WO2001036411A1 - Sels cristallins de (s)-4-(3-[n-(2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-1,1-dimethylethyl) amino]-2-hydroxypropoxy) indole - Google Patents

Sels cristallins de (s)-4-(3-[n-(2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-1,1-dimethylethyl) amino]-2-hydroxypropoxy) indole Download PDF

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Publication number
WO2001036411A1
WO2001036411A1 PCT/US2000/028873 US0028873W WO0136411A1 WO 2001036411 A1 WO2001036411 A1 WO 2001036411A1 US 0028873 W US0028873 W US 0028873W WO 0136411 A1 WO0136411 A1 WO 0136411A1
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Prior art keywords
salt
para
ethanol
toluate
salts
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PCT/US2000/028873
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English (en)
Inventor
Julie Kay Bush
Jack Wayne Fisher
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Eli Lilly And Company
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Priority to AU15722/01A priority Critical patent/AU1572201A/en
Publication of WO2001036411A1 publication Critical patent/WO2001036411A1/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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Example #209 of Bell disclosed a non-crystalline hydrochloride salt of (S) -4- (3- [N- (2- [4- (5-carbamoyl-2- pyridyloxy) phenyl] -1, 1-dimethylethyl) amino] -2- hydroxypropoxy) indole, shown below, hereafter referred to as A-HCl:
  • A-HCl could be used as a pharmaceutical, it would be highly desired and advantageous to find a salt form of A which was highly crystalline, stable to heat, light and moisture and which could be reproducibly and efficiently prepared on a commercial scale.
  • the present invention relates to crystalline salts of (S)-4- (3AN- (2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-l,l- dimethylethyl ) amino] -2-hydroxypropoxy) indole (A) .
  • the present invention relates to crystalline benzoic acid and substituted benzoic acid salts of (S)-4-(3-[N- (2- [4- (5-carbamoyl-2-pyridyloxy)phenyl]-l,l- dimethylethyl) amino] -2-hydroxypropoxy) indole .
  • Substituted benzoic acid salts include al yl and certain hydroxy substituted benzoic acid salts.
  • the present invention relates to the crystalline para-hydroxybenzoate, para-toluate, benzoate, ortho-toluate, meta-toluate, para-toluate and glycolate salts of (S)-4- (3- [N- (2- [4- (5-carbamoyl-2- pyridyloxy) phenyl] -1 , 1-dimethylethyl) amino] -2- hydroxypropoxy) indole .
  • the para-toluate salt is preferred, the para-hydroxybenzoate is more preferred and the glycolate is most preferred.
  • the present invention further relates to a pharmaceutical formulation containing a crystalline salt of the present invention associated with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the present invention relates to methods for treating obesity and Type II Diabetes and to a method for agonizing the ⁇ 3 receptor which comprise administering to a mammal in need thereof a crystalline salt of the present invention.
  • the present invention is related to a crystalline salt of the present invention for treating obesity and Type II diabetes and for agonizing the ⁇ 3 receptor .
  • the present invention is further related to a process for preparing a crystalline salt of the present invention which comprises salifying (S) -4- (3- [N- (2- [4- (5-carbamoyl-2- pyridyloxy)phenyl] -1, 1-dimethylethyl) mino] -2- hydroxypropoxy) indole free base with an acid selected from the group consisting of: benzoic, ortho-toluic, meta-toluic, para-toluic, para-hydroxybenzoic and glycolic acid.
  • A is basic enough (pK a of secondary amine about 8.75) that it can react with many common salt forming acids. Therefore, when making a salt selection of A, it was expected that many crystalline salt forms would be available to choose from. However, numerous attempts to obtain a crystalline salt by reaction with many common salt-forming acids failed to give a crystalline solid.
  • Typical solvents for salt precipitation included ethanol, ethyl acetate, methanol, isopropanol, n-propanol, acetonitrile, methyl-t- butylether, isopropyl acetate, tetrahydrofuran, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide and mixtures thereof.
  • amorphous solids, gums and oils, or no precipitate was obtained by reaction with the following acids: hydrochloric, phosphoric, sulfuric, methanesulfonic, succinic, fumaric, 3-hydroxybenzoic, 1-naphthoic, acetic, citric, 4-anisic, D-tartaric, D,L-malic, -tartaric, -ascorbic, 2-acetoxybenzoic, 4-acetoxybenzoic, aceturic, adipic, 2-anisic, D-iso ascorbic, benzenesulfonic, camphorsulfonic, trans-cinnamic, formic, D-gluconic, -pyro glutamic, glutaric, hippuric, D,L-lactic, L-lactic, maleic, malonic, L-mandelic
  • Crystallinity of each of the salts was determined via examination of their respective XRD patterns.
  • the ability of a sample to produce an XRD pattern is indicative of crystalline material.
  • XRD patterns with high signal-to-noise ratios and flat baselines are indicative of highly crystalline materials.
  • XRD patterns were obtained on a Siemens D5000 X-ray powder diffractometer , equipped with a
  • the percent water was determined by Karl Fischer titration. Solubility was measured as the concentration of A in a saturated solution of purified water after 24 hours on a wrist action shaker. The studies indicated that the glycolate salt is non- hygroscopic ( ⁇ 1% water sorbed at 95% R.H.), water soluble (>1 mg of A/mL) , stable to heat ( ⁇ 1% TRS at 85°C) and light ( ⁇ 1% TRS in the light box) and displays a low ambient TRS profile ( ⁇ 1% TRS) .
  • para- hydroxybenzoate salt is non-hygroscopic (about 1.0% water sorbed at 85% R.H.), water soluble (>1 mg of A/mL), stable to heat ( ⁇ 1.5% TRS at 85°C) and light ( ⁇ 1.5% TRS in the light box) , and displays a low ambient total related substances (TRS) profile ( ⁇ 1.5% TRS) .
  • glycolate is especially preferred since it is most crystalline, is readily prepared from several solvent systems in high yield, has no tendency to retain significant amounts of organic solvents, and requires only minimal drying to remove residual solvents.
