Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
  • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • 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
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T428/00—Stock material or miscellaneous articles
  • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
  • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

• the present invention relates to a novel carbamate stereoisomer, to a process for preparing the carbamate stereoisomer, to a pharmaceutical composition comprising the carbamate stereoisomer and to the use of the carbamate stereoisomer in therapy, in particular in the treatment of bronchoconstriction associated with reversible obstructive airways diseases including but not limited to asthma, cystic fibrosis and chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.
• reversible obstructive airways diseases including but not limited to asthma, cystic fibrosis and chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.
• Patients suffering from bronchoconstriction associated with reversible obstructive airways diseases are generally treated using a bronchodilator, to relax the bronchial smooth muscle.
• Bronchodilators in use today generally fall into two classes, the ⁇ 2 -selective adrenoceptor agonists, such as albuterol (salbutamol), salmeterol and formoterol, and the muscarinic receptor antagonists, such as ipratropium and tiatropium.
• the ⁇ 2 -selective adrenoceptor agonists such as albuterol (salbutamol), salmeterol and formoterol
• muscarinic receptor antagonists such as ipratropium and tiatropium.
• ⁇ 2-Selective adrenoceptor agonists may cause adverse effects, and these may in part be due to activation of the ⁇ i -adrenoceptor.
• the selectivity of an agonist for the ⁇ 2 - adrenoceptor receptor is therefore very important, because it limits the dose that can be given and so affects the magnitude of bronchodilations and the frequency of dosing.
• a long duration of action is important to patients, not only to minimize the time spent taking the drug, but also to avoid having to take the drug during inconvenient times, for example at work, school or during the night.
• Formoterol has a particular advantage that it also has a fast onset of action.
• formoterol is extremely potent, which makes it very difficult to formulate, especially for administration using a metered dose inhaler in a manner that results in uniform drug delivery via aerosol dose after dose (i.e., dose content uniformity).
• it is unstable in aqueous solution, which means that solutions for administration using a nebuliser have to be kept refrigerated for a majority of their post-manufacture shelf life.
• Formoterol is one of a group of ⁇ -aminomethylbenzyl alcohol derivatives for which patent applications were filed during the early nineteen seventies, for example US 3,994,974.
• the invention of this compound built on earlier work by others, such as described in US 3,657,319 (equivalent to BE 765,986, cited in US 3,994,974). Perhaps because of the difficulties associated with formulating the compound, it took a long time to be commercialized.
• the compound contains two chiral centers, and hence is capable of existing and being isolated in four stereoisomeric forms.
• the compound was firstly commercialized as a racemic mixture of the active (R,R)- and inactive (S, S)- isomers, in a dry powder formulation, then more recently as the active (R,R)-isomer in a nebuliser solution. It is also known, for example from US 6,303,145, that the (S,R) isomer of formoterol is active. However, like the (R,R)-isomer, this compound is unstable at ambient temperature in aqueous solution and hence nebuliser solutions would need to be stored refrigerated.
• the present invention provides a compound of formula (I)
• the compound of formula (I) may also be referred to by the chemical name methyl [2-hydroxy-5-[(lS)-l-hydroxy-2-[[(lR)-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]- phenyl] carbamate, which is indexed in Chemical Abstracts as carbamic acid, [2-hydroxy-5- [(lS)-l-hydroxy-2-[[(lR)-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]-phenyl]-, methyl ester.
• the isomer of formula (I) has been found to possess particularly advantageous properties. In particular, it possesses good, but not very high affinity for the ⁇ 2-adrenoceptor, high selectivity for the ⁇ 2- over the ⁇ l- adrenoceptor, a long duration of action and good stability in aqueous solution at ambient temperature.
• the figure shows the effects of methyl [2-hydroxy-5-[(l S)-I -hydroxy-2-[[(lR)-2- (4-hydroxyphenyl)-l-methylethyl]amino]ethyl]-phenyl] carbamate on acetylcholine effects on airway resistance.
