US20070112027A1 - Crystalline forms of a biphenyl compound - Google Patents

Crystalline forms of a biphenyl compound Download PDF

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US20070112027A1
US20070112027A1 US11/371,445 US37144506A US2007112027A1 US 20070112027 A1 US20070112027 A1 US 20070112027A1 US 37144506 A US37144506 A US 37144506A US 2007112027 A1 US2007112027 A1 US 2007112027A1
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Prior art keywords
compound
crystalline
ester
ethyl
piperidin
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Sabine Axt
Timothy Church
Viengkham Malathong
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Theravance Biopharma R&D IP LLC
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Theravance Inc
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Priority to US11/371,445 priority Critical patent/US20070112027A1/en
Application filed by Theravance Inc filed Critical Theravance Inc
Assigned to THERAVANCE, INC. reassignment THERAVANCE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AXT, SABINE, CHURCH, TIMOTHY J., MALATHONG, VIENGKHAM
Publication of US20070112027A1 publication Critical patent/US20070112027A1/en
Priority to US11/890,880 priority patent/US7700777B2/en
Priority to US12/563,727 priority patent/US8242137B2/en
Priority to US12/563,788 priority patent/US20100048622A1/en
Priority to US12/817,543 priority patent/US8377965B2/en
Priority to US13/740,465 priority patent/US8716313B2/en
Priority to US14/219,296 priority patent/US8921395B2/en
Assigned to THERAVANCE BIOPHARMA R&D IP, LLC reassignment THERAVANCE BIOPHARMA R&D IP, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THERAVANCE, INC.
Priority to US14/552,893 priority patent/US9249099B2/en
Priority to US14/974,980 priority patent/US9656993B2/en
Priority to US15/486,796 priority patent/US10577347B2/en
Priority to US16/744,557 priority patent/US11390603B2/en
Priority to US17/843,569 priority patent/US20220388981A1/en
Abandoned legal-status Critical Current

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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
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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to novel crystalline forms of a biphenyl compound and solvates thereof, which are expected to be useful for treating pulmonary disorders.
  • the invention also relates to pharmaceutical compositions comprising the crystalline compounds or prepared from such compounds, processes and intermediates for preparing such crystalline compounds and methods of using such compounds to treat a pulmonary disorder.
  • Therapeutic agents useful for treating pulmonary or respiratory disorders are advantageously administered directly into the respiratory tract by inhalation.
  • several types of pharmaceutical inhalation devices have been developed for administering therapeutic agents by inhalation including dry powder inhalers (DPI), metered-dose inhalers (MDI) and nebulizer inhalers.
  • DPI dry powder inhalers
  • MDI metered-dose inhalers
  • nebulizer inhalers When preparing pharmaceutical compositions and formulations for use in such devices, it is highly desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent and which has a relatively high melting point (typically greater than about 150° C.) thereby allowing the material to be micronized without significant decomposition.
  • the present invention provides crystalline forms of biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester (formula I).
  • the crystalline form can be a freebase, a pharmaceutically acceptable salt such as a diphosphate, monosulfate or dioxalate salt, or a pharmaceutically acceptable solvate of such salt.
  • crystalline forms of the invention have been found not to be deliquescent, even when exposed to atmospheric moisture. Additionally, the crystalline forms of the invention have acceptable levels of hygroscopicity and acceptable melting points, greater than about 70° C. For example, the diphosphate salt has a melting point around 150° C.
  • crystalline forms of the compound of formula I are useful for preparing pharmaceutical compositions expected to have utility in treating pulmonary disorders. Accordingly, one aspect of the invention pertains to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a crystalline form of the compound of formula I.
  • compositions comprising a crystalline form of the compound of formula I in combination with one or more other therapeutic agents.
  • the invention is directed to a composition comprising (a) a pharmaceutically acceptable carrier and a therapeutically effective amount of a crystalline form of the compound of formula I; and (b) a therapeutically effective amount of an agent selected from a steroidal anti-inflammatory agent such as a corticosteroid; a ⁇ 2 adrenergic receptor agonist; a phosphodiesterase-4 inhibitor; or a combination thereof; wherein the crystalline form and the agent are formulated together or separately.
  • a pharmaceutically acceptable carrier may be included.
  • a pharmaceutical composition comprising an aqueous isotonic saline solution comprising a crystalline form of the compound of formula I, wherein the solution has a pH in the range of from about 4 to 6.
  • an aqueous nebulizer formulation is buffered with citrate buffer to a pH of about 5.
  • the aqueous nebulizer formulation contains about 0.5 mg/mL free base equivalents of biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl) benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester.
  • this invention provides a drug delivery device comprising a dry powder inhaler containing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of the compound of formula I.
  • the compound of formula I has muscarinic receptor antagonist activity. Accordingly, crystalline forms of the compound of formula I are useful for treating pulmonary disorders such as asthma and chronic obstructive pulmonary disease.
  • another aspect of the invention pertains to a method for treating a pulmonary disorder comprising administering to a patient a therapeutically effective amount of a crystalline form of the compound of formula I.
  • Still another aspect of the invention relates to a method of producing bronchodilation in a patient comprising administering to the patient a bronchodilation-producing amount of a crystalline form of the compound of formula I.
  • the compound is administered by inhalation.
  • the invention also provides a method of treating chronic obstructive pulmonary disease or asthma comprising administering to a patient a therapeutically effective amount of a crystalline form of the compound of formula I.
  • Another aspect of the invention is directed to a method for antagonizing a muscarinic receptor in a mammal comprising administering to the mammal a therapeutically effective amount of a crystalline form of the compound of formula I.
  • the invention is also directed to processes for preparing crystalline forms of the compound of formula I.
  • the invention also provides a process for purifying the compound of formula I comprising forming a crystalline salt or a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester.
  • the invention is further directed to products prepared by the processes described herein.
  • the invention is also directed to a crystalline form of the compound of formula I in a micronized form; and to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a micronized crystalline form of the compound of formula I.
  • the invention is also directed to a crystalline form of the compound of formula I for use in therapy or as a medicament. Additionally, the invention relates to the use of a crystalline form of the compound of formula I for the manufacture of a medicament; especially for the manufacture of a medicament for the treatment of a pulmonary disorder or for antagonizing a muscarinic receptor in a mammal.
  • FIG. 1 shows a powder x-ray diffraction (PXRD) pattern of a crystalline diphosphate salt of biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester (the compound of formula I).
  • PXRD powder x-ray diffraction
  • FIG. 2 shows a differential scanning calorimetry (DSC) trace for this crystalline salt.
  • FIG. 3 shows a thermal gravimetric analysis (TGA) trace for this crystalline salt.
  • FIG. 4 shows a dynamic moisture sorption (DMS) trace for this crystalline salt.
  • FIG. 5 is a micrographic image of this crystalline salt.
  • FIG. 6 and FIG. 7 show a PXRD pattern and a DSC trace, respectively, for a less stable form of a crystalline diphosphate salt.
  • FIG. 8 shows a PXRD pattern of a crystalline monosulfate salt of the compound of formula I.
  • This crystalline salt is further characterized by the TGA trace in FIG. 9 , the DSC trace in FIG. 10 , the DMS trace in FIG. 11 , and the micrographic image in FIG. 12 .
  • FIG. 13 shows a PXRD pattern of a crystalline dioxalate salt of the compound of formula I.
  • This crystalline salt is further characterized by the TGA trace in FIG. 14 , the DSC trace in FIG. 15 , the DMS trace in FIG. 16 , and the micrographic image in FIG. 17 .
  • FIG. 18 shows a PXRD pattern of Form I of the crystalline freebase of the compound of formula I.
  • This crystalline freebase is further characterized by the DSC trace in FIG. 19 , the TGA trace in FIG. 20 , the DMS trace in FIG. 21 , and the micrographic image in FIG. 22 .
  • FIG. 23 shows a PXRD pattern of Form II of the crystalline freebase of the compound of formula I.
  • This crystalline freebase is further characterized by the DSC trace in FIG. 24 , the TGA trace in FIG. 25 , and the DMS trace in FIG. 26 .
  • the invention provides crystalline forms of biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester.
  • the crystalline form can be a freebase, a pharmaceutically acceptable salt such as a diphosphate, monosulfate or dioxalate salt, or a pharmaceutically acceptable solvate of such salt.
  • the crystalline form is a diphosphate salt.
  • solvate means a complex or aggregate formed by one or more molecules of a solute, i.e. a crystalline compound of formula I, and one or more molecules of a solvent. Such solvates typically have a substantially fixed molar ratio of solute and solvent. This term also includes clathrates, including clathrates with water. Representative solvents include, by way of example, water, methanol, ethanol, isopropanol, acetic acid and the like. When the solvent is water, the solvate formed is a hydrate.
  • Form I refers to the crystalline freebase that is prepared by a method that uses water as part of a solvent mixture as the inert diluent.
  • Form II refers to the crystalline freebase that is prepared by a method that uses an organic solvent mixture as the inert diluent, i.e. no water.
  • terapéuticaally effective amount means an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • a therapeutically effective amount for antagonizing a muscarinic receptor is that amount which will achieve the desired antagonizing effect.
  • a therapeutically effective amount for treating a pulmonary disorder is that amount that will achieve the desired therapeutic result, which may be disease prevention, amelioration, suppression or alleviation, as described below.
  • treating means the treating or treatment of a disease or medical condition (such as COPD) in a patient such as a mammal (particularly a human) that includes:
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable.
  • pharmaceutically acceptable carrier refers to a material that can be incorporated into a composition and administered to a patient without causing undesirable biological effects or interacting in a deleterious manner with other components of the composition.
  • Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug administration.
  • unit dosage form refers to a physically discrete unit suitable for dosing a patient, i.e., each unit containing a predetermined quantity of a compound of the invention calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units.
  • unit dosage forms may be capsules, tablets, pills, and the like.
  • the crystalline compounds of the invention can be synthesized from readily available starting materials as described below and in the Examples. It will be appreciated that while specific process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Generally, the reactions are conducted in a suitable inert diluent, examples of which include, but are not limited to, methanol, ethanol, isopropanol, isobutanol, ethyl acetate, acetonitrile, dichloromethane, methyl t-butyl ether, and the like, and mixtures thereof, typically containing water. Upon completion of any of the foregoing reactions, the crystalline compounds can be isolated from the reaction mixture by any conventional means such as precipitation, concentration, centrifugation and the like.
  • biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester employed in the invention can be readily prepared from commercially available starting materials and reagents using the procedures described in the Examples, or using the procedures described in U.S. patent Publication No. 2005/0203133 to Mammen et al.