  • the glycolate salt may be prepared from A dissolved in punctilious ethanol, 3A ethanol, or methanol or from a mixture of ethanol and ethyl acetate. After salt and crystal formation, and filtration of the crystals, crystallization solvents may be removed upon minimal vacuum drying without compromising the crystallinity of the solid.
  • the crystalline para-toluate salt may be prepared from
  • crystallization solvents may be removed upon vacuum drying without compromising the crystallinity of the solid.
  • the para-hydroxybenzoate salt may be prepared from A dissolved in ethanol or a mixture of ethanol and heptane. Filtration and vacuum drying results in a crystalline solid containing only minimal residual solvent ( ⁇ 0.5%) .
  • the benzoate generally retained considerable crystallization solvent compared to the para-toluate, para- hydroxybenzoate and glycolate salts. Prolonged vacuum drying of the benzoate was required causing this salt to become substantially amorphous.
  • salts of the present invention may be prepared contiguous with the hydrolysis of a cyano precursor to A, as illustrated in Scheme 1 below.
  • X o-toluate, m-toluate p-toluate, benzoate, p-hydroxy-benzoate or glycolate
  • the process of Scheme 1 may be carried out via extraction of the hydrolysis product A with ethyl acetate followed by solvent exchange: for the para-hydroxybenzoate, to ethanol or to a mixture of ethanol and heptane; for the ortho-, meta- and para-toluates , to a mixture of ethanol and ethyl acetate; and for the glycolate, to ethanol/ethyl acetate mixtures, punctilious ethanol, methanol or 3A ethanol .
  • the acid addition salt may then be formed by reacting A, prepared as described above, with an equimolar or slight excess amount of acid. Typically, about one equivalent of acid is employed.
  • the salt normally precipitates out of solution within about one hour to ten days and can be isolated by filtration, or the solvent can be stripped off by conventional means .
  • reaction mixture was poured into a 250 ml beaker with 40 ml of ethyl acetate rinse and the excess peroxide quenched by addition of a solution of Na2SC>3 (840 mg, 6.66 mmol) in deionized H2O (32ml) .
  • the mixture was diluted with 24 ml of deionized H2O and stirred to obtain two clear layers.
  • the aqueous layer was separated and extracted again with 10 ml of ethyl acetate. The extracts were combined and washed with 2 x 20 ml of deionized H2O.
  • the extract was then concentrated on a roto-evaporator in vacuo to 13 g (about 10 ml ethyl acetate) .
  • the concentrate was diluted with 20 ml of 3A ethanol absolute and concentrated to 12 g (about 11 ml ethanol) .
  • ⁇ H NMR showed about 9.8% ethyl acetate by weight (8.6% by volume) .
  • Another 10 ml of 3A ethanol was added and the solution warmed to 38 2 C.
  • a solution of glycolic acid (0.505 g, 6.64 mmol) in 3A ethanol (13 ml) was added and the resulting crystallization (containing about 2.9% ethyl acetate) was stirred at 35-38 2 C for 30 minutes.
  • the quenched reaction mixture is transferred to a vessel containing 10 volumes of ethyl acetate and 15 volumes of deionized H2O at room temperature. This biphasic mixture is stirred for approximately 5-15 minutes and then allowed to separate until the upper layer is clear (10-15 minutes) . The resulting aqueous layer is then back extracted with 3 volumes ethyl acetate and the two organic layers are combined. Two additional washes are performed with 6 volumes (each) of deionized H2O. Following these extractions, the solution containing A is cooled to 5-10°C for 4-16 hours. Any additional aqueous layer formed is then removed and 5-6 weight % Silica Gel 60 is added to the solution for a 30 minute stir. Removal of the silica is accomplished through vacuum or pressure filtration and the cake rinsed with 2 volumes of ethyl acetate.
  • the filtrate is concentrated to approximately 3 volumes (based on theoretical yield A-HOCHoCO ⁇ H) under vacuum (200- 300mmHg) at a temperature of 30-40°C. Dilution with 4 volumes of 3A ethanol precedes a second distillation to approximately 3 volumes under conditions similar to the first part. After being cooled to 15-25°C, the concentrate is then reconstituted to 5 volumes (total based on theoretical A) using 3A ethanol .
  • the A in ethanol solution from above is heated to 35- 40°C.
  • To a separate vessel is added 4 volumes (based on theoretical A) of 3A ethanol and 1.0 equivalent of glycolic acid and the mixture is heated to 35-40°C.
  • This warm acid solution is then quickly added (1-10 minutes) to the preheated A solution.
  • the mixture is stirred at 35-40°C for 30-60 minutes or until crystals begin to form (seeding as necessary) .
  • the mixture is cooled to 20-25°C and stirred at this temperature for at least 2 hours.
  • the selective ⁇ 3 adrenergic receptor agonist nature of the salts of the present invention is determined in the functional agonist ⁇ 3 assay.
  • h ⁇ 2 DNA is expressed from a plasmid 57537 obtained from American Type Culture Collection
  • h ⁇ i and h ⁇ 3 adrenergic receptors are cloned from human genomic libraries using the polymerase chain reaction method with degenerate probes.
  • Full length receptors are cloned, expressed and sequenced to verify identity according to published sequences (h ⁇ : T. Frielle et . al . (1993) Mol . Pharm . ,
  • Rat ⁇ 3 receptor expressing CHO cell line is known in the art. Mol . Pharm . , 40:895-99, 1991. CHO cells are grown in 10% dialyzed FBS . /high glucose DMEM/0.1% proline.
  • Cell membranes are harvested from the above cell line using hypotonic 25 mM Hepes (pH 7.4), 1 mM EDTA, 20 ⁇ g/mL leupeptin, 1 mM PMSF buffer with scraping followed by differential centrifugation .
  • Membranes are incubated in 25 mM Tris (pH 7.6), 0.2% BSA, 2.6 mM Mg, 0.8 mM ATP, 0.1 mM GTP, 5 mM creatine phosphate, creatine kinase 50 U/mL, 0.2 mM IBMX at 32 °C.
  • a salt of the present invention is added and incubation continued for 15 minutes.
  • cAMP produced is assayed using a fluorescent tracer-immuno assay method.
