c to give the required product as an off-white solid in 47% yield.
Mass spectrum: m/e 500 / 502 / 504 (M+l) M.p.: 134-135°C
C25H19Cl2NO6 requires: C 60.0 H 3.8 N 2.8 % found: C 59.8 H 3.8 N 3.0 % EXAMPLE 29 2-f3-r4-(Phenylpentyloxy)phenvn-l-oxopropynbenzoxazole-5- carboxylic acid
a) Methyl 3-(4-(5-phenylpentyloxy)phenyl propionate
A solution of methyl 3-(4-hydroxyphenyl)propionate (4.6g) in dry DMF (100 ml) was treated with sodium hydride (60% oil suspension, 1.02g) and stirred at 25°C, under an atmosphere of nitrogen for 10 mins. A solution of phenylpentyl mesylate (6.18g) in DMF (20 ml) was added dropwise and stirring was continued for 18 hrs. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO4), evaporated and the resulting oil passed down a silica gel column eluted with hexane:ethyl acetate (20: 1 , v/v) to give the product as a white solid (5.85g).
Mass spectrum: m/e 326
!H NMR: CDC13 d: 1.45-1.85 (m, 6H), 2.61 (m, 4H), 2.88 (t, 2H),
3.66 (s,3H), 3.92 (t, 2H), 6.81-7.10 (m, 4H), 7.27-7.9 (m, 5H).
b) 3-(4-(5-Phenylpentyloxy)phenyl)propionic acid
The procedure described in example 9b was used with the product of 29a to give the product as a white solid in 94% yield.
Mass spectrum: m/e 312 H NMR: CDC13 d: 1.50 (m, 2H), 1.68 (m, 2H), 1.80 (m, 2H),
2.64 (m,4H), 2.90 (t, 2H), 3.92 (t, 2H), 6.82 (d, 2H), 7.11 (d, 2H), 7.1-7.3 (m, 5H).
c) N-Methyl.N-methoxy-3-f4-(5-phenylpentyloxy)phenyllpropionamide
The product of 29b (5.2g) was dissolved in thionyl chloride (50 ml) and heated at reflux for 4 hrs. The mixture was evaporated and then co-evaporated with toluene (50 ml), the residue was dissolved in dry dichloromethane (100 ml) and the solution was cooled to 0°C under a nitrogen atmosphere. N,O-dimethylhydroxyamine (1.78g) was added followed by the dropwise addition of pyridine (2.96 ml). The reaction was stirred at 25°C for 3 hrs then washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried (MgSO4) and evaporated to give an orange oil. The oil was passed down a silica gel column eluted with hexane:ethyl acetate (2: 1, v/v) to give the product as a colourless oil, (4.14g).
Mass spectrum: m e 355 lH NMR: CDC13 d: 1.50 (m, 2H), 1.71 (m, 2H), 1.80 (m, 2H),
2.64 (t, 2H), 2.70 (m, 2H), 2.88 (m, 2H), 3.17 (s, 3H), 3.60 (s, 3H), 3.94 (t, 2H), 6.81 (d, 2H), 7.15 (d, 2H), 7.15-7.3 (m, 5H).
d) 3-r4-(5-Phenylpentyloxy)phenvnpropionaldehvde
The amide product of 29c (4. Ig) was dissolved in dry THF (30 ml), cooled to 0°C and stirred under a nitrogen atmosphere. A IM solution of lithium aluminium hydride in THF
(7 ml) was added dropwise and stirring continued for 0.5 hr. A solution of sodium hydrogenphosphate (4g) in water (80 ml) was added and the mixture was extracted with ether. The extract was washed with water, brine, dried (MgSO4) and evaporated to give the product as a yellow oil (3.4g).
Mass spectrum: m/e 296 H NMR: CDCI3 d: 1.51 (m, 2H), 1.71 (m, 2H), 1.82 (m, 2H),
2.65 (m, 2H), 2.76 (t, 2H), 2.91 (t, 2H), 3.92 (t, 2H), 6.82 (d, 2H), 7.10 (d, 2H), 7.15-7.85 (m, 5H), 9.81 (s, IH).
e) 4-r4-(5-Phenylpentyloxy)phenyll-2-hydroxy-butyronitrile
The procedure described in example lg was used with the product from 29d to give the product as a white solid in 68% yield.
Mass spectrum: m/e 324 H NMR: CDCI3 d: 1.51 (m, 2H), 1.67 (m, 2H), 1.80 (m, 2H),
2.12 (m, 2H), 2.59 (d,lH), 2.62 (t, 2H), 2.79 (t, 2H), 3.93 (t, 2H), 4.41 (m, IH), 6.82 (d, 2H),
7.10 (d, 2H), 7.15-7.30 (m, 5H). f) 4-r4-(5-Phenylpentyloxy)phenyn-2-hvdroxy-l -ethoxy-1 -iminobutane hvdrochloride
The procedure described in example lh was used with the product from 29e to give the product as a white solid in 80% yield.
Mass spectrum: m/e 370 (M+l) H NMR: DMSO-D6 d: 1.32 (t, 3H), 1.43 (m, 2H), 1.63 (m, 2H),
1.72 (m, 2H), 1.90 (m, 2H), 2.60 (m, 4H), 3.91 (t, 2H), 4.36 (m, IH), 4.39 (m, 2H),
6.78 (s, IH), 6.83 (d, 2H),7.10 (d, 2H),
7.15-7.32 (m, 5H), 1 1.17 (bs, 2H).
g) 2-r3-(4-(5-Phenylpentyloxy)phenyl)-l -hvdroxypropyll benzoxazole-5-carboxylic acid
The procedure described in example li was used with the product from 29f to give the product as a white solid in 51 % yield.
Mass spectrum: m/e 460 (M+l) M.p.: 136-137°C
C28H29NO5 requires: C 73.2 H 6.4 N 3.1 % found: C 73.1 H 6.5 N 3.1 %
h) 2-r3-(4-(5-Phenylpentyloxy)phenyl)-l-oxopropynbenzoxazole-5- carboxylic acid
The procedure described in example lj was used with the product from 29g to give the product as a white solid in 74% yield which analysed as the hemihydrate.
Mass spectrum: m/e 458 (M+l) M.p.: 141-142°C
C28H27NO50.5H2O requires: C 72.1 H 6.1 N 3.0 % found: C 72.6 H 6.0 N 3.4 % EXAMPLE 30
2-r3-(4-(5-Phenylpentyloxy)phenyl)-l -oxopropyllbenzoxazole-6- carboxylic acid
a) 2-f3-(4-(5-Phenylpentyloxy)phenyl -l -hvdroxypropyll benzoxazole-6-carboxylic acid
The procedure described in example li was used with the product from 29f and 3-hydroxy- 4-aminobenzoic acid to give the product as a white solid in 45% yield.
Mass spectrum: m/e 460 (M+l) M.p.: 123-124°C
C28H29NO5 requires: C 73.2 H 6.4 N 3.1 % found: C 73.0 H 6.5 N 3.2 %
b) 2-r3-(4-(5-Phenylpentyloxy)phenyl)-l-oxopropyl]benzoxazole-5- carboxylic acid
The procedure described in example lj was used with the product from 30a to give the product as a white solid in 53% yield.
Mass spectrum: m/e 457 M.p.: 152-153°C
C28H27NO5 requires: C 73.5 H 6.0 N 3.1 % found: C 72.5 H 6.1 N 3.3 %
EXAMPLE 31
3-[2-(2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethyl)-4- ethylthiazol-5-vnpropionic acid
5-Oxo-hexanoic acid was subjected to the sequence of reactions described in example 10 to give the title compound as a white solid as the monohydrate.
Mass spectrum: m/e 484 (M+l) M.p.: 99-101°C