  • molar ratios described in the methods of the invention can be readily determined by various methods available to those skilled in the art. For example, such molar ratios can be readily determined by 1 H NMR. Alternatively, elemental analysis and HPLC methods can be used to determine the molar ratio.
  • a diphosphate salt of the invention typically contains between about 1.8 and 2.2 molar equivalents of phosphate per molar equivalent of the compound of formula I; including between about 1.9 and 2.1 molar equivalents of phosphate per molar equivalent of the compound of formula I.
  • a crystalline diphosphate salt of the compound of formula I or a pharmaceutically acceptable solvate thereof can be prepared by contacting biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester with phosphoric acid.
  • the ester can be contacted with dilute aqueous phosphoric acid to form an amorphous diphosphate salt, which is then contacted with an inert diluent.
  • the ester is typically dissolved in aqueous phosphoric acid, diluted with water and isolated by lyophilization. Generally, this reaction is conducted at a temperature ranging from about 0 to 30° C., such as about 24° C. The ratio of milligrams of the ester to microliters of 1M phosphoric acid is about 1:3 to about 1:4, including about 1:3.5.
  • the resulting amorphous diphosphate salt is then typically contacted with about 15 mg/ml to about 25 mg/ml of inert diluent. Generally, this reaction is conducted at a temperature ranging from about 50 to 70° C., such as about 60° C.
  • 500 mg of the ester is taken up in 5 ml of water and 1.5 ml of 1M phosphoric acid.
  • the pH is adjusted to approximately pH 5.3 with additional 1M phosphoric acid (equaling 2.1 molar equivalents).
  • the clear solution is filtered, frozen and lyophilized to dryness to provide an amorphous diphosphate salt.
  • the resulting amorphous diphosphate salt is added to an isopropanol:acetonitrile (1:1) solution, followed by the addition of water.
  • the ratio of milligrams of the amorphous diphosphate salt to milliliters of isopropanol:acetonitrile is about 2:0.9 to about 2:2, including about 2:1.
  • a crystalline diphosphate salt can be prepared by contacting the ester with about 2.0 to about 2.1 molar equivalents of phosphoric acid.
  • this reaction is conducted in an inert diluent at a temperature ranging from about 40 to 60° C., such as about 50° C.
  • the ester is added to an isopropanol:acetonitrile (1:1) solution, followed by the addition of water. After heating, phosphoric acid is added.
  • the ratio of grams of the ester to milliliters of phosphoric acid is about 5:14 to about 5:18, including about 5:16.
  • FIG. 6 and FIG. 7 show a PXRD pattern and a DSC trace, respectively, for this less stable form.
  • the more stable diphosphate crystal is the prevalent form; however, when the less stable diphosphate form is present, it can be readily converted to the more stable crystal by increasing the water content in the solvent mixture, and reheating the suspension to about 50° C. to about 70° C., typically about 60° C., for about 2 to about 6 hours, typically about 2 hours, followed by cooling to room temperature overnight with slow stirring.
  • a monosulfate salt of the invention typically contains between about 0.8 and 1.2 molar equivalents of sulfate per molar equivalent of the compound of formula I; including between about 0.9 and 1.1 molar equivalents of sulfate per molar equivalent of the compound of formula I.
  • a crystalline monosulfate salt of the compound of formula I or a pharmaceutically acceptable solvate thereof can be prepared by contacting biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester with sulfuric acid.
  • the ester can be contacted with 1N aqueous sulfuric acid to form a monosulfate salt, which is then contacted with an inert diluent.
  • the ester is typically dissolved in 1:1 acetonitrile:water, diluted with aqueous sulfuric acid, diluted with water and isolated by lyophilization. Generally, this reaction is conducted at a temperature ranging from about 0 to 30° C., such as about 24° C.
  • the ratio of milligrams of the ester to milliliters of 1N sulfuric acid in water is about 325 mg/ml to about 285 mg/ml, including about 305 mg/ml.
  • 442 mg of the ester is taken up in 5 ml of 1:1 acetonitrile:water and 1.45 ml of 1N sulfuric acid is added slowly, while monitoring the pH.
  • the pH is then adjusted to approximately pH 3.3.
  • the clear solution is filtered, frozen and lyophilized to dryness to provide a monosulfate salt.
  • the resulting monosulfate salt is then typically contacted with about 10 mg/ml to about 20 mg/ml of inert diluent.
  • this reaction is conducted at a first temperature and then at a lower second temperature, both temperatures ranging from about 50 to 80° C., such as about 60° C. to 70° C.
  • the monosulfate salt is added to an isopropanol:acetonitrile (10:1) solution.
  • the ratio of milligrams of the monosulfate salt to milliliters of isopropanol:acetonitrile is about 15:3 to about 15:0.8, including about 15:1.
  • this reaction is conducted at a first temperature and then at two lower temperature cycles.
  • the first temperature ranges from about 50 to 80° C., such as about 70° C.
  • the first lower temperature cycle varies from about 60° C. to 30° C.
  • the second lower temperature cycle varies from about 40° C. to 30° C.
  • the monosulfate salt is added to an isopropanol:acetonitrile (10:1) solution.
  • the ratio of milligrams of the monohydrate salt to milliliters of isopropanol:acetonitrile is about 161:7 to about 161:11, including about 161:9.
  • a dioxalate salt of the invention typically contains between about 1.8 and 2.2 molar equivalents of oxalate per molar equivalent of the compound of formula I; including between about 1.9 and 2.1 molar equivalents of oxalate per molar equivalent of the compound of formula I.
  • a crystalline dioxalate salt of biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof can be prepared by contacting biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester with oxalic acid.
  • the ester can be contacted with 1M aqueous oxalic acid to form a dioxalate salt, which is then contacted with an inert diluent.
  • the ester is typically dissolved in 1:1 acetonitrile:water, diluted with aqueous oxalic acid, diluted with water and isolated by lyophilization. Generally, this reaction is conducted at a temperature ranging from about 0 to 30° C., such as about 24° C.
  • the ratio of milligrams of the ester to milliliters of 1M aqueous oxalic acid is about 320 mg/ml to about 280 mg/ml, including about 300 mg/ml.
  • 510 mg of the ester is taken up in 5 ml of 1:1 acetonitrile:water and 1.7 ml of 1M aqueous oxalic acid is added slowly, while monitoring the pH. The pH is adjusted to approximately pH 3.0. The clear solution is filtered, frozen and lyophilized to dryness to provide a dioxalate salt.
  • the resulting dioxalate salt is then typically contacted with about 5 mg/ml to about 15 mg/ml of inert diluent. Generally, this reaction is conducted at a temperature ranging from about 50 to 70° C., such as about 60° C.
  • the dioxalate salt is added to an isopropanol:water (94:6) solution. In this reaction, the ratio of milligrams of the dioxalate salt to milliliters of isopropanol:water is about 10:0.8 to about 10:3, including about 10:1.
  • a crystalline dioxalate salt can also be prepared by forming a seed crystal of a crystalline dioxalate salt of the ester (synthesized as described above), forming a dioxalate salt of the ester by contacting the ester with oxalic acid and dissolving the salt in an inert diluent to form a solution, and adding the seed crystal to the solution.
  • a dioxalate salt is typically contacted with about 5 mg/ml to about 15 mg/ml of inert diluent.
  • this reaction is conducted at a first temperature ranging from about 50 to 70° C., such as about 60° C.
  • the mixture is then cooled to a second temperature ranging from about 3 to 10° C., such as about 4° C.
  • the seed crystal of a crystalline dioxalate salt of the ester is then added.
  • the dioxalate salt is added to an isopropanol:water (94:6) solution.
  • the ratio of milligrams of the dioxalate salt to milliliters of isopropanol:water is about 150:10 to about 150:16, including about 150:13.
  • a crystalline freebase biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof can be prepared by contacting biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester with an inert diluent.
  • the ester is typically contacted with about 5 mg/ml to about 15 mg/ml of inert diluent. Generally, this reaction is conducted at a temperature ranging from about 20 to 30° C., such as about 25° C. In a particular embodiment, the ester is added to a water:acetonitrile (1:1) solution. In this reaction, the ratio of milligrams of the ester to milliliters of water:acetonitrile is about 100:0.3 to about 100:1, including about 100:0.5. Alternately, the reaction can be conducted at a first temperature ranging from about 20 to 30° C., such as about 25° C., and then cooled to a second temperature ranging from about 3 to 10° C., such as about 4° C.
  • a crystalline freebase can also be prepared by forming a seed crystal of a crystalline freebase (synthesized as described above), forming a crystalline freebase by contacting the ester with an inert diluent and dissolving the resulting crystalline ester to form a solution, and adding the seed crystal to the solution.
  • the ester is typically contacted with about 5 mg/ml to about 15 mg/ml of inert diluent.
  • this reaction is conducted at a first temperature ranging from about 50 to 70° C., such as about 60° C.
  • the mixture is then cooled to a second temperature ranging from about 3 to 10° C., such as about 4° C.
  • the seed crystal of a crystalline freebase of the ester is then added, followed by several heating and cooling cycles.
  • the first heating cycle goes, for example, from about 30 to 40° C. and then to about 50° C., followed by cooling to room temperature.
  • the second, third and forth heating cycles involve heating the sample to a temperature ranging from about 50 to 70° C., such as about 60° C., followed by cooling to room temperature.
  • the ester is added to water:acetonitrile (1:1) solution, followed by the addition of water and further acetonitrile.
  • the ratio of milligrams of the ester to milliliters of acetonitrile and water is about 230:0.1 to about 230:0.5, including about 230:0.2.
  • the ester is typically contacted with about 200 mg/ml to about 100 mg/ml of inert diluent. Generally, this reaction is conducted at a temperature ranging from about 20 to 30° C., such as about 25° C.
  • a particularly suitable inert diluent is a combination of acetonitrile and methyl t-butyl ether.
  • biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4 carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester is added to acetonitrile, followed by the addition of methyl t-butyl ether and additional acetonitrile.
  • the ratio of milligrams of the ester to milliliters of acetonitrile:methyl t-butyl ether (1:2 solution) is about 200 mg/ml to about 100 mg/ml, including about 70:0.45.
  • the crystalline diphosphate salt has a purity greater than 96%, and typically greater than 98%.
  • the crystalline compounds of the invention are characterized by a PXRD pattern having certain peak positions.
