Classifications

• • 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
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the compound (+)- -(2,3-dimethoxyphenyl)-l -[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol, also known as MDL 100,907, is a potent 5HT 2A receptor antagonist which is being evaluated in the clinic for treatment of schizophrenia. J. Pharm. Exp. Ther. 277:968- 9881 (1996) incorporated herein by reference. It was described in U.S. patent 5,134,149, incorporated herein by reference.
• MDL 100,907 antagonizes the effects of serotonin at the 5HT 2A receptor and thus is useful for treating a variety of conditions.
• this compound may also act directly or indirectly act to achieve therapeutic effects other than by its 5HT 2 ⁇ antagonism.
• MDL 100,907 has been shown to exert a tonic inhibitory influence on dopamine efflux in the medial prefrontal cortex.
• Patent 5,169,096 claimed compounds having a generic scope which encompassed the Ml 00,907 and disclosed uses of the treatment of anorexia nervosa, variant angina, Raynaud' s phenomenon, coronary vasospasms, prophylactic treatment of migraine, cardiovascular diseases such as hypertension, peripheral vascular disease, thrombotic episodes, cardiopulmonary emergencies and arrythmias, and has anesthetic properties. See also U.S. Patent nos. 4,783,471 ; 4,912,117; and 5,021,428, which are divisions of U. S. Patent 5,169,096. See also U. S. Patent nos.
• 5,134,149 which disclosed uses of antagonizing serotonin at the 5Ht2 receptor, treating anxiety, variant angina, anorexia nervosa, Raynaud' s phenomenon, intermittent claudication, coronary or peripheral vasospasms, fibromyalgia, extrapyramidal symptoms, arrythmias, thrombotic illness, transient ischemic attacks, drug abuse, and psychotic illness such as schizophrenia and mania. See also U. S. Patent nos. 5,561,144; 5,700,812; 5,700,813; 5,721,249- divisionals of U. S. Patent no. 5,134,149- and also U. S. Patent nos.5,618,824 (obsessive compulsive disorder) and
• PCT/US97/02597 depressive disorders including major depressive episode and dysthymia, and bipolar disorder
• insomnia and sleep apnea as described in patent application number , incorporated herein by reference.
• An object of the present invention is to provide a new compound which after administration, releases a therapeutically effective amount of MDL 100,907 over an extended period of time.
• the extended period of time means a time longer than a single dose of MDL 100,907, and would last for several days, several weeks, about one month up to about 6 to about 8 weeks , and preferably from about 2 weeks to about one month.
• sustained release formulations While the concept of sustained release formulations is not new, not all compounds are capable of being chemically altered to produce a new compound capable of being metabolized into the active ingredient at a desirable rate and over the desired length of time. Other factors contribute to the difficulty of preparing a sustained release formulation such as protein binding and other physiological processes which can affect the therapeutic effect of the active ingredient, see for example Biochemical Pharmacology, Vol. 36, No. 10 ppl715-1722 (1987), incorporated herein by reference. Also, the chemically altered compound must be compatible with pharmaceutically acceptable carriers and be stable enough not to substantially degrade on the shelf to the active ingredient. In short, the design of an acceptable sustained release formulation is a difficult, unpredictable task.
• the present invention is a compound of Formula I:
• the present invention also comprises: a pharmaceutical composition comprising the compound of formula I and a pharmaceutically acceptable carrier; a method of antagonizing the effects of serotonin at the 5HT 2A receptor comprising administering a compound of formula I to a patient in need thereof; a method of treating a patient for a disease state comprising administering to the patient in need of such therapy a therapeutically effective amount of a compound of formula I wherein the disease state is psychoses (including schizophrenia), obsessive compulsive disorder, thrombotic illness, coronary vasospasm, anxiety, anorexia nervosa , Raynaud' s phenomenon, fibromyalgia, extra-pyramidal side effects, anxiety, arrhythmia, depression, bipolar depression, insomnia, sleep apnea, Raynaud's phenomenon, or drug abuse; and a method of making the compounds comprising
• “Pharmaceutically acceptable salts” means either an acid addition salt or a basic addition salt whichever is possible to make with the compounds of the present invention.
