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WO1998023612A1 - Composes 2-imidazolinylaminobenzothiazole utiles en tant qu'agonistes de l'adrenorecepteur alpha-2 - Google Patents

Composes 2-imidazolinylaminobenzothiazole utiles en tant qu'agonistes de l'adrenorecepteur alpha-2 Download PDF

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Publication number
WO1998023612A1
WO1998023612A1 PCT/US1997/020549 US9720549W WO9823612A1 WO 1998023612 A1 WO1998023612 A1 WO 1998023612A1 US 9720549 W US9720549 W US 9720549W WO 9823612 A1 WO9823612 A1 WO 9823612A1
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Prior art keywords
unsubstituted
alkanyl
halo
alkoxy
alkylthio
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PCT/US1997/020549
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English (en)
Inventor
Thomas Lee Cupps
Sophie Eva Bogdan
Raymond Todd Henry
Russell James Sheldon
William Lee Seibel
Jeffrey Joseph Ares
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The Procter & Gamble Company
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Priority to AU54338/98A priority Critical patent/AU5433898A/en
Publication of WO1998023612A1 publication Critical patent/WO1998023612A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain substituted (2- imidazolinylamino)benzothiazole compounds.
  • the compounds have been found to be alpha-2 adrenoceptor agonists and are useful for treatment of disorders modulated by alpha-2 adrenoceptors.
  • alpha-2 adrenoceptor agonists have been discussed in the literature: Ruffolo, R.R., A.J. Nichols, J.M. Stadel, & J.P. Hieble, "Pharmacologic and Therapeutic Applications of Alpha-2 Adrenoceptor Subtypes", Annual Review of Pharmacology & Toxicology. Vol. 32 (1993) pp. 243-279.
  • COPD chronic obstructive pulmonary disease
  • diseases and disorders associated with sympathetic nervous system activity including benign prostatic hypertrophy, cardiovascular disorders comprising myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and hypertension.
  • ocular disorders such as ocular hypertension, glaucoma, hyperemia, conjunctivitis and uveitis.
  • gastrointestinal disorders such as diarrhea, irritable bowel syndrome, hyperchlorhydria (hyperacidity) and peptic ulcer (ulcer).
  • This invention relates to compounds having the following structure:
  • R-j , R2 and R3 are each independently selected from hydrogen; unsubstituted C-1-C3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C1-C3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C1-C3 alkylamino or C1-C3 dialkylamino and halo; b) R4 is selected from hydrogen; unsubstituted C-1-C3 alkanyl; amino, hydroxy, mercapto; C1-C3 alkylthio or alkoxy; C1-C3 alkylamino or C1-C3 dialkylamino and halo; c) R5 is hydrogen; or alkyl or nil; d) where R5 is nil, bond (a) is a double bond; and e) the imidazol
  • alkanyl means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted.
  • alkenyl means a hydrocarbon substituent with one double bond, straight or branched chain, unsubstituted or substituted.
  • alkylthio means a substituent having the structure Q-S-, where Q is alkanyl or alkenyl.
  • alkoxy means a substituent having the structure Q-0-, where Q is alkanyl or alkenyl.
  • alkylamino means a substituent having the structure Q-NH-, where Q is alkanyl or alkenyl.
  • dialkylamino means a substituent having the structure Q ⁇
  • Halo is a chloro, bromo, fluoro or iodo.
  • a "pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group.
  • Preferred cationic salts include the alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium) and organic salts.
  • Preferred anionic salts include halides, sulfonates, carboxylates, phosphates, and the like.
  • addition salts that may provide an optical center, where once there was none.
  • a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts.
  • the compounds of the invention are sufficiently basic to form acid- addition salts.
  • the compounds are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention.
  • the acid-addition salts are in some cases a more convenient form for use. In practice, the use of the salt form inherently amounts to the use of the base form of the active.
  • Acids used to prepare acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts. These salts have anions that are relatively innocuous to the animal organism, such as a mammal, in medicinal doses of the salts so that the beneficial property inherent in the free base are not vitiated by any side effects ascribable to the acid's anions.
  • acids-addition salts include, but at not limited to hydrochloride, hydrobromide, hydroiodiode, sulfate, hydrogensulfate, acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate, stearate, succinate, mallate, malonate, adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate, cyclohexanesulfamate, and the like.
  • salts within the scope of the invention are those derived from other mineral acids and organic acids.
  • the acid-addition salts of the basic compounds are prepared by several methods.
  • the free base can be dissolved in an aqueous alcohol solution containing the appropriate acid and the salt is isolated by evaporation of the solution.
  • they may be prepared by reacting the free base with an acid in an organic solvent so that the salt separates directly. Where separation of the salt is difficult, it can be precipitated with a second organic solvent, or can be obtained by concentration of the solution.
  • all acid-addition salts are within the scope of the present invention. All acid-addition salts are useful as sources of the free base form, even if the particular salt per se is desired only as an intermediate product. For example, when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange procedures, these salts are clearly contemplated to be a part of this invention.
  • Biohydrolyzable amide refers to an amide of the compound of the invention that is readily converted m vivo by a mammal subject to yield an active compound of the invention.
  • a “biohydrolyzable ester” refers to an ester of the compound of the invention that is readily converted by a mammal subject to yield an active compound of the invention.
  • Optical isomer "stereoisomer”, “enantiomer,” “diastereomer,” as referred to herein have the standard art recognized meanings (Cf., Hawlevs Condensed Chemical Dictionary. 11th Ed.).
  • an addition salt may provide an optical center, where once there was none.
  • a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts. It will be apparent to the skilled artisan that disclosure of the racemic mixture alone discloses any enantiomers therein. Thus by one disclosure, more than one compound is taught.
  • animal includes “mammals” which includes “humans”.
  • substituent groups may themselves be substituted. Such substitution may be with one or more substituents.
  • substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein.
  • Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyacetyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
  • alkyl alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyacetyl (e.g., carboethoxy, etc.), thiol,
  • This invention includes compounds having the following structure:
  • , R2 and R3 are each independently selected from hydrogen; unsubstituted C1-C3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C1-C3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C1-C3 alkylamino or C-1-C3 dialkylamino and halo; b) R4 is selected from hydrogen; unsubstituted C1-C3 alkanyl; amino, hydroxy, mercapto; C1-C3 alkylthio or alkoxy; C1-C3 alkylamino or C1-C3 dialkylamino and halo; c) R5 is hydrogen; or alkyl or nil; d) where R5 is nil, bond (a) is a double bond; and e) the imidazoliny
  • R-j is preferably unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms and R2 is preferably alkanyl or halo. R1 and R2 are most preferably methyl.
  • R2 is preferably selected from unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; cycloalkyi and cycloalkenyl; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano; and halo.
  • R-j is preferably hydrogen, cyano, halo or methyl.
  • R2 is also preferably alkanyl, more preferably methyl or ethyl, most preferably ethyl.
  • R2 is also preferably cycloalkyi, more preferably cyclopropyl; R2 which is alkenyl is preferably ethenyl. R2 which is alkylthio or alkoxy is preferably saturated, also preferably Ci or C2, most preferably methylthio or methoxy. R2 which is halo is preferably chloro or bromo.