  • a crystalline diphosphate salt of the compound of formula I is characterized by a PXRD pattern having two or more diffraction peaks at 2 ⁇ values selected from 6.4 ⁇ 0.2, 7.6 ⁇ 0.2, 8.6 ⁇ 0.2, 13.7 ⁇ 0.2, 15.0 ⁇ 0.2, 19.4 ⁇ 0.2, 21.6 ⁇ 0.2, 22.1 ⁇ 0.2, 22.9 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • this crystalline form is characterized by a PXRD pattern comprising diffraction peaks at 2 ⁇ values of 15.0 ⁇ 0.2, 19.4 ⁇ 0.2, 21.6 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • a crystalline diphosphate salt is characterized by a PXRD pattern in which the peak positions are substantially in accordance with those shown in FIG. 1 . Note the differences between the PXRD pattern in FIG. 1 and the PXRD pattern for the less stable diphosphate salt as depicted in FIG. 6 .
  • a crystalline monosulfate salt of the compound of formula I is characterized by a PXRD pattern having two or more diffraction peaks at 2 ⁇ values selected from 7.7 ⁇ 0.2, 8.4 ⁇ 0.2, 8.8 ⁇ 0.2, 12.6 ⁇ 0.2, 13.7 ⁇ 0.2, 14.1 ⁇ 0.2, 15.3 ⁇ 0.2, 16.0 ⁇ 0.2, 19.7 ⁇ 0.2, 20.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 24.4 ⁇ 0.2.
  • this crystalline form is characterized by a PXRD pattern comprising diffraction peaks at 2 ⁇ values of 12.6 ⁇ 0.2, 19.7 ⁇ 0.2, 23.0 ⁇ 0.2, and 24.4 ⁇ 0.2.
  • a crystalline monosulfate salt is characterized by a PXRD pattern in which the peak positions are substantially in accordance with those shown in FIG. 8 .
  • a crystalline dioxalate salt of the compound of formula I is characterized by a PXRD pattern having two or more diffraction peaks at 2 ⁇ values selected from 7.7 ⁇ 0.2, 8.7 ⁇ 0.2, 13.5 ⁇ 0.2, 14.0 ⁇ 0.2, 14.8 ⁇ 0.2, 15.4 ⁇ 0.2, 15.8 ⁇ 0.2, 19.4 ⁇ 0.2, 22.9 ⁇ 0.2, 23.3 ⁇ 0.2, and 24.6 ⁇ 0.2.
  • this crystalline form is characterized by a PXRD pattern comprising diffraction peaks at 2 ⁇ values of 8.7 ⁇ 0.2, 14.0 ⁇ 0.2, 19.4 ⁇ 0.2, and 22.9 ⁇ 0.2.
  • a crystalline dioxalate salt is characterized by a PXRD pattern in which the peak positions are substantially in accordance with those shown in FIG. 13 .
  • a crystalline freebase (Form I) of the compound of formula I is characterized by a PXRD pattern having two or more diffraction peaks at 2 ⁇ values selected from 4.7 ⁇ 0.2, 9.6 ⁇ 0.2, 12.7 ⁇ 0.2, 13.7 ⁇ 0.2, 16.7 ⁇ 0.2, 17.4 ⁇ 0.2, 18.5 ⁇ 0.2, 19.4 ⁇ 0.2, 20.8 ⁇ 0.2, 21.4 ⁇ 0.2, 24.2 ⁇ 0.2, and 25.6 ⁇ 0.2.
  • this crystalline form is characterized by a PXRD pattern comprising diffraction peaks at 2 ⁇ values of 4.7 ⁇ 0.2, 18.5 ⁇ 0.2, 20.8 ⁇ 0.2, and 25.6 ⁇ 0.2.
  • a crystalline freebase (Form I) is characterized by a PXRD pattern in which the peak positions are substantially in accordance with those shown in FIG. 18 .
  • a crystalline freebase (Form II) of the compound of formula I is characterized by a PXRD pattern having two or more diffraction peaks at 2 ⁇ values selected from 4.6 ⁇ 0.2, 9.3 ⁇ 0.2, 12.9 ⁇ 0.2, 13.6 ⁇ 0.2, 14.0 ⁇ 0.2, 14.6 ⁇ 0.2, 16.5 ⁇ 0.2, 18.6 ⁇ 0.2, 19.1 ⁇ 0.2, 20.9 ⁇ 0.2, 22.1 ⁇ 0.2, 22.7 ⁇ 0.2, and 25.7 ⁇ 0.2.
  • this crystalline form is characterized by a PXRD pattern comprising diffraction peaks at 2 ⁇ values of 4.6 ⁇ 0.2, 18.6 ⁇ 0.2, 22.1 ⁇ 0.2, and 22.7 ⁇ 0.2.
  • a crystalline freebase (Form II) is characterized by a PXRD pattern in which the peak positions are substantially in accordance with those shown in FIG. 23 .
  • the crystalline compounds of formula I are characterized by their differential scanning calorimetry (DSC) trace.
  • DSC differential scanning calorimetry
  • a crystalline diphosphate salt of the compound of formula I is characterized by its DSC trace which showed a maximum endothermic heat flow at about 154.5° C., as illustrated in FIG. 2 .
  • the DSC trace for the stable crystalline diphosphate salt shows a typical low temperature transition followed by a relatively sharp peak at about 154.5° C.
  • the DSC trace for the unstable crystalline diphosphate salt FIG. 7 shows a distinct shoulder prior to a much smaller melting transition at about 150.3° C.
  • a crystalline monosulfate salt of the compound of formula I is characterized by its DSC trace which showed a maximum endothermic heat flow at about 76.5° C., as illustrated in FIG. 10 ;
  • a crystalline dioxalate salt is characterized by its DSC trace which showed a maximum endothermic heat flow at about 73.7° C., as illustrated in FIG. 15 ;
  • a crystalline freebase is characterized by its DSC trace which showed a maximum endothermic heat flow at about 102.7° C., as illustrated in FIG. 19 ;
  • a crystalline freebase (Form II) is characterized by its DSC trace which showed a maximum endothermic heat flow at about 98.6° C., as illustrated in FIG. 24 .
  • the crystalline compounds of the invention have been demonstrated to have a reversible sorption/desorption profile with an acceptable, moderate level of hygroscopicity: a crystalline diphosphate salt of the compound of formula I exhibits less than 2% weight gain when exposed to up to 90% relative humidity; a crystalline monosulfate salt exhibits less than 4% weight gain when exposed to up to 90% relative humidity; a crystalline dioxalate salt exhibits less than 3% weight gain when exposed to up to 90% relative humidity; a crystalline freebase (Form I) exhibits less than 6% weight gain when exposed to up to 90% relative humidity; and a crystalline freebase (Form II) exhibits less than 4% weight gain when exposed to up 90% relative humidity.
  • the crystalline compounds of the invention have been found to be stable upon exposure to elevated temperature and humidity. For example, after storage for 1 month at 40° C. and 75% relative humidity, analysis by high performance liquid chromatography (HPLC) showed no detectable chemical degradation (i.e., less than 0.5% degradation) for the crystalline compounds of the invention.
  • HPLC high performance liquid chromatography
  • the crystalline compound of formula I is typically administered to a patient in the form of a pharmaceutical composition or formulation.
  • Such pharmaceutical compositions may be administered to the patient by any acceptable route of administration including, but not limited to, inhaled, oral, nasal, topical (including transdermal) and parenteral modes of administration.
  • routes of administration including, but not limited to, inhaled, oral, nasal, topical (including transdermal) and parenteral modes of administration.
  • the salt may be dissolved in a suitable carrier.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a crystalline biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.
  • the pharmaceutical composition may contain other therapeutic and/or formulating agents if desired.
  • compositions of the invention typically contain a therapeutically effective amount of a crystalline biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof, as the active agent.
  • such pharmaceutical compositions will contain from about 0.01 to about 95% by weight of the active agent; including, from about 0.01 to about 30% by weight; such as from about 0.01 to about 10% by weight of the active agent.
  • any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention.
  • the choice of a particular carrier or excipient, or combination of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state.
  • the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts.
  • the ingredients for such compositions are commercially available from, for example, Sigma, P.O. Box 14508, St. Louis, Mo. 63178.
  • conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20 th Edition, Lippincott Williams & White, Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 th Edition, Lippincott Williams & White, Baltimore, Md. (1999).
  • compositions that can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's
  • compositions of the invention are typically prepared by thoroughly and intimately mixing or blending a compound of the invention with a pharmaceutically acceptable carrier and one or more optional ingredients. If necessary or desired, the resulting uniformly blended mixture can then be shaped or loaded into tablets, capsules, pills, canisters, cartridges, dispensers and the like using conventional procedures and equipment.
  • the pharmaceutical compositions of the invention are suitable for inhaled administration.
  • Suitable pharmaceutical compositions for inhaled administration will typically be in the form of an aerosol or a powder.
  • Such compositions are generally administered using well-known delivery devices such as a nebulizer inhaler, a metered-dose inhaler (MDI), a dry powder inhaler (DPI) or a similar delivery device.
  • MDI metered-dose inhaler
  • DPI dry powder inhaler
  • the pharmaceutical composition comprising the active agent is administered by inhalation using a nebulizer inhaler.
  • nebulizer devices typically produce a stream of high velocity air that causes the pharmaceutical composition comprising the active agent to spray as a mist that is carried into the patient's respiratory tract.
  • the active agent is typically dissolved in a suitable carrier to form a solution.
  • Suitable nebulizer devices are commercially available, for example, by PARI GmbH (Stamberg, German).
  • Other nebulizer devices include Respimat (Boehringer Ingelheim) and those described, for example, in U.S. Pat. No. 6,123,068 to Lloyd et al. and WO 97/12687 (Eicher et al.), the disclosures of which are incorporated herein by reference in their entirety.
  • a representative pharmaceutical composition for use in a nebulizer inhaler comprises an aqueous solution comprising from about 0.05 ⁇ g/mL to about 10 mg/mL of a crystalline compound of formula I or a pharmaceutically acceptable solvate thereof.
  • the aqueous formulation is isotonic.
  • the aqueous formulation has a pH in the range of from about 4 to 6.
  • the aqueous formulation is buffered with citrate buffer to a pH of about 5.
  • the aqueous formulation contains from about 0.1 mg/mL to about 1.0 mg/mL free base equivalents of biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester.
  • the pharmaceutical composition comprising the active agent is administered by inhalation using a DPI.
  • DPIs typically administer the active agent as a free-flowing powder that is dispersed in a patient's air-stream during inspiration.
  • the active agent is typically formulated with a suitable excipient such as lactose or starch.
  • Micronization is a common method of reducing crystal size to that suitable for pulmonary delivery.
  • the active agent is micronized and combined with a suitable carrier to form a suspension of micronized particles of respirable size, where “micronized particles” or “micronized form” means at least about 90% of the particles have a diameter of less than about 10 ⁇ m.