C26H29NO4S2 requires: C 62.3 H 6.2 N 2.8 S 12.8 % found: C 61.5 H 5.7 N 3.0 S 12.6 % EXAMPLE 32 4-f2-(2-(4-(Decylthio)phenoxy)-l-oxoethyl)-4-methylthiazol-5-yl1butanoic acid
a) Ethyl 2-r4-(decylthio)phenoxy)1 acetate
The procedure described for example 2a was used with 4-(decylthio)phenol and ethyl 2- bromoacetate to give the required compound as a yellow solid in 95% yield.
Mass spectrum: m/e 353 (M+l) !H NMR: CDC13 d: 0.88 (t, 3H), 1.2-1.35 (m, 15H), 1.4 (m, 2H),
1.6 (m, 2H), 2.82 (t, 2H), 4.29 (q, 2H), 4.6 (s, 2H), 6.86 (d, 2H), 7.33 (d, 2H).
b) 4-r2-(2-(4-(Decylthio)phenoxy)-l-oxoethyl)-4-methylthiazol-5-yllbutanoicacid
The procedure described in example lOe was used with the product of 32a and the product from lOd to afford the product as a yellow solid in 25% yield.
Mass spectrum: m/e 492 (M+l) H NMR: CDCI3 d: 0.88 (t, 3H), 1.2- 1.3 (m, 12H), 1.4 (m, 2H),
1.61 (m, 2H), 2.0 (m, 2H), 2.44 (s, 3H), 2.46 (t, 2H), 2.8 (t, 2H), 2.9 (t, 2H), 5.45 (s, 2H) 6.92 (d, 2H), 7.32 (d, 2H).
EXAMPLE 33
4-f2-(2-(4-(Decylsulfonyl)phenoxy)-l-oxoethyl -4-methylthiazol-5-yllbutanoic acid
The procedure described in example 13b was used with the product from example 32b to afford the required product as a yellow solid in 33% yield. This was converted to the dicyclohexylamine salt and analysed as the monohydrate.
Mass spectrum: m e 524 (M+l) M.p.: 139°C
C38H6oN2O6S2 • H2O requires: C 63.1 H 8.6 N 3.9 S 8.9 % found: C 63.5 H 8.4 N 4.0 S 8.8 % EXAMPLE 34
2-r2-(2-(4-(3.5-Dichlorobenzyloxy)phenoxy)-l-oxoethyl)benzothiazol-6-oxy1acetic acid
a) (l.l-Dimethyl)ethyl 2-(benzothiazol-6-oxy)acetate
Using the procedure described in example 5a with 6-hydroxybenzothiazole and (1,1- dimethyl)ethyl 2-bromoacetate gave the required product as a yellow oil in 97% yield.
Mass spectrum: m/e 266 (M+l) Η NMR, CDC13 , d: 1.49 (s, 9H), 4.60 (s, 2H), 7.17 (dd, IH)),
7.39 (d, IH), 8.04 (d, IH), 8.86 (s, IH).
b) 2-(Benzothiazol-6-oxy)acetic acid
The procedure described in example 5b was used with the product from 34a to give the required product as an off-white solid in quantitative yield.
Mass spectrum: m/e 210 (M+l)
Η NMR, CDC13 , d: 4.77 (s, 2H), 7.16 (dd, IH)), 7.70 (d, IH), 7.98 (d, IH), 8.35 (s, IH), 9.20(s, IH).
c) 2-r2-(2-(4-(3,5-Dichlorobenzyloxy)phenoxy)-l-oxoethyl)benzothiazol-6-oxy1acetic acid
The procedure described in example 8 was used with the product from 34b and the product from 1 lb to give the required product as a yellow solid in 22% yield.
Mass spectrum: m/e 518 / 520 / 522 (M+l ) M.p.: 179-180°C C24Hι7Cl2NO6S requires: C 55.6 H 3.3 N 2.7 S 6.2 % found: C 55.6 H 3.3 N 2.5 S 5.9 % EXAMPLE 35
4-r2-(2-(4-(5-Phenylpentyloxy)phenoxy)-l-oxoethyl)-4-methylthiazol-5-yllbutanoic acid
a) 5-Phenylpentyl tosylate
5-Phenylpentanol (12.7g) was dissolved in chloroform (200 ml) and the solution cooled to 0°C. Pyridine (6.9 ml) was added followed by portionwise addition of tosyl chloride (16.2g). The reaction mixture was stirred at ambient temperature for 16 hrs then washed with water, dried (MgSO ) and evaporated to leave a colourless oil. The oil was passed down a silica gel column eluted with hexane:ethyl acetate (4: 1) to afford the product as a colourless oil (17.7g).
Η NMR, CDC13 , d: 1.32-1.4 (m, 2H), 1.5-1.59 (m, 2H), 1.6-1.69 (m, 2H) 2.44 (s, 3H), 2.56 (t, 2H), 4.01 (t, 2H), 7.1-7.2 (m, 3H)
7.24-7.29 (m, 2H), 7.35 (d, 2H), 7.75 (d, 2H).
b) 4-(5-Phenylpentyloxy)phenol
Quinol (8.3g) was dissolved in acetonitrile (200 ml) and treated with caesium carbonate (24.5g) and the tosylate from 35a (8.0g). The mixture was heated at 85oC for 24 hrs. The mixture was cooled to ambient temperature, poured into 2N hydrochloric acid (200 ml) and extracted into ethyl acetate. The extract was washed with water, brine, dried (MgSO4) and evaporated to give a solid. The solid was passed down a silica gel column eluted with hexane:ethyl acetate (4: 1) to afford the product as a white solid (3.0g).
Mass spectrum: m/e 256
Η NMR, CDC13 , d: 1.47-1.53 (m, 2H), 1.65-1.7 (m, 2H), 1.75-1.8 (m, 2H)
2.64 (t, 2H), 3.9 (t, 2H), 4.4 (s, IH), 6.74-6.8 (dd, 4H) 7.16-7.2 (m, 3H), 7.26-7.3 (m, 2H).
c) Ethyl 2-f4-(5-phenvIpentyloxy)phenoxylacetate.
The procedure described in example 2a was used with the product from 35b to give the required product as a yellow solid in 90% yield. Mass spectrum: m/e 342
Η NMR, CDC13 , d: 1.29 (t, 3H), 1.47-1.52 (m, 2H), 1.65-1.71 (m, 2H), 1.74-
1.79 (m, 2H)
2.64 (t, 2H), 3.89 (t, 2H), 4.26 (q, 2H), 4.56 (s, 2H) 6.8-6.86 (dd, 4H), 7.18 (m, 3H), 7.26-7.29 (m, 2H).
d) 4-r2-(2-(4-(5-Phenylpentyloxy)phenoxy)-l-oxoethyl)-4-methylthiazol-5-vnbutanoic acid
The procedure described in example 8 was used with the product from 35c and the product from lOd to give the required product as a yellow solid in 20% yield.
Mass spectrum: m/e 482 (M+l)
M.p.: °C 127-128
C27H31NO5S requires: C 67.3 H 6.5 N 2.9 S 6.7 % found: C 66.8 H 6.4 N 2.9 S 6.4 %
EXAMPLE 36
5-r2-(2-(4-(5-Phenylpentyloxy phenoxy)-l-oxoethyl)thiazol-4-yllpentanoic acid
a) Methyl 7-bromo-6-oxo-heptanoate
To a solution of 6-oxoheptanoic acid (6.06g) in methanol (100 ml) was added dropwise a solution of bromine (7.2g) in «*ethanol {20 ml). The mixture was then stirred at 25°C for 18 hrs. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). This was washed with a saturated solution of sodium bicarbonate, water, brine, dried (MgSO4) and evaporated to a gum which was passed down a silica gel column eluted with hexane:ether (3:1, v/v). The appropriate fractions were combined and evaporated to give the product as a pale yellow oil, (3.05g).
Mass spectrum: m/e 236 / 238 (M+)
Η NMR, CDC13 , d: 1.6- 1.7 (m, 4H), 2.3-2.4 (m, 2H)),