• the compound provided by the present invention is an isomer.
• This isomer may exist and be isolated in enantiomerically pure form, or in admixture with one or more of its other isomers.
• the present invention provides the isomer in any mixture of isomers other than a racemic mixture, which is described in Example 6 of US 3,657,319.
• the isomer is substantially free of the (R 5 R)- enantiomer, which can exhibit a different potency, resulting in significant variations in the potency of admixtures. It may exist as a 1:1 diastereomeric mixture with the (R,S)-isomer, but is most preferably enantiomerically pure (i.e.
• the isomer may comprise at least 50% by weight of all carbamic acid, [2-hydroxy-5-[l- hydroxy-2-[[(2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-, methyl ester present, preferably at least 75%, such as at least 90%, at least 95% or at least 99%.
• the term "pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, relatively non-toxic acid, including inorganic acids and organic acids. Suitable acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carbonic, citric, dihydrogenphosphoric, ethenesulfonic, fumaric, galactunoric, gluconic, glucuronic, glutamic, hydrobromic, hydrochloric, hydriodic, isobutyric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, monohydrogencarbonic, monohydrogenphosphoric, monohydrogensulfuric, mucic, nitric, pamoic, pantothenic, phosphoric, phthalic, propionic, suberic, succinic, sulfuric, tartaric, toluenesulfonic, including />-toluenes
• salts of other relatively non-toxic compounds that possess acidic character including amino acids, such as arginine and the like, and other compounds, such as aspirin, ibuprofen, saccharin, and the like.
• Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. As solids, salts can exist in crystalline or amorphous modifications.
• An example of an acid addition salt is the D-tartrate salt.
• the compounds of the present invention may also be prepared in deuterated form, i.e., in which one or more hydrogen atoms, for example on the methoxycarbonyl group, are replaced with deuterium.
• the methyl group in the methoxycarbonyl group in the compound of formula (I) may be replaced with a fluoromethyl group (i.e. a group in which one, two or three of the methyl hydrogen atoms is replaced with a fluorine atom).
• a fluoromethyl group i.e. a group in which one, two or three of the methyl hydrogen atoms is replaced with a fluorine atom.
• Such compounds may be prepared by a process analogous to that described herein for the preparation of the carbamate isomer.
• the carbamate isomer and its pharmaceutically acceptable salts can be prepared by a process, which comprises reacting a compound of general formula (II)
• the protecting groups may be any suitable protecting group, for example as described in Green et al, "Protective Groups in Organic Chemistry," (Wiley, 2 nd ed. 1991).
• hydroxyl protecting groups include aralkyl groups, such as benzyl, and trialkylsilyl groups, such as t-butyl-dimethylsilyl (TBDMS).
• benzylic amine protecting group examples include benzyl groups optionally substituted on the benzene ring by one or more, for example 1, 2 or 3 optional substituents, for example selected from halo, (1-4C) alkyl and (l-4C)alkoxy; for example unsubstituted benzyl.
• reaction between the compounds of formula (II) and (III) is conveniently performed by melting the two compounds together, for example by heating in the range of from 50 to 130 0 C, such as about 75 0 C.
• Any protecting groups represented by P 1 , P 2 and P 3 may be removed using a conventional procedure.
• a benzyl group can be removed by catalytic hydrogenation in the presence of palladium on carbon, and a trialkylsilyl group by treatment with tetrabutylammonium fluoride.
• Z represents a leaving atom or group, such as a bromine atom, with a base, for example an alkali metal carbonate such as potassium carbonate.
• the hydroxyl group may then be protected, for example by reaction with a trialkylsilyl halide, such as t-butyldimethylsilyl chloride.
• a trialkylsilyl halide such as t-butyldimethylsilyl chloride.
• the present invention provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein, together with a pharmaceutically acceptable carrier.