• “Pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I.
• Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
• Illustrative organic acids which form suitable salts include the mono-, di- and tri- carboxylic acids.
• Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p- toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2- hydroxyethanesulfonic acid.
• Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form.
• the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points.
• “Pharmaceutically acceptable basic addition salts” means non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of its intermediates. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline. The selection of the appropriate salt may be important so that the ester is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
• “Stereoisomers” is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
• Alkyl means a branched or straight chain alkyl group specified by the amount of carbons in the alkyl group, e.g., C4-C20 alkyl means a four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty carbon branched or straight chain alkyl or any ranges thereof, for example, but not limited to C5-C20, C1-C15, C3-C15, C5-C15, C7-C15, and C7-C9.
• Patient means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
• Treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
• “Therapeutically effective amount” means an amount of the compound which is effective in treating the named disorder or condition.
• “Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
• a pharmaceutically acceptable oil typically used for parenteral administration
• the term “Restorative Sleep” means sleep which produces a rested state upon waking; i) the term “Sleep Disorder” means Insomnia and Obstructive Sleep Apnea; j) the term "Insomnia” means Primary Insomnia, Insomnia related to another Mental
• Principal Insomnia means difficulty in initiating sleep, in maintaining sleep or having restorative sleep which is not caused by a Mental Disorder or due to physiological effects of taking or withdrawing from certain substances (substance- induced).
• Circadian Rhythm Insomnia which is insomnia due to a change in the normal sleep- wake schedule (shift changes, jet lag, etc.);
• the term "Insomnia related to another Mental Disorder” means difficulty in initiating sleep, in maintaining sleep or having restorative sleep which is caused by an underlying Mental Disorder such as, for example, depression, anxiety or schizophrenia;
• the term "Substance-Induced Insomnia” means difficulty in initiating sleep, in maintaining sleep or having restorative sleep which is caused by physiological effects of taking or withdrawing from certain substances such as caffeine, alcohol, amphetamine, opioids, sedatives, hypnotics and anxiolytics; and
• the term "Obstructive Sleep Apnea” means repeated episodes of upper-airway obstruction during sleep and is normally characterized by loud snores or brief gasps that alternate with episodes of silence.
• (+)-isomer of ⁇ -(2,3-dimethoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol can be prepared by methods described in U.S. patent no. 5,134,149. One suitable method follows.
• Step A of Reaction Scheme I an esterification reaction is carried out between racemic alpha-(2,3-dimethoxyphenyl)- 1 -[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (structure 1) and the (+)-isomer of alphamethoxyphenylacetic acid (structure 2).
• This esterification produces the diastereomeric mixture identified as structure 3.
• These diastereomers are subjected to silica gel chromatography which separates the two diastereomers, thereby isolating the (+,+) diastereomer as is depicted in Step B.
• Step C the (+,+) diastereomer is hydrolyzed which produces the (+)-isomer of alpha(2,3-dimethoxy- phenyl)-l-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
• the esterification reaction can be carried out using techniques known in the art. Typically approximately equivalent amounts of racemic alpha-(2,3-dimethoxyphenyl)-l-[2-(4- fluorophenyl)ethyl]-4-piperidinemethanol and the (+)-isomer of alpha-methoxyphenylacetic acid are contacted in an organic solvent such as methylene chloride, THF, chloroform, or toluene and heated to reflux for a period of time ranging from 5 to 24 hours.
• the esterification is typically carried out in the presence of an equivalent amount of dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridine (DMAP).
• DCC dicyclohexylcarbodiimide
• DMAP 4-dimethylaminopyridine
• the diastereomers are then subjected to silica gel chromatography which separates the (+,+) and the (-,+) diastereomers. This chromatographic separation may be carried out as is known in the art.
• a 1 :1 mixture of hexane and ethyl acetate is one suitable eluent.
• the resulting (+,+) diastereomer is then subjected to a hydrolysis reaction which produces the (+)-enantiomer of alpha-(2,3-dimethoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol.
