WO1992017467A1 - Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques - Google Patents

Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques Download PDF

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Publication number
WO1992017467A1
WO1992017467A1 PCT/EP1991/000659 EP9100659W WO9217467A1 WO 1992017467 A1 WO1992017467 A1 WO 1992017467A1 EP 9100659 W EP9100659 W EP 9100659W WO 9217467 A1 WO9217467 A1 WO 9217467A1
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Prior art keywords
formula
compound
alkyl
group
compound according
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PCT/EP1991/000659
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English (en)
Inventor
Vittorio Vecchietti
Roberto Colle
Giulio Dondio
Giuseppe Giardina
Original Assignee
Dr Lo. Zambeletti S.P.A.
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Application filed by Dr Lo. Zambeletti S.P.A. filed Critical Dr Lo. Zambeletti S.P.A.
Priority to PCT/EP1991/000659 priority Critical patent/WO1992017467A1/fr
Publication of WO1992017467A1 publication Critical patent/WO1992017467A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention is concerned with novel substituted azacyclic compounds, processes for their preparation, and their use in medicine, particularly as analgesics.
  • kappa-receptor agonists through interaction with kappa opioid receptors.
  • a novel class of substituted azacyclic compounds has now been discovered which also exhibit potent kappa-receptor agonism without the aforementioned undesirable behavioural effects.
  • the novel class of compounds also possess diuretic activity which indicates that they are of potential use in the treatment of hyponatraemic disease states in mammals. The compounds are also of potential use in the treatment of cerebral ischaemia.
  • ROC- is an acyl group linked to the nitrogen atom of group (A) in which the group R contains a substituted or
  • R 1 and R 2 are substituents on the same or different carbon atoms and are independently hydrogen or C 1-6 alkyl;
  • R a is a fused substituted or unsubstituted heterocyclic or carbocyclic aromatic ring.
  • the C 1-6 alkyl groups of R 1 and R 2 may be either straight or branched chain and examples are methyl, ethyl, propyl, n-butyl, n-pentyl or n-hexyl.
  • R 1 and R 2 are preferably hydrogen or methyl, especially gem-dimethyl.
  • p is preferably 2 so that (A) has the character of a piperidine ring.
  • the term ''carbocyclic aromatic'' includes single or fused rings, having 6 to 12 ring carbon atoms
  • the term ''heterocyclic aromatic'' includes single or fused rings having 5 to 12 ring atoms, comprising up to four hetero-atoms in the or each ring, selected from oxygen, nitrogen and sulphur.
  • the carbocyclic or heterocyclic group is a fused two ring system
  • one or both rings may be aromatic in character.
  • one of the rings is aromatic and the other is non-aromatic.
  • R a When R a forms a heterocyclic group, it may be a single ring having aromatic character, containing up to 6 ring atoms and comprising up to 2 hetero-atoms in the ring selected from oxygen, nitrogen and sulphur.
  • R a forms an optionally substituted phenyl ring
  • substituents are one or more of C 1-6 alkyl, preferably methyl, halogen,, hydroxy, C 1-6 alkoxy, thiol or C 1-6 alkyl thio.
  • R x represents thienyl, imidazolyl and unsubstituted phenyl.
  • the group R preferably has the formula (II) :
  • n 0, 1 or 2;
  • n' is 0, 1 or 2
  • m + m' ⁇ 2 X is a direct bond, or 0, S or NR 8 in which R 8 is hydrogen or C 1-6 alkyl
  • each of R 6 and R 6 a is C 1-6 alkyl, C 2-6 alkenyl, C 2-6
  • each of R 9 to R 15 is independently hydrogen, C 1-6 alkyl, optionally substituted phenyl or optionally substituted phenyl C 1-6 alkyl;
  • R 6 or R 6 a is bromine, chlorine, or CF 3 ,
  • a further preferred group R has the formula (IIa)
  • each of R x and R y is C 1-6 alkyl, or
  • R x and R y are linked together and R x represents -(Z) m - where m is 0 or 1 and Z is O, S or NR Z where R z is hydrogen or C 1-6 alkyl,
  • R y represents -(CH 2 ) q - where q is an integer of from 1 to 4, preferably 2 or 3.
  • each of R x and R is C 1-6 alkyl, preferably methyl, and the position of -CH 2 - is as defined in formula (IIa)
  • the compounds of formula I or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula I or its salt or solvate.