  • Other methods of reducing particle size may also be used such as fine milling, chopping, crushing, grinding, milling, screening, trituration, pulverization, and so forth, as long as the desired particle size can be obtained.
  • a representative pharmaceutical composition for use in a DPI comprises dry lactose having a particle size between about 1 ⁇ m and about 100 ⁇ m and micronized particles of a crystalline compound of formula I, or a pharmaceutically acceptable solvate thereof.
  • a dry powder formulation can be made, for example, by combining the lactose with the active agent and then dry blending the components.
  • the active agent can be formulated without an excipient.
  • the pharmaceutical composition is then typically loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device.
  • DPI delivery devices examples include Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.; see, e.g., U.S. Pat. No. 5,035,237 to Newell et al.); Diskus (GlaxoSmithKline; see, e.g., U.S. Pat. No. 6,378,519 to Davies et al.); Turbuhaler (AstraZeneca, Wilmington, Del.; see, e.g., U.S. Pat. No. 4,524,769 to Wetterlin); Rotahaler (GlaxoSmithKline; see, e.g., U.S. Pat. No.
  • the pharmaceutical composition comprising the active agent is administered by inhalation using an MDI, which typically discharges a measured amount of the active agent or a pharmaceutically acceptable salt or solvate or stereoisomer thereof using compressed propellant gas.
  • MDI typically discharges a measured amount of the active agent or a pharmaceutically acceptable salt or solvate or stereoisomer thereof using compressed propellant gas.
  • pharmaceutical compositions administered using an MDI typically comprise a solution or suspension of the active agent in a liquefied propellant.
  • Any suitable liquefied propellant may be employed including chlorofluorocarbons such as CCl 3 F, and hydrofluoroalkanes (HFAs) such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane, (HFA 227).
  • a representative pharmaceutical composition for use in a metered-dose inhaler comprises from about 0.01 to 5% by weight of a crystalline compound of formula I, or a pharmaceutically acceptable solvate thereof; from about 0 to 20% by weight ethanol; and from about 0 to 5% by weight surfactant; with the remainder being an HFA propellant.
  • compositions are typically prepared by adding chilled or pressurized hydrofluoroalkane to a suitable container containing the active agent, ethanol (if present) and the surfactant (if present).
  • the active agent is micronized and then combined with the propellant.
  • the formulation is then loaded into an aerosol canister, which forms a portion of a metered-dose inhaler device. Examples of metered-dose inhaler devices developed specifically for use with HFA propellants are described in U.S. Pat. No. 6,006,745 to Marecki and U.S. Pat. No. 6,143,277 to Ashurst et al.
  • a suspension formulation can be prepared by spray drying a coating of surfactant on micronized particles of the active agent. See, for example, WO 99/53901 (Glaxo Group Ltd.) and WO 00/61108 (Glaxo Group Ltd.).
  • the disclosures of the aforementioned patents and publications are incorporated herein by reference in their entirety.
  • the pharmaceutical compositions of the invention are suitable for oral administration.
  • Suitable pharmaceutical compositions for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; and the like; each containing a predetermined amount of a salt of the invention as an active ingredient.
  • the pharmaceutical composition may be packaged in a unit dosage form.
  • compositions of the invention When intended for oral administration in a solid dosage form (i.e., as capsules, tablets, pills and the like), the pharmaceutical compositions of the invention will typically comprise a crystalline compound of the present invention as the active ingredient and one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate.
  • such solid dosage forms may also comprise: fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants such as glycerol; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and/or sodium carbonate; solution retarding agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and/or glycerol monostearate; absorbents such as kaolin and/or bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and/or mixtures thereof; coloring agents;
  • antioxidants can also be present in the pharmaceutical compositions of the invention.
  • pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodium sulfite and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal-chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
  • Coating agents for tablets, capsules, pills and like include those used for enteric coatings such as cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymers, cellulose acetate trimellitate (CAT), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and the like.
  • enteric coatings such as cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymers, cellulose acetate trimellitate (CAT), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and the like.
  • enteric coatings such as cellulose acetate phthalate
  • compositions of the invention may also be formulated to provide slow or controlled release of the active ingredient using, by way of example, hydroxypropyl methyl cellulose in varying proportions; or other polymer matrices, liposomes and/or microspheres.
  • compositions of the invention may optionally contain opacifying agents and may be formulated so that they release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Suitable liquid dosage forms for oral administration include, by way of illustration, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Such liquid dosage forms typically comprise the active ingredient and an inert diluent such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • an inert diluent such as, for example, water or other solvents, solubilizing agents and emulsifiers such as eth
  • Suspensions in addition to the active ingredient, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • the crystalline compounds of the invention can also be administered transdermally using known transdermal delivery systems and excipients.
  • a compound of the invention can be admixed with permeation enhancers such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like, and incorporated into a patch or similar delivery system.
  • permeation enhancers such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like
  • Additional excipients including gelling agents, emulsifiers and buffers, may be used in such transdermal compositions if desired.
  • the crystalline compounds of the invention can also be co-administered with other therapeutic agents.
  • This combination therapy involves using a compound of the invention combined with one or more of these secondary agents, either formulated together (e.g., packaged together in a single formulation) or formulated separately (e.g., packaged as separate unit dosage forms). Methods of formulating multiple agents together in the same formulation or in separate unit dosage forms, are well known in the art.
  • the additional therapeutic agent(s) can be selected from other bronchodilators (e.g., PDE 3 inhibitors, adenosine 2b modulators and ⁇ 2 adrenergic receptor agonists); anti-inflammatory agents (e.g., steroidal anti-inflammatory agents such as corticosteroids; non-steroidal anti-inflammatory agents (NSAIDs), and PDE 4 inhibitors); other muscarinic receptor antagonists (i.e., antichlolinergic agents); antiinfective agents (e.g., Gram positive and Gram negative antibiotics or antivirals); antihistamines; protease inhibitors; and afferent blockers (e.g., D 2 agonists and neurokinin modulators).
  • bronchodilators e.g., PDE 3 inhibitors, adenosine 2b modulators and ⁇ 2 adrenergic receptor agonists
  • anti-inflammatory agents e.g., steroidal anti-inflammatory agents such as corticosteroids
  • One particular embodiment of the invention is directed to a composition
  • a composition comprising (a) a pharmaceutically acceptable carrier and a therapeutically effective amount of a crystalline form of the compound of formula I; and (b) a pharmaceutically acceptable carrier and a therapeutically effective amount of an agent selected from a steroidal anti-inflammatory agent such as a corticosteroid; a ⁇ 2 adrenergic receptor agonist; a phosphodiesterase-4 inhibitor; or a combination thereof; wherein the compound of formula I and the agent are formulated together or separately.
  • (b) is a pharmaceutically acceptable carrier and a therapeutically effective amount of a ⁇ 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.
  • the secondary agents can be used in the form of pharmaceutically acceptable salts or solvates, and if appropriate, as optically pure stereoisomers.
  • Representative ⁇ 2 adrenergic receptor agonists that can be used in combination with crystalline compounds of the invention include, but are not limited to, salmeterol, salbutamol, formoterol, salmefamol, fenoterol, terbutaline, albuterol, isoetharine, metaproterenol, bitolterol, pirbuterol, levalbuterol and the like, or pharmaceutically acceptable salts thereof.
  • ⁇ 2 adrenergic receptor agonists that can be used include, but are not limited to, 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl ⁇ amino)-hexyl]oxy ⁇ butyl)benzenesulfonamide and 3-(-3- ⁇ [7-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ -amino)heptyl]oxy ⁇ -propyl)benzenesulfonamide and related compounds described in WO 02/066422 (Glaxo Group Ltd.); 3-[3-(4- ⁇ [6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl)-phenyl]imidazolidine-2,4-dione and related compounds described in WO 02
  • the ⁇ 2 -adrenoreceptor agonist is a crystalline monohydrochloride salt of N- ⁇ 2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl ⁇ -(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine.
  • the ⁇ 2 -adrenoreceptor agonist will be present in the pharmaceutical composition in a therapeutically effective amount.
  • the ⁇ 2 -adrenoreceptor agonist will be present in an amount sufficient to provide from about 0.05 ⁇ g to 500 ⁇ g per dose.
  • An exemplary combination is a crystalline form of the compound of formula I or solvate thereof, co-administered with salmeterol as the ⁇ 2 adrenergic receptor agonist, and fluticasone propionate as the steroidal anti-inflammatory agent.
  • Another exemplary combination is a crystalline form of the compound of formula I or solvate thereof, co-administered with a crystalline monohydrochloride salt of N- ⁇ 2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl ⁇ -(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine as the ⁇ 2 -adrenoreceptor agonist, and 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxoandrosta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester as the steroidal anti-inflammatory agent.
  • these agents can be formulated together or separately.
  • NSAIDs e.g., sodium cromoglycate, nedocromil sodium, and phosphodiesterase (PDE) inhibitors such as theophylline, PDE4 inhibitors and mixed PDE3/PDE4 inhibitors
  • leukotriene antagonists e.g., monteleukast
  • inhibitors of leukotriene synthesis iNOS inhibitors
  • protease inhibitors such as tryptase and elastase inhibitors
  • beta-2 integrin antagonists and adenosine receptor agonists or antagonists e.g., adenosine 2a agonists
  • cytokine antagonists e.g., chemokine antagonists such as, an interleukin antibody ( ⁇ IL antibody), specifically, an ⁇ IL-4 therapy, an ⁇ IL-13 therapy, or a combination thereof
  • inhibitors of cytokine synthesis e.g., other anti-inflammatory agents, e.g., NSAIDs (e
  • Representative phosphodiesterase-4 (PDE4) inhibitors or mixed PDE3/PDE4 inhibitors that can be used in combination with the crystalline compounds of the invention include, but are not limited to cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid and the like, or pharmaceutically acceptable salts thereof.
  • PDE4 or mixed PDE4/PDE3 inhibitors include AWD-12-281 (elbion); NCS-613 (INSERM); D-4418 (Chiroscience and Schering-Plough); CI-1018 or PD-168787 (Pfizer); benzodioxole compounds described in WO99/16766 (Kyowa Hakko); K-34 (Kyowa Hakko); V-11294A (Napp); roflumilast (Byk-Gulden); pthalazinone compounds described in WO99/47505 (Byk-Gulden); Pumafentrine (Byk-Gulden, now Altana); arofylline (Almirall-Prodesfarma); VM554/UM565 (Vemalis); T-440 (Tanabe Seiyaku); and T2585 (Tanabe Seiyaku).