• the hydrolysis is carried out by contacting the diastereomer with an excess of a base such as potassium carbonate in an aqueous alcoholic solution.
• the hydrolysis is carried out at a temperature of about 15 to 30°C for a period of time ranging from 2 to 24 hours.
• (+)-isomer of alpha-(2,3-dimethoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]- 4-piperidinemethanol may then be recovered by dilution with water and extraction with methylene chloride. It is then purified by recrystallization from a solvent system such as cyclohexane/hexane or ethyl acetate/hexane.
• 4-hydroxypiperidine is subjected to an N-alkylation reaction with p-fluorophenylethyl bromide which produces 4- hydroxy-l-[2-(4-fluorophenyl)ethyl]-piperidine.
• This compound is brominated with Ph 3 P • Br 2 which produces 4-bromo-l-[2-(4-fluorophenyl)ethyl]piperidine.
• This compound is contacted with Mg thereby forming a Grignard Reagent which is then reacted with 2,3- dimethoxybenzaldehyde which produces the desired product ( ⁇ )-alpha-(2,3- dimethoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.
• the (+)-isomer of alphamethoxyphenylacetic acid is known in the art.
• the alcohol (5) is reacted with an acid halide (RC(O)X), RCO 2 H or acid anhydride (RCO) 2 O in the presence of an a sufficient amount of an appropriate base.
• An appropriate base is one that permits ester formation from the acid halide or anhydride.
• Examples of appropriate bases are trialkylamines, pyridine such as dimethylamino pyridine, diisopropyl ethyl amines, N-methyl morpholines, with triethylamine being preferred.
• a sufficient amount of the base can be ascertained by one skilled in the art which permits the formation of the compounds of Formula I.
• the base is added to the alcohol (5) and that mixture added dropwise to the acid halide or acid anhydride in an appropriate solvent.
• appropriate solvents are chloroform, methylene chloride, or toluene, all of which are readily available, with chloroform being preferred.
• the temperature of the reaction may be at a range of about 0-25 °C.
• the reaction mixture may be stirred for from a few hours to overnight to enhance the reaction.
• Catalysts may also be added for enhancement of reaction times, e.g., 4-dimethylaminopyridine or the like.
• the starting materials for the acid halide are readily available for those skilled in the art.
• Aldrich Chemical company provides stearoyl chloride, heptadecanoyl chloride, palmitoyl chloride, myristoyl chloride, isovaleryl chloride, valeryl chloride, hexanoyl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, undecanoyl chloride and lauroyl chloride.
• those acid halides not readily available, one skilled in the art may prepare the acid halide desired.
• a carboxylic acid may be mixed with a halide donor to produce the desired acid halide.
• a halide donor for example, a carboxylic acid may be mixed with a halide donor to produce the desired acid halide.
• carboxylic acid (0.17 mol), methylene chloride (660 mL) and dimethylformamide (0.5 mL) under a nitrogen atmosphere.
• oxalyl chloride 0.2 mol
• Another method is to dissolve the carboxylic acid (10 mmol) in methylene chloride (50 mL). Cool to 0 ° C, place under a nitrogen atmosphere and add, by dropwise addition, thionyl chloride (11 mmol). Stir at room temperature for several hours and evaporate the volatiles in vacuo to give the acid chloride.
• the carboxylic acids are readily available or can be easily made by those skilled in the art.
• the starting materials for the acid anhydrides (RCO) 2 O are readily available for those skilled in the art.
• Aldrich Chemical company provides butryic anhydride, isobutyric anhydride, valeric anhydride, 2-2,dimethylglutaric anhydride, and phthalic anhydride.
• acid anhydrides may be synthesized by methods well known in the art.
• RCO 2 H The starting materials for the acids (RCO 2 H) are readily available or may be synthesized by methods well know in the art. For example, see Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons,, New York 1992, incorporated herein by reference.