• the pharmaceutical composition according to the invention may be adapted for administration to patients by any convenient route, such as by oral, mucosal (e.g. nasal, sublingual, vaginal, buccal or rectal), parenteral or transdermal administration. It may be in the form of, for example, a solution, suspension, powder, tablet, aerosol formulation, lozenge, suppository, emulsion, hard or soft gelatin capsule or syrup.
• the compound of formula (I) may be dissolved in the carrier, diluted by the carrier or supported by the carrier.
• the carrier may be a support for the compound of formula (I), such as a capsule, sachet, paper or other pharmaceutical container.
• the pharmaceutical composition is an aqueous solution adapted for administration using a nebuliser.
• the aqueous formulation may be isotonic and buffered at an optimal pH for stability.
• the aqueous formulation for nebulization could also be a suspension of nanoparticles or a micronized suspension of free base or an insoluble salt or a cyclodextrin adduct.
• the pharmaceutical composition is an aerosol formulation adapted for administration using a metered dose inhaler, the aerosol formulation comprising the acetamide isomer in crystalline form and a propellant or in solution with an appropriate propellant, combination of propellants or combination of propellant(s) and an acceptable co- solvent or other solubilizing agent.
• the propellant may be any suitable propellant used in aerosol formulations, for example, a hydrofluoroalkane (HFA), such as 1,1,1,2-tetrafluoroethane (HFAl 34) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227) or a combination of propellants. HFA134 is preferred.
• the propellant may comprise at least 90% by weight of the aerosol formulation, which may also include, inter alia, inert gases to aide in aerosol formation.
• the aerosol formulation may further comprise a surfactant.
• the surfactant serves to stabilize and disperse the carbamate isomer in a suspension, and may also serve as a valve lubricant in the metered dose inhaler. It may be any suitable surfactant used in aerosol formulations. Examples of surfactants used in aerosol formulations are described in United States patent number 5,225,183, which is hereby incorporated by reference. A preferred surfactant is oleic acid. The surfactant, when present, may generally be present in an amount of from 1 : 100 to 1: 10 surfactant: carbamate isomer, preferably about 1 :20.
• the aerosol formulation may further comprise a co-solvent.
• a function of the co- solvent in the aerosol formulation is to facilitate dissolution of the surfactant, which may have poor solubility in the propellant. It may be any suitable carrier used in aerosol formulations.
• a co-solvent such as glycerol or ethanol may be used.
• a preferred co-solvent is ethanol, especially dehydrated ethanol. The content of ethanol may conveniently be up to 30% by weight of the aerosol formulation, such as from 2 to 6%.
• Metered dose inhalers typically comprise a canister containing an aerosol formulation, a metering valve, a valve stem and an actuator which accepts the valve stem.
• a patient depresses the canister into the actuator and inhales, causing a dose of the formulation to be administered and taken into the patient's lungs.
• the present invention provides a metered dose inhaler comprising a canister containing an aerosol formulation as described herein, a metering valve and an actuator.
• the interior surface of the canister is coated, for example with a protective polymer, or otherwise treated to minimize chemical or physical interaction between the formulation and the canister.
• the inhaler preferably has an aperture with a diameter in the range of from 0.2 to 0.60 mm.
• the pharmaceutical composition is in the form of a dry powder suitable for inhalation or insufflation.
• the composition may comprise carbamate isomer crystals alone (e.g. having a mass median aerodynamic diameter of from 1 to 10 microns, preferably from 2 to 7 microns), or carbamate isomer blended, co-precipitated, co- crystallized or spray dried together with a suitable pharmaceutically acceptable carrier or carriers.
• Suitable pharmaceutically acceptable carriers include, without limitation, solvates of one or more natural or synthetic carbohydrates, such as a monosaccharides, disaccharides, trisaccharides, oligosaccharides, polysaccharides, polyols, amino acids and proteins, and/or in the form of their pharmaceutically acceptable esters, acetals, or salts (where such derivatives exist).
• the carrier is preferably lactose, more preferably lactose monohydrate.