  • muscarinic antagonists i.e., anticholinergic agents
  • Representative muscarinic antagonists include, but are not limited to, atropine, atropine sulfate, atropine oxide, methylatropine nitrate, homatropine hydrobromide, hyoscyamine (d, l) hydrobromide, scopolamine hydrobromide, ipratropium bromide, oxitropium bromide, tiotropium bromide, methantheline, propantheline bromide, anisotropine methyl bromide, clidinium bromide, copyrrolate (Robinul), isopropamide iodide, mepenzolate bromide, tridihexethyl chloride (Pathilone), hexocyclium methylsulfate, cyclopentolate hydrochloride, tropicamide, trihexyphenidyl hydrochloride, piren
  • antihistamines i.e., H 1 -receptor antagonists
  • H 1 -receptor antagonists include, but are not limited to, ethanolamines such as carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride and dimenhydrinate; ethylenediamines such as pyrilamine amleate, tripelennamine hydrochloride and tripelennamine citrate; alkylamines such as chlorpheniramine and acrivastine; piperazines such as hydroxyzine hydrochloride, hydroxyzine pamoate, cyclizine hydrochloride, cyclizine lactate, meclizine hydrochloride and cetirizine hydrochloride; piperidines such as astemizole, levocabastine hydrochloride, loratadine or its descarboethoxy analogue, terfenadine and fexofenadine hydrochloride; a
  • exemplary suitable doses for the other therapeutic agents administered in combination with a crystalline compound of the invention are in the range of about 0.05 ⁇ g/day to 100 mg/day.
  • One or more secondary agents can optionally be formulated with the crystalline compound of the invention (primary active agent). Alternately, the secondary agents(s) can be formulated separately and co-administered with the primary active agent, either simultaneously or sequentially.
  • a single dry powder formulation can be manufactured to include both the crystalline compound of the invention and one or more secondary agents.
  • one formulation is manufactured to contain the crystalline compound of the invention and separate formulation(s) are manufactured to contain the secondary agent(s). Such dry powder formulations can then be packaged in separate blister packs and administered with a single DPI device.
  • 0.2 mg of a crystalline compound of the invention is micronized and then blended with 25 mg of lactose.
  • the blended mixture is then loaded into a gelatin inhalation cartridge.
  • the contents of the cartridge are administered using a powder inhaler.
  • a dry powder is prepared having a bulk formulation ratio of micronized crystalline compound of the invention (active agent) to lactose of 1:200.
  • the powder is packed into a dry powder inhalation device capable of delivering between about 10 ⁇ g and 100 ⁇ g of active agent per dose.
  • a suspension containing 5 wt % of a crystalline compound of the invention (active agent) and 0.1 wt % lecithin is prepared by dispersing 10 g of the active agent as micronized particles with a mean size less than 10 ⁇ m in a solution formed from 0.2 g of lecithin dissolved in 200 mL of demineralized water. The suspension is spray dried and the resulting material is micronized to particles having a mean diameter less than 1.5 ⁇ m. The particles are loaded into cartridges with pressurized 1,1,1,2-tetrafluoroethane.
  • a suspension containing 5 wt % of the active agent, 0.5 wt % lecithin, and 0.5 wt % trehalose is prepared by dispersing 5 g of the active agent as micronized particles with a mean size less than 10 ⁇ m in a colloidal solution formed from 0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 mL of demineralized water.
  • the suspension is spray dried and the resulting material is micronized to particles having a mean diameter less than 1.5 ⁇ m.
  • the particles are loaded into canisters with pressurized 1,1,1,2-tetrafluoroethane.
  • a pharmaceutical composition is prepared by dissolving 0.5 mg of a crystalline compound of the invention (active agent) in 1 mL of a 0.9% sodium chloride solution acidified with citric acid. The mixture is stirred and sonicated until the active agent is dissolved. The pH of the solution is adjusted to a value in the range of from 3 to 8 (typically about 5) by the slow addition of NaOH.
  • composition containing 100 mg of active ingredient per 10 mL of suspension.
  • Ingredients Amount Crystalline compound of the invention 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum k (Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilled water q.s. to 100 mL
  • the compound of formula I possesses muscarinic receptor antagonist activity and therefore, the crystalline form of the compound of formula I is expected to be useful for treating medical conditions mediated by muscarinic receptors, i.e., medical conditions that are ameliorated by treatment with a muscarinic receptor antagonist.
  • medical conditions include, by way of example, pulmonary disorders or diseases including those associated with reversible airway obstruction such as chronic obstructive pulmonary disease (e.g., chronic and whez bronchitis and emphysema), asthma, pulmonary fibrosis, allergic rhinitis, rhinorrhea, and the like.
  • muscarinic receptor antagonists include genitourinary tract disorders such as overactive bladder or detrusor hyperactivity and their symptoms; gastrointestinal tract disorders such as irritable bowel syndrome, diverticular disease, achalasia, gastrointestinal hypermotility disorders and diarrhea; cardiac arrhythmias such as sinus bradycardia; Parkinson's disease; cognitive disorders such as Alzheimer's disease; dismenorrhea; and the like.
  • the invention is directed to a method for treating a pulmonary disorder, the method comprising administering to a patient a therapeutically effective amount of a crystalline biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoyl piperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.
  • the crystalline compound of the invention will typically be administered by inhalation in multiple doses per day, in a single daily dose or a single weekly dose.
  • the dose for treating a pulmonary disorder will range from about 10 ⁇ g/day to 200 ⁇ g/day.
  • the crystalline compounds of the invention When administered by inhalation, the crystalline compounds of the invention typically have the effect of producing bronchodilation. Accordingly, in another embodiment, the invention is directed to a method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a crystalline biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.
  • the therapeutically effective dose for producing bronchodilation will range from about 10 ⁇ g/day to 200 ⁇ g/day.
  • the invention is directed to a method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient a therapeutically effective amount of a crystalline biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.
  • the salt of the invention will typically be administered by inhalation in multiple doses per day or in a single daily dose.
  • the dose for treating COPD or asthma will range from about 10 ⁇ g/day to 200 ⁇ g/day.
  • COPD includes chronic obstructive bronchitis and emphysema (see, for example, Barnes, Chronic Obstructive Pulmonary Disease, N Engl J Med 343:269-78 (2000)).
  • the crystalline compounds of the invention are optionally administered in combination with other therapeutic agents.
  • the pharmaceutical compositions and methods of the invention further comprise a therapeutically effective amount of a ⁇ 2 -adrenoreceptor agonist, a corticosteroid, a non-steroidal anti-inflammatory agent, or combination thereof.
  • the crystalline compounds of the invention are used to antagonize a muscarinic receptor in biological system, and a mammal in particular such as mice, rats, guinea pigs, rabbits, dogs, pigs, humans and so forth.
  • a therapeutically effective amount of a crystalline compound of formula I is administered to the mammal. If desired, the effects of antagonizing the muscarinic receptor can then determined using conventional procedures and equipment.
  • HPLC analysis was conducted using an Agilent (Palo Alto, Calif.) Series 1100 instrument equipped with a Zorbax Bonus RP 2.1 ⁇ 50 mm column (Agilent) having a 3.5 micron particle size. Detection was by UV absorbance at 214 nm.
  • the mobile phases employed were as follows (by volume): A is ACN (2%), water (98%) and TFA (0.1%); and B is acetonitrile (90%), water (10%) and TFA (0.1%).
  • HPLC 10-70 data was obtained using a flow rate of 0.5 mL/minute of 10 to 70% B over a 6 minute gradient (with the remainder being A).
  • HPLC 5-35 data and HPLC 10-90 data were obtained using 5 to 35% B; or 10 to 90% B over a 5 minute gradient.
  • LCMS Liquid chromatography mass spectrometry
  • Biphenyl-2-isocyanate 97.5 g, 521 mmol
  • 4-hydroxy-N-benzylpiperidine 105 g, 549 mmol
  • the reaction mixture was then cooled to 50° C. and ethanol (1 L) was added and then 6M HCl (191 mL) was added slowly.
  • the resulting mixture was then cooled to ambient temperature and ammonium formate (98.5 g, 1.56 mol) was added and then nitrogen gas was bubbled through the solution vigorously for 20 minutes.
  • Palladium on activated carbon (20 g, 10 wt % dry basis) was then added and the reaction mixture was heated at 40° C. for 12 hours, and then filtered through a pad of Celite.
  • N-benzyl-N-methylethanolamine 30.5 g, 0.182 mol
  • DCM 0.5 L
  • DIPEA 95 mL, 0.546 mol
  • DMSO DMSO
  • the reaction was stirred at ⁇ 10° C. for 2 hours. Before removing the ice-bath, the reaction was quenched by adding water (0.5 L). The aqueous layer was separated and the organic layer was washed with water (0.5 L) and brine (0.5 L) and then dried over magnesium sulfate and filtered to provide the title compound which was used without further purification.
  • the title compound was prepared by mesylation of N-benzyl-N-methyl ethanolamine, which was then reacted with biphenyl-2-ylcarbamic acid piperidin-4-yl ester in an alkylation reaction.
  • the reactor flask was charged with NaOH (1M solution; 100 mL), stirred, and the layers allowed to settle. The organic layer was separated, washed (NaCl satd. solution), its volume partially reduced under vacuum, and subjected to repeated IPA washings. The solids were collected and allowed to air-dry (25.85 g, 98% purity). Additional solids were obtained from further processing of the mother liquor (volume reduction, IPA, cooling).
  • reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10° C.
  • Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with 1N HCl (200 mL) to pH 3.
  • the resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3 ⁇ 250 mL).
  • the aqueous phase was then cooled to 0-5° C. with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10.
  • biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester (0.853 mmol of 96% pure material; prepared as described in Example 1) was taken up in 5 ml of H 2 O:ACN (1:1) and 1.7 ml of 1M aqueous oxalic acid was added slowly, while monitoring the pH. The pH was adjusted to approx. pH 3.0. The clear solution was filtered through a 0.2 micron filter, frozen and lyophilized to dryness to yield a dioxalate salt.
  • biphenyl-2-ylcarbamic acid 1-(2- ⁇ [4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino ⁇ ethyl)piperidin-4-yl ester (prepared as described in Example 1) was dissolved in 0.2 ml of H 2 O:ACN (1:1), using slight heat. The mixture was then heated in a 70° C. water bath for 2 hours. The heat was turned off and the mixture was allowed to cool to room temperature, then refrigerated at 4° C. for 1 hour. 50 ⁇ l of water was then added (oiled out), followed by the addition of 40 ⁇ l of ACN to get the sample back into solution.