  • Examples of a pharmaceutically acceptable salt of a compound of formula I include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • conventional pharmaceutical acids for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • Examples of a pharmaceutically acceptable solvate of a compound of formula I include the hydrate.
  • the compounds of formula I have at least one asymmetric centre and therefore exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates.
  • the present invention also provides a process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (III):
  • R 1 ' and R 2 ' are R 1 and R 2 respectively as defined for formula (I), or each is a group or atom convertible to R 1 or R 2 respectively, and p is 1, 2 or 3. with a compound of formula R'CO.OH or an active derivative thereof, in which R' is R as defined for formula (I), or a group convertible to R, to form a compound of formula (I')
  • the compound of formula (III) may be coupled: a) with an acid chloride in the presence of an inorganic or organic base, b) with the acid in the presence of dicyclohexyl
  • carbodiimide N-dimethylaminopropyl-N'-ethyl carbodiimide or carbonyl diimidazole, c) with a mixed anhydride generated in situ from the acid and an alkyl (for example ethyl) chloroformate.
  • alkyl for example ethyl
  • R 1 ' and R 2 ' are preferably R 1 and R 2 respectively.
  • the compound R'CO.OH is typically of the formula (IId):
  • R 6 ' is R 6 and (R 6 a )' is R 6 a are as defined for formula (II), or a group or atom convertible to R 6 or R 6 a , the other variables being as defined for formula (II).
  • Conversions of substituents R 6 ' or (R 6 a )' on the aromatic group to obtain R 6 or R 6 a are generally known in the art
  • R 6 ' is preferably R 6 and (R 6 a )' is preferably R 6 a .
  • a preferred reagent is the equivalent acid halide of formula (lid) in which the halide is typically chlorine or bromine.
  • the compounds of formula (I) may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.
  • salts or solvates also form part of this invention.
  • the compounds of formula (I) and their intermediates exist in more than one stereoisomeric form and the processes of the invention produces mixtures thereof.
  • the individual enantiomers may be obtained by resolution of the compounds of formula (I) using an optically active acid such as tartaric acid or by resolution of the intermediate diamines of formula (III), for example by first protecting the NH group with an alkyl or benzyl chloroformate, resolving the compound thus formed using an active acid, such as
  • the compounds of formula (III) may be conveniently prepared by reduction of a compound of formula (IV):
  • the compounds of formula (IV) may be obtained by reaction of an N-carbethoxy-protected amino acid of formula (V): firstly with thionyl chloride, then with 3-pyrroline.
  • the overall reaction from (V) to (III) is illustrated in the following reaction scheme I:
  • the subsequent reduction preferably uses a mixed hydride such as LiAlH 4 in an inert solvent, preferably THF.
  • reaction with pyrroline may take place in a suitable solvent, such as methanol, typically at 0 to 50°C.
  • a suitable solvent such as methanol
  • the reduction of the resulting intermediate may be carried out with a mixed hydride such as NaBH 4 or NaCNBH 3 , preferably in a protic solvent, again conveniently methanol
  • the activity of the compounds of formula (I) in standard tests indicates that they are of potential therapeutic utility in the treatment of pain, hyponatraemic disease states, and cerebral ischaemia.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance
  • the present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • Such a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • compositions of known analgesic agents diuretics, or agents for treating cerebral ischaemia may be employed for example as in the preparation of compositions of known analgesic agents diuretics, or agents for treating cerebral ischaemia.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • the compound or composition of the invention may be any organic compound or composition of the invention.
  • composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration.
  • Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin,
  • sorbitol tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or
  • microcrystalline cellulose or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
  • compositions When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
  • the compounds of this invention may also be administered by a non-oral route.
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an
  • the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the present invention also provides a method for the
  • reaction mixture was stirred three hours at room temperature, washed with water, 5% NaOH solution and dried over Na 2 SO 4 ; the solvent was evaporated in vacuo to dryness to afford 1.6 g of the crude product which was dissolved in 40 ml of ethyl acetate and the solution brought to acidic pH with HCl/diethyl ether.
  • Example No. 1 Prepared as Example No. 1 from 0.50 g (2.77 mmoles) of 2-(3-pyrrolin-1-yl)methyl-3,3-dimethyl piperidine, 0.28 g (2.9 mmoles) of anhydrous potassium carbonate and 0.64 g (2.9 mmoles) of 3,4-dichlorophenylacetyl chloride in 25 ml of dry chloroform.