2.66-2.72 (m, 2H), 3.67 (s, 3H), 3.88 (s, 2H). b) Methyl 5-(thiazol-4-yl)pentanoate
Formamide (10 ml) in toluene (30 ml) was treated with phosphorus pentasulphide (3.5g). Methyl 7-bromo-6-oxoheptanoate (2.6g) was added and the mixture was heated at 75 °C for 2 hrs. The reaction mixture was allowed to cool to ambient temperature, neutralised with 10% sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO4) and evaporated to give a gum. This was passed down a silica gel column eluted with hexane:ethyl acetate (3:2, v/v) to afford the product as a colourless oil (1.37g).
Mass spectrum: m/e 200 (M+l)
Η NMR, CDC13 , d: 1.6- 1.8 (m, 4H), 2.36 (t, 2H)), 2.86 (t, 2H),
3.67 (s, 3H), 6.96 (d, IH), 8.74(d, IH).
c) 5-(Thiazol-4-yl)pentanoic acid
The procedure described in example lOd was used with the product from 36a to give the required product as a yellow solid in 94% yield.
Mass spectrum: m/e 186 (M+l)
1H NMR, CDC13 , d: 1.7- 1.9 (m, 4H), 2.40 (t, 2H)), 2.87 (t, 2H),
6.97 (d, IH), 8.79(d, IH).
d) 5-r2-(2-(4-(5-Phenylpentyloxy)phenoxy)-l -oxoethyl)thiazol-4-yllpentanoic acid
The procedure described in example 8 was used with the product from 36b and the product from 35b to give the required product as a yellow solid in 24% yield.
Mass spectrum: m/e 482 (M+l) M.p.: 78-80°C
C27H31NO5S requires: C 67.3 H 6.5 N 2.9 S 6.7 % found: C 67.8 H 6.5 N 2.9 S 6.1 % EXAMPLE 37
4-r2-(2-(4-(5-Phenylpentyloxy)phenyl)-l-oxopropyl) -4-methylthiazol-5-yllbutanoic acid
a) Methyl 4-(4-methylthiazol-5-yl)butanoate
Using the procedure described in 36b, with methyl 5-bromo-6-oxo-heptanoate led to the required product as a yellow solid in 74% yield.
!H NMR, CDC13, d: 1.95 (m, 2H), 2.36 (t, 2H), 2.38 (s, 3H), 2.82 (t, 2H), 3.68 (s,
3H), 8.56 (s, IH).
b) 4-(4-methylthiazol-5-yl)butanoic acid
Using the procedure described in 9b, with the product from 37a, led to the required product as a white solid in 63% yield.
Mass spectrum : m/e 186 (M+l) lK NMR, DMSOd6, d: 1.76 (m, 2H), 2.26 (t, 2H), 2.29 (s, 3H), 2.77 (t, 2H), 8.81 (s, IH), 12.11 (s, IH).
c) 4-r2-(2-(4-(5-Phenylpentyloxy)phenyl)-l-oxopropyl) -4-methylthiazol-5-yllbutanoic acid
The procedure described in example 8 was used with the product from 37b and the product from 29a to give the required product as a yellow solid in 10% yield.
Mass spectrum: m e 480 M.p.: 121-122°C
EXAMPLE 38 4-r2-(2-(4-(Benzylthio)phenoxy)-l-oxoethyl)-4-methylthiazol-5-yllbutanoic acid
The procedure described in example 8 was used with the product from 37b and the product from 15b to give the required product as a white solid in 25% yield. Mass spectrum: m/e 442 (M+H) M.p.: °C 131-132
C23H23NO4S2 requires: C 62.6 H 5.3 N 3.2 S 14.5 % found: C 61.8 H 5.1 N 3.3 S 14.0 %
EXAMPLE 39
2-r2-(4-(3,5-Dichlorobenzyloxy)phenoxy)-l -oxoethvπbenzothiazole-6- carboxylic acid
The procedure described in example 8 was used with the product from 1 lb to give the required product as a white solid in 20% yield.
Mass spectrum: m/e 486 / 488 / 490 (M+H) M.p.: °C 205-205
C23H15Cl2NO5S requires: C 56.6 H 3.1 N 2.9 S 6.6 % found: C 55.4 H 3.1 N 3.0 S 6.6 %
EXAMPLE 40 4-r2-(2-(4-(5-Phenylpentylthio)phenoxy)-l-oxopropyl)-4-methylthiazol-5-vnbutanoic acid
a) Ethyl 2-r4-(5-phenylpentylthio)phenoxylpropionate
The procedure described in example 2a was used starting with ethyl 2-bromopropionate to give the product as a colourless oil in 87% yield.
Mass spectrum: m/e 373 (M+H)
1H NMR, CDC13 , d: 1.24 (t, 3H), 1.41 (m, 2H), 1.51-1.65 (m & d, 7H), 2.59 (t, 2H), 2.80 (t, 2H), 4.21 (q, 2H), 4.70 (q, 1 H), 6.80 (d, 2H),
7.14-7.21 (m, 3H), 7.24-7.31(m, 4H). b) 4-r2-(2-(4-(5-Phenylpentylthio)phenoxy)-l-oxopropyl)-4-methylthiazol-5- yllbutanoic acid
The procedure described in example lOe was used with the product from 40a to give the required product as a pale yellow gum in 43% yield. The product was converted to the dicyclohexylamine salt which was a pale yellow solid.
Mass spectrum: m/e 512 (M+H) M.p.: °C 107-108 C40H56N2O4S2 requires: C 69.3 H 8.2 N 4.0 S 9.3 % found: C 69.6 H 8.2 N 4.3 S 9.3 %
EXAMPLE 41
4- 2-(2-(4-(5-Phenylpentylthio)phenoxy)-l-oxo-2-methyl-propyl)-4-methylthiazol-5- yllbutanoic acid
a) Ethyl 2-f4-(5-phenylpentylthio)phenoxyl2-methylpropionate
The procedure described in example 40a was used starting with ethyl 2-bromo-2- methylpropionate to give the product as a colourless oil in 45% yield.
b) 4-r2-(2-(4-(5-Phenylpentylthio)phenoxy)-l-oxo-2-methylpropyl)-4-methylthiazol-5- yllbutanoic acid
The procedure described in example lOe was used with the product from 41a to give the required product as a pale yellow gum in 22% yield.
Mass spectrum: m/e 526 (M+H)
Η NMR, CDC13 , d: 1.42 (m, 2H), 1.61 (m, 4H), 1.76 (s, 6H), 1.95 (m, 2H), 2.44 (s & m, 5H), 2.60 (t, 2H), 2.83 (m, 4H), 6.77 (d, 2H), 7.13-
7.29 (m, 7H). EXAMPLE 42
4- 2-(2-(4-(5-Phenylpentylthio)phenoxy)-2-phenyl-l-oxyethyl)-4-methylthiazol-5- yllbutanoic acid
a) Methyl 2-r4-(5-phenylpentylthio)phenoxyl2-phenylacetate
The procedure described in example 40a was used starting with methyl 2-bromo-2- phenylacetate to give the product as a white solid in 75% yield.
Mass spectrum: m/e 421 (M+H)
1H NMR, CDC13 , d: 1.44 (m, 2H), 1.61 (m, 4H), 2.58 (t, 2H), 2.81 (t, 2H), 3.74
(s,3H), 5.60 (s, IH), 6.85(d, 2H), 7.15 (m, 3H), 7.25 (m, 4H), 7.41 (m,3H), 7.55 (m,2H).
b) 4-r2-(2-(4-(5-Phenylpentylthio)phenoxy)-l-oxo-2-phenylethyl)-4-methylthiazol-5- yllbutanoic acid
The procedure described in example lOe was used with the product from 42a to give the required product as a pale yellow gum in 8% yield. This was converted to the dicyclohexyllamine salt to afford a white solid, which analysed as the hydrate.
Mass spectrum: m/e 574 (M+H) M.p.: °C 121-122
