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WO2009151613A1 - Dérivés d’oxybutynine - Google Patents

Dérivés d’oxybutynine Download PDF

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Publication number
WO2009151613A1
WO2009151613A1 PCT/US2009/003512 US2009003512W WO2009151613A1 WO 2009151613 A1 WO2009151613 A1 WO 2009151613A1 US 2009003512 W US2009003512 W US 2009003512W WO 2009151613 A1 WO2009151613 A1 WO 2009151613A1
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WO
WIPO (PCT)
Prior art keywords
compound
composition
compounds
disease
deuterium atom
Prior art date
Application number
PCT/US2009/003512
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English (en)
Inventor
Julie F. Liu
Original Assignee
Concert Pharmaceuticals, Inc.
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 Concert Pharmaceuticals, Inc. filed Critical Concert Pharmaceuticals, Inc.
Publication of WO2009151613A1 publication Critical patent/WO2009151613A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Oxybutynin also known as 2-cyclohexyl-2-phenylglycolic acid 4- diethylaminobut-2-ynyl ester hydrochloride, competitively antagonizes the Ml, M2, and M3 subtypes of the muscarinic acetylcholine receptor on smooth muscle and exerts a direct anti-spasmodic effect on smooth muscle.
  • Oxybutynin is currently indicated for the relief of symptoms resulting from urinary incontinence and/or overactive bladder.
  • the metabolic products of oxybutynin include desethyloxybutynin, known to have pharmacological activity comparable to parent in vitro (http://www.fda.gov/cder/pediatric/labels/Oxybutynin.pdf). Much of the adverse effects associated with the use of oxybutynin can be attributed to the desethyloxybutynin metabolite. Plasma levels of this active metabolite reach 5- 10- fold that of the parent.
  • oxybutynin Common adverse events associated with oxybutynin include, but are not limited to, dry mouth, dizziness, constipation, somnolence, impaired urination, nausea, blurred vision, dyspepsia, abdominal pain and headache. [4] Despite the beneficial activity of oxybutynin, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.
  • This invention relates to novel compounds that are phenylglycolic acid derivatives, and pharmaceutically acceptable salts thereof. More specifically, the invention relates to novel phenylglycolic acid compounds that are derivatives of the muscarinic acetylcholine receptor antagonist, oxybutynin.
  • This invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are treated by administering muscarinic acetylcholine receptor antagonists, such as oxybutynin.
  • the invention also relates to the use of one or more of the disclosed compounds as reagents in analytical studies involving oxybutynin.
  • ameliorate and “treat” are used interchangeably and include both therapeutic treatment and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • a disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • deuterium the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015%
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • isotopologue refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.
  • compound when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules.
  • the relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.
  • the invention also provides salts, of the compounds of the invention.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1 ,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylene sulfonate, phenylacetate, pheny
  • the compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • substantially free of other stereoisomers means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present.
  • stable compounds refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
  • D and “d” both refer to deuterium.
  • Stepoisomer refers to both enantiomers and diastereomers.
  • Tet and t- each refer to tertiary.
  • US refers to the United States of America.
  • variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R 1 , R 2 , R 3 , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.
  • R 1 is -CH 2 CH 3 , wherein one or more hydrogen atoms is optionally replaced with a deuterium atom;
  • R 2 is selected from H and -CH 2 CH 3 , wherein one or more hydrogen atoms is optionally replaced with a deuterium atom;
  • R 3 and R 4 are independently selected from H and D; and at least one R variable is or contains deuterium.
  • R 1 is -CD 2 CD 3
  • R 2 is -CD 2 CD 3 or H
  • at least one of R 3 and R 4 is D
  • at least one of R 1 and R 2 contains deuterium.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 , more specifically R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 ;
  • R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 , more specifically R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 ; or e) R 3 and R 4 are the same, more specifically R 3 and R 4 are deuterium.
  • a compound of Formula I has the features set forth in two or more of c) through e), above.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 , more specifically R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 ;
  • R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 , more specifically R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 ; or h) R and R 4 are the same, more specifically R 3 and R 4 are deuterium.
  • a compound of Formula I has the features set forth in two or more of c) through e), above.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 and R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 .
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 and R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 .
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 and R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 .
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 and R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 .
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3 and R 3 and R 4 are the same.
  • R 3 and R 4 are deuterium.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3 and R 3 and R 4 are the same.
  • R 3 and R 4 are deuterium.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3
  • R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3
  • R 3 and R 4 are the same.
  • R 3 and R 4 are deuterium.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3
  • R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3
  • R 3 and R 4 are the same.
  • R 3 and R 4 are deuterium.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 , -CH 2 CD 3 and -CD 2 CD 3
  • R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3
  • R 3 and R 4 are the same.
  • R and R 4 are deuterium.
  • R 1 is selected from -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3
  • R 2 is selected from H, -CH 2 CH 3 , -CD 2 CH 3 and -CD 2 CD 3
  • R 3 and R 4 are the same.
  • R 3 and R 4 are deuterium.
  • the compound of Formula (I) is selected from any one of the compounds set forth in Table 1 (below): Table 1 : Specific Examples of Compounds of Formula (I)
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • the synthesis of compounds of Formula (I) can be readily achieved by synthetic chemists of ordinary skill. Relevant procedures and intermediates are disclosed, for instance in US 3176019; WO 2000023414; and Lindeke, B et al., Biomedical Mass Spectrometry, 1981, 8(10):506-13.
  • Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.
  • the known alkyne XI may be treated with an optional ly-deuterated formaldehyde XII and an optionally-deuterated amine XIII to yield a compound of Formula I.
  • the amine XIII, wherein each of R 1 and R 2 is -CD 2 CH 3 may be synthesized by the reduction of diacetyl amine with LiAlD 4 according to the procedure described in Boulanger, Y et al., J Label Comp Radiopharm, 1981, 18(8): 1 197.
  • the amine XIII, wherein each of R 1 and R 2 is -CH 2 CD 3 and that where each of R 1 and R 2 is -CD 2 CD 3 are both commercially available.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al., Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
  • the invention also provides pyrogen-free pharmaceutical compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., including any of the formulae herein
  • the carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphate
  • the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water- Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