  • Preferred compounds of this invention have the following structure:
  • Imidazolinylamino groups are conveniently prepared from nitro and amino compounds via the following example synthetic sequence:
  • these compounds are made from nitro or amino compounds, for example those described above.
  • the above starting nitro and amino compounds are obtained via one or more synthetic steps comprising alkylations, halogenations (usually brominations), and halogen displacement reactions. These reaction types are summarized below;
  • chlorination is accomplished using CI2, and iodination, by ICI using the same reactions.
  • Z O, S, NR
  • the starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available as a starting material.
  • A. 4-Methyl-5-nitrobenzothiazole To a solution of 135 mg of 5- nitrobenzothiazole in 7 mL of tetrahydrofuran is added 0.59 mL of a 1.4 M solution of methylmagnesium bromide in toluene/tetrahydrofuran. The mixture is stirred at 0 °C for 30 minutes, and then a solution of 204 mg of 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone in 2 mL of tetrahydrofuran is added. The mixture is stirred for 1 hour, poured into a solution of 5% aqueous acetic acid, and extracted with methylene chloride.
  • A. 4-Ethyl-5-nitrobenzothiazole To a solution of 50 mg of 5- nitrobenzothiazole in 3.5 mL of tetrahydrofuran is added 0.306 mL of a 1 M solution of ethylmagnesium bromide in tetrahydrofuran. The mixture is stirred at 0 °C for 10 minutes, and then a solution of 75 mg of 2,3- dichloro-5,6-dicyano-1 ,4-benzoquinone in 3 mL of tetrahydrofuran is added. The mixture is stirred for 30 minutes, poured into a solution of 5% aqueous acetic acid, and extracted with methylene chloride.
  • Example 3 7-Cvano-5-(2-imidazolinylamino)-4-methylbenzothiazole.
  • 91 mg of silver sulfate and 2 mL of concentrated sulfuric acid is added 0.042 mL of bromine, and the mixture is stirred at room temperature for 2 days.
  • the reaction mixture is subsequently poured into ice and extracted with ether.
  • the combined ether extracts are washed with aqueous sodium bicarbonate solution and brine. Evaporation affords 72 mg of 7-bromo-4- methyl-5-nitrobenzothiazole.
  • D. 7-Cvano-5-isothiocvanato-4-methylbenzothiazole A solution of 65 mg of 5-amino-7-cyano-4-methylbenzothiazole, 86 mg of di-2-pyridyl thionocarbonate, 9 mg of 4-dimethylaminopyridine and 12 mL of methylene chloride is stirred at room temperature for 2 hours. After evaporation, the crude product is dissolved in benzene and purified by silica gel chromatography to provide 61 mg of 7-cyano-5-isothiocyanato- 4-methylbenzothiazole.
  • A. 5-Amino-4-cyclopropylbenzothiazole To a cooled (0 °C) solution of 0.2 g of 5-nitrobenzothiazole in 3 mL of dry tetrahydrofuran are added dropwise 2.78 mL of 1M cyclopropylmagnesium bromide ' ' (1M in tetrahydrofuran). The mixture is stirred at room temperature for 3 hours, then cooled to 0 °C. A solution of 0.25 g of 2,3-dichloro-5,6-dicyano-1 ,4- benzoquinone (DDQ) in 2 mL of tetrahydrofuran is added dropwise and the mixture is stirred at room temperature for 30 minutes.
  • DDQ 2,3-dichloro-5,6-dicyano-1 ,4- benzoquinone
  • the reaction mixture is diluted with water (7 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers are dried over sodium sulfate, filtered, and rotary evaporated. The residue is combined with 1.25 g of stannous chloride dihydrate and 25 mL of ethanol and is heated to 60 °C for 2 hours. After cooling to room temperature, the mixture is diluted with water (50 mL), basified with 50% aqueous sodium hydroxide and extracted with ethyl acetate (3 x 75 mL). The combined organic layers are dried over sodium sulfate, filtered, and rotary evaporated.
  • reaction mixture is rotary evaporated and the residue is purified by an aspirator vacuum filtration on silica gel eluting with 8:2:0.1- methylene chloride:methanol:concentrated ammonium hydroxide to provide 11 mg of 4-cyclopropyl-5-(2-imidazolinylamino)benzothiazole.
  • A. 4-Methoxy-5-nitrobenzothiazole Sodium methoxide (1.88 g) is added to a well-stirred suspension of 4-bromo-5-nitrobenzothiazole (0.90 g) in 55 mL of methanol. The reaction mixture is heated to gentle reflux for 4 hours. Methanol is removed by evaporation, and the residue is dissolved in water and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give 0.83 g of the crude product. Purification by flash column chromatography on silica gel (10% ethyl acetate/hexane) produces 0.44 g of 4-methoxy-5- nitrobenzothiazole as a light yellow solid.
  • B 5-Amino-4-methoxybenzothiazole.
  • a mixture of 0.44 g of 4-methoxy-5- nitrobenzothiazole, 0.70 g of iron powder, 0.18 g of ammonium chloride, and 42 mL of 2:1 ethanol:water is heated to reflux for 1 hour.
  • the hot mixture is filtered through Celite, and the filtrate is concentrated in vacuo.
  • the resulting residue is diluted with water and extracted with ethyl acetate.
  • the organic extract is dried over magnesium sulfate and concentrated to give 0.37 g of 5-amino-4-methoxybenzothiazole as a light brown solid.
  • C 5-lsothiocvanato-4-methoxybenzothiazole.
  • Di-2-pyridyl thionocarbonate (0.47 g) and 4-dimethylaminopyridine (0.06 g) are added to a solution of 5-amino-4-methoxybenzothiazole (0.37 g) in 40 mL of methylene chloride. The mixture is stirred at room temperature for 1 hour. The reaction mixture is directly added to a column of silica gel using 5 % ethyl acetate/hexane as the eluant to produce 0.43 g of 5-isothiocyanato-4- methoxybenzothiazole as a colorless solid.
  • D. 5-f/V-(2-Aminoethyl)thioureidol-4-methoxybenzothiazole A solution of 0.43 g of 5-isothiocyanato-4-methoxybenzothiazole in 10 mL of methylene chloride is added dropwise to a well-stirred solution of 0.7 mL of 1,2-ethylenediamine in 40 mL of toluene. A white precipitate appears after 2 to 3 minutes. Stirring is continued for 2 hours, and the precipitate is collected and washed with ether to afford 0.52 g of 5-[/V-(2- aminoethyl)thioureido]-4-methoxybenzothiazole as a colorless solid.
  • A. 7-Methyl-6-nitrobenzothiazole To an ice-cooled solution of 1.0 g of 6- nitrobenzothiazole in 30 mL of tetrahydrofuran are added 8 mL of 1.4 M methyl magnesium bromide in toluene/tetrahydrofuran. The reaction mixture is stirred at room temperature for 2 hours, and 2.22 g of 2,3- dichloro-5,6-dicyano-1 ,4-benzoquinone are added. After stirring at room temperature for 1.5 hours, 15 mL of 5% aqueous acetic acid solution are added. The mixture is extracted six times with ether, and the combined ether extracts are washed with water, brine and evaporated. Purification by flash silica gel chromatography with 10% ethyl acetate in hexane as eluent provides 0.43 g of 7-methyl-6-nitrobenzothiazole.