C45H58N2O4S2 .H20 requires: C 69.9 H 7.8 N 3.6 S 8.3 % found: C 70.0 H 7.4 N 3.5 S 7.8 %
EXAMPLE 43
4. 2-(2-(4-(5-Phenylpentylthio)phenoxy -3-methyl-l-oxobutyl)-4-methylthiazol-5- yllbutanoic acid
a) Ethyl 2-r4-(5-phenylpentylthio)phenoxyl3-nιethylbutanoate
The procedure described in example 40a was used starting with ethyl 2-bromo-3- methylbutanoate to give the product as a clear oil in 35% yield.
Mass spectrum: m/e 401 (M+H) Η NMR, CDC13 , d: 1.05-1.09 (2xt, 6H), 1.24 (t,3H), 1.43 (m, 2H), 1.60 (m, 4H),
2.27 (m, IH), 2.59 (t,2H), 2.80 (t, 2H), 4.21 (q, 2H), 4.32 (d, IH), 6.82 (d, 2H), 7.17 (m, 3H), 7.24-7.30 (m, 4H).
b) 4-r2-(2-(4-(5-Phenylpentylthio)phenoxy)-3-methyl-l-oxobutyl)-4-methylthiazol-5- yllbutanoic acid
The procedure described in example lOe was used with the product from 42a to give the required product as a pale yellow gum in 1 1 % yield. This was converted to the dicyclohexyllamine salt to afford a white solid.
Mass spectrum: m/e 540 (M+H) M.p.: °C 111-1 12
C42H60N2O4S2 requires: C 69.9 H 8.4 N 3.9 S 8.9 % found: C 69.8 H 8.5 N 3.9 S 9.2 %
EXAMPLE 44 2-r2-(4-(5-PhenvIpentylthio)phenoxy)-l-oxoethvnbenzimidazole-5-carboxylic acid
a) 2-r2-(4-(5-Phenylpentylthio)phenoxy)-l-hydroxyethvnbenzimidazole-5-carboxylic acid
The procedure described in example li was used with 3,4-diaminobenzoic acid to afford the required product as a light brown solid in 70% yield.
Mass spectrum: m/e 478 (M+H)
Η NMR, CDCI3, d: 1.36 (m, 2H), 1.53 (m, 4H), 2.53 (t, 2H), 2.82 (t, 2H),
4.26-4.45 (m, 2H) 5.20 (m, IH), 6.37 (d,lH) 6.94 (d, 2H), 7.12-7.29 (m, 7H), 7.58 (dd, IH), 7.80 (m, IH), 8.12 (d, IH).
b) 2-r2-(4-(5-Phenylpentylthio)phenoxy)-l -oxoethyllbenzimidazole-5-carboxylic acid
The procedure described in example li was used with the product from 44a to afford the required product as a cream coloured solid in 32% yield, as the hemi-hydrate.
Maββ-βpectrum: m/e 475 (M+H) M.p.: °C 186-188
C27H26N2O4S.0.5H2O requires: C 67.1 H 5.6 N 5.8 S 6.6 % found: C 67.7 H 5.6 N 5.9 S 6.7 %
EXAMPLE 45
2-r2-r4-(5-Phenylpentylthio)phenoxyl-l-oxoethvπimidazole
a) l-Triphenylmethyl-2-r2-r4-(5-Phenylpentylthio)phenoxyl-l-oxoethvnimidazole
The procedure described in example 2b was used with 1-triphenylmethylimidazole to afford the required product as a colourless oil in 37% yield.
1H NMR, CDC13, d: 1.44 (m, 2H), 1.60 (m, 4H), 2.59 (t, 2H), 2.76 (t, 2H),
5.18 (s, 2H), 6.33 (d,2H) 7.06 (m, 6H), 7.12-7.19 (m, 7H), 7.25-7.28 (m, 11H).
b) 2-r2-r4-(5-Phenylpentylthio)phenoxyl-l-oxoethvni idazole
The product from example 45a (0.64g) was dissolved in dichloromethane (50 mis) and treated with trifluoroacetic acid (8 mis) and stirred at 25°C for 0.5 hr. The reaction mixture was then poured into a 5% solution of sodium hydroxide in water (200 mis) and extracted with dichloromethane. The extract was dried (MgSO4) and evaporated to dryness. The residue was passed down a silica gel columned eluted with hexane:ethyl acetate (2:1) to afford the required product as a white solid (0.32g).
Mass spectrum: m/e 381 (M+H) M.p.: °C 162-163
C22H24N2O4S requires: C 69.4 H 6.4 N 7.4 S 8.4 % found: C 69.6 H 6.5 N 7.0 S 8.2 %
EXAMPLE 46
3-f2-f2-r4-(5-Phenylpentylthio)phenoxyl-l-oxoethyll-4- ethylimidazol-5-yllpropenoic acid
a) (l-Triphenylmethyl-4-methylimidazol-5-yl)carboxaldehyde 4-Methyl-imidazole-5-carboxaldehyde (2.0 g) was dissolved in DMF (40 mis) and treated with triethylamine (1.84 g). Triphenylmethylchloride (5.06g) in DMF (40 mis) was added over 0.5 hr and the reaction was stirred at ambient temperature for 18 hrs. The reaction mixture was poured into water and extracted into ethyl acetate. The extract was washed with water, brine, dried (MgSO4) and evaporated to afford an oil. This was passed down a silica gel column eluted with hexane:ethyl acetate (1:1) to give the product as a white solid (2.39 g).
H NMR, CDC13, d: 1.6 (s, IH), 7.10-7.19 (m, 6H), 7.34-7.38 (m, 9H),7.39(s,lH), 10.00 (s, IH).
b) Ethyl 3-(l-Triphenylmethyl-4-methylimidazol-5-yl)propenoate
The product from example 46a (2.39 g) was dissolved in dichloromethane (50 mis) and treated with (carbethoxymethylene)phosphorane (2.36 g) and stirred at ambient temperature for 24 hrs. The reaction was then stirred at reflux for 72 hrs. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography, eluted with hexane:ethyl acetate (3:2), to give the required product as a white solid (1.45g).
H NMR, CDC13, d: 1.29 (t, 3H), 1.57 (s, 3H), 4.22 (q, 2H), 6.58 (d,
IH), 7.12-7.17 (m, 6H), 7.26-7.36 (m, 10H), 7.55 (d,lH).
c) 3-(l-Triphenylmethyl-4-methylimidazol-5-yl)propenoic acid
The product from example 46b (1.45 g) was dissolved in tetrahydrofuran (40 mis) and water (10 mis) was added. Lithium hydroxide monohydrate (0.43 g) was added followed by a few drops of methanol and the mixture stirred at room temperature for 18 hrs. The mixture was then heated at reflux for 6 hrs, then poured into a saturated solution of ammonium chloride (30 mis) and extracted into ethyl acetate. The extracts were washed with water, brine, dried (MgSO4) and evaporated to dryness to give the product as a white solid (1.27 g).
H NMR, CDCI3, d: 1.57 (s, 3H), 6.60 (d, IH), 7.11-7.19 (m, 6H), 7.32-7.36 (m, 9H), 7.41 (s, IH), 7.62 (d, IH). cQ 3-r2-r2-r4-f5-Phenylpentylthio)phenoxyl-l-oxoethyll-l-triphenylmethyl-4- methylimidazol-5-yllpropenoic acid
The procedure described in example 8 was used with the product from example 46c to give the required product in 21% yield.
Η NMR, CDC13, d: 1.44 (m, 2H), 1.59 (m, 4H), 1.74 (s, 3H), 2.59 (m, 2H)
2.79 (t, 2H), 5.1 1 (s, 2H), 6.85 (d,lH), 6.75 (d,2H) 7.1-7.19 (m, 9H), 7.24-7.39 (m, 13H), 7.62 (d,lH).