  • the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
  • composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
  • a composition of this invention further comprises a second therapeutic agent.
  • the second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as oxybutynin.
  • Such agents include those indicated as being useful in combination with oxybutynin, including but not limited to, those described in WO 2004084879,
  • the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from urinary incontinence, overactive bladder, benign prostatic hyperplasia, irritable bowel syndrome, pain, cystitis, and respiratory disorders.
  • a disease or condition selected from urinary incontinence, overactive bladder, benign prostatic hyperplasia, irritable bowel syndrome, pain, cystitis, and respiratory disorders.
  • the second therapeutic agent is selected from gabapentin, pregabalin, gabapentin enacarbil, and desloratadine.
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another.
  • associated with one another means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • the compound of the present invention is present in an effective amount.
  • the term "effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • the interrelationship of dosages for animals and humans is described in Freireich et al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.
  • an effective amount of a compound of this invention can range from about 0.025 to 300 mg per treatment. In more specific embodiments the range is from about 0.25 to 150 mg or from 0.5 to 60 mg or most specifically from 2.5 to 30 mg per treatment. Treatment typically is administered from once daily to four times daily.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for oxybutynin.
  • an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70% and 100% of the normal monotherapeutic dose.
  • the normal monotherapeutic dosages of these second therapeutic agents are well known in the art.
  • the invention provides a method of blocking the activity of a muscarinic acetylcholine receptor in a cell, comprising contacting a cell with one or more compounds of Formula I herein.
  • the invention provides a method of treating a disease that is beneficially treated by a muscarinic acetylcholine receptor antagonist, such as oxybutynin, in a patient in need thereof comprising the step of administering to said patient an effective amount of a compound or a composition of this invention.
  • a muscarinic acetylcholine receptor antagonist such as oxybutynin
  • Such diseases include, but are not limited to, urinary incontinence, overactive bladder, benign prostatic hyperplasia, irritable bowel syndrome, pain, cystitis and respiratory disorders.
  • the respiratory disorder is associated with the production of mucus glycoprotein, associated with a skin disorder, or associated with allergic conjunctivitis.
  • the method of this invention is used to treat a patient suffering from a disease or condition selected from urinary incontinence and overactive bladder in a patient in need thereof.
  • Identifying a patient in need of such treatment can be in the judgment of a patient or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • any of the above methods of treatment comprises the further step of co-administering to the patient in need thereof one or more second therapeutic agents.
  • the choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with oxybutynin.
  • the choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.
  • the combination therapies of this invention include coadministering a compound of Formula I and a second therapeutic agent for treatment of the following conditions: urinary incontinence, irritable bowel syndrome and pain (gabapentin, pregabalin, and gabapentin enacarbil); and respiratory disorders associated with the production of mucus glycoprotein, skin disorders, and allergic conjunctivitis (desloratadine).
  • co-administered means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and a second therapeutic agent, to a patient does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said patient at another time during a course of treatment.
  • Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.
  • the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
  • the invention provides the use of a compound of Formula I alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a patient of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I for use in the treatment or prevention in a patient of a disease, disorder or symptom thereof delineated herein.
  • the invention provides a method of determining the concentration, in a solution or a biological sample, of oxybutynin, comprising the steps of: a) adding a known concentration of a compound of Formula I to the solution of biological sample; b) subjecting the solution or biological sample to a measuring device that distinguishes oxybutynin from a compound of Formula I; c) calibrating the measuring device to correlate the detected quantity of the compound of Formula I with the known concentration of the compound of Formula I added to the biological sample or solution; and d) measuring the quantity of oxybutynin in the biological sample with said calibrated measuring device; and e) determining the concentration of oxybutynin in the solution of sample using the correlation between detected quantity and concentration obtained for a compound of Formula I
  • Measuring devices that can distinguish oxybutynin from the corresponding compound of Formula I include any measuring device that can distinguish between two compounds that differ from one another only in isotopic abundance.
  • Exemplary measuring devices include a mass spectrometer, NMR spectrometer, or IR spectrometer.
  • the invention provides a method of evaluating the metabolic stability of a compound of Formula I comprising the steps of contacting the compound of Formula I with a metabolizing enzyme source for a period of time and comparing the amount of the compound of Formula I with the metabolic products of the compound of Formula I after the period of time.
  • the invention provides a method of evaluating the metabolic stability of a compound of Formula I in a patient following administration of the compound of Formula I.
  • This method comprises the steps of obtaining a serum, urine or feces sample from the patient at a period of time following the administration of the compound of Formula I to the subject; and comparing the amount of the compound of Formula I with the metabolic products of the compound of Formula I in the serum, urine or feces sample.
  • the present invention also provides kits for use to treat urinary incontinence and/or overactive bladder.
  • kits comprise (a) a pharmaceutical composition comprising a compound of Formula I or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat urinary incontinence and/or overactive bladder.
  • the container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • a pharmaceutically acceptable material for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn
  • kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition.
  • a device to administer or to measure out a unit dose of the pharmaceutical composition may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.
  • kits of this invention may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this invention.
  • EXAMPLE 1. EVALUATION OF METABOLIC STABILITY [90] Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.
  • 7.5 mM stock solutions of test compounds are prepared in DMSO.
  • the 7.5 mM stock solutions are diluted to 12.5 - 50 ⁇ M in acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 .
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ L aliquot of the 12.5 - 50 ⁇ M test compound is added to the microsomes and the mixture is pre- warmed for 10 minutes.
  • Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25 - 1.0 ⁇ M test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl 2 .
  • the reaction mixtures are incubated at 37 °C, and 50 ⁇ L aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 ⁇ L of ice-cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 °C for 20 minutes after which 100 ⁇ L of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.