  • Seeds (crystalline material from Example 8) were added under slow stirring at room temperature. Crystals started to form, and the mixture was allowed to sit overnight, with slow stirring. The next day, a heat cool cycle was applied (30° C. for 10 minutes, 40° C. for 10 minutes, then 50° C. for 20 minutes). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, a second heat/cool cycle was applied (60° C. for 1 hour, with dissolving observed at 70° C.). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, crystals were present and a third heat cool cycle was applied (60° C. for 3 hours). The heat was turned off and the mixture allowed to cool overnight, with slow stirring.
  • Powder X-ray diffraction patterns were obtained with a Rigaku diffractometer using Cu K ⁇ (30.0 kV, 15.0 mA) radiation. The analysis was performed with the goniometer running in continuous-scan mode of 3° per minute with a step size of 0.03° over a range of 2 to 45°. Samples were prepared on quartz specimen holders as a thin layer of powdered material. The instrument was calibrated with a silicon metal standard.
  • the PXRD pattern for a sample of the diphosphate salt of Example 2 showed the material to be crystalline.
  • a representative PXRD pattern for a sample of the crystalline diphosphate salt of Example 3 is shown in FIG. 1 .
  • the PXRD pattern for a sample of the monosulfate salt of Example 4 showed the material to be crystalline.
  • a representative PXRD pattern for a sample of the crystalline monosulfate salt of Example 5 is shown in FIG. 8 .
  • the PXRD pattern for a sample of the dioxalate salt of Example 6 showed the material to be crystalline.
  • a representative PXRD pattern for a sample of the crystalline dioxalate salt of Example 7 is shown in FIG. 13 .
  • the PXRD pattern for a sample of the freebase (Form I) of Examples 8 and 9 showed the material to be crystalline.
  • a representative PXRD pattern for a sample of the freebase (Form 1) of Example 10 is shown in FIG. 18 .
  • a representative PXRD pattern for a sample of the freebase (Form 11) of Example 11 is shown in FIG. 23 .
  • DSC Differential scanning calorimetry
  • a representative DSC trace for a sample of the crystalline diphosphate salt of Example 3 showed two transitions at about 63.8° C. and 154.3° C., as seen in FIG. 2 .
  • This DSC trace demonstrate that this crystalline diphosphate salt has acceptable to good thermal stability with the melting peak at about 154.5° C. and no thermal decomposition below 150° C.
  • the DSC trace also showed an onset of endothermic heat flow at about 135° C.
  • a representative DSC trace for a sample of the monosulfate salt of Example 4 showed two transitions at about 57° C. and 73.2° C.
  • a representative DSC trace for a sample of the crystalline monosulfate salt of Example 5 showed a transition at 76° C., as seen in FIG. 10 , demonstrating that this crystalline monosulfate salt has a melting peak at about 76.5° C.
  • a representative DSC trace for a sample of the crystalline dioxalate salt of Example 6 showed two transitions at 69.2° C. and 122.8° C.
  • a representative DSC trace for a sample of the crystalline dioxalate salt of Example 7 showed a transition at 73° C., as seen in FIG. 15 .
  • This DSC trace demonstrate that this crystalline dioxalate salt has a melting peak at about 73.7° C.
  • a representative DSC trace for a sample of the crystalline freebase (Form I) of Example 8 showed a transition at 90.4° C.
  • the DSC trace for a sample of the crystalline freebase (Form I) of Example 9 showed two transitions at 86.1° C. and 103.6° C.
  • a representative DSC trace for a sample of the crystalline freebase of Example 10 (Form I) showed two transitions in a closed pan (83.9° C. and 102.1° C.), but one transition at 102.5° C. in an open pan (the early peak is due to water and/or solvents), as seen in FIG. 19 .
  • This DSC trace demonstrate that this crystalline freebase has excellent thermal stability with the melting peak at about 102.7° C. and no thermal decomposition below 80° C.
  • the DSC trace also showed an onset of endothermic heat flow at about 90° C.
  • a representative DSC trace for a sample of the crystalline freebase (Form II) of Example 11 showed a transition at 98.6° C., as seen in FIG. 24 , demonstrating that this crystalline freebase has excellent thermal stability with the melting peak at about 98.6° C. and no thermal decomposition below 75° C.
  • the DSC trace also showed an onset of endothermic heat flow at about 75° C.
  • Thermogravimetric analysis was performed using a TA Instruments Model Q-50 module equipped with high resolution capability. Data were collected and analyzed using TA Instruments Thermal Solutions software. A sample weighing about 10 mg was placed onto a platinum pan and scanned with a high resolution-heating rate from ambient temperature to 300° C. The balance and furnace chambers were purged with nitrogen flows during use.
  • a representative TGA trace for a sample of the crystalline diphosphate salt of Example 3 showed a loss of solvents and/or water (8.2%) at temperatures below 155° C., as seen in FIG. 3 .
  • the TGA trace for a sample of the crystalline monosulfate salt of Example 4 showed a loss of solvents and/or water (12.6%) at temperatures below 116° C.
  • a representative TGA trace for a sample of the crystalline monosulfate salt of Example 5 showed a loss of solvents and/or water (13.7%) at temperatures below 150° C., as seen in FIG. 9 .
  • the TGA trace for a sample of the crystalline dioxalate salt of Example 6 showed a loss of solvents and/or water (15.4%) at temperatures below 125° C.
  • a representative TGA trace for a sample of the crystalline dioxalate salt of Example 7 showed a loss of solvents and/or water (12.7%) at temperatures below 125° C., as seen in FIG. 14 .
  • the TGA trace for a sample of the crystalline freebase (Form I) of Example 8 showed a loss of solvents and/or water (7.3%) at temperatures below 75° C.
  • the TGA trace for a sample of the crystalline freebase (Form I) of Example 9 showed a loss of solvents and/or water (5.2%) at temperatures below 70° C.
  • a representative TGA trace for a sample of the crystalline freebase (Form I) of Example 10 showed a loss of solvents and/or water (3.8%) at temperatures below 98° C., as seen in FIG. 20 .
  • a representative TGA trace for a sample of the crystalline freebase (Form II) of Example 11 showed a loss of solvents and/or water (3.0%) at temperatures below 98° C., as seen in FIG. 25 .
  • TGA traces indicate that the crystalline compounds of the present invention lose a small amount of weight from room temperature to moderately elevated temperatures (e.g., 75-150° C.), which is consistent with the loss of residual moisture or solvent.
  • a dynamic moisture sorption (DMS) assessment (also known as a moisture sorption-desorption profile) was performed using a VTI atmospheric microbalance, SGA-100 system (VTI Corp., Hialeah, Fla. 33016). A sample size of approximately 10 mg was used and the humidity was set at the ambient value at the start of the analysis. A typical DMS analysis consisted of three scans: ambient to 2% relative humidity (RH), 2% RH to 90% RH, 90% RH to 5% RH at a scan rate of 5% RH/step. The mass was measured every two minutes and the RH was changed to the next value (+/ ⁇ 5% RH) when the mass of the sample was stable to within 0.01% for 5 consecutive points.
  • RH relative humidity
  • RH relative humidity
  • the mass was measured every two minutes and the RH was changed to the next value (+/ ⁇ 5% RH) when the mass of the sample was stable to within 0.01% for 5 consecutive points.
  • a representative DMS trace for a sample of the crystalline diphosphate salt of Example 3 showed a reversible sorption/desorption profile with low hygroscopicity, with a 3.3% weight gain when exposed to 2-90% RH and a 0.6% weight gain in the humidity range of 40-75% RH, as shown in FIG. 4 .
  • a representative DMS trace for a sample of the crystalline monosulfate salt of Example 5 showed a reversible sorption/desorption profile with low hygroscopicity, with a 10% weight gain when exposed to 2-90% RH and a 1.8% weight gain in the humidity range of 40-75% RH, as shown in FIG. 11 .
  • a representative DMS trace for a sample of the crystalline dioxalate salt of Example 7 showed a reversible sorption/desorption profile with low hygroscopicity, with a 5.3% weight gain when exposed to 2-90% RH and a 1.1% weight gain in the humidity range of 40-75% RH, as shown in FIG. 16 .
  • a representative DMS trace for a sample of the crystalline freebase (Form I) of Example 10 showed a reversible sorption/desorption profile with low hygroscopicity, with a 10% weight gain when exposed to 2-90% RH and a 1.2% weight gain in the humidity range of 40-75% RH, as shown in FIG. 21 .
  • a representative DMS trace for a sample of the crystalline freebase (Form II) of Example 11 showed a reversible sorption/desorption profile with low hygroscopicity, with a 9% weight gain when exposed to 2-90% RH and a 1.3% weight gain in the humidity range of 40-75% RH, as shown in FIG. 26 .
  • DMS traces demonstrate that the crystalline compounds of the present invention have a reversible sorption/desorption profile with low hygroscopicity.
  • the crystalline compounds have an acceptable weight gain when exposed to a broad humidity range.
  • the reversible moisture sorption/desorption profiles demonstrate that the crystalline compounds of the present invention possess an acceptable hygroscopicity and are not deliquescent.
  • the initial purity of the samples was 98.3% as determined by HPLC area percentage. After storage for six weeks, for the samples kept under all conditions, there was no detectable change in chemical purity, no observable change in the appearance of the material, and analysis by DSC and TGA showed no detectable differences.
  • Example 7 For the crystalline dioxalate salt of Example 7: 54.54% carbon, 6057% hydrogen, 8.15% nitrogen, and 30.74% oxygen (expected); 56.33% carbon, 6.90% hydrogen, 8.22% nitrogen, and 26.32% oxygen (results).
  • a 13 g sample of the crystalline diphosphate salt of Example 3 was micronized with a jet mill to give 8.7 g of a free-flowing white powder with birefringence observed upon microscopic examination (67% recovery).
  • the crystalline diphosphate had an initial purity of 98.1% as determined by HPLC area percentage.
  • the purity of the micronized material was the same.
  • the water content of the pre-micronized material was 6.54 wt %, and the water content of the micronized material was 6.23 wt %.
  • Example 14 No significant changes were observed in the powder x-ray diffraction pattern, TGA, DSC, DMS, chemical purity, chiral purity and moisture content for the micronized material compared to the unmicronized material.
  • a representative DMS trace for a sample of the crystalline diphosphate salt of Example 3 showed a 0.6% weight gain in the humidity range of 40-75% RH, while the micronized material showed a 0.7% weight gain in this humidity range.
  • a solution was prepared with 0.5 mg/mL freebase equivalents (using a crystalline diphosphate salt prepared as described in Example 3) in 10 mM citrate buffered normal saline, pH 5.