e) 3-r2-r2-r4-(5-Phenylpentylthio)phenoxyl-l-oxoethyll-4-methyliιnidazol-5- yllpropenoic acid
The procedure described in example 45b was used with the product from example 46d to afford the required product in 10% yield.
Mass spectrum: m/e 465 (M+H)
Η NMR, CDC13, d: 1.44 (m, 2H), 1.61 (m, 4H), 2.40 (s, 3H), 2.60 (t, 2H)
2.81 (t, 2H), 5.45 (s, 2H), 6.60 (d,lH), 6.93 (d,2H) 7.14 (m, 3H), 7.16-7.32 (m, 4H), 7.61 (d,lH)> 13.1 (bs, IH).
EXAMPLE 47 2-r2-(4-(5-Phenylpentylthio)phenoxy)-l-oxoethyHpyridine
Using the procedure described for example 5d but using 2-bromopyridine in place of 1- methylimidazole led to the preparation of the required compound as a white solid in 57% yield.
Mass spectrum: m/e 392 (M+H) M.p.: 68°C
C24H25NO2S requires: C 73.6 H 6.4 N 3.6 S 8.2 % found: C 74.6 H 6.5 N 3.7 S 8.1 %
EXAMPLE 48 4-r2-(2-(4-(5-Phenylpentyloxy)phenoxy)-l-oxopropyl)-4-methylthiazol-5-vnbutanoic acid a) Ethyl 2-r4-(5-phenylpentyloxy)phenoxylpropionate
The procedure described in example 2a was used starting with ethyl 2-bromopropionate and (5-phenylpentyloxy)phenol to give the product as a colourless gum.
Mass spectrum: m/e 366 (M+H)
Η NMR, CDC13 , d: 1.27 (t, 3H), 1.49 (m, 2H), 1.56-1.83 (m & d, 7H), 2.64 (t,
2H), 3.89 (t, 2H), 4.16 (q, 2H), 4.64 (q, IH), 6.77-6.84 (m, 4H), 7.15-7.30 (m, 5H).
b) 4-f2-(2-(4-(5-Phenylpentvoxy)phenoxyH-oxopropyl)-4-methylthiazol-5- yllbutanoic acid
The procedure described in example lOe was used with the product from 48a to give the required product as a pale yellow gum. The product was converted to the dicyclohexylamine salt which was a pale yellow solid.
Mass spectrum: m/e 496 (M+H) M.p.: °C 91-93
C40H56N2O5S requires: C 70.9 H 8.3 N 4.1 S 4.7 % found: C 70.7 H 8.2 N 4.1 S 4.9 %
EXAMPLE 49 4-f2-(2-(4-(4-Chlorobenzylthio)phenoxy)-l-oxopropyl)-4-methylthiazol-5-ynbutanoic acid
a) 4-(4-Chlorobenzylthio phenol
The procedure described in example 13a was used with 4-hydroxythiophenol and 4- chlorobenzyl chloride to give the required product as a pale yellow solid in 59% yield.
1H NMR, CDC13, d: 3.91 (s, 2H), 4.94 (s, IH), 6.70 (d, 2H), 7.1 (d, 2H)
7.21 (dd, 4H).
b Ethyl 2-r4-(4-chlorobenzylthio)phenoxylpropionate The procedure described in example 2a was used with ethyl 2-bromopropionate and 4-(4- chlorobenzylthio)phenol to give the required product as a white solid in 93% yield.
Η NMR, CDC13, d: 1.26 (t, 3H), 1.60 (d, 3H), 3.92 (s, 2H),
4.20 (q, 2H), 4.71 (q, IH), 6.77 (d, 2H), 7.1 (d, 2H), 7.22 (m, 4H).
c) 4-r2-(2-(4-(4-Chlorobenzylthio)phenoxy)-l-oxopropyl)-4-methylthiazol-5- yllbutanoic acid
The procedure described in example lOe was used with the product from 49b to give the required product as a pale yellow gum. The product was converted to the dicyclohexylamine salt which was a pale yellow solid.
Mass spectrum: m e 490 / 492 (M+H) M.p.: °C 106-107 C36H47CIN2O4S2 requires: C 64.4 H 7.1 N 4.2 S 9.6 % found: C 63.7 H 7.1 N 4.1 S 9.3 %
EXAMPLE 50
4-r2-(2-(4-(4-Chlorobenzylthio)phenoxy)-l-oxobutyl)-4-methylthiazol-5-yllbutanoic acid
a) Ethyl 2-r4-(4-chlorobenzylthio)phenoxylbutanoate
The procedure described in example 2a was used with ethyl 2-bromobutanoate and 4-(4- chlorobenzylthio)phenol to give the required product as a white solid in 94% yield.
1H NMR, CDC13, d: 1.07 (t, 3H), 1.25 (t, 3H), 1.98 (m, 2H), 3.92 (s, 2H),
4.20 (q, 2H), 4.50 (t, IH), 6.77 (d, 2H), 7.1 (d, 2H), 7.21 (m, 4H).
b) 4-r2-(2-(4-(4-Chlorobenzylthio)phenoxy)-l-oxobutyl)-4-methylthiazol-5- yllbutanoic acid
The procedure described in example lOe was used with the product from 50a to give the required product as a pale yellow gum. The product was converted to the dicyclohexylamine salt which was a pale yellow solid.
Mass spectrum: m/e 504 / 506 (M+H) M.p.: °C 114-116 C37H49CIN2O4S2 requires: C 64.8 H7.2 N4.1 S 9.4 %, found: C 64.9 H7.5 N4.2 S 9.2 %
Pharmacological Data
In vivo, PLA2 is responsible for the release of arachidonic acid and lysophospholipid from cell membrane phospholipids. Arachidonic acid and certain lysophospholipids are metabolised to substances which are important mediators of the inflammatory response. The usefulness of the compounds according to the invention as anti-inflammatory agents was therefore tested in vitro by measuring their ability to inhibit arachidonic acid release from PLA2 enzyme provided with a suitable substrate.
Cell Assay
Compounds according to the invention were assayed for inhibition of release of
[3H] arachidonic acid from DMSO-differentiated HL60 cells in response to Ca2+ ionophore challenge.
Cells of the human leukaemic line HL60 are differentiated to a Polymoφhonuclear cell-like phenotype by treatment with 1.3% DMSO for 4 days. During the final 24 hours of differentiation, the cells are incubated with [3H] arachidonic acid. After washing to remove unincoφorated [3H]arachidonic acid, the cells (at 2.6x106/ml) are incubated for 10 minutes at 37°C with the compound of interest at concentrations up to lOμM. Arachidonic acid release is then stimulated by the addition of the Ca2+ ionophore A23187. Control cells are incubated with vehicle alone. After 3 minutes, ice-cold MeOH is added to terminated the reaction and precipitate cellular protein and membranes. The assay reactions are then filtered to separate cellular material from the supernatant, containing the released [3H] arachidonic acid. The amount of released H in the supernatant is then measured, and the inhibition of the stimulated release by the compounds is calculated.
In this screen, the compounds of the examples 1, 3, 8-10, 12, 13, 15, 16, 18, 20, 21, 24-28, 31-40, 42-44, 46 and 47-50 were tested and gave ID50 values less than 10 μM, indicating that they had useful activity.

