Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

• the present invention is related to novel processes for preparing anhydrous and hydrated forms of piperidine derivatives, polymorphs and pseudomorphs thereof which are useful as antihistamines, antiallergic agents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981 and U.S. Pat. No. 4,285,958, Apr. 25, 1981].
• the present invention provides a process for preparing anhydrous, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formulas
• R 1 represents hydrogen or hydroxy
• R 2 represents hydrogen
• n is an integer of from 1 to 5;
• R 3 is —CH 2 OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
• each of A is hydrogen or hydroxy
• the present invention also provides a process for preparing anhydrous, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula
• R 1 represents hydrogen or hydroxy
• R 2 represents hydrogen
• R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 ;
• n is an integer of from 1 to 5;
• R 3 is —CH 2 OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
• each of A is hydrogen or hydroxy
• the present invention provides a process for preparing the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula
• R 1 represents hydrogen or hydroxy
• R 2 represents hydrogen
• R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 ;
• n is an integer of from 1 to 5;
• R 3 is —CH 2 OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
• each of A is hydrogen or hydroxy
• the present invention provides processes for preparing polymorphs of anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride designated herein as Form I and Form III and processes for preparing psuedomorphs of hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride designated herein as Form II and Form IV.
• the Form I polymorph may be identified by the following characteristics: a visual melting point (capillary tube) in the range of about 196-201° C.; a melt endotherm with extrapolated onset in the range of about 195-199° C. as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern essentially as shown in Table 1 wherein the XRPD patterns were measured using a powder diffractometer equipped with a Co X-ray tube source. The sample was illuminated with Co K ⁇ l radiation and XRPD data were collected from 5 to 55° 2 ⁇ . (intensities may vary radically due to preferred orientation). TABLE 1 D-Space, Angstroms Intensity, I/I O , % 11.8 30 7.3 30 6.3 65 5.9 35 5.0 45 4.8 100 4.4 45 3.9 60 3.8 75 3.7 30
• the Form III polymorph may be identified by the following characteristics: a visual melting point (capillary tube) in the range of about 166-171° C.; a broad endotherm below about 90° C., a melt endotherm with an extrapolated onset of about 166° C. as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern essentially as shown in Table 2 wherein the XRPD patterns were measured using a powder diffractometer equipped with a Co X-ray tube source. The sample was illuminated with Co K ⁇ l radiation and XRPD data were collected from 5 to 55° 2 ⁇ . (intensities may vary radically due to preferred orientation). TABLE 2 D-Space, Angstroms Intensity, I/I O , % 9.0 95 4.9 100 4.8 35 4.6 25 4.5 25 3.7 25
• the Form II pseudomorph may be identified by the following characteristics: a visual melting point (capillary tube) in the range of about 100-105° C.; a large broad endotherm below about 100° C. and a small endothermic peak (about 2 joules/gram) with extrapolated onsets in the range of about 124-126° C. as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern essentially as shown in Table 3 wherein the XRPD patterns were measured using a powder diffractometer equipped with a Co X-ray tube source. The sample was illuminated with Co K ⁇ l radiation and XRPD data were collected from 5 to 55° 2 ⁇ . (intensities may vary radically due to preferred orientation). TABLE 3 D-Space, Angstroms Intensity, I/I O , % 7.8 45 6.4 44 5.2 85 4.9 60 4.7 80 4.4 55 4.2 50 4.1 60 3.7 75 3.6 60 3.5 50
• the Form IV pseudomorph may be identified by the following characteristics: a visual melting point (capillary tube) in the range of about 113-118° C.; two broad overlapping endotherms below about 100° C. and an additional endotherm with an extrapolated onset at approximately 146° C. as determined by differential scanning calorimetry and an X-ray powder diffraction pattern essentially as shown in Table 4 wherein the XRPD patterns were measured using a powder diffractometer equipped with a Co X-ray tube source. The sample was illuminated with Co K ⁇ l radiation and XRPD data were collected from 5 to 55° 2 ⁇ . (intensities may vary radically due to preferred orientation). TABLE 4 D-Space, Angstroms Intensity, I/I O , % 10.4 60 7.0 45 6.4 50 5.3 100 5.2 55 4.3 75 4.1 50 4.0 45 3.8 60 3.5 55
• Pharmaceutically acceptable acid addition salts of the compounds of formula (I) and (II), both anhydrous and hydrated, are those of any suitable inorganic or organic acid.
• suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric, and phosphoric acids.
• Suitable organic acids include carboxylic acids, such as, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids, such as, methanesulfonic, ethanesulfonic and ⁇ -hydroxyethanesulfonic acid.
• carboxylic acids such as, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, and dihydroxy
• hydrate refers to a combination of water with a compound of formula (I) or (II) wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the substrate molecule of formula (I) or (II).
• the term “adsorped” refers to the physical state wherein the water molecule in the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) is distributed over the surface of the solid hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II).
• the term “absorbed” refers to the physical state wherein the water molecule in the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) is distributed throughout the body of the solid hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II).
• Hydrated, pharmaceutically acceptable acid addition salts of the compounds of formula (I) and (II) are those hydrates ranging from essentially 0.10 to 5 molecules of water per molecule of substrate salt of formula (I) or (II).
• azeotropic mixture refers to a liquid mixture of two or more substances which behaves like a single substance in that the vapor produced by partial evaporation of liquid has the same composition as the liquid.
• the constant boiling mixture exhibits either a maximum or minimum boiling point as compared with that of other mixtures of the same substance.
• azeotropic distillation refers to a type of distillation in which a substance is added to the mixture to be separated in order to form an azeotropic mixture with one or more of the constituents of the original mixture.
• the azeotrope or azeotropes thus formed will have boiling points different from the boiling points of the original mixture.
• azeotropic distillation also refers to co-distillation.
• water-minimizing recrystallization refers to a recrystallization wherein the ratio of anhydrous solvent to substrate hydrate is such that the percentage of water present is minimized, thereby inducing precipitation of the anhydrous form of the substrate.
• aqueous recrystallization refers to those processes wherein either 1) a solid material is dissolved in a volume of water or a water/organic solvent mixture sufficient to cause dissolution and the solid material recovered by evaporation of the solvent; 2) a solid material is treated with a minimal amount of water or a water/organic solvent mixture which is not sufficient to cause dissolution, heated to obtain dissolution and cooled to induce crystallization or 3) a solid material is dissolved in a volume of water or a water/organic solvent mixture sufficient to cause dissolution and then the solvent is partially evaporated to form a saturated solution which induces crystallization.
• crystal digestion refers to that process wherein a solid material is treated with a minimal amount of water or water/organic solvent mixture which is not sufficient to cause dissolution and either heating or stirring at ambient temperature until the desired transformation has taken place.
• antisolvent refers to a poor solvent for the substance in question which when added to a solution of the substance, causes the substance to precipitate.
• suitable temperature refers to that temperature which is sufficient to cause dissolution and to permit the precipitation of the desired substance either upon addition of an antisolvent or upon removal of the co-solvent by azeotropic distillation.
• the anhydrous, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) may be prepared from the corresponding hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) by subjecting the corresponding hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) to an azeotropic distillation.
• the appropriate hydrated, pharmaceutically acceptable acid addition salt of piperidine derivatives of the formula (I) and (II) is first dissolved in a volume of a suitable solvent or solvent mixture which is sufficient to cause dissolution.
• suitable solvent or solvent mixture examples include water, C 1 -C 5 alkanols such as methanol, ethanol and the like; ketone solvents such as acetone, methyl ethyl ketone and the like; aliphatic ester solvents such as ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl acetate and the like and aqueous mixtures of these solvents, such as acetone/water, methyl ethyl ketone/water, water/acetone and water/acetone/ethyl acetate.
• Suitable anhydrous antisolvents for use in the azeotropic distillation are, for example, ketone solvents such as acetone, methyl ethyl ketone and the like; aliphatic ester solvents such as ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl acetate and the like; C 5 -C 8 aliphatic solvents such as pentane, hexane and the like; aliphatic nitrites, such as acetonitrile and mixtures of these solvents such as acetone/ethyl acetate and the like.
• the azeotropic mixture of water and solvent is removed by distillation until the temperature changes, indicating that the azeotropic mixture is completely removed.
• the reaction mixture is cooled and the corresponding anhydrous, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) is recovered from the reaction zone by, for example filtration.