• Aldrich Chemical Company also provides isovaleric acid, valeric acid, tert-butylacetic acid , 2, 2dimethylbutyric acid, 2-ethylbutyric acid, hexanoic acid, 3-methylvaleric acid, 4-methylvaleric acid, heptanoic acid, octanoic acid, 2- propylpentanoic acid, nanoic acid, decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristoleic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, as well as others wherein R is between four and twenty alkyl groups.
• Example 1 demonstrates the preparation of the starting material ( ⁇ )-alpha(2,3- dimethoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, structure 1, Scheme I.
• A) l-[2-(4-Fluorophenyl)ethyl]-4-piperidinecarboxamide
• Example 2 demonstrate an alternative manner of preparing ( ⁇ )-alpha(2,3- dimethoxyphenyl)- 1 -[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol, structure 1.
• n-Butyl lithium (14.5 mL of a 2.5 M solution in hexane, 36.3 mmol) was added via syringe to a stirred solution of veratrole (5.00 g, 36.2 mmol) in THF (50 mL, anhydrous) under argon at 0°C. The ice bath was removed and the mixture was allowed to stir for 90 minutes. The mixture was cooled to -78°C and treated with 4-(N-methoxy-N-methylcarboxamido)-l- > piperidinecarboxylic acid 1,1-dimethylethyl ester (9.20 g, 33.8 mmol) in THF (50 mL, anhydrous) via syringe.
• This example demonstrates the preparation of the alcohol, structure 5.
• the reaction mixture was diluted with 500 mL of CH 2 Cl 2 and washed with 250 mL of 5% K 2 CO 3 , 250 mL of H 2 0 and 250 mL of saturated NaCl.
• the organic phase was dried over 500 g of MgSO 4 and filtered.
• the filter cake was washed with 200 mL of CH 2 C1 2 .
• the filtrate was concentrated at 40°C/50 torr to give an oil.
• the crude product was purified by flash chromatography (14 x 29 cm column, 2.035 kg of 230-400 mesh silica gel). The crude product was loaded onto the column by dissolving it in 75 mL of CH 2 C1 2CH2C12 . The column was eluted with 24 L of 1/4 EtOAc/CH 2 Cl 2 collecting 24 x one liter fractions. The fractions which were homogenous by TLC were combined and concentrated at 35°C/50 torr followed by 70°C/0.5 torr for one hour to give a colorless oil.
• reaction mixture was allowed to warm to ambient temperature and to the reaction mixture was added 65 mg (0.536 mmol) of 4- dimethylaminopyridine after which the solution was stirred under nitrogen overnight.
• the reaction mixture was poured into 50 mL of 0.5 N sodium hydroxide and 50 mL of diethyl ether. Some precipitate was observed and the resultant suspension was extracted with methylene chloride. The methylene chloride layer was washed with water and brine, and dried over sodium sulfate, filtered, and concentrated to a yellow oil.
• 2-Hexene-l-mesylate is prepared by adding N,N-diisopropyl ethylamine (12.9g, 0.1m) to a solution of trans-2-hexene-l-ol (10. Og, 0.1m) (Aldrich) in 100 mL of methylene chloride. Methanesulfonyl chloride (12.6g, 0.1 lm) in methylene chloride (50 mL) is added dropwise to the solution with stirring at room temperature for 4 hours. The reaction mixture is transferred to a separatory funnel and washed with cold IN HC1 (2 times) and then with saturated NaHCO 3 solution (2 times). The solution is dried over anhydrous MgSO 4 , filtered and concentrated, under vacuum at 40 °C to give 2-hexene-l-mesylate.
• 2,2-Dimethyl-3-octene nitrile is prepared by adding 2-hexene-l-mesylate (11.02g, 0.05m) in anhydrous THF (lOOmL) to a solution prepared by the addition of isobutyro nitrile
• 2,2-Dimethyl-3-octenoic acid is prepared by adding 2,2-dimethyl-3-octene nitrile (1.51g, 0.01m) to a solution prepared from 15 % NaOH in butanol/H 2 O (2:3) (30mL). The reaction mixture is stirred and refluxed for 7 hours, is cooled and made acidic with 10% hydrochloric acid. The reaction mixture is extracted with diethyl ether and the extract washed , 5 with saturated NaCl and dried over MgSO 4 , filtered and concentrated to give 2,2-dimethyl-3- octenoic acid.