  • reaction mixture is added to 10 mL of saturated aqueous potassium fluoride and 10 mL of ether and stirred. After filtration and separation of the layers, the aqueous layer is extracted with ether. The combined ether layers are washed with water, brine, evaporated, and the product purified by flash silica gel chromatography, eluting with 10% ethyl acetate in hexane. Evaporation affords 0.265 g of 4,7-dimethyl-6-nitrobenzothiazole as a white solid.
  • D. 6-Amino-4.7-dimethylbenzothiazole A mixture of 0.34 g of 4,7-dimethyl- 6-nitrobenzothiazole, 0.5 g of iron powder, 0.051 g of ammonium chloride, 2 mL of water and 6 mL of ethanol is refluxed at 90 °C for 24 hours. The reaction mixture is concentrated and the product purified by flash silica gel chromatography, eluting with 15% ethyl acetate in hexane, to afford 0.13 g of 6-amino-4,7-dimethylbenzothiazole as a yellow solid.
  • E. 4.7-Dimethyl-6-isothiocvanatobenzothiazole A mixture of 0.118 g of 6- amino-4,7-dimethylbenzothiazole, 0.16 g di-2-pyridyl thionocarbonate, 0.017 g of 4-dimethylaminopyridine and 5 mL of methylene chloride is stirred at room temperature for 3 hours, concentrated, and the product purified by flash silica gel chromatography, eluting with 5% ethyl acetate in hexane, to afford 0.137 g of 4,7-dimethyl-6- isothiocyanatobenzothiazole as a white solid.
  • A. 5-Nitrobenzothiazole A mixture of 10 g of 1-chloro-2,4-dinitrobenzene and 20.26 g of N,N-dimethylthioformamide is heated to 60 °C for 3 hours. Xylene (25 mL) is then added to the resulting yellow solid and the mixture is heated to reflux for 4 hours. After stirring at room temperature for 18 hours, the mixture is diluted with ethanol (15 mL), filtered, and washed with a minimum amount of ethanol. The resulting brown solid is dissolved in ethanol (120 mL), heated to boiling and filtered hot to remove trace solids. The mixture is rotary evaporated to a volume of about 100 mL and is allowed to stand overnight at room temperature. The solid that forms is filtered and washed with ethanol to provide 4.68 g of 5- nitrobenzothiazole as reddish-brown needles.
  • the residue is purified by an aspirator vacuum filtration on silica gel, eluting with 15% to 30% ethyl acetate in hexane to provide 2.44 g of 5-amino-4- bromobenzothiazole as a reddish solid.
  • D. 4-Bromo-5-isothiocvanatobenzothiazole A mixture of 1.21 g of 5-amino- 4-bromobenzothiazole, 1.32 g of di-2-pyridyl thionocarbonate and 0.14 g of 4-dimethylaminopyridine in 90 mL of methylene chloride is stirred at room temperature for 3 hours. The mixture is rotary evaporated and the residue is purified by an aspirator vacuum filtration on silica gel eluting with 30% ethyl acetate in hexane to provide 1.26 g of 4-bromo-5- isothiocyanatobenzothiazole.
  • Example 8 4-Ethenyl-5-(2-imidazolinylamino)benzothiazole A. 5-Amino-4-ethenylbenzothiazole. A mixture of 0.5 g of 5-amino-4- bromobenzothiazole, as made according to Example 7, 0.76 g of tributyl(vinyl)tin, 91 mg of tetrakis(triphenylphosphine)palladium, 0.28 g of lithium chloride and a few crystals of 2,6-di-tetf-butyl-4-methylphenol in 16 mL of N,N-dimethylformamide is stirred at 90-100 °C for 3.5 hours.
  • reaction mixture is cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with 5% aqueous ammonium hydroxide (2 x 40 mL).
  • aqueous layers are extracted with ethyl acetate (2 x 15 mL) and the combined organic layers are washed with water (20 mL), dried over sodium sulfate, filtered through silica gel with an ethyl acetate wash and rotary evaporated to provide 5-amino-4-ethenylbenzothiazole. This material is used in the next step without further purification.
  • compositions which comprise a safe and effective amount of a subject compound, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.
  • safe and effective amount means an amount of the subject compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • a safe and effective amount of the subject compound will vary with the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • a dosage form is within the purview of the skilled artisan. Examples are provided for the skilled artisan, but are non-limiting, and it is contemplated that the skilled artisan can prepare variations of the compositions claimed.
  • compositions of this invention preferably comprise from about 0.0001% to about 99% by weight of the subject compound, more preferably from about 0.01% to about 90% of the compound of the invention.
  • the dosage form has preferably from about 10% to about 50%, also preferably from about 5% to about 10%, also preferably from about 1% to about 5%, and also preferably from about 0.01% to about 1% of the subject compound.
  • the frequency of dosing of the subject compound is dependent upon the pharmacokinetic properties of each specific agent (for example, biological half-life) and can be determined by the skilled artisan.
  • compositions of this invention contain a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • the compounds of the invention are soluble in the components of the composition.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the mammal being treated.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof are 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 methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water
  • the preferred unit dosage form is therefore tablets, capsules, lozenges, chewable tablets, and the like.
  • Such unit dosage forms comprise a safe and effective amount of the subject compound, which is preferably from about 0.01 mg to about 350 mg, more preferably from about 0.1 mg to about 35 mg, based on a 70 kg person.
  • the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose
  • binders such as starch, gelatin and sucrose
  • disintegrants such as starch, alginic acid and croscar
  • Capsules typically comprise one or more solid diluents disclosed above.
  • the selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Such liquid oral compositions preferably comprise from about 0.001% to about 5% of the subject compound, more preferably from about 0.01% to about 0.5%.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel® RC-591 , tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual and buccal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • Compositions can also be used to deliver the compound to the site where activity is desired: intranasal doses for nasal decongestion, inhalants for asthma, and eye drops, gels and creams for ocular disorders.
  • compositions of this invention include solutions or emulsions, preferably aqueous solutions or emulsions comprising a safe and effective amount of a subject compound intended for topical intranasal administration.
  • Such compositions preferably comprise from about 0.001% to about 25% of a subject compound, more preferably from about 0.01% to about 10%.
  • Similar compositions are preferred for systemic delivery of subject compounds by the intranasal route.
  • Compositions intended to deliver the compound systemically by intranasal dosing preferably comprise similar amounts of a subject compound as are determined to be safe and effective by peroral or parenteral administration.
  • compositions used for intranasal dosing also typically include safe and effective amounts of preservatives, such as benzalkonium chloride and thimerosal and the like; chelating agents, such as edetate sodium and others; buffers such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcystine, sodium metabisulfate and others; aromatic agents; viscosity adjustors, such as polymers, including cellulose and derivatives thereof, and polyvinyl alcohol and acids and bases to adjust the pH of these aqueous compositions as needed.
  • the compositions may also comprise local anesthetics or other actives. These compositions can be used as sprays, mists, drops, and the like.