• anhydrous, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) may be prepared from the corresponding hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) by subjecting the corresponding hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) to a water-minimizing recrystallization.
• the appropriate hydrated, pharmaceutically acceptable acid addition salt of piperidine derivatives of the formula (I) and (II) is dissolved in a volume of a suitable anhydrous solvent or solvent mixture which is sufficient to cause dissolution and heated to reflux.
• solvents examples include water, C 1 -C 5 alkanols such as methanol, ethanol and the like; ketone solvents such as acetone, methyl ethyl ketone and the like; aliphatic ester solvents such as ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl acetate and the like and aqueous mixtures of these solvents, such as acetone/water, methyl ethyl ketone/water, water/acetone and water/acetone/ethyl acetate.
• Suitable anhydrous antisolvents are, for example, ketone solvents such as acetone, methyl ethyl ketone and the like;
• aliphatic ester solvents such as ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl acetate and the like; mixtures of ketone solvents and aliphatic ester solvents such as acetone/ethyl acetate and the like;
• C 5 -C 8 aliphatic solvents such as pentane, hexane and the like; aliphatic nitriles, such as acetonitrile and mixtures of these solvents such as acetone/ethyl acetate and the like as well as mixtures of water and ketone solvents such as acetone/water and the like; and mixtures of water, ketone solvents and aliphatic ester solvents such as acetone/water/ethyl acetate.
• the reaction mixture is cooled and the corresponding anhydrous, pharmaceutically acceptable acid addItion salt of piperidine derivatives of the formula (I) and (II) is recovered from the reaction zone by, for example filtration.
• anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride may be prepared from anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form III), by subjecting the anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form III) to a crystal digestion as described above.
• anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride may be prepared from hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form II), by subjecting the hydrated 4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form II) to water-minimizing recrystallization as described above.
• anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride may be prepared from hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form II), by subjecting the hydrated 4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form II) to water-minimizing recrystallization as described above or by subjecting the hydrated 4-[4-[4-[4-(Hydroxydiphenylmethyl)-1piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (For
• anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride may be prepared from hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form IV), by subjecting the hydrated 4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form IV) to water-minimizing recrystallization or to an azeotropic distillation as described above.
• the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) may be prepared from the corresponding compound of the formula (II) wherein R 3 is —COOalkyl by subjecting the corresponding compound of the formula (II) wherein R 3 is —COOalkyl to a reduction using an appropriate reducing agent, such as sodium borohyride, potassium borohydride, sodium cyanoborohydride, or tetramethylammonium borohydride in a suitable solvent, such as, methanol, ethanol, isopropyl alcohol or n-butanol, aqeuous mixtures thereof or basic solutions thereof, at temperatures ranging from about 0° C.
• an appropriate reducing agent such as sodium borohyride, potassium borohydride, sodium cyanoborohydride, or tetramethylammonium borohydride in a suitable solvent, such as, methanol, ethanol, isopropyl alcohol or n-butanol,
• reaction time varies from about 1 ⁇ 2 hour to 8 hours.
• an suitable acid such as hydrochloric acid
• the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) are recovered from the reaction zone by crystallization and filtration.
• the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II) may be prepared from the corresponding anhydrous, pharmaceutically acceptable acid addition salts of the formula (I) and (II) by subjecting the corresponding anhydrous, pharmaceutically acceptable acid addition salts of formula (I) and (II) to an aqueous recrystallization.
• the appropriate anhydrous, pharmaceutically acceptable acid addition salt of piperidine derivatives of the formula (I) and (II) is treated with a minimal volume of water or suitable water/organic solvent mixture which is insufficient to cause dissolution and heated to reflux.
• the reaction mixture is cooled and the corresponding hydrated, pharmaceutically acceptable acid addition salt of piperidine derivatives of the formula (I) and (II) is recovered from the reaction zone by, for example filtration.
• the appropriate anhydrous, pharmaceutically acceptable acid addition salt of piperidine derivatives of the formula (I) and (II) is treated with a volume of water or a suitable water/organic solvent mixture which is sufficient to cause dissolution and the water or water/organic solvent is partially or completely evaporated to a volume which induces crystallization of the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) and (II).
• Suitable solvents for use in the above recrystallization are water, acetone/water, ethanol/water, methyl ethyl ketone/aqueous methanol, methyl ethyl ketone/water and the like.