• 2,2-Dimethyl octanoic acid is prepared by dissolving 2,2-dimethyl-3-octenoic acid (0.20g, 1.1 mmol) in absolute ethanol blanketed with N 2 and 10% palladium on carbon which is then hydrogenated for 6 hours. The catalyst is removed by filtration and the filtrate 20 concentrated under vacuum to give 2,2-dimethyl octanoic acid.
• This example demonstrates one pharmaceutical composition of the present invention.
• a suitable 100 mL volumetric vessel place 70 mL of Sesame Oil, NF (Sigma), 1.2g of Benzyl Alcohol, NF and 14.129g of (+)- ⁇ -(2,3-Dimethyoxyphenyl)-l-[2-(4- fluorophenyl)ethyl]-4-piperidinementhanol decanoate.
• NF Sesame Oil
• NF 1.2g
• Benzyl Alcohol 1.2g
• NF Benzyl Alcohol
• This example describes a behavioral test (antagonism of DOI-induced behaviors) designed to identify compounds which possess antagonist activity at the 5HT 2A receptor.
• the compound of the present invention used in this test was (+)- ⁇ -(2,3-Dimethyoxyphenyl)-l-[2- (4-fluorophenyl)ethyl]-4-piperidinemethanol decanoate - Example 4 herein.
• the 5-HT2A/2C agonist ( ⁇ )-DOI HC1 (l-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) induces several quantifiable behaviors in rats. These behaviors include "shakes" (a quick head and body shake, a.k.a.
• the 5-HT2 antagonists mianserin, ritanserin and methysergide as well as the selective 5-HT2A antagonist MDL 100,907 have been demonstrated to dose-dependently block the behavioral effects of DOI (Pranzatelli, 1990, Neurosci. Let. 11 : 74-80; Wettstein et al., 1996, Soc. Neurosci. Abs. 22: 481).
• drugs with 5-HT 2A antagonist activity have been proposed to have atypical antipsychotic properties in schizophrenic patients (Meltzer et al., 1989, JPET. 251 : 238-246), as well as potential therapeutic activity in a number of other CNS disorders including depression, dysthymia, and anxiety (Stefanski & Goldberg, 1997, CNS Drugs, 7: 399-409) Methods
• mice Male Sprague-Dawley rats (180 ⁇ 50 g) were housed seven per cage and allowed 1 week to acclimate to the vivarium. Food and water were freely available. The temperature and light cycle (12 h on- 12 h offjwere automatically maintained. Individual rats were tested once. Each testing group contained seven animals. Experiments took place in the vivarium room where the animals were housed.
• (+)- ⁇ -(2,3-Dimethyoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol decanoate 120 mg/kg equivalent to MDL 100,907 was dissolved in sesame oil and administered intramuscularly to separate groups of rats on Day 0 in a volume equal to 60 mL/lOOg body weight. Vehicle control animals were injected with sesame oil alone. ( ⁇ )-DOI HC1 (3.0 mg/kg, ImL/kg body weight) was dissolved in distilled water with the aid an ultrasonic bath, and injected intraperitoneally on appropriate testing days.
• (+)- ⁇ -(2,3-Dimethyoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4-piperidinementhanol decanoate -treated rats were tested for antagonism of DOI-induced behaviors 1, 5, 7, 14, 21, 28 and 40 days after the single (+)- ⁇ -(2,3-Dimethyoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4- piperidinementhanol decanoate intramuscular injection. Each rat was tested once. Immediately after DOI injection rats were placed under inverted clear plastic boxes (28L x 25 W x 25H cm) which were arranged on top of clean absorbent paper.