• the dry powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
• the dry powder composition may be presented in multi dose form metered with the aid of an inhaler or insufflator, or pre-metered into discrete doses within the device for serial administrations.
• dry powder formulations are administered using multidose dry powder inhalers.
• the present invention therefore also provides a multidose dry powder inhaler, comprising a dry powder reservoir containing a dry powder aerosol formulation of carbamate isomer as described hereinabove, and a metering chamber.
• the compound of formula (I) according to the present invention may be coadministered with one of more other active ingredients, for example selected from steroids, such as beclomethasone, triamcinolone, funisolide, mometasone, budesonide or fluticasone, muscarinic receptor antagonists, such as ipratropium, tiatropium, or glycopyrrolate.
• the pharmaceutical composition in accordance with the present invention may further comprise a steroid and/or a muscarinic receptor antagonist and/or a controller agent or bronchodilator with a novel mechanism.
• the pharmaceutical composition in accordance with the present invention may further comprise anti-inflammatory agents such as inhibitors of tumor necrosis factor alpha (TNF ⁇ ), dipeptidyl peptidase IV, and antibodies to pro-inflammatory interleukins such as IL4 and ILl 3.
• anti-inflammatory agents such as inhibitors of tumor necrosis factor alpha (TNF ⁇ ), dipeptidyl peptidase IV, and antibodies to pro-inflammatory interleukins such as IL4 and ILl 3.
• the pharmaceutical composition in accordance with the present invention may further comprise mucolytic agents such as cromoglycate, acetylcysteine, arginine, or 2-mercaptoethanesulphonate.
• mucolytic agents such as cromoglycate, acetylcysteine, arginine, or 2-mercaptoethanesulphonate.
• the present invention provides a method of treating bronchoconstrictive disease, which comprises administering to a patient in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the bronchoconstrictive disease may be, for example, chronic obstructive pulmonary disease (such as emphysema or bronchitis), cystic fibrosis, or asthma.
• chronic obstructive pulmonary disease such as emphysema or bronchitis
• cystic fibrosis or asthma.
• the patient may be a human or a non-human mammal, such as a dog, cat, horse, cow, sheep or pig.
• a human Preferably, the patient is a human.
• a dose administered to a human may contain from 75 to 5,000 ⁇ g of the carbamate isomer (calculated as the free base). The dose may be administered, for example, once or twice per day.
• the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy.
• the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the treatment of chronic obstructive pulmonary disease, or for use as a bronchodilator.
• THF refers to tetrahydrofuran
• EtOAc refers to ethyl acetate
• Et 2 O refers to diethyl ether.
• step A (lS)-l-(3-nitro-4-benzyloxyphenyl)-2-bromoethan-l-ol
• step B) (lS)-l-(3-amino-4-benzyloxyphenyl)-2-bromoethan-l-ol
• Step F) [(lR)-N-Benzyl-2-(4-t-butyldimethylsilyloxyphenyl)-l- methy lethyl] amine
• Step G Carbamic acid, [2-benzyIoxy-5-[QS)-l-hydroxy-2-[[(lR)-2-(4-t- butyldimethylsilyloxyphenyl)-l-methylethyl]-N-benzylamino]ethyl]phenyl]-, methyl ester
• Step H Carbamic acid, [2-benzyloxy-5-[(lS)-l-hydroxy-2-[[(lR)-2-(4- hydroxyphenyl)-l-methylethyl]-N-benzylamino]-ethyl]phenyl]-, methyl ester
• the crude material was purified by silica gel column chromatography (2 x 200 g columns), packed in and eluted with 1 : 1 EtOAc/hexanes [the crude product was loaded onto the column as a solution in CH 2 Cl 2 ]. Fractions containing the purified product were combined and concentrated to give an oil. A total of 2.6 g of starting material was deblocked to give a total of 1.2 g (56%) of the title compound after purification.