  • Example No. 1 Prepared as Example No. 1 from 0.50 g (2.77 mmoles) of 2-(3-pyrrolin-1-yl)methyl-3,3-dimethyl piperidine, 0.28 g (2.9 mmoles) of anhydrous potassium carbonate and 0.65 g (2.9 mmoles) of 4-trifluoromethylphenylacetyl chloride in 25 ml of dry chloroform.
  • the organic layer was dried over sudium sulphate and evaporated in vacuo to dryness.
  • the oily residue was taken up in 30 ml of ethyl acetate and brought to acidic pH with HCl/diethyl ether.
  • Example No. 1 Prepared as Example No. 1 from 1.44 g (6.73 mmoles) of 1-(3-pyrrolin-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline, 1.8 g (13.05 mmoles) of anhydrous potassium carbonate and 1.8 g (8.05 mmoles) of 3,4-dichlorophenylacetyl chloride in 50 ml of dry chloroform.
  • Example No. 1 Prepared as Example No. 1 from 1.18 g (4.76 mmoles) of 4-(3-pyrrolin-1-yl)methyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1.30 g (9.42 mmoles) of anhydrous potassium carbonate and 1.16 g (5.19 mmoles) of 3,4-dichlorophenylacetyl chloride in 50 ml of dry chloroform.
  • Example No. 1 Prepared as Example No. 1 from 1.8 g (10.8 mmoles) of (2S)- (3-pyrrolin-1-yl)methyl piperidine, 3.0 g (21.74 mmoles) of anhydrous potassium carbonate and 2.6 g (11.68 mmoles) of 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 50 ml of dry chloroform.
  • mice Male Charles River mice (Swiss Strain), 25-36g body weight, were used. Animals were allowed food and water ad libitum and were randomized into groups of 10 prior to
  • Test compounds were dissolved in either distilled water or distilled water plus 0.1 M AMS, and administered by the subcutaneous route in a final volume of 10 ml/Kg. Control animals received 10 ml/Kg of the
  • mice were injected intraperitoneally with p-phenylquinone, 2 mg/Kg at 37°C in a final volume of 10 mg/Kg.
  • mice were placed, in groups of 3, in a compartmented perspex box maintained at room temperature and were observed for a period of 8 min. During this period the number of abdominal writhing responses per animal were recorded where writhing consists of an intermittent
  • the degree of antinociceptive protection afforded by the test compound was determined as the mean number of writhing responses observed in the treated group (T) expressed as a percentage of the mean number of writhing responses in the control group (C) according to the following formula:
  • the reaction time of each animal was determined by focusing a beam of light onto the tail, eliciting a reflex withdrawal after a certain latency; only mice exhibiting a latency between 3-8 sec. were used subsequently in the evaluation of drug effects.
  • Test compounds were dissolved in either distilled water or distilled water plus 0.1 M AMS and administered by the subcutaneous route in a final volume of 10 ml/Kg. Control animals received 10 ml/kg of the appropriate vehicle alone. Following a pretreatment period of 30 min., the mice were again placed under the heat source and the reaction tine re-determined.
  • Percentage quantal protection was determined as the number of mice in which the reaction time was doubled compared to pretreatment values, expressed as a percentage of the total number of mice in the group.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé, ou solvate ou sel de celui-ci, répondant à la formule (I), dans laquelle (A) représente (II) ou (III); p est 1, 2 ou 3; ROC- représente un groupe acyle lié à l'atome d'azote du groupe (A) et dans lequel R contient un carbocycle ou hétérocycle aromatique et substitué ou non; R1 et R2 sont des substituants sur les mêmes atomes de carbone ou sur d'autres, et représentent, indépendamment l'un de l'autre, hydrogène ou alkyle C1-6; et Ra représente un carbocycle ou hétérocycle aromatique, fusionné et substitué ou non. Ledit composé est utilisé pour le traitement des douleurs, des maladies hyponatrémiques ou des accès ischémiques cérébraux.