• Ethyl Ester/Ketone to Form II Hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form IV) may be prepared from ethyl 4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]- ⁇ , ⁇ -dimethylbenzeneacetate, hydrochloride or free base as described above for the general preparation of the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) from the corresponding compound of the formula (II) wherein R 3 is —COOalkyl, but rapdily adding water over a period of time ranging from 1 minute to 45 minutes at a temperature range of about ⁇ 20° C.
• Hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride may be prepared from ethyl 4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]- ⁇ , ⁇ -dimethylbenzeneacetate, hydrochloride or free base as described above for the general preparation of the hydrated, pharmaceutically acceptable acid addition salts of piperidine derivatives of the formula (I) from the corresponding compound of the formula (II) wherein R 3 is —COOalkyl, but slowly adding water over a period of time ranging from about 30 minutes to 24 hours and at a temperature range of about 0° C.
• Hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride may be prepared from anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form I) by subjecting hydrated 4-[4-[4(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride (Form II) to an aqueous recrystallization as defined above.
• g refers to grams; “mol” refers to mole; “mmol” refers to millimoles; “mL” refers to milliliters; “bp” refers to boiling point; “mp” refers to melting point; “° C.” refers to degrees Celsius; “mm Hg” refers to millimeters of mercury; “uL” refers to microliters; “Ugg” refers to micrograms; and “ ⁇ M” refers to micromolar.
• the samples were loaded into a quartz (zero scatter) sample holder for the XRPD pattern measurement.
• the XRPD patterns were measured using a powder diffractometer equipped with a Co X-ray tube source, primary beam monochromator, and position sensitive detector (PSD). The incident beam was collimated using a 10 divergence slit. The active area on the PSD subtended approximately 5° 2 ⁇ .
• the source was operated at 35 kV and 30 mA and the sample was illuminated with Co K ⁇ l radiation.
• XRPD data were collected from 5 to 55° 2 ⁇ at a rate of 0.25° 2 ⁇ /minute and a step width of 0.02° 2 ⁇ .
• the XRPD patterns were measured without the addition of an internal calibrant.
• Peak positions and intensities for the most prominent features were measured using a double-derivative peak picking method. X-ray peaks with I/I o greater than 20% were reported. The cutoff was chosen arbitrarily. The intensities are rounded to the nearest 5%. Certain peaks appear sensitive to preferred orientation that is caused by changes in crystallite morphology. This results in large changes in the I/Io value.
• XRPD Table 5 reflux. Reflux for 10 minutes, then slowly add additional ethyl acetate (23 mL over 10 minutes) and reflux for an additional 15 minutes. Add additional ethyl acetate (60 mL over 5-10 minutes) and continue refluxing for 15 minutes. Cool to approximately 8° C. in an ice bath, filter the solid and wash with ethyl acetate (85 mL). Vacuum dry at 55° C. for 1.5 hours to give the title compound (18.16 g, 95%).
• polymorphic and pseudomorphic 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compounds of this invention are useful as antihistamines, antiallergy agents and bronchodilators and may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions or emulsions.
• polymorphic and pseudomorphic 4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compounds of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or by application to mucous membranes, such as, that of the nose, throat and bronchial tubes, for example, in an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form.
• the quantity of polymorphic or pseudomorphic 4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compound administered will vary depending on the patient and the mode of administration and can be any effective amount.
• the quantity of polymorphic or pseudomorphic 4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compound administered may vary over a wide range to provide in a unit dosage an effective amount of from about 0.01 to 20 mg/kg of body weight of the patient per day to achieve the desired effect.
• the desired antihistamine, antiallergy and bronchodilator effects can be obtained by consumption of a unit dosage form such as a tablet containing 1 to 500 mg of a polymorphic or pseudomorphic 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compound of this invention taken 1 to 4 times daily.
• a unit dosage form such as a tablet containing 1 to 500 mg of a polymorphic or pseudomorphic 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compound of this invention taken 1 to 4 times daily.
• the solid unit dosage forms can be of the conventional type.
• the solid form can be a capsule which can be the ordinary gelatin type containing a polymorphic or pseudomorphic 4-[4-[4-(hydroxydiphenylmethyl)-1piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compound of this invention and a carrier, for example, lubricants and inert fillers such as lactose, sucrose or cornstarch.