• Rats were continuously watched by trained observers (blind to treatment) for 30 minutes for the occurrence of DOI-induced behaviors (shakes, skin-jerks and forepaw tapping bouts) and then returned to their home cages. Rats were later used for pharmacokinetic studies. The frequencies of DOI-induced behaviors were recorded and then summed to provide a single behavioral score for each animal. Data Analysis
• the mean and standard error of the behavioral scores of each group was determined. Each treatment group's mean was then compared separately to the mean of the vehicle-control 5 group using a one-way analysis of variance test (AN OVA), followed by a Bonferroni/Dunn post-hoc comparison. Differences between groups were considered statistically significant if p values were less than or equal to 0.05.
• AN OVA one-way analysis of variance test
• Plasma is removed and stored at -20 ° C until assay.
• the plasma samples are analyzed by an appropriate HPLC method.
• Brains will also be collected at the above timepoints and stored at -80 ° C until analyzed by the appropriate HPLC method. The results are shown in Table 1. TABLE 1
• the dosage range at which the compounds of Formula I exhibits their ability to block the effects of serotonin at the 5HT 2A receptor can vary depending upon the particular disease or condition being treated and its severity, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient.
• the compounds of Formula I will exhibit their serotonin 5HT 2A antagonist properties at dosages of between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day.
• the sustained release formulations may contain multiples of the foregoing dosages depending upon over what period the active ingredient is released.
• the dosage of the compounds of the present invention may be determined by administering the compound to an animal and determining the plasma level of the active ingredient.
• the compounds of the present invention may be mixed with a pharmaceutically acceptable carrier capable of being administered by the preferred route in order to produce a sustained release of the compound of the present invention so that a therapeutically effective amount of the compound (+)- ⁇ -(2,3-Dimethoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol can be supplied to the patient over a period of days or weeks.
• the sustained release formulation comprises a compound of Formula I and a pharmaceutically acceptable carrier for parenteral administration as either an aqueous suspension, oil solution, oil suspension or emulsion.
• oils which may be used for intramuscular injection are sesame, olive, arachnis, maize, almond, cottonseed, peanut and castor oil, with sesame oil being preferred.
• a pharmaceutically acceptable preservative such as benzyl alcohol may also be added.
• the sustained release formulation is preferably administered intramuscularly or subcutaneously, with intramuscular administration preferred although other routes of administration such as oral, transdermal, nasal spray, etc. could be used if appropriate to the needs of the patient.
• the compounds of the present invention release (+)- ⁇ -(2,3-Dimethoxyphenyl)-l- [2-(4-fluorophenyl)ethyl]-4-piperidinemethanol ("Active Ingredient") into the patient for the therapeutic effect
• the compounds of the present invention are useful for all indications of use for which the Active Ingredient is useful. Some of these indications of use have been described in the patents issued generically encompassing the Active Ingredient (U.S. Patent no.4,783,471) or specifically covering the Active Ingredient (U.S. Patent nos. 5,134,149; 5,561,144; 5,618,824; and PCT/US97/02597), all incorporated herein by reference.
• Psychoses as used herein are a conditions where the patient experiences a major mental disorder of organic and/or emotional origin characterized by derangement of the personality and loss of contact with reality, often with delusions, hallucinations or illusions.
• Representative examples of psychotic illnesses which can be treated with the compounds of the present invention include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder not otherwise specified, and substance-induced psychotic disorder. See Diagnostic and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association, incorporated herein by reference.
• the Active Ingredient is currently in clinical trials for the treatment of schizophrenia.
• OCD obsessive-compulsive disorders
• the Active Ingredient is also effective in the prevention of acute thrombosis, especially those of the coronary arteries. This compound decreases the rate at which platelets aggregate as the result of minor alterations in the endothelial lining of the vasculature and therefore prevent the formation of acute pathological thrombi. See U.S. Patent no. 5,561,144 for description.
• Fibromyaligia is a chronic disease state wherein the patient suffers from numerous symptoms such as, for example, widespread generalized musculoskeletal pains, aching, fatigue, morning stiffness and a sleep disturbance which can be characterized as inadequacy of stage 4 sleep.
• Extra-pyramidal side effects often accompany the administration of neuroleptic agents such as haloperidol and chlorpromazine.