  • Intact cell assays are performed using suspended cells removed from culture flasks by trypsin treatment. Cells are preincubated with 0.5 mM IBMX at 37°C. A salt of the present invention is added and incubation continued for 15 minutes. Incubation is stopped by heating suspension in boiling water. cAMP or cGMP in these and the soleus incubations are assayed by RIA (Amersham) .
  • the salts of the present invention are agonists of the ⁇ 3 receptor.
  • Isoproterenol is accepted in the art as a non- selective ⁇ 3 agonist and is widely used as a comparator in evaluating the activity of compounds. See Trends in Pharm . Sci . 15 : 3 (1994) .
  • the salts of the present invention demonstrate at least 30%, preferably 50% and most preferably over 85% of isoproterenol ' s response at a single dose of 50 ⁇ mol.
  • Dose response titrations on the salts of the present invention reveal EC 50 values of ⁇ 10 UM, preferably ⁇ lmmol .
  • dose titration furnishes an EC 50 for isoproterenol of 1. l ⁇ O .5 ⁇ M.
  • dose titration experiments indicate that greatly reduced or no receptor stimulation is observed with the salts of the present invention. This is defined by measuring the intrinsic activity (maximal response achieved) as compared to isoproterenol.
  • the salts of the present invention are selective ⁇ 3 receptor agonists and have an intrinsic activity of ⁇ 3% of isoproterenol ' s response.
  • the salts of the present invention are selective ⁇ 3 adrenergic receptor agonists.
  • the salts of the present invention are useful in treating conditions in a mammal in which the ⁇ 3 receptor has been demonstrated to play a role.
  • mammals include livestock and companion animals.
  • the preferred mammal of treatment is a human.
  • Livestock animals are animals raised for food production. Ruminants or "cud-chewing" animals such as cows, bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock.
  • Other examples of livestock include pigs and avians (poultry) such as chickens, ducks, turkeys and geese.
  • livestock include fish, shell, fish and crustaceans raised in aquaculture.
  • ⁇ 3 receptor e.g., emu, rheas or ostriches
  • Companion animals are those traditionally viewed as pets including cats, dogs, and birds .
  • gastrointestinal disorders such as gastrointestinal motility, asthma, and depression.
  • the salts of the present invention are useful in the treatment of inflammatory bowel disease (Crohn's disease or ulcerative colitis), irritable bowel syndrome, non-specific diarrhea dumping syndrome, asthma, and depression.
  • the salts of the present invention are useful for increasing weight gain and/or improving the feed utilization efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate.
  • compositions of the present invention are preferably formulated prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a salt of the present invention and one or more pharmaceutically acceptable carriers, diluents or excipients .
  • the present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients .
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to about
  • the therapeutic dosage administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore, the above dosage ranges are not intended to limit the scope of the invention in any way.
  • the salts of the present invention can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal routes. For all indications, a typical daily dose will contain from about 0.05 mg/kg to about 20 mg/kg of the active compound of this invention.
  • Preferred daily doses will be about 0.1 to about 10 mg/kg, ideally about 0.1 to about 5 mg/kg.
  • a typical dosage is about 1 to about 500 ⁇ g compound per cm ⁇ of an affected tissue.
  • the applied amount of compound will range from about 30 to about 300 ⁇ g/cm ⁇ , more preferably, from about 50 to about 200 ⁇ g/cm ⁇ , and, most preferably, from about 60 to about 100 ⁇ g/c ⁇ .2.
  • the following formulation example is illustrative only and is not intended to limit the scope of the invention in any way .
  • Hard gelatin capsules are prepared using the following ingredients:
  • Quantity (mg/capsule) Salt of the present invention 25 starch, dried 425 magnesium stearate 10
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • a salt of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which a salt of the present invention is useful.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a salt of the present invention.
  • a pharmaceutical unit dosage form containing such other drugs in addition to the salt of the present invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a salt of the present invention. Examples of other active ingredients that may be combined with a salt of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:
  • insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like) , and compounds disclosed in W097/27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;
  • sulfonylureas such as tolbutamide and glipizide
  • alpha-glucosidase inhibitors such as acarbose
  • cholesterol lowering agents such as i. HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), ii . sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran) , iii. nicotinyl alcohol nicotinic acid or a salt thereof, iv.
  • HMG-CoA reductase inhibitors lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins
  • sequestrants cholesterolestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran
  • nicotinyl alcohol nicotinic acid or a salt thereof iv.
  • proliferator-activater receptor a agonists such as fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate) , v. inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA: cholesterol acyltransferase) inhibitors for example melinamide, vi . probucol, vii . vitamin E, and viii. thyromimetics;
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, and other ⁇ 3 adrenergic receptor agonists
  • Y antagonists e.g. neuropeptide Y5
  • neuropeptide Y5 e.g. neuropeptide Y5
  • WO 97/19682 WO 97/20820, WO 97/20821, WO
  • Glaxo Glaxo; (j) PPAR ⁇ antagonists as described in W097/10813; and (k) serotonin reuptake inhibitors such as fluoxetine and sertraline .