• polymorphic or pseudomorphic 4-[4-[4(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compound is tableted with conventional tablet bases such as lactose, sucrose or cornstarch or gelatin, disintegrating agents such as cornstarch, potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.
• the polymorphic or pseudomorphic 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzeneacetic acid hydrochloride compounds of this invention may also be administered in injectable dosages by solution or suspension of the compounds in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
• oils there can be mentioned those of petroleum, animal, vegatable or synthetic origin, for example, peanut oil, soybean oil or mineral oil.
• water, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
• the compounds of this invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants such as, propane, butane or isobutane with the usual adjuvants as may be administered in a non-pressurized form such as in a nebulizer or atomizer.
• suitable propellants for example, hydrocarbon propellants such as, propane, butane or isobutane with the usual adjuvants as may be administered in a non-pressurized form such as in a nebulizer or atomizer.
• patient as used herein is taken to mean warm blooded animals, birds, mammals, for example, humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.

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• 1995
  • 1995-04-28 CN CN95193122A patent/CN1148849A/zh active Pending
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  • 1995-04-28 EP EP10180285A patent/EP2354125A1/en not_active Withdrawn
  • 1995-04-28 AT AT95918278T patent/ATE220667T1/de active
  • 1995-04-28 CA CA002189007A patent/CA2189007C/en not_active Expired - Lifetime
  • 1995-04-28 CN CN2006101031426A patent/CN1907967B/zh not_active Expired - Lifetime
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  • 1995-04-28 EP EP01124314A patent/EP1178041A1/en not_active Withdrawn
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  • 1995-04-28 CA CA2585705A patent/CA2585705C/en not_active Expired - Lifetime
  • 1995-04-28 EP EP95918278A patent/EP0766668B1/en not_active Expired - Lifetime
  • 1995-04-28 DK DK95918278T patent/DK0766668T3/da active
  • 1995-04-28 CN CNA2003101007654A patent/CN1623985A/zh active Pending
  • 1995-05-16 IL IL11374795A patent/IL113747A/en not_active IP Right Cessation
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• 1996
  • 1996-11-14 FI FI964565A patent/FI964565A0/fi unknown
  • 1996-11-15 NO NO19964859A patent/NO315319B1/no not_active IP Right Cessation
• 2000
  • 2000-03-07 IL IL13491700A patent/IL134917A0/xx unknown
• 2001
  • 2001-03-09 US US09/803,389 patent/US20010012896A1/en not_active Abandoned
  • 2001-03-09 US US09/803,476 patent/US20010025106A1/en not_active Abandoned
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• 2002
  • 2002-03-01 JP JP2002055431A patent/JP2002308849A/ja active Pending
  • 2002-03-01 JP JP2002055434A patent/JP4503909B2/ja not_active Expired - Lifetime
  • 2002-03-01 JP JP2002055435A patent/JP2002316978A/ja not_active Withdrawn
  • 2002-03-01 JP JP2002055432A patent/JP4503907B2/ja not_active Expired - Lifetime
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  • 2002-04-24 US US10/128,926 patent/US20020193600A1/en not_active Abandoned
  • 2002-06-03 US US10/160,883 patent/US7135571B2/en not_active Expired - Fee Related
  • 2002-06-03 US US10/162,011 patent/US7138524B2/en not_active Expired - Fee Related
  • 2002-08-07 US US10/214,262 patent/US20030045721A1/en not_active Abandoned
• 2003
  • 2003-03-10 US US10/386,812 patent/US20040014976A1/en not_active Abandoned
• 2006
  • 2006-09-25 US US11/534,828 patent/US7666881B2/en not_active Expired - Fee Related
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• 2007
  • 2007-05-04 HK HK07104744.4A patent/HK1098467A1/xx not_active IP Right Cessation
  • 2007-10-30 US US11/978,669 patent/US20080167469A1/en not_active Abandoned
  • 2007-10-30 US US11/978,670 patent/US20080167471A1/en not_active Abandoned
• 2010
  • 2010-02-05 HK HK10101357.3A patent/HK1137742A1/xx not_active IP Right Cessation
  • 2010-02-24 JP JP2010038971A patent/JP2010120969A/ja active Pending

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