  • the solubility of the crystalline salt was greater than 40 mg/mL of freebase equivalent in the buffer. Less than 0.5% degradation was observed after storage for one month at 40° C./75% RH.
  • membrane preparation For membrane preparation, cell pellets were resuspended in lysis buffer and homogenized with a Polytron PT-2100 tissue disrupter (Kinematica AG; 20 seconds ⁇ 2 bursts). Crude membranes were centrifuged at 40,000 ⁇ g for 15 minutes at 4° C. The membrane pellet was then resuspended with resuspension buffer and homogenized again with the Polytron tissue disrupter. The protein concentration of the membrane suspension was determined by the method described in Lowry, O. et al., Journal of Biochemistry 193:265 (1951). All membranes were stored frozen in aliquots at ⁇ 80° C. or used immediately. Aliquots of prepared hM 5 receptor membranes were purchased directly from Perkin Elmer and stored at ⁇ 80° C. until use.
  • Radioligand binding assays were performed in 96-well microtiter plates in a total assay volume of 100 ⁇ L.
  • CHO cell membranes stably expressing either the hM 1 , hM 2 , hM 3 , hM 4 or hM 5 muscarinic subtype were diluted in assay buffer to the following specific target protein concentrations ( ⁇ g/well): 10 ⁇ g for hM 1 , 10-15 ⁇ g for hM 2 , 10-20 ⁇ g for hM 3 , 10-20 ⁇ g for hM 4 , and 10-12 ⁇ g for hM 5 .
  • the membranes were briefly homogenized using a Polytron tissue disruptor (10 seconds) prior to assay plate addition.
  • the addition order and volumes to the assay plates were as follows: 25 ⁇ L radioligand, 25 ⁇ L diluted test compound, and 50 ⁇ L membranes. Assay plates were incubated for 60 minutes at 37° C. Binding reactions were terminated by rapid filtration over GF/B glass fiber filter plates (PerkinElmer Inc., Wellesley, Mass.) pre-treated in 1% BSA. Filter plates were rinsed three times with wash buffer (10 mM HEPES) to remove unbound radioactivity. Plates were then air dried, and 50 ⁇ L Microscint-20 liquid scintillation fluid (PerkinElmer Inc., Wellesley, Mass.) was added to each well.
  • K i values for test compounds were calculated from observed IC 50 values and the K D value of the radioligand using the Cheng-Prusoff equation (Cheng Y; Prusoff W. H. Biochemical Pharmacology 22(23):3099-108 (1973)). K i values were converted to pK i values to determine the geometric mean and 95% confidence intervals. These summary statistics were then converted back to K i values for data reporting.
  • a lower K i value indicates that the test compound has a higher binding affinity for the receptor tested.
  • the compound of formula I was found to have a K i value of less than about 5 nM for the M 3 muscarinic receptor subtype when tested in this or a similar assay.
  • the functional potency of a test compound was determined by measuring the ability of the test compound to block oxotremorine-inhibition of forskolin-mediated cAMP accumulation in CHO-K1 cells expressing the hM 2 receptor.
  • cAMP assays were performed in a radioimmunoassay format using the Flashplate Adenylyl Cyclase Activation Assay System with 125 I-cAMP (NEN SMP004B, PerkinElmer Life Sciences Inc., Boston, Mass.), according to the manufacturer's instructions.
  • test compound was initially dissolved to a concentration of 400 ⁇ M in dilution buffer (dPBS supplemented with 1 mg/mL BSA (0.1%)), and then serially diluted with dilution buffer to final molar concentrations ranging from 100 ⁇ M to 0.1 nM.
  • Oxotremorine was diluted in a similar manner.
  • oxotremorine inhibition of AC activity 25 ⁇ L forskolin (25 ⁇ M final concentration diluted in dPBS), 25 ⁇ L diluted oxotremorine, and 50 ⁇ L cells were added to agonist assay wells.
  • 25 ⁇ L forskolin and oxotremorine 25 ⁇ M and 5 ⁇ M final concentrations, respectively, diluted in dPBS
  • 25 ⁇ L diluted test compound 25 ⁇ L diluted test compound, and 50 ⁇ L cells were added to remaining assay wells.
  • the Cheng-Prusoff equation was used to calculate the K i , using the EC 50 of the oxotremorine concentration-response curve and the oxotremorine assay concentration as the K D and [L], respectively.
  • the K i values were converted to pK i values to determine the geometric mean and 95% confidence intervals. These summary statistics were then converted back to K i values for data reporting.
  • K i value indicates that the test compound has a higher functional activity at the receptor tested.
  • the compound of formula I was found to have a K i value of less than about 5 nM for blockade of oxotremorine-inhibition of forskolin-mediated cAMP accumulation in CHO-K1 cells expressing the hM 2 receptor, when tested in this or a similar assay.
  • the functional potency of test compounds can be determined by measuring the ability of the compounds to block oxotremorine-stimulated [ 35 S]GTP ⁇ S-binding in CHO-K1 cells expressing the hM 2 receptor.
  • test compound To determine the ability of a test compound to inhibit oxotremorine-stimulated [ 35 S]GTP ⁇ S binding, the following was added to each well of 96 well plates: 25 ⁇ L of assay buffer with [ 35 S]GTP ⁇ S (0.4 nM), 25 ⁇ L of oxotremorine (EC 90 ) and GDP (3 ⁇ M), 25 ⁇ L of diluted test compound and 25 ⁇ L CHO cell membranes expressing the hM 2 receptor. The assay plates were then incubated at 37° C. for 60 minutes. The assay plates were filtered over 1% BSA-pretreated GF/B filters using a PerkinElmer 96-well harvester.
  • the plates were rinsed with ice-cold wash buffer for 3 ⁇ 3 seconds and then air or vacuum dried.
  • Microscint-20 scintillation liquid 50 ⁇ L was added to each well, and each plate was sealed and radioactivity counted on a topcounter (PerkinElmer).
  • Data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, Calif.) using the non-linear regression, one-site competition equation.
  • the Cheng-Prusoff equation was used to calculate the K i , using the IC 50 values of the concentration-response curve for the test compound and the oxotremorine concentration in the assay as the K D and [L], ligand concentration, respectively.
  • K i value indicates that the test compound has a higher functional activity at the receptor tested.
  • the compound of formula I was found to have a K i value of less than about 5 nM for blockade of oxotremorine-stimulated [ 35 S]GTP ⁇ S-binding in CHO-K1 cells expressing the hM 2 receptor, when tested in this or a similar assay.
  • Muscarinic receptor subtypes (M 1 , M 3 and M 5 receptors), which couple to G q proteins, activate the phospholipase C (PLC) pathway upon agonist binding to the receptor.
  • PLC phospholipase C
  • activated PLC hydrolyzes phosphatyl inositol diphosphate (PIP 2 ) to diacylglycerol (DAG) and phosphatidyl-1,4,5-triphosphate (IP 3 ), which in turn generates calcium release from intracellular stores, i.e., endoplasmic and sarcoplasmic reticulum.
  • the FLIPR (Molecular Devices, Sunnyvale, Calif.) assay capitalizes on this increase in intracellular calcium by using a calcium sensitive dye (Fluo-4AM, Molecular Probes, Eugene, Oreg.) that fluoresces when free calcium binds. This fluorescence event is measured in real time by the FLIPR, which detects the change in fluorescence from a monolayer of cells cloned with human M 1 and M 3 , and chimpanzee M 5 receptors.
  • Antagonist potency can be determined by the ability of antagonists to inhibit agonist-mediated increases in intracellular calcium.
  • CHO cells stably expressing the hM 1 , hM 3 and cM 5 receptors are seeded into 96-well FLIPR plates the night before the assay is done. Seeded cells are washed twice by Cellwash (MTX Labsystems, Inc.) with FLIPR buffer (10 mM HEPES, pH 7.4, 2 mM calcium chloride, 2.5 mM probenecid in HBSS without calcium and magnesium) to remove growth media and leaving 50 ⁇ L/well of FLIPR buffer. The cells are then incubated with 50 ⁇ L/well of 4 ⁇ M FLUO-4AM (a 2 ⁇ solution was made) for 40 minutes at 37° C., 5% carbon dioxide. Following the dye incubation period, cells are washed two times with FLIPR buffer, leaving a final volume of 50 ⁇ L/well.
  • FLIPR buffer 10 mM HEPES, pH 7.4, 2 mM calcium chloride, 2.5 mM probenecid in HBSS without calcium and magnesium
  • the dose-dependent stimulation of intracellular Ca 2+ release for oxotremorine is first determined so that antagonist potency can later be measured against oxotremorine stimulation at an EC 90 concentration.
  • Cells are first incubated with compound dilution buffer for 20 minutes, followed by agonist addition, which is performed by the FLIPR.
  • An oxotremorine concentration of 3 ⁇ EC F is prepared in stimulation plates such that an EC 90 concentration of oxotremorine is added to each well in the antagonist inhibition assay plates.
  • the parameters used for the FLIPR are: exposure length of 0.4 seconds, laser strength of 0.5 watts, excitation wavelength of 488 nm, and emission wavelength of 550 nm. Baseline is determined by measuring the change in fluorescence for 10 seconds prior to addition of agonist. Following agonist stimulation, the FLIPR continuously measured the change of fluorescence every 0.5 to 1 second for 1.5 minutes to capture the maximum fluorescence change.
  • the change of fluorescence is expressed as maximum fluorescence minus baseline fluorescence for each well.
  • the raw data is analyzed against the logarithm of drug concentration by nonlinear regression with GraphPad Prism (GraphPad Software, Inc., San Diego, Calif.) using the built-in model for sigmoidal dose-response.
  • Antagonist K i values are determined by Prism using the oxotremorine EC 50 value as the K D and the oxotremorine EC 90 for the ligand concentration according to the Cheng-Prusoff equation (Cheng & Prusoff, 1973).
  • a lower K i value indicates that the test compound has a higher functional activity at the receptor tested.
  • the compound of formula I was found to have a K i value of less than about 5 nM for blockade of agonist-mediated calcium release in CHO cells stably expressing the hM 3 receptor, when tested in this or a similar assay.
  • This in vivo assay is used to assess the bronchoprotective effects of test compounds exhibiting muscarinic receptor antagonist activity.
  • Groups of six male guinea pigs (Duncan-Hartley (HsdPoc:DH) Harlan, Madison, Wis.) weighing between 250 and 350 g are individually identified by cage cards. Throughout the study animals are allowed access to food and water ad libitum.
  • Test compounds are administered via inhalation over 10 minutes in a whole-body exposure dosing chamber (R&S Molds, San Carlos, Calif.).
  • the dosing chambers are arranged so that an aerosol was simultaneously delivered to 6 individual chambers from a central manifold.