Claims

CLAIMS:
1. A compound of formula I
Figure imgf000069_0001
wherein :-
R represents hydrogen, Cl to 12 alkyl, phenyl or a 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S, which alkyl, phenyl or heterocyclic ring is optionally substituted by halogen, or which alkyl is optionally substituted by a group J, where J is phenyl or phenyl fused with one or two benzene rings, or biphenylyl, optionally ring substituted by 1 to 3 heteroatoms selected from O, N or S, each group J being optionally substituted by Cl to 6 alkyl, -hydroxy, Cl to 6 alkoxy, nitro or halogen;
2 3 for R and R :-
2 10
(i) R represents hydrogen, Cl to 6 alkyl or R -B; and
3 10
R represents hydrogen, Cl to 6 hydroxyalkyl, C3 to 9 alkenylcarboxyl or R -B, wherein R10 represents Cl to 6 alkyl and B represents COOH, PO3H2, OPO3H2,
SO3H, OSO3H, tetrazolyl, CONR1 ^H or CONHSO2R1 R1 representing hydrogen or C l to 6 alkyl; or
2 3
(ii) R and R together represent a benzo ring or a six membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms, which benzo or heterocyclic
4 4 ring is optionally substituted by R , wherein R represents hydrogen, Cl to 6 alkoxy, Cl to 6 carboxyalkoxy, C3 to 9 alkenylcarboxyl, R -B or -(CH2)pCO2PG, wherein R represents Cl to 6 alkyl and B represents COOH, PO3H2, OPO3H ,
SO3H, OSO3H, tetrazolyl, CONR1 OH or CONHSO2R1 \ R1 representing hydrogen or Cl to 6 alkyl, and PG is allyl or tert-butyl and p represents zero or an integer from 1 to 6;
8 9 R and R independently represent hydrogen, methyl, Cl to 6 alkyl, aryl or heteroaryl, or
8 9 together R and R represent C3 to 6 cycloalkyl or a 3, 4, 5 or 6 membered heterocyclic ring containing from 1 to 3 atoms selected from O, N or S; Ar represents phenyl, or phenyl fused with one or two benzo rings, or biphenylyl optionally ring substituted with 1 to 3 heteroatoms selected from O, N or S, each Ar group being optionally substituted by Cl to 6 alkyl, hydroxy, Cl to 6 alkoxy, nitro or halogen; X represents O, S, SO , CH2 or SO;
5 ς
YY rreepprreesseennttss OO,, N NRR oorr ((CCHH22))aa,, whheer: e a represents an integer from 1 to 12 and R" represents hydrogen or Cl to 6 alkyl;
Z represents O, S, CH=CH, N=N, N=CH or NR , where R represents hydrogen or Cl to 6 alkyl; and n represents an integer from 1 to 12; or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
2. A compound according to claim 1 wherein R represents phenyl, dichlorophenyl or methyl.
2 3. The compound according to claim 1 or 2 wherein R is according to option (i) and represents hydrogen, methyl or -(CH2)4CO2H.
3
4. The compound according to claim 1, 2 or 3 wherein R is according to option (i), it represents hydrogen, -(CH2)2OH, -CO2H, -(CH2)3CO2H, -(CH2)2CO2H or CH=CH- CO2H..
2 3
5. The compound according to claim 1 or 2 wherein R and R are according to option
(ii) and R4 represents -CO2H, methoxy, -(CH2)2CO2H, -OCH2CO2H or -(CH2)pCO2PG, where PG is allyl or tert-butyl and p represents zero or an integer from 1 to 6.
6. The compound according to any preceding claim wherein a represents an integer from l to 3.
7. The compound according to any preceding claim wherein Y represents O or CH2.
8. The compound according to any preceding claim wherein X represents O or S or SO2.
9. The compound according to any preceding claim wherein Z represents O, S, CHCH or NR , R representing hydrogen or methyl. 0
10. The compound according to any preceding claim wherein R represents hydrogen or methyl.
9
11. The compound according to any preceding claim wherein R represents hydrogen, methyl, phenyl or isopropyl.
12. A compound of formula (I) selected from:
2-[2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyl]benzoxazole-5-carboxylic acid; or 1 -methyl-2-[2-[4-(5-phenylpentylthio)phenoxy]- 1 -oxoethyl]benzimidazole; or 5-(2-hydroxyethyl)-4-methyl-2-[2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethyl]thiazole; or 6-methoxy-2-[2-[4-(5-phenylpentylthio)phenoxy]-l-oxoethyl]benzothiazole; or 1 -methyl-2-[2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyl]imidazole; or 2-[2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyllbenzothiazole; or 2-[2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyl jthiazole; or 2-[2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethyllbenzothiazole-6-carboxylic acid; or 4-methyl-2-[2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyl]thiazole-5-carboxylic acid; or 4-[2-(2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyl)-4-methylthiazol-5-yl]butanoic acid; or 2-[2-(4-(3 ,5-dichlorobenzyloxy)phenoxy)- 1 -oxoethyllthiazole; or 5-(2-hydroxyethyl)-4-methyl-2-[2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l- oxoethyl]thiazole; or
5-(2-hydroxyethyl)-4-methyl-2-[2-(4-(decylsulfonyl)phenoxy)-l -oxoethyllthiazole; or 5-(2-hydroxyethyl)-4-methyl-2-[2-(4-(benzyloxy)phenoxy)- 1 -oxoethyllthiazole; or 5-(2-hydroxyethyl)-4-methyl-2-[2-(4-(benzylthio)phenoxy)- 1 -oxoethyllthiazole; or 5-(2-hydroxyethyl)-4-methyl-2-[2-(4-(3,5-dichlorobenzylthio)phenoxy)- 1 - oxoethyllthiazole; or
1 -methyl-2-[2-(4-(5-phenylpentylsulfonyl)phenoxy)- 1 -oxoethyllbenzimidazole; or 2-[2-(4-(5-phenylpentylsulfonyl)phenoxy)- 1 -oxoethyllbenzothiazole; or 2-[2-(4-(5-phenylpentylsulfonyl)phenoxy)- 1 -oxoethyl]-6-methoxybenzothiazole; or 5-(2-hydroxyethyl)-4-methyl-2-[2-(4-(3,5-dichlorobenzylsulfonyl)phenoxy)-l- oxoethyllthiazole; or
2-[2-(4-(3,4-dichlorobenzylthio)phenoxy)- 1 -oxoethyllbenzoxazole; or 2-[2-(4-(3,4-dichlorobenzylthio)phenoxy)- 1 -oxoethyl] benzimidazole; or 2-[2-(4-(3,4-dichlorobenzylthio)phenoxy)-l-oxoethyl]-6-methoxy benzoxazole; or 2-[2-(4-(3,4-dichlorobenzylthio)phenoxy)-l-oxoethyl]benzoxazole-5-carboxylic acid; or 2-[2-(4-(3 ,4-dichlorobenzylthio)phenoxy)- 1 -oxoethyl]benzoxazole-6-carboxylic acid; or 2-[2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l-oxoethyllbenzoxazole-5-carboxylic acid; or
2-[2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l-oxoethyllbenzimidazole-5-carboxylic acid; or
3-[2-(2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l-oxoethyl)benzoxazol-5-yl]propionic acid; or 5 2-[3-[4-(phenylpentyloxy)phenyll-l-oxopropyl]benzoxazole-5- carboxylic acid; or
2-[3-(4-(5-phenylpentyloxy)phenyl)-l-oxopropyl]benzoxazole-6- carboxylic acid; or
3-[2-(2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyl)-4-methylthiazol-5-yl]propionic acid; or
4-[2-(2-(4-(decylthio)phenoxy)- 1 -oxoethyl)-4-methylthiazol-5-yllbutanoic acid; or o 4-[2-(2-(4-(decylsulfonyl)phenoxy)- 1 -oxoethyl)-4-methylthiazol-5-yl]butanoic acid; or
2-[2-(2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l-oxoethyl)benzothiazol-6-oxy]acetic acid; or
4-[2-(2-(4-(5-phenylpentyloxy)phenoxy)- 1 -oxoethyl)-4-methylthiazol-5-yllbutanoic acid; or
5-[2-(2-(4-(5-phenylpentyloxy)phenoxy)- 1 -oxoethyl)thiazol-4-yl]pentanoic acid; or s 4-[2-(2-(4-(5-phenylpentyloxy)phenyl)- 1 -oxopropyl)-4-methylthiazol-5-yl]butanoic acid; or
4-[2-(2-(4-(benzylthio)phenoxy)- l-oxoethyl)-4-methylthiazol-5-yl]butanoic acid; or
2-[2-(4-(3,5-dichlorobenzyloxy)phenoxy)-l-oxoethyl]benzothiazole-6-carboxylic acid; or
4-[2-(2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxopropyl)-4-methylthiazol-5-yllbutanoic acid; o or
4-[2-(2-(4-(5-phenylpentylthio)phenoxy)-l-oxo-2-methyl-propyl)-4-methylthiazol-5- yI]butanoic acid; or
4-[2-(2-(4-(5-phenylpentylthio)phenoxy)-2-phenyl-l-oxyethyl)-4-methylthiazol-5- yl]butanoic acid; or 5 4-[2-(2-(4-(5-phenylpentylthio)phenoxy)-3-methyl- 1 -oxobutyl)-4-methylthiazol-5- yllbutanoic acid; or
2-[2-(4-(5-phenylpentylthio)phenoxy)- 1 -oxoethyl]benzimidazole-5-carboxylic acid; or
2-[2-[4-(5-phenylpentylthio)phenoxyl-l-oxoethyllimidazole; or
3-[2-[2-[4-(5-phenylpentylthio)phenoxyl-l-oxoethyl]-4-methylimidazol-5-yl]propenoic o acid; or
2-[2-(4-(5-phenylpentylthio)phenoxy)-l-oxoethyl]pyridine; or
4-[2-(2-(4-(5-phenylpentyloxy)phenoxy)- 1 -oxopropyl)-4-methylthiazol-5-yllbutanoic acid; or
4-[2-(2-(4-(4-chlorobenzylthio)phenoxy)- 1 -oxopropyl)-4-methylthiazol-5-yllbutanoic acid; 5 or 4-[2-(2-(4-(4-chlorobenzylthio)phenoxy)- 1 -oxobutyl)-4-methylthiazol-5-yl]butanoic acid; or or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
13. The compound according to any preceding claim for use as a pharmaceutical.
14. A pharmaceutical composition including a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
15. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.
16. The use according to claim 15, wherein the disease is asthma.
17. A method of treating, or reducing the risk of, inflammatory disease in a patient suffering from, or at risk of, said disease, wherein the method comprises administering to the patient the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt, enantiomer or tautomer thereof.
18. The method of claim 17, wherein the disease is asthma.
19. A process for preparing the compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein the process comprises:-
(a) reacting a compound of formula IN, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, with a compound of formula N, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formulae rv and V are as defined in claim 19 or 20; or
(b) reacting a compound of formula V, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, with a compound of formula NI, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formulae IN and NI are as defined in claim 19 or 20; or (c) oxidising a compound of formula XII, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein formula XII is as defined in claim 19 or 21; or (d) preparing a compound of formula I, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein X represents SO2, by oxidising a compound of formula I, or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, wherein X represents S, and optionally after (a), (b), (c) or (d) forming a pharmaceutically acceptable salt.
PCT/SE1999/002226 1998-12-04 1999-11-30 Novel compounds WO2000034254A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP99963777A EP1135377A1 (en) 1998-12-04 1999-11-30 Novel compounds
JP2000586701A JP2002531553A (en) 1998-12-04 1999-11-30 New compound
AU20148/00A AU2014800A (en) 1998-12-04 1999-11-30 Novel compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9804212-0 1998-12-04
SE9804212A SE9804212D0 (en) 1998-12-04 1998-12-04 Compounds