  • compositions of this invention include aqueous solutions, suspensions, and dry powders comprising a safe and effective amount of a subject compound intended for atomization and inhalation administration.
  • Such compositions preferably comprise from about 0.1% to about 50% of a subject compound, more preferably from about 1% to about 20%; of course, the amount can be altered to fit the circumstance of the patient contemplated and the package.
  • Such compositions are typically contained in a container with attached atomizing means.
  • compositions also typically include propellants such as chlorofluorocarbons 12/11 and 12/114, and more environmentally friendly fluorocarbons, or other nontoxic volatiles; solvents such as water, glycerol and ethanol, these include cosolvents as needed to solvate or suspend the active; stabilizers such as ascorbic acid, sodium metabisulfite; preservatives such as cetylpyridinium chloride and benzalkonium chloride; tonicity adjustors such as sodium chloride; buffers; and flavoring agents such as sodium saccharin.
  • propellants such as chlorofluorocarbons 12/11 and 12/114, and more environmentally friendly fluorocarbons, or other nontoxic volatiles
  • solvents such as water, glycerol and ethanol, these include cosolvents as needed to solvate or suspend the active
  • stabilizers such as ascorbic acid, sodium metabisulfite
  • preservatives such as cetylpyridinium chloride and benzalkonium chloride
  • compositions of this invention include aqueous solutions comprising a safe and effective amount of a subject compound intended for topical intraocular administration.
  • Such compositions preferably comprise from about 0.0001% to about 5% of a subject compound, more preferably from about 0.01% to about 0.5%.
  • compositions also typically include one or more of preservatives, such as benzalkonium chloride, thimerosal, phenylmercuric acetate; vehicles, such as poloxamers, modified celluloses, povidone and purified water; tonicity adjustors, such as sodium chloride, mannitol and glycerin; buffers such as acetate, citrate, phosphate and borate; antioxidants such as sodium metabisulfite, butylated hydroxy toluene and acetyl cysteine; acids and bases may be used to adjust the pH of these formulations as needed.
  • preservatives such as benzalkonium chloride, thimerosal, phenylmercuric acetate
  • vehicles such as poloxamers, modified celluloses, povidone and purified water
  • tonicity adjustors such as sodium chloride, mannitol and glycerin
  • buffers such as acetate, citrate, phosphate and borate
  • compositions of this invention useful for peroral administration include solids, such as tablets and capsules, and liquids, such as solutions, suspensions and emulsions (preferably in soft gelatin capsules), comprising a safe and effective amount of a subject compound.
  • Such compositions preferably comprise from about 0.01 mg to about 350 mg per dose, more preferably from about 0.1 mg to about 35 mg per dose.
  • Such compositions can be coated by conventional methods, typically with pH or time- dependent coatings, such that the subject compound is released in the gastrointestinal tract at various times to extend the desired action.
  • Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit® coatings, waxes and shellac.
  • compositions of this invention may optionally include other drug actives.
  • drug actives include: Antihistamines. including;
  • Hydroxyzine preferably at a dosage range of from about 25 to about 400 mg; Doxylamine, preferably at a dosage range of from about 3 to about 75 mg; Pyrilamine, preferably at a dosage range of from about 6.25 to about 200 mg; Chlorpheniramine, preferably at a dosage range of from about 1 to about 24 mg; Phenindamine, preferably at a dosage range of from about 6.25 to about 150 mg; Dexchlorpheniramine, preferably at a dosage range of from about 0.5 to about 12 mg; Dexbrompheniramine, preferably at a dosage range of from about 0.5 to about 12 mg; Clemastine, preferably at a dosage range of from about 1 to about 9 mg; Diphenhydramine, preferably at a dosage range of from about 6.25 to about 300 mg; Azelastine, preferably at a dosage range of from about 140 to about 1 ,680 ⁇ g (when dosed intranasally); 1 to about 8 mg (when dosed orally); Acri
  • Codeine preferably at a dosage range of from about 2.5 to about 120 mg; Hydrocodone, preferably at a dosage range of from about 2.5 to about 40 mg; Dextromethorphan, preferably at a dosage range of from about 2.5 to about 120 mg; Noscapine, preferably at a dosage range of from about 3 to about 180 mg; Benzonatate, preferably at a dosage range of from about 100 to about 600 mg; Diphenhydramine, preferably at a dosage range of from about 12.5 to about 150 mg; Chlophedianol, preferably at a dosage range of from about 12.5 to about 100 mg; Clobutinol, preferably at a dosage range of from about 20 to about 240 mg; Fominoben, preferably at a dosage range of from about 80 to about 480 mg; Glaucine; Pholcodine, preferably at a dosage range of from about 1 to about 40 mg; Zipeprol, preferably at a dosage range of from about 75 to about 300 mg; Hydromorphone, preferably at a dosage
  • Antiinflammatories preferably Non-Steroidal Anti-inflammatories, (NSAIDS) including:
  • Ibuprofen preferably at a dosage range of from about 50 to about 3,200 mg; Naproxen, preferably at a dosage range of from about 62.5 to about 1 ,500 mg; Sodium naproxen, preferably at a dosage range of from about 110 to about 1 ,650 mg; Ketoprofen, preferably at a dosage range of from about 25 to about 300 mg; Indoprofen, preferably at a dosage range of from about 25 to about 200 mg; Indomethacin, preferably at a dosage range of from about 25 to about 200 mg; Sulindac, preferably at a dosage range of from about 75 to about 400 mg; Diflunisal, preferably at a dosage range of from about 125 to about 1 ,500 mg; Ketorolac, preferably at a dosage range of from about 10 to about 120 mg; Piroxicam, preferably at a dosage range of from about 10 to about 40 mg; Aspirin, preferably at a dosage range of from about 80 to about 4,000 mg; Meclofenamate,
  • Acetaminophen preferably at a dosage range of from about 80 to about 4,000 mg; and others:
  • Guaifenesin preferably at a dosage range of from about 50 to about 2,400 mg;
  • N-Acetylcysteine preferably at a dosage range of from about 100 to about 600 mg; Ambroxol, preferably at a dosage range of from about 15 to about 120 mg;
  • Bromhexine preferably at a dosage range of from about 4 to about 64 mg;
  • Terpin hydrate preferably at a dosage range of from about 100 to about 1 ,200 mg; Potassium iodide, preferably at a dosage range of from about 50 to about
  • Anticholinergics e.g.. Atropinics
  • intranasallv or orally administered anticholinergics e.g., atropinics
  • Ipratroprium preferably intranasally, preferably at a dosage range of from about 42 to about 252 ⁇ g
  • Atropine sulfate preferably oral
  • Belladonna preferably as an extract
  • Scopolamine preferably at a dosage range of from about 400 to about 3,200 ⁇ g
  • Scopolamine methobromide preferably at a dosage range of from about 2.5 to about 20 mg
  • Homatropine methobromide preferably at a dosage range of from about 2.5 to about 40 mg
  • Hyoscyamine preferably oral), preferably at a dosage range of from about 125 to about 1 ,000 ⁇ g
  • Hyoscyamine preferably oral
  • Isopropramide preferably oral, preferably at a dosage range of from about 5 to about 20 mg
  • Orphenadrine preferably oral, preferably at a dosage range of from about 50 to about 400 mg
  • Benzalkonium chloride preferably intranasally preferably a 0.005 to about 0.1% solution and others;