  • Guinea pigs are exposed to an aerosol of a test compound or vehicle (WFI).
  • WFI test compound or vehicle
  • the gas flow through the nebulizer at this operating pressure is approximately 3 L/minute.
  • the generated aerosols are driven into the chambers by positive pressure. No dilution air is used during the delivery of aerosolized solutions. During the 10 minute nebulization, approximately 1.8 mL of solution is nebulized. This is measured gravimetrically by comparing pre-and post-nebulization weights of the filled nebulizer.
  • test compounds administered via inhalation are evaluated using whole body plethysmography at 1.5, 24, 48 and 72 hours post-dose.
  • each guinea pig is anesthetized with an intramuscular injection of ketamine (43.75 mg/kg), xylazine (3.50 mg/kg) and acepromazine (1.05 mg/kg).
  • ketamine 43.75 mg/kg
  • xylazine 3.50 mg/kg
  • acepromazine 1.05 mg/kg
  • a 2-3 cm midline incision of the ventral aspect of the neck was made.
  • the jugular vein is isolated and cannulated with a saline-filled polyethylene catheter (PE-50, Becton Dickinson, Sparks, Md.) to allow for intravenous infusions of ACh (Sigma-Aldrich, St. Louis, Mo.) in saline.
  • PE-50 saline-filled polyethylene catheter
  • the trachea is then dissected free and cannulated with a 14G teflon tube (#NE-014, Small Parts, Miami Lakes, Fla.). If required, anesthesia is maintained by additional intramuscular injections of the aforementioned anesthetic mixture. The depth of anesthesia is monitored and adjusted if the animal responds to pinching of its paw or if the respiration rate is greater than 100 breaths/minute.
  • the animal is placed into a plethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, Conn.) and an esophageal pressure cannula (PE-160, Becton Dickinson, Sparks, Md.) is inserted to measure pulmonary driving pressure (pressure).
  • PE-160 Becton Dickinson, Sparks, Md.
  • the teflon tracheal tube is attached to the opening of the plethysmograph to allow the guinea pig to breathe room air from outside the chamber. The chamber is then sealed.
  • a heating lamp is used to maintain body temperature and the guinea pig's lungs are inflated 3 times with 4 mL of air using a 10 mL calibration syringe (#5520 Series, Hans Rudolph, Kansas City, Mo.) to ensure that the lower airways do not collapse and that the animal does not suffer from hyperventilation.
  • a Buxco pulmonary measurement computer program enables the collection and derivation of pulmonary values.
  • Baseline values are collected for 5 minutes, after which time the guinea pigs are challenged with ACh.
  • ACh (0.1 mg/mL) is infused intravenously for 1 minute from a syringe pump (sp210iw, World Precision Instruments, Inc., Sarasota, Fla.) at the following doses and prescribed times from the start of the experiment: 1.9 ⁇ g/minute at 5 minutes, 3.8 ⁇ g/minute at 10 minutes, 7.5 ⁇ g/minute at 15 minutes, 15.0 ⁇ g/minute at 20 minutes, 30 ⁇ g/minute at 25 minutes and 60 ⁇ g/minute at 30 minutes.
  • syringe pump sp210iw, World Precision Instruments, Inc., Sarasota, Fla.
  • the guinea pig's lungs are inflated 3 times with 4 mL of air from a 10 mL calibration syringe.
  • Recorded pulmonary parameters includes respiration frequency (breaths/minute), compliance (mL/cm H 2 O) and pulmonary resistance (cm H 2 O mL per second).
  • the data are evaluated in one or both of the following ways:
  • Pulmonary resistance (a) Pulmonary resistance (R L , cm H 2 O/mL per second) is calculated from the ratio of “change in pressure” to “the change in flow.”
  • the R L response to ACh (60 ⁇ g/min, IH) is computed for the vehicle and the test compound groups.
  • the mean ACh response in vehicle-treated animals, at each pre-treatment time, is calculated and used to compute % inhibition of ACh response, at the corresponding pre-treatment time, at each test compound dose.
  • Inhibition dose-response curves for ‘R L ’ are fitted with a four parameter logistic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, Calif.) to estimate bronchoprotective ID 50 (dose required to inhibit the ACh (60 ⁇ g/min) bronchoconstrictor response by 50%).
  • the quantity PD 2 which is defined as the amount of ACh or histamine needed to cause a doubling of the baseline pulmonary resistance, is calculated using the pulmonary resistance values derived from the flow and the pressure over a range of ACh or histamine challenges using the following equation (which is derived from a equation used to calculate PC 20 values described in American Thoracic Society. Guidelines for methacholine and exercise challenge testing-1999 . Am J Respir Crit Care Med.
  • PD 2 antilog ⁇ [ log ⁇ ⁇ C 1 + ( log ⁇ ⁇ C 2 - log ⁇ ⁇ C 1 ) ⁇ ( 2 ⁇ R 0 - R 1 ) R 2 - R 1 ]
  • C 1 is the concentration of ACh or histamine preceding C 2
  • C 2 is the concentration of ACh or histamine resulting in at least a 2-fold increase in pulmonary resistance (R L )
  • R 0 is the baseline R L value
  • R 1 is the R L value after C 1
  • R 2 is the R L value after C 2 .
  • An efficacious dose is defined as a dose that limits the bronchrestriction response to a 50 ⁇ g/mL dose of ACh to a doubling of the baseline pulmonary resistance (PD 2(50) ).
  • test compounds having a PD 2(50) less than about 200 ⁇ g/mL for ACh-induced bronchoconstriction at 1.5 hours post-dose in this assay are preferred.
  • the compound of formula I is expected to have a PD 2 (50) less than about 200 ⁇ g/mL for ACh-induced bronchoconstriction at 1.5 hours post-dose, when tested in this or a similar assay.
  • Guinea pigs (Charles River, Wilmington, Mass.) weighing 200-350 g are acclimated to the in-house guinea pig colony for at least 3 days following arrival.
  • Test compound or vehicle are dosed via inhalation (IH) over a 10 minute time period in a pie shaped dosing chamber (R&S Molds, San Carlos, Calif.).
  • Test solutions are dissolved in sterile water and delivered using a nebulizer filled with 5.0 mL of dosing solution.
  • Guinea pigs are restrained in the inhalation chamber for 30 minutes. During this time, guinea pigs are restricted to an area of approximately 110 sq. cm. This space is adequate for the animals to turn freely, reposition themselves, and allow for grooming.
  • guinea pigs are exposed to an aerosol generated from a LS Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, Va.) driven by house air at a pressure of 22 psi.
  • a LS Star Nebulizer Set Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, Va.
  • guinea pigs are evaluated at 1.5, 6, 12, 24, 48, or 72 hrs after treatment.
  • Guinea pigs are anesthetized one hour before testing with an intramuscular (IM) injection of a mixture of ketamine 43.75 mg/kg, xylazine 3.5 mg/kg, and acepromazine 1.05 mg/kg at an 0.88 mL/kg volume.
  • Animals are placed ventral side up on a heated (37° C.) blanket at a 20 degree incline with their head in a downward slope.
  • a 4-ply 2 ⁇ 2 inch gauze pad (Nu-Gauze General-use sponges, Johnson and Johnson, Arlington, Tex.) is inserted in the guinea pig's mouth.
  • the mean weight of saliva in vehicle-treated animals, at each pre-treatment time, is calculated and used to compute % inhibition of salivation, at the corresponding pre-treatment time, at each dose.
  • the inhibition dose-response data are fitted to a four parameter logistic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, Calif.) to estimate anti-sialagogue ID 50 (dose required to inhibit 50% of pilocarpine-evoked salivation).
  • the ratio of the anti-sialagogue ID 50 to bronchoprotective ID 50 is used to compute the apparent lung selectivity index of the test compound.
  • compounds having an apparent lung selectivity index greater than about 5 are preferred.
  • the compound of formula I is expected to have an apparent lung-selectivity index greater than about 5, when tested in this or a similar assay.
  • the animals are weighed and the carotid artery catheter on each animal is connected to a transducer for recording arterial pressure. Arterial pressure and heart rate are recorded using a Biopac MP-100 Acquisition System. Animals are allowed to acclimate and stabilize for a period of 20 minutes.
  • Each animal is challenged with MCh (0.3 mg/kg, IV) administered through the jugular venous line and the cardiovascular response is monitored for 10 minutes.
  • the animals are then placed into the whole body dosing chamber, which is connected to a nebulizer containing the test compound or vehicle solution.
  • the solution is nebulized for 10 minutes using a gas mixture of breathable air and 5% carbon dioxide with a flow rate of 3 liters/minute.
  • the animals are then removed from the whole body chamber and returned to their respective cages.
  • the animals are re-challenged with MCh (0.3 mg/kg, IV) and the hemodynamic response is determined. Thereafter, the animals are euthanized with sodium pentobarbital (150 mg/kg, IV).
  • MCh produces a decrease in mean arterial pressure (MAP) and decrease in heart rate (bradycardia).
  • MAP mean arterial pressure
  • MAP heart rate
  • the peak decrease, from baseline, in MAP (depressor responses) is measured for each MCh challenge (before and after IH dosing).
  • the effects of treatment on the MCh responses are expressed as % inhibition (mean+/ ⁇ SEM) of the control depressor responses.
  • Two-way ANOVA with the appropriate post-hoc test is used to test the effects of treatment and pre-treatment time.
  • the depressor responses to MCh are expected to be relatively unchanged at 1.5 and 24 hours after inhalation dosing with vehicle.
  • the ratio of the anti-depressor ID 50 to bronchoprotective ID 50 is used to compute apparent lung-selectivity of the test compound. Generally, compounds having an apparent lung-selectivity index greater than 5 are preferred. The compound of formula I is expected to have an apparent lung-selectivity index greater than 5, when tested in this or a similar assay.

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US12/563,727 US8242137B2 (en) 2005-03-10 2009-09-21 Crystalline forms of a biphenyl compound
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US12/817,543 US8377965B2 (en) 2005-03-10 2010-06-17 Crystalline forms of a biphenyl compound
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US14/552,893 US9249099B2 (en) 2005-03-10 2014-11-25 Crystalline forms of a biphenyl compound
US14/974,980 US9656993B2 (en) 2005-03-10 2015-12-18 Crystalline forms of a biphenyl compound
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WO2011008809A1 (en) 2009-07-15 2011-01-20 Theravance, Inc. Crystalline freebase forms of a biphenyl compound
WO2011083387A1 (en) * 2010-01-07 2011-07-14 Pfizer Limited Hydrochloride salt of biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl}-piperidin-4-yl ester
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