Publications (1)

Publication Number Publication Date
WO2000034254A1 true WO2000034254A1 (en) 2000-06-15

Family

ID=20413558

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1999/002226 WO2000034254A1 (en) 1998-12-04 1999-11-30 Novel compounds

Country Status (5)

Country Link
EP (1) EP1135377A1 (en)
JP (1) JP2002531553A (en)
AU (1) AU2014800A (en)
SE (1) SE9804212D0 (en)
WO (1) WO2000034254A1 (en)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009651A2 (en) * 2000-08-02 2002-02-07 Smithkline Beecham Corporation Fatty acid synthase inhibitors
US7781595B2 (en) 2003-09-22 2010-08-24 S*Bio Pte Ltd. Benzimidazole derivatives: preparation and pharmaceutical applications
US20100249078A1 (en) * 2007-05-25 2010-09-30 The Scrips Research Institute Tetracyclic inhibitors of fatty acid amide hydrolase
WO2011039365A1 (en) * 2009-10-02 2011-04-07 Avexxin As Anti inflammatory 2-oxothiazoles and 2 -oxooxazoles
EP2431029A2 (en) 2002-06-07 2012-03-21 Kieran Francis Scott Method of inhibiting prostate cancer cell proliferation
US8343970B2 (en) 2010-03-12 2013-01-01 Omeros Corporation PDE10 inhibitors and related compositions and methods
WO2014118195A1 (en) * 2013-01-29 2014-08-07 Avexxin As Antiinflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
WO2016016472A1 (en) * 2014-08-01 2016-02-04 Avexxin As 2-oxothiatole compounds having activity as cpla2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US9650368B2 (en) 2014-04-28 2017-05-16 Omeros Corporation Processes and intermediates for the preparation of a PDE10 inhibitor
AU2015268638B2 (en) * 2009-10-02 2017-08-31 Avexxin As Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
US9850238B2 (en) 2014-04-28 2017-12-26 Omeros Corporation Optically active PDE10 inhibitor
US9879002B2 (en) 2015-04-24 2018-01-30 Omeros Corporation PDE10 inhibitors and related compositions and methods
US9920045B2 (en) 2015-11-04 2018-03-20 Omeros Corporation Solid state forms of a PDE10 inhibitor
WO2019039515A1 (en) 2017-08-22 2019-02-28 三菱ケミカル株式会社 Bisphenol composition and method for producing same, and polycarbonate resin and method for producing same
US10626092B2 (en) 2016-05-02 2020-04-21 Mei Pharma, Inc. Polymorphic forms of 3-[(2-butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide and uses thereof
US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1760071A4 (en) * 2004-06-23 2008-03-05 Ono Pharmaceutical Co Compound having s1p receptor binding potency and use thereof
GB201806663D0 (en) * 2018-04-24 2018-06-06 Avexxin As 2-Oxothiazole compositions for treatment of fibrotic disease

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2063901A1 (en) * 1970-12-28 1972-07-20 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler, 6000 Frankfurt Phenylalkylaminoalkylthiazoles - as antiphlogistics
EP0351194A2 (en) * 1988-07-12 1990-01-17 Imperial Chemical Industries Plc Thiazole derivatives having a 5-lipoxygenase-inhibiting activity
EP0577003A1 (en) * 1992-07-02 1994-01-05 F. Hoffmann-La Roche Ag Thiazolylvinylphenyl derivatives
WO1996003392A1 (en) * 1994-07-27 1996-02-08 G.D. Searle & Co. Substituted thiazoles for the treatment of inflammation
EP0735029A1 (en) * 1995-03-28 1996-10-02 Nippon Zoki Pharmaceutical Co., Ltd. Benzothiazole derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2063901A1 (en) * 1970-12-28 1972-07-20 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler, 6000 Frankfurt Phenylalkylaminoalkylthiazoles - as antiphlogistics
EP0351194A2 (en) * 1988-07-12 1990-01-17 Imperial Chemical Industries Plc Thiazole derivatives having a 5-lipoxygenase-inhibiting activity
EP0577003A1 (en) * 1992-07-02 1994-01-05 F. Hoffmann-La Roche Ag Thiazolylvinylphenyl derivatives
WO1996003392A1 (en) * 1994-07-27 1996-02-08 G.D. Searle & Co. Substituted thiazoles for the treatment of inflammation
EP0735029A1 (en) * 1995-03-28 1996-10-02 Nippon Zoki Pharmaceutical Co., Ltd. Benzothiazole derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S.N. SAWHNEY ET AL.: "Synthesis of Some 2-Mercaptoimidazole Derivatives as Potential Antiinflammatory Agents", INDIAN JOURNAL OF CHEMISTRY, vol. 22B, 1983, pages 584 - 589, XP002926657 *