• Step I Carbamic acid, [2-hydroxy-5-[(lS)-l-hydroxy-2-[[(lR)-2-(4- hydroxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-, methyl ester
• Step J) Carbamic acid, [2-hydroxy-5-[(lS)-l-hydroxy-2-[[(lR)-2-(4- hydroxyphenyl)-l-methylethyl]amino]ethyl]-phenyl]-, methyl ester, (2S,3S)-2,3- dihydroxybutanedioate (1:1) (salt)
• the affinity of a test compound for adrenergic ⁇ i and ⁇ 2 receptors is investigated by evaluating the ability of the compound to displace specific binding of [ 125 I]-cyanopidolol or [ 3 H]-CGP- 12177 at human recombinant ⁇ i and ⁇ 2 receptors, respectively (expressed in CHO cells).
• the IC50 is defined as the concentration that inhibits 50% of specific binding of the radioligand.
• the K 1 is calculated from the IC50 and the known K D of the radioligand (Cheng and Prusoff s equation).
• Example 1 the compound of Example 1 was found to afford a K 1 of >10 ⁇ M with only 44% inhibition of specific binding at a concentration of 20 ⁇ M for the ⁇ i receptor and 0.99 ⁇ M for the ⁇ 2 receptor.
• the ⁇ i/ ⁇ 2 binding ratio was found to be >10.
• the intrinsic activity of a test compound is assessed by evaluating its ability to increase cAMP production from human recombinant ⁇ 2 receptors expressed in CHO cells. Data are expressed as % response relative to a procaterol-induced cAMP increase.
• Example 1 The compound of Example 1 was found to have an intrinsic activity of 79%.
• arformoterol and (S,R)-formoterol were found to have intrinsic activities of 98% and 91% respectively.
• Solution A is prepared from ⁇ 30 mg of the test compound in 150 mL of 0.005 M citrate buffer, pH 5.0 ( ⁇ 0.2 mg/mL).
• Solution B is prepared as follows: approximately 30 mL aliquot of Solution A is transferred to a separated container and the pH of the solution is adjusted to pH 3.0 with 1 N HCl ( ⁇ 0.2 mL).
• Solution C is prepared as follows: approximately 30 mL aliquot of Solution A is transferred to a separated container and the pH of the solution is adjusted to pH -8.0 with 1 N NaOH ( ⁇ 0.2 mL).
• Example 2 At pH 3 or 5, the compound of Example 1 was found to be very stable for at least 12 weeks when stored at 30 C. [0078] Example 2:
• K 1 values were established using recombinant human transporters expressed in Rexl ⁇ cells ( ⁇ l) or CHO cells ( ⁇ 2).
• the K 1 for arformoterol at ⁇ 2 was 3.76 nM.
• the ⁇ i functional activity EC 50 is the concentration that resulted in a 50% increase in atrial rate relative to 50 nM isoproterenol response in atria isolated from Dunkin Hartley Guinea pigs.
• the values in parentheses are the % increase in atrial rate at a concentration of 30 ⁇ M.
• ⁇ 2 functional activity EC50 is the concentration that resulted in a 50% relaxation of spontaneous tone relative to a response induced by 15 nM isoproterenol in trachea isolated from Dunkin Hartley Guinea pigs.
• the intrinsic activity describes the increase in cAMP relative to the procaterol response in CHO cells expressing the human ⁇ 2 adrenoceptor.
• ⁇ l ⁇ l adrenoceptors
• SERT 5-HT transporter
• NT not tested.
• compounds were evaluated for their ability to inhibit specific binding or activity (CYP450s) in a panel of 72 assays. The targets listed are only those where a >50% specific binding or activity was determined.
• Figure 1 shows the effects of the compound of formula I, methyl [2-hydroxy-5-[( IS)-I- hydroxy-2-[[( 1 R)-2-(4-hydroxyphenyl)- 1 -methylethyl]amino]ethyl]-phenyl] carbamate, compound of Formula 1

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