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Abstract

La présente invention concerne de nouveaux composés qui sont des dérivés de l’acide phénylglycolique, et leurs sels pharmaceutiquement acceptables. Plus spécifiquement, l’invention concerne de nouveaux composés d’acide phénylglycolique qui sont des dérivés de l’antagoniste des récepteurs acétylcholinergiques muscariniques, l’oxybutynine. La présente invention concerne également des compositions pharmaceutiques apyrogènes comprenant un ou plusieurs composés selon l’invention et un excipient, et l’utilisation des composés et compositions décrits dans des méthodes de traitement de maladies et d’affections qui sont traitées par l’administration d’antagonistes des récepteurs acétylcholinergiques muscariniques. L’invention concerne également l’utilisation d’un ou de plusieurs composés décrits en tant que réactifs dans des études analytiques impliquant l’oxybutynine.
PCT/US2009/003512 2008-06-13 2009-06-11 Dérivés d’oxybutynine WO2009151613A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026564A2 (fr) * 2001-09-27 2003-04-03 Pharmacia Ab Composition pharmaceutique
WO2004084879A1 (fr) * 2003-03-21 2004-10-07 Dynogen Pharmaceuticals, Inc. Methodes de traitement de troubles des voies urinaires inferieures utilisant des modulateurs des muscles lisses et des modulateurs des canaux calciques de la sous-unite $g(a)2$g(d)
WO2006047427A1 (fr) * 2004-10-25 2006-05-04 Schering Corporation Antagonistes des recepteurs m1 et/ou m3 combines a d'autres agents actifs pour le traitement de maladies respiratoires
US20080299219A1 (en) * 2007-06-01 2008-12-04 Protia, Llc Deuterium-enriched oxybutynin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026564A2 (fr) * 2001-09-27 2003-04-03 Pharmacia Ab Composition pharmaceutique
WO2004084879A1 (fr) * 2003-03-21 2004-10-07 Dynogen Pharmaceuticals, Inc. Methodes de traitement de troubles des voies urinaires inferieures utilisant des modulateurs des muscles lisses et des modulateurs des canaux calciques de la sous-unite $g(a)2$g(d)
WO2006047427A1 (fr) * 2004-10-25 2006-05-04 Schering Corporation Antagonistes des recepteurs m1 et/ou m3 combines a d'autres agents actifs pour le traitement de maladies respiratoires
US20080299219A1 (en) * 2007-06-01 2008-12-04 Protia, Llc Deuterium-enriched oxybutynin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FOSTER A B: "Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design", ADVANCES IN DRUG RESEARCH, ACADEMIC PRESS, LONDON, GB, vol. 14, 1 January 1985 (1985-01-01), pages 1 - 40, XP009086953, ISSN: 0065-2490 *
KUSHNER DJ ET AL: "Pharmacological uses and perspectives of heavy water and deuterated compounds", CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, OTTAWA, ONT, CA, vol. 77, no. 2, 1 February 1999 (1999-02-01), pages 79 - 88, XP009086918 *

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