  • Mast Cell Stabilizers preferably intranasallv. or orally administered mast cell stabilizers, including;
  • Cromalyn preferably at a dosage range of from about 10 to about 60 mg;
  • Nedocromil preferably at a dosage range of from about 10 to about 60 mg;
  • Oxatamide preferably at a dosage range of from about 15 to about 120 mg;
  • Ketotifen preferably at a dosage range of from about 1 to about 4 mg;
  • Lodoxamide preferably at a dosage range of from about 100 to about 3,000 ⁇ g and others;
  • Leukotriene Antagonists including Zileuton and others
  • Methylxanthines including; Caffeine, preferably at a dosage range of from about 65 to about 600 mg; Theophylline, preferably at a dosage range of from about 25 to about 1 ,200 mg; Enprofylline; Pentoxifylline, preferably at a dosage range of from about 400 to about 3,600 mg; Aminophylline, preferably at a dosage range of from about 50 to about 800 mg; Dyphylline, preferably at a dosage range of from about 200 to about 1 ,600 mg and others; Antioxidants or radical inhibitors, including;
  • Ascorbic acid preferably at a dosage range of from about 50 to about 10,000 mg; Tocopherol, preferably at a dosage range of from about 50 to about 2,000 mg; Ethanol, preferably at a dosage range of from about 500 to about 10,000 mg and others;
  • Steroids preferably intranasally administered steroids, including: Beclomethasone, preferably at a dosage range of from about 84 to about 336 ⁇ g; Fluticasone, preferably at a dosage range of from about 50 to about 400 ⁇ g; Budesonide, preferably at a dosage range of from about 64 to about 256 ⁇ g; Mometasone, preferably at a dosage range of from about 50 to about 300 mg; Triamcinolone, preferably at a dosage range of from about 110 to about 440 ⁇ g; Dexamethasone, preferably at a dosage range of from about 168 to about 1 ,008 ⁇ g; Flunisolide, preferably at a dosage range of from about 50 to about 300 ⁇ g; Prednisone (preferably oral), preferably at a dosage range of from about 5 to about 60 mg; Hydrocortisone (preferably oral), preferably at a dosage range of from about 20 to about 300 mg and others; Bronchodilators, preferably for inhal
  • Albuterol preferably at a dosage range of from about 90 to about 1 ,080 ⁇ g; 2 to about 16 mg (if dosed orally); Epinephrine, preferably at a dosage range of from about 220 to about 1 ,320 ⁇ g; Ephedrine, preferably at a dosage range of from about 15 to about 240 mg (if dosed orally); 250 to about 1,000 ⁇ g (if dosed intranasally); Metaproterenol, preferably at a dosage range of from about 65 to about 780 ⁇ g or 10 to about 80 mg if dosed orally; Terbutaline, preferably at a dosage range of from about 200 to about 2,400 ⁇ g; 2.5 to about 20 mg (if dosed orally); Isoetharine, preferably at a dosage range of from about 340 to about 1,360 ⁇ g; Pirbuterol, preferably at a dosage range of from about 200 to about 2,400 ⁇ g; Bitolterol, preferably at a dosage range of from about 90
  • Amantadine preferably at a dosage range of from about 50 to about 200 mg; Rimantadine, preferably at a dosage range of from about 50 to about 200 mg; Enviroxime; Nonoxinols, preferably at a dosage range of from about 2 to about 20 mg (preferably an intranasal form); Acyclovir, preferably at a dosage range of from about 200 to about 2,000 mg (oral); 1 to about 10 mg (preferably an intranasal form); Alpha-lnterferon, preferably at a dosage range of from about 3 to about 36 MIU; Beta-lnterferon, preferably at a dosage range of from about 3 to about 36 MIU and others;
  • Ocular Drug actives acetylcholinesterase inhibitors, e.g., echothiophate from about 0.03% to about 0.25% in topical solution and others; and Gastrointestinal actives: antidiarrheals, e.g., loperamide from about 0.1 mg to about 1.0 mg per dose, and bismuth subsalicylate from about 25 mg to about 300 mg per dose and others.
  • acetylcholinesterase inhibitors e.g., echothiophate from about 0.03% to about 0.25% in topical solution and others
  • Gastrointestinal actives antidiarrheals, e.g., loperamide from about 0.1 mg to about 1.0 mg per dose, and bismuth subsalicylate from about 25 mg to about 300 mg per dose and others.
  • alpha-2 agonists provide efficacy is by intervening in the biological cascade responsible for disorder(s) and/or manifestation(s) thereof. It may be that there is no deficit in alpha-2 adrenoceptor activity: such activity may be normal. However, administration of an alpha-2 agonist may be a useful way of rectifying a disorder, condition or manifestation thereof.
  • the terms “disease,” “disorder” and “condition” are used interchangeably to refer to maladies related to or modulated by alpha-2 adrenoceptor activity.
  • a disorder described by the terms “modulated by alpha-2 adrenoceptors,” or “modulated by alpha-2 adrenoceptor activity” refers to a disorder, condition or disease where alpha-2 adrenoceptor activity is an effective means of alleviating the disorder or one or more of the biological manifestations of the disease or disorder; or interferes with one or more points in the biological cascade either leading to the disorder or responsible for the underlying disorder; or alleviates one or more symptoms of the disorder.
  • disorders subject to "modulation” include those for which:
  • the lack of alpha-2 activity is a "cause" of the disorder or one or more of the biological manifestations, whether the activity was altered genetically, by infection, by irritation, by internal stimulus or by some other cause;
  • the disease or disorder or the observable manifestation or manifestations of the disease or disorder are alleviated by alpha-2 activity.
  • the lack of alpha-2 activity need not be causally related to the disease or disorder or the observable manifestations thereof;
  • Alpha-2 activity interferes with part of the biochemical or cellular cascade that results in or relates to the disease or disorder.
  • the alpha- 2 activity alters the cascade, and thus controls the disease, condition or disorder.
  • the compounds of this invention are particularly useful for the treatment of nasal congestion associated with allergies, colds, and other nasal disorders, as well as the sequelae of congestion of the mucous membranes (for example, sinusitis and otitis media). At effective doses, it has been found that undesired side effects can be avoided.
  • the subject compounds are believed to provide advantages in the treatment of nasal decongestion over related compounds through their ability to interact with alpha- 2 adrenoceptors.
  • the subject compounds have been found to be alpha-2 adrenoceptor agonists which cause constriction of peripheral vascular beds in the nasal turbinates.
  • Alpha-2 adrenoceptors are distributed both inside and outside of the central nervous system. Thus, though not essential for activity or efficacy, certain disorders preferably are treated with compounds that act on alpha-2 adrenoceptors in only one of these regions.
  • Compounds of this invention vary in their ability to penetrate into the central nervous system and, thus, to produce effects mediated through central alpha-2 adrenoceptors. Thus, for example, a compound which displays a higher degree of central nervous system activity is preferred for central nervous system indications over other compounds as described below. However, even for compounds that exhibit primarily peripheral activity, central nervous system actions can be evoked by an increase in the dose of the compound. Further specificity of action of these compounds can be achieved by delivering the agent to the region where activity is desired (for example, topical administration to the eye, nasal mucosa or respiratory tract).