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009651A3 (en) * 2000-08-02 2002-03-28 Smithkline Beecham Corp Fatty acid synthase inhibitors
WO2002009651A2 (en) * 2000-08-02 2002-02-07 Smithkline Beecham Corporation Fatty acid synthase inhibitors
EP2431029A2 (en) 2002-06-07 2012-03-21 Kieran Francis Scott Method of inhibiting prostate cancer cell proliferation
US9024029B2 (en) 2003-09-22 2015-05-05 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US7781595B2 (en) 2003-09-22 2010-08-24 S*Bio Pte Ltd. Benzimidazole derivatives: preparation and pharmaceutical applications
US10736881B2 (en) 2003-09-22 2020-08-11 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US10201527B2 (en) 2003-09-22 2019-02-12 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US8551988B2 (en) 2003-09-22 2013-10-08 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9717713B2 (en) 2003-09-22 2017-08-01 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9402829B2 (en) 2003-09-22 2016-08-02 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US20100249078A1 (en) * 2007-05-25 2010-09-30 The Scrips Research Institute Tetracyclic inhibitors of fatty acid amide hydrolase
US8372823B2 (en) * 2007-05-25 2013-02-12 The Scripps Research Institute Tetracyclic inhibitors of fatty acid amide hydrolase
AU2015268638B2 (en) * 2009-10-02 2017-08-31 Avexxin As Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
US10370344B2 (en) 2009-10-02 2019-08-06 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
WO2011039365A1 (en) * 2009-10-02 2011-04-07 Avexxin As Anti inflammatory 2-oxothiazoles and 2 -oxooxazoles
AU2010302584B2 (en) * 2009-10-02 2015-09-10 Avexxin As Anti inflammatory 2-oxothiazoles and 2 -oxooxazoles
KR101997163B1 (en) 2009-10-02 2019-07-08 아벡신 에이에스 Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
CN103772312B (en) * 2009-10-02 2016-08-17 埃维克辛公司 The 2-carbonyl thiazole of anti-inflammatory and 2-carbonyl oxazole
US9597318B2 (en) 2009-10-02 2017-03-21 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
EP3431084A1 (en) * 2009-10-02 2019-01-23 Avexxin AS Antiinflammatory 2-oxothiazoles
CN103772312A (en) * 2009-10-02 2014-05-07 埃维克辛公司 Anti inflammatory 2-oxothiazoles and 2 -oxooxazoles
KR20180114228A (en) * 2009-10-02 2018-10-17 아벡신 에이에스 Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
KR101907535B1 (en) * 2009-10-02 2018-10-15 아벡신 에이에스 Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
US8343970B2 (en) 2010-03-12 2013-01-01 Omeros Corporation PDE10 inhibitors and related compositions and methods
US8685975B2 (en) 2010-03-12 2014-04-01 Omeros Corporation PDE10 inhibitors and related compositions and methods
US10106516B2 (en) 2010-03-12 2018-10-23 Omeros Corporation PDE10 inhibitors and related compositions and methods
WO2014118195A1 (en) * 2013-01-29 2014-08-07 Avexxin As Antiinflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
AU2016266022B2 (en) * 2013-01-29 2018-04-26 Avexxin As Antiinflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US11034666B2 (en) 2013-01-29 2021-06-15 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
CN105102438A (en) * 2013-01-29 2015-11-25 埃维克辛公司 Antiinflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US10259801B2 (en) 2013-01-29 2019-04-16 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US11691959B2 (en) 2013-01-29 2023-07-04 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US9850238B2 (en) 2014-04-28 2017-12-26 Omeros Corporation Optically active PDE10 inhibitor
US9650368B2 (en) 2014-04-28 2017-05-16 Omeros Corporation Processes and intermediates for the preparation of a PDE10 inhibitor
CN107074840A (en) * 2014-08-01 2017-08-18 埃维克辛公司 The 2 active oxothiazoiium compounds having as cPLA2 inhibitor for treating inflammatory disease and excess proliferative disease
US10150781B2 (en) 2014-08-01 2018-12-11 Avexxin As 2-oxothiatole compounds having activity as CPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
WO2016016472A1 (en) * 2014-08-01 2016-02-04 Avexxin As 2-oxothiatole compounds having activity as cpla2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US10851114B2 (en) 2014-08-01 2020-12-01 Avexxin As 2-oxothiatole compounds having activity as cPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
AU2015295220B2 (en) * 2014-08-01 2018-10-11 Avexxin As 2-oxothiazole compounds having activity as cPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
CN107074840B (en) * 2014-08-01 2022-04-26 埃维克辛公司 2-oxothiazole compounds having activity as cPLA2 inhibitors for the treatment of inflammatory and hyperproliferative diseases
US9879002B2 (en) 2015-04-24 2018-01-30 Omeros Corporation PDE10 inhibitors and related compositions and methods
US9920045B2 (en) 2015-11-04 2018-03-20 Omeros Corporation Solid state forms of a PDE10 inhibitor
US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases
US10626092B2 (en) 2016-05-02 2020-04-21 Mei Pharma, Inc. Polymorphic forms of 3-[(2-butyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-N-hydroxy-acrylamide and uses thereof
WO2019039515A1 (en) 2017-08-22 2019-02-28 三菱ケミカル株式会社 Bisphenol composition and method for producing same, and polycarbonate resin and method for producing same

Also Published As

Publication number Publication date
JP2002531553A (en) 2002-09-24
EP1135377A1 (en) 2001-09-26
SE9804212D0 (en) 1998-12-04
AU2014800A (en) 2000-06-26

Similar Documents

Publication Publication Date Title
EP1135377A1 (en) Novel compounds
JP5048017B2 (en) Substituted phenylalkanoic acid derivatives and uses thereof
EP1248612B1 (en) Novel compounds and compositions as protease inhibitors
WO2011078370A1 (en) Novel parabanic acid derivative and drug having the same as active ingredient
OA11163A (en) Nicotinamide derivatives
JPH01143856A (en) 2-aryl substituted heterocyclic compound for antiallergic and anti-inflammatory agent
JPWO2009072581A1 (en) Lactam compound or salt thereof and PPAR activator
EP3059224A1 (en) 4-aminomethylbenzoic acid derivative
JP2000515133A (en) Hypoglycemic and hypolipidemic compounds
FR2567123A1 (en) NOVEL HETEROCYCLIC POLYCYCLIC COMPOUNDS DERIVED FROM BENZIMIDAZOLE, BENZOXAZOLE OR BENZOTHIAZOLE, PROCESS AND INTERMEDIATE FOR THEIR PREPARATION AND THEIR PHARMACEUTICAL USE, ESPECIALLY FOR THE TREATMENT OF GASTRIC DISORDERS
WO2009109998A1 (en) Novel protein tyrosine phosphatase - ib inhibitors
EP0629624B1 (en) Tetrazole derivatives, their production and use
JPH11171848A (en) Aromatic amide derivative
KR100969979B1 (en) Phenylalkylcarboxylic acid derivatives and dionic phenylalkylheterocyclic derivatives and their use as medicines with serum glucose and/or serum lipid lowering activity
JP4191269B2 (en) Novel anilide compound and pharmaceutical containing the same
JPH06510786A (en) Pyridine compounds for the treatment of leukotriene-related diseases
PT1502590E (en) Heterocyclic oxime derivatives, process for their preparation and use thereof in the treatment of type ii diabetes
JP2003505367A (en) 3-arylsulfonyl-2- (substituted methyl) propanoic acid derivatives as matrix metalloproteinase inhibitors
US4791114A (en) 2-Benzimidazolylalkylthio (or -sulfinyl or -sulfonyl) derivatives, their preparation and their application as medicinal products
US5232941A (en) Caffeic acid derivatives and pharmaceutical compositions containing the same
IE904522A1 (en) Pharmacologically Active Amide Carboxylate Derivatives
ES2245026T3 (en) NEW ANILIDA COMPOUNDS AND MEDICINES CONTAINING THEM.
LU85780A1 (en) NOVEL ENOLIC ESTERS PRECURSOR OF DRUGS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
US5091403A (en) Sulfinyl imidazole derivatives and antiulcer agents containing the same
RU2144533C1 (en) Derivatives of tetrazole, method of their synthesis and pharmaceutical compositions based on them

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 09462299

Country of ref document: US

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 586701

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999963777

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1999963777

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1999963777

Country of ref document: EP