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Diabetes (AREA)
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Abstract

La présente invention concerne des sels cristallins de (S)-4-(3-[N-(2-[4-(5-carbamoyl-2-pyridyloxy)phényl]-1,1-diméthyléthyl)amino]-2-hydroxypropoxy)indole, une formulation pharmaceutique contenant ces sels, un procédé de préparation de ces sels, des méthodes de traitement de l'obésité et du diabète de type II à l'aide de ce sel et une méthode utilisant ces sels qui a des effets agonistes sur le récepteur β3.
PCT/US2000/028873 1999-11-15 2000-11-02 Sels cristallins de (s)-4-(3-[n-(2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-1,1-dimethylethyl) amino]-2-hydroxypropoxy) indole WO2001036411A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15722/01A AU1572201A (en) 1999-11-15 2000-11-02 Crystalline salts of (S)-4-(3-(N-(2-(4-(5-carbamoyl-2-pyridyloxy)phenyl)-1,1- dimethylethyl)amino)-2-hydroxypropoxy)indole

Applications Claiming Priority (4)

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US16545099P 1999-11-15 1999-11-15
US16574199P 1999-11-15 1999-11-15
US60/165,741 1999-11-15
US60/165,450 1999-11-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090140A1 (fr) 2007-01-22 2008-07-31 4Sc Ag Aryloxypropanolamines, procédé de fabrication de celles-ci et utilisation d'aryloxypropanolamines comme médicaments

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0764640A1 (fr) * 1995-09-21 1997-03-26 Eli Lilly And Company Agonistes adrénergiques bêta-3 spécifiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0764640A1 (fr) * 1995-09-21 1997-03-26 Eli Lilly And Company Agonistes adrénergiques bêta-3 spécifiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090140A1 (fr) 2007-01-22 2008-07-31 4Sc Ag Aryloxypropanolamines, procédé de fabrication de celles-ci et utilisation d'aryloxypropanolamines comme médicaments

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