  • Compounds preferred for, but not limited to, the treatment of certain cardiovascular disorders, pain, substance abuse and/or withdrawal, ulcer and hyperacidity include those compounds that are centrally acting.
  • centrally acting what is meant is that they have some action on the alpha-2 adrenoceptors in the central nervous system in addition to their action at peripheral alpha-2 adrenoceptors.
  • peripherally acting what is meant is that these compounds act primarily on alpha-2 adrenoceptors in the periphery, rather than those in the central nervous system. Methods are available in the art to determine which compounds are primarily peripherally acting and which are primarily centrally acting.
  • compounds of the subject invention are also useful for the treatment of ocular disorders such as ocular hypertension, glaucoma, hyperemia, conjunctivitis, and uveitis.
  • the compounds are administered either perorally, or topically as drops, sprays, mists, gels or creams directly to the surface of the mammalian eye.
  • the compounds of this invention are also useful for controlling gastrointestinal disorders, such as diarrhea, irritable bowel syndrome, hyperchlorhydria and peptic ulcer.
  • the compounds of this invention are also useful for diseases and disorders associated with sympathetic nervous system activity, including hypertension, myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and benign prostatic hypertrophy. Due to their sympatholytic effect, compounds are also useful as an adjunct to anesthesia during surgical procedures.
  • the compounds of this invention are also useful for relieving pain associated with various disorders.
  • the compounds are administered perorally, parenterally, and/or by direct injection into the cerebrospinal fluid.
  • the compounds of this invention are also useful for the prophylactic or acute treatment of migraine.
  • the compounds are administered perorally, parenterally or intranasally.
  • the compounds of this invention are also useful for treatment of substance abuse, in particular abuse of alcohol and opiates, and alleviating the abstinence syndromes evoked by withdrawal of these substances.
  • the compounds of this invention are also useful for other diseases and disorders where vasoconstriction, particularly of veins, would provide a benefit, including septic or cardiogenic shock, elevated intracranial pressure, hemmorhoids, venous insufficiency, varicose veins, and menopausal flushing.
  • the compounds of this invention are also useful for neurologic diseases and disorders, including spasticity, epilepsy, attention deficit hyperactive disorder, Tourette's syndrome, and cognitive disorders.
  • the pharmacological activity and selectivity of these compounds can be determined using published test procedures.
  • the alpha-2 selectivity of the compounds is determined by measuring receptor binding affinities and in vitro functional potencies in a variety of tissues known to possess alpha-2 and/or alpha-1 receptors. (See, e.g., The Alpha-2 Adrenergic Receptors. L.E. Limbird, ed., Humana Press, Clifton, NJ.)
  • the following in vivo assays are typically conducted in rodents or other species.
  • Central nervous system activity is determined by measuring locomotor activity as an index of sedation. (See, e.g., Spyraki, C. & H.
  • Antidiarrheal activity is determined by measuring the ability of the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g., Thollander, M., P. Hellstrom & T. Svensson, "Suppression of Castor Oil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists", Alimentary Pharmacology and Therapeutics. Vol. 5 (1991), pp. 255-262).
  • Efficacy in treating irritable bowel syndrome is determined by measuring the ability of compounds to reduce the stress-induced increase in fecal output. (See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro & H. Ormsbee III, "Cold-restraint stress increases rat fecal pellet output and colonic transit", American Journal of Physiology. Vol. 258 (1990), pp. G329-G337). Antiulcer and reduction of hyperchlorhydria efficacy is determined by measuring the reduction in gastric acid secretion produced by these compounds (See, e.g., Tazi-Saad, K., J. Chariot, M.
  • Antiasthma activity is determined by measuring the effect of the compound on bronchoconstriction associated with pulmonary challenges such as inhaled antigens. (See, e.g., Chang, J. J. Musser & J.
  • Activity in cough is determined by measuring the number and latency of the cough response to respiratory challenges such as inhaled citric acid.
  • respiratory challenges such as inhaled citric acid.
  • inhaled citric acid See, e.g., Callaway, J. & R. King, "Effects of Inhaled ⁇ 2- Adrenoceptor and GABA ⁇ Receptor Agonists on Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs", European Journal of Pharmacology. Vol. 220 (1992), pp. 187-195.
  • the sympatholytic activity of these compounds is determined by measuring the reduction of plasma catecholamines (See, e.g., R. Urban, B. Szabo & K.
  • hypotensive effect of these compounds is measure directly as a reduction in mean blood pressure (See, e.g., Timmermans, P. & P. Van Zwieten, "Central and peripheral ⁇ -adrenergic effects of some imidazolidines", European Journal of Pharmacology. Vol. 45 (1977), pp. 229-236).
  • Clinical studies have demonstrated the beneficial effect of alpha-2 agonists in the prevention of myocardial ischemia during surgery (See, e.g., Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D.
  • vasoconstrictor activity of these compounds is demonstrated by measuring the contractile properties on isolated arteries and veins in vitro (See, e.g., Flavahan, N., T. Rimele, J. Cooke & M. Vanhoutte, "Characterization of Postjunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenous or Nerve-Released Norepinephrine in the Canine Saphenous Vein", Journal of Pharmacology and Experimental Therapeutics. Vol. 230 (1984), pp. 699-705).
  • the antinociceptive and pain reducing properties of these compounds is demonstrated by measuring the increase in pain threshold in the rodent writhing and hot plate antinociceptive models (See, e.g., Millan, M., K. Bervoets, J. Rivet, R. Widdowson, A. Renouard, S, Le Marouille-Girardon & A. Gobert, "Multiple Alpha-2 Adrenergic Receptor Subtypes. II. Evidence for a Role of Rat Alpha-2A Adrenergic Receptors in the Control of Nociception, Motor Behavior and Hippocampal Synthesis of Noradrenaline", Journal of Pharmacology and Experimental Therapeutics. Vol. 270 (1994), pp. 958-972).
  • the antimigraine effect of these compounds is demonstrated by measuring the reduction of dural neurogenic inflammation to trigeminal ganglion stimulation in the rat (See, e.g., Matsubara, T., M. Moskowitz & Z. Huang, "UK-14,304, R(-)-alpha-methyl- histamine and SMS 201-995 block plasma protein leakage within dura mater by prejunctional mechanisms", European Journal of Pharmacology. Vol. 224 (1992), pp. 145-150).
  • the ability of these compounds to suppress opiate withdrawal is demonstrated by measuring the suppression of enhanced sympathetic nerve activity (See, e.g., Franz, D., D. Hare & K.
  • alpha-2 agonists in the management of neurologic disorders
  • attention-deficit hyperactive disorder and Tourette's syndrome See, e.g., Chappell P., M. Riddle, L. Scahill, K. Lynch, R. Schultz, A. Arnsten, J. Leckman & D. Cohen, "Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette's syndrome: preliminary clinical experience", Journal of American Academy of Child and Adolescent Psychiatry. Vol. 34 (1995), pp. 1140-1146), cognitive disorders (See, e.g., Coull, J., "Pharmacological manipulations of the ⁇ 2- noradrenergic system.