PCT/EP1991/000659 1991-04-06 1991-04-06 Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques WO1992017467A1 (fr)

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PCT/EP1991/000659 WO1992017467A1 (fr) 1991-04-06 1991-04-06 Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques

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PCT/EP1991/000659 WO1992017467A1 (fr) 1991-04-06 1991-04-06 Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387924B2 (en) 1994-09-13 2002-05-14 G.D. Searle & Co. Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6420417B1 (en) 1994-09-13 2002-07-16 G. D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
US6458850B1 (en) 1998-12-23 2002-10-01 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications
US6458851B1 (en) 1998-12-23 2002-10-01 G. D. Searle, Llc Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications
US6462091B1 (en) 1998-12-23 2002-10-08 G.D. Searle & Co. Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications
US6489366B1 (en) 1998-12-23 2002-12-03 G. D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6562860B1 (en) 1998-12-23 2003-05-13 G. D. Searle & Co. Combinations of ileal bile acid transport inhibitors and bile acid sequestering agents for cardiovascular indications
US6569905B1 (en) 1998-12-23 2003-05-27 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications
US6586434B2 (en) 2000-03-10 2003-07-01 G.D. Searle, Llc Method for the preparation of tetrahydrobenzothiepines
US6638969B1 (en) 1998-12-23 2003-10-28 G.D. Searle, Llc Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular indications
US6642268B2 (en) 1994-09-13 2003-11-04 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors
US6740663B2 (en) 2001-11-02 2004-05-25 G.D. Searle, Llc Mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US6852753B2 (en) 2002-01-17 2005-02-08 Pharmacia Corporation Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
US8277807B2 (en) 2006-10-12 2012-10-02 Astex Therapeutics Limited Pharmaceutical combinations
US8383619B2 (en) 2008-04-11 2013-02-26 Astex Therapeutics Limited Pharmaceutical compounds
US8653084B2 (en) 2006-10-12 2014-02-18 Astex Therapeutics Ltd. Hydrobenzamide derivatives as inhibitors of Hsp90
US8779132B2 (en) 2006-10-12 2014-07-15 Astex Therapeutics Limited Pharmaceutical compounds
US8883790B2 (en) 2006-10-12 2014-11-11 Astex Therapeutics Limited Pharmaceutical combinations
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations
US9730912B2 (en) 2006-10-12 2017-08-15 Astex Therapeutics Limited Pharmaceutical compounds

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EP0370732A2 (fr) * 1988-11-24 1990-05-30 SmithKline Beecham Farmaceutici S.p.A. Composés hétérocycliques azotés
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EP0330467A1 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Composés hétérocycliques
EP0330469A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de la tétrahydroisoquinoléine
EP0361791A2 (fr) * 1988-09-26 1990-04-04 Smithkline Beecham Farmaceutici S.p.A. Composés azacycliques, utiles commes médicaments
EP0370732A2 (fr) * 1988-11-24 1990-05-30 SmithKline Beecham Farmaceutici S.p.A. Composés hétérocycliques azotés
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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6642268B2 (en) 1994-09-13 2003-11-04 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors
US6420417B1 (en) 1994-09-13 2002-07-16 G. D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
US6943189B2 (en) 1994-09-13 2005-09-13 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG CO-A reductase inhibitors
US6784201B2 (en) 1994-09-13 2004-08-31 G.D. Searle & Company Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6387924B2 (en) 1994-09-13 2002-05-14 G.D. Searle & Co. Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6462091B1 (en) 1998-12-23 2002-10-08 G.D. Searle & Co. Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications
US6562860B1 (en) 1998-12-23 2003-05-13 G. D. Searle & Co. Combinations of ileal bile acid transport inhibitors and bile acid sequestering agents for cardiovascular indications
US6569905B1 (en) 1998-12-23 2003-05-27 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications
US6638969B1 (en) 1998-12-23 2003-10-28 G.D. Searle, Llc Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular indications
US6489366B1 (en) 1998-12-23 2002-12-03 G. D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6458851B1 (en) 1998-12-23 2002-10-01 G. D. Searle, Llc Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications
US6890958B2 (en) 1998-12-23 2005-05-10 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6458850B1 (en) 1998-12-23 2002-10-01 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications
US6586434B2 (en) 2000-03-10 2003-07-01 G.D. Searle, Llc Method for the preparation of tetrahydrobenzothiepines
US6740663B2 (en) 2001-11-02 2004-05-25 G.D. Searle, Llc Mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US6852753B2 (en) 2002-01-17 2005-02-08 Pharmacia Corporation Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US8816087B2 (en) 2005-04-13 2014-08-26 Astex Therapeutics Limited Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US8101648B2 (en) 2005-04-13 2012-01-24 Astex Therapeutics, Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US9914719B2 (en) 2005-04-13 2018-03-13 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US8530469B2 (en) 2005-04-13 2013-09-10 Astex Therapeutics Ltd. Therapeutic combinations of hydroxybenzamide derivatives as inhibitors of HSP90
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