  • Another aspect of this invention involves methods for preventing or treating nasal congestion by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing nasal congestion.
  • nasal congestion may be associated with human diseases or disorders which include, but are not limited to, seasonal allergic rhinitis, acute upper respiratory viral infections, sinusitis, perennial rhinitis, and vasomotor rhinitis.
  • other disorders can be generally associated with mucous membrane congestion (for example, otitis media and sinusitis.)
  • Each administration of a dose of the subject compound preferably administers a dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.
  • the frequency of administration of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • Such doses and frequencies are also preferred for treating other respiratory conditions, such as, cough, chronic obstructive pulmonary disease (COPD) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Such doses and frequencies are also preferred for treating conditions that are associated with mucous membrane congestion (for example, sinusitis and otitis media).
  • Another aspect of this invention involves methods for preventing or treating glaucoma by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing glaucoma.
  • each administration of a dose of the subject compound preferably administers a dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.
  • intraocular dosing is used then preferably one administers a typical volume (for example, 1 or 2 drops) of a liquid composition, comprising from about 0.0001% to about 5% of a subject compound, more preferably from about 0.01% to about 0.5% of the compound.
  • the frequency of administration of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • Another aspect of this invention involves methods for preventing or treating gastrointestinal disorders, such as diarrhea, irritable bowel syndrome, and peptic ulcer by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing gastrointestinal disorders.
  • Each administration of a dose of the subject compound preferably administers a dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroral administration of such doses is preferred.
  • the frequency of administration of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • Another aspect of this invention involves methods for preventing or treating migraine, by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing migraine.
  • Each administration of a dose of the subject compound preferably administers a dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.
  • Peroral, parenteral or intranasal administration of such doses is preferred.
  • the frequency of peroral administration of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • the frequency of parenteral dosing of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily or by infusion to the desired effect.
  • the frequency of intranasal dosing of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • Another aspect of this invention involves methods for preventing or treating disorders related to sympathetic nervous system activity, such as hypertension, myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, and benign prostatic hypertrophy, by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing these diseases or disorders.
  • Each administration of a dose of the subject compound preferably administers a dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroral and parenteral administration of such doses are preferred.
  • the frequency of peroral administration of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • the frequency of parenteral dosing of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily or by infusion to the desired effect.
  • Another aspect of this invention involves methods for preventing or treating pain, by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing pain.
  • Each administration of a dose of the subject compound preferably administers a dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.
  • Peroral or parenteral administration of such doses is preferred.
  • the frequency of peroral administration of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • the frequency of parenteral dosing of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily or by infusion to the desired effect.
  • Another aspect of this invention involves methods for preventing or treating substance abuse and the abstinence syndrome resulting from withdrawal of these substances, such as alcohol and opiates, by administering a safe and effective amount of a subject compound to a mammal experiencing or at risk of experiencing substance abuse or withdrawal symptoms.
  • Each administration of a dose of the subject compound preferably administers a dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroral administration of such doses is preferred.
  • the frequency of administration of a subject compound according to this invention is preferably from about once to about six times daily, more preferably from about once to about 4 times daily.
  • Example A Oral Tablet Composition Ingredient Amount per tablet (mg)
  • One tablet is swallowed by a patient with nasal congestion.
  • the congestion is substantially diminished.
  • Microcrystalline cellulose (Avicel PH 101 ®) 100.8
  • One tablet is chewed and swallowed by a patient with nasal congestion.
  • the congestion is substantially reduced.
  • Example C Sublingual Tablet Composition Ingredient Amount per tablet (mg)
  • Microcrystalline cellulose (Avicel PH 101®) 29.00
  • One tablet is placed under the tongue of a patient with nasal congestion and allowed to dissolve. The congestion is rapidly and substantially diminished.
  • Example D Intranasal Solution Composition
  • Ingredient Composition (% w/v)
  • One-tenth of a mL of the composition is sprayed from a pump actuator into each nostril of a patient with nasal congestion. The congestion is substantially diminished.
  • Example E Intranasal Gel Composition
  • Ingredient Composition (% w/v)
  • One-fifth of a mL of the composition is applied as drops from a dropper into each nostril of a patient with nasal congestion. The congestion is substantially reduced.
  • Other compounds having a structure according to Formula I are used with substantially similar results.
  • Two-puffs of the aerosol composition is inhaled from a metered-dose inhaler by a patient with asthma.
  • the asthmatic condition is effectively relieved.
  • One-tenth of a mL of the composition is administered directly into each eye of a patient with glaucoma.
  • the intraocular pressure is substantially reduced.
  • Example H Oral Liquid Composition Ingredient Amount/15 mL Dose
  • One 15 mL dose of the liquid composition is swallowed by a patient with nasal congestion and runny nose due to allergic rhinitis. The congestion and runny nose are effectively reduced.
  • One 15 mL dose of the alcohol-free liquid medication is swallowed by a patient with nasal congestion. The congestion is substantially diminished.
  • Example K Oral Tablet Composition Ingredient Amount per tablet (mg)
  • One tablet is swallowed by a patient with migraine.
  • the pain and aura of migraine is substantially diminished.
  • Example L Oral Tablet Composition Ingredient Amount per tablet (mg)
  • Example M Oral Caplet Composition Ingredient Amount per tablet (mg)
  • Example O Oral Tablet Composition Ingredient Amount per caplet (mg)
  • Example Q Oral Tablet Composition Ingredient Amount per tablet (mg)
  • Citric acid, anhydrous, USP 50 Citric acid, anhydrous, USP 50
  • Citric acid, anhydrous, USP 50 Citric acid, anhydrous, USP 50
  • Total 28795 mg/fl oz
  • composition for parenteral administration is made comprising:
  • the above ingredients are mixed, forming a solution. Approximately 2.0 ml of the solution is administered, intravenously, to a human subject suffering from septic or cardiogenic shock. The symptoms subside.
  • Example V Oral Tablet Composition Ingredient Amount per tablet (mg)
  • combination actives are contemplated.
  • medicaments which can be combined with the primary active are included in U.S. Patent No. 4,552,899 to Sunshine, et al., hereby incorporated by reference. All other references referred to throughout this specification are hereby incorporated by reference.

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Abstract

L'invention concerne des composés correspondant à la formule (I) dans laquelle: a) R1, R2 et R3 représentent chacun indépendamment hydrogène, alcanyle C1-C3 non substitué, alcényle ou alcynyle, cycloalcanyle, cycloalcényle, alkylthio C1-C3 non substitué ou alcoxy, hydroxy, thio, nitro, cyano, amino, alkylamino C1-C3 ou dialkylamino C1-C3 ou halo, b) R4 représente hydrogène, alcanyle C1-C3 non substitué, amino, hydroxy, mercapto, alkylthio C1-C3 ou alcoxy, alkylamino C1-C3 ou dialkylamino C1-C3 ou halo, c) R5 représente hydrogène, alkyle ou zéro, d) si R5 vaut zéro, la liaison (a) est une liaison double, et f) la fraction imidazolinylamino est fixée en position 5- ou 6- du noyau benzothiazole. L'invention concerne également des énantiomères, isomères optiques, stéréo-isomères, diastéréomères, tautomères, sels d'addition, amides et esters biohydrolysables de ces composés, ainsi que des compositions pharmaceutiques contenant de tels composés nouveaux. Elle concerne encore l'utilisation de tels composés dans le traitement ou la prévention de troubles modulés par les adrénorécepteurs alpha-2.
PCT/US1997/020549 1996-11-25 1997-11-21 Composes 2-imidazolinylaminobenzothiazole utiles en tant qu'agonistes de l'adrenorecepteur alpha-2 WO1998023612A1 (fr)

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AU54338/98A AU5433898A (en) 1996-11-25 1997-11-21 2-imidazolinylaminobenzothiazole compounds useful as alpha-2 adrenoceptor agonists

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0900080A4 (fr) * 1996-02-29 2000-12-13 Synaptic Pharma Corp Nouveaux derives d'indole et de benzothiazole
WO2002019996A3 (fr) * 2000-09-08 2002-06-13 Warner Lambert Co Prevention de sinusite aigue et d'attaque aux sinus
WO2013015984A1 (fr) * 2011-07-25 2013-01-31 Allergan, Inc. Dérivés de n-(imidazolidin-2-ylidène)hétérocyclopenta[b]pyridine utilisés comme modulateurs des récepteurs adrénergiques alpha-2
US9161912B2 (en) 2008-12-23 2015-10-20 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
CN112538074A (zh) * 2020-12-24 2021-03-23 艾希尔（深圳）药物研发有限公司 一种溴莫尼定脱溴杂质的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2040374A1 (de) * 1969-08-14 1971-02-25 Beecham Group Ltd Imidazoline,ihre Saeureadditionssalze und Verfahren zu ihrer Herstellung
US3890319A (en) * 1972-02-29 1975-06-17 Pfizer (2-imidazolin-2-y(amino) substituted quinolines, -quinoxalines and -quinazolines as antihypertensive agents
EP0086126A1 (fr) * 1982-02-05 1983-08-17 Synthelabo Dérivés d'imidazolidine, leur préparation et leur application en thérapeutique
EP0399791A1 (fr) * 1989-05-22 1990-11-28 Allergan, Inc Combinaisons d'agonistes et d'antagonistes alpha-adrénergiques sélectifs pour diminuer la pression intra-oculaire
US5091528A (en) * 1990-09-12 1992-02-25 Allergan, Inc. 6- or 7- (2-imino-2-imidazolidine)-1,4-benzoxazines as α adrenergic agents
WO1992021349A1 (fr) * 1991-05-30 1992-12-10 Allergan, Inc. Combinaisons d'agents agonistes adrenergiques alpha-2 avec des agents antagonistes alpha-3 pour abaisser la pression intra-oculaire
WO1997031636A1 (fr) * 1996-02-29 1997-09-04 Synaptic Pharmaceutical Corporation Nouveaux derives d'indole et de benzothiazole

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2040374A1 (de) * 1969-08-14 1971-02-25 Beecham Group Ltd Imidazoline,ihre Saeureadditionssalze und Verfahren zu ihrer Herstellung
US3890319A (en) * 1972-02-29 1975-06-17 Pfizer (2-imidazolin-2-y(amino) substituted quinolines, -quinoxalines and -quinazolines as antihypertensive agents
EP0086126A1 (fr) * 1982-02-05 1983-08-17 Synthelabo Dérivés d'imidazolidine, leur préparation et leur application en thérapeutique
EP0399791A1 (fr) * 1989-05-22 1990-11-28 Allergan, Inc Combinaisons d'agonistes et d'antagonistes alpha-adrénergiques sélectifs pour diminuer la pression intra-oculaire
US5091528A (en) * 1990-09-12 1992-02-25 Allergan, Inc. 6- or 7- (2-imino-2-imidazolidine)-1,4-benzoxazines as α adrenergic agents
WO1992021349A1 (fr) * 1991-05-30 1992-12-10 Allergan, Inc. Combinaisons d'agents agonistes adrenergiques alpha-2 avec des agents antagonistes alpha-3 pour abaisser la pression intra-oculaire
WO1997031636A1 (fr) * 1996-02-29 1997-09-04 Synaptic Pharmaceutical Corporation Nouveaux derives d'indole et de benzothiazole

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 109, no. 21, 21 November 1988, Columbus, Ohio, US; abstract no. 190313u, page 704; XP002059773 *
CHEMICAL ABSTRACTS, vol. 95, no. 9, 31 August 1981, Columbus, Ohio, US; abstract no. 73170b, page 34; XP002059772 *
F. L. MERCHAN ET AL., SYNTHESIS, 1982, pages 1066 - 7, XP002059771 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0900080A4 (fr) * 1996-02-29 2000-12-13 Synaptic Pharma Corp Nouveaux derives d'indole et de benzothiazole
US6303643B1 (en) 1996-02-29 2001-10-16 Synaptic Pharmaceutical Corporation Substituted indoles and uses thereof
US6498177B2 (en) 1996-02-29 2002-12-24 Synaptic Pharmaceutical Corporation Indole and benzothiazole derivatives
US6723741B2 (en) 1996-02-29 2004-04-20 Synaptic Pharmaceutical Corporation Benzimidazoles and benzothiazoles and uses thereof
WO2002019996A3 (fr) * 2000-09-08 2002-06-13 Warner Lambert Co Prevention de sinusite aigue et d'attaque aux sinus
US9161912B2 (en) 2008-12-23 2015-10-20 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
US8513419B2 (en) 2011-07-25 2013-08-20 Allergan, Inc. N-(imidazolidin-2-ylidene)-heterocyclopenta[b]pyridine derivatives as modulators of alpha 2 adrenergic receptors
CN103781785A (zh) * 2011-07-25 2014-05-07 阿勒根公司 作为α2肾上腺素能受体的调节剂的N-(咪唑烷-2-亚基)-杂环戊并[b]吡啶衍生物
US8741921B2 (en) 2011-07-25 2014-06-03 Allergan, Inc. N-(imidazolidin-2-ylidene)-heterocyclopenta[b]pyridine derivatives as modulators of alpha 2 adrenergic receptors
JP2014521642A (ja) * 2011-07-25 2014-08-28 アラーガン インコーポレイテッド α２アドレナリン受容体の調節因子としてのＮ−（イミダゾリジン−２−イリデン）−ヘテロシクロペンタ［ｂ］ピリジン誘導体
US9034896B2 (en) 2011-07-25 2015-05-19 Allergan, Inc. N-(imidazolidin-2-ylidene)-heterocyclopenta[b]pyridine derivatives as modulators of alpha 2 adrenergic receptors
WO2013015984A1 (fr) * 2011-07-25 2013-01-31 Allergan, Inc. Dérivés de n-(imidazolidin-2-ylidène)hétérocyclopenta[b]pyridine utilisés comme modulateurs des récepteurs adrénergiques alpha-2
CN112538074A (zh) * 2020-12-24 2021-03-23 艾希尔（深圳）药物研发有限公司 一种溴莫尼定脱溴杂质的制备方法

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AU5433898A (en) 1998-06-22

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