• Patient often experiences a parkinsonian-like syndrome, wherein they experience muscular rigidity and tremors. Others experience akathisia and acute dystonic reactions.
• the Active Ingredient increases the duration of the action potential of myocardial tissue producing an increase in the refractory period of that tissue, which under the classification system of Vaughan Williams, exhibits Class III anti-arrhythmic activity.
• the compounds of the present invention may be used to treat drug abuse in the patient. See T. F. Meert, et al., European Journal of Pharmocology 183: 1924 where 5HT 2 antagonist abolished preference for both alcohol and cocaine in the rodent model of the drug abuse.
• Other animal models such as the rodent self-stimulation model described in R. A. Frank, et. al., Behavioral Neuroscience 101 : 546-559 (1987) may be used to demonstrate the ability of the compounds of the present invention to treat drug abuse.
• the compounds of the present invention are useful in treating patients with Depressive Disorders and Bipolar Disorders.
• Depressive Disorders are defined as Major Depression, Dysthymia and Depressive Disorder NOS. We also include in this category Major Depressive Episode including Chronic Type, Melancholia, and Seasonal Pattern.
• Bipolar Disorders include Bipolar Disorder, Cyclothymia and Bipolar Disorder NOS.
• a feature of Depressive Disorders is one or more periods of depression without a history of either Manic or Hypomanic episodes.
• a feature of Bipolar Disorders is the presence of one or more Manic or Hypomanic Episodes usually accompanied by one or more Major Depressive Episodes.
• a Manic or Hypomanic Episode is a distinct period during which the predominant mood is either elevated, expansive or irritable and there are associated symptoms of the Manic Syndrome as defined in DSM-III-R. The disturbance is severe enough to cause marked impairment in occupational or social functioning.
• Major Depression has one or more Major Depressive Episodes.
• a Major Depressive Episode is characterized by: (1) at least five of the following) depressed mood, loss of interest in pleasure (anhedonia), significant weight loss or weight gain when not dieting, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, or recurrent thoughts of death including suicide; (2) it cannot be established that an organic factor initiated and maintained the disturbance; (3) there are no delusions or hallucinations for as long as two weeks in the absence of prominent mood symptoms; and (4) it is not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder NOS.
• Dysthymia has a history of a depressed mood more days than not for at least two years and during the first two years of the disturbance, the condition does not meet the criteria for a Major Depressive Episode.
• the depressed mood in children and adolescents can be exhibited as irritability.
• Also present is at least two of the following: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions or feeling of hopelessness. These symptoms are not superimposed on a chronic psychotic disorder such as Schizophrenia or Delusional Disorder. Also it cannot be determined that an organic factor initiated and maintained the disturbance.
• CMS Chronic Mild Stress Model of Depression
• CMS uses mild stressors, such as food and water deprivation, small temperature changes, changes of cage mates, etc. Over a period of weeks of exposure to the mild stressors, the animals gradually reduce their consumption of a highly preferred sucrose solution which persists (in untreated animals) for several weeks following the cessation of stress. This decreased sensitivity to reward (the sucrose solution) reflects anhedonia, a symptom of a Major Depressive Episode (see for example, Behavioral Pharmacol.5: Suppl.l, p.
• MDL 100,907 Active Ingredient of the compounds of the present invention
• Imipramine known anti- depressant compound Imipramine
• the animals were first trained to consume a 1% sucrose solution; training consisted of eight 1 hour baseline tests in which sucrose was presented, in the home cage, following 14 hours food and water deprivation; intake was measured by weighing pre-weighed bottles containing the sucrose solution at the end of the test. Subsequently, sucrose consumption was monitored, under similar conditions, at weekly intervals throughout the whole experiment.
• each week of stress regime consisted of: two periods of food or water deprivation (12 and 14 hour), two periods of 45 degree cage tilt (12 and 14h), two periods of intermittent overnight illumination (lights on and off every 2 hours), two 14 hour periods of soiled cage (200 ml water in sawdust bedding), two 14 hour periods of paired housing, two 14 hour periods of low intensity stroboscopic illumination (150 flashes/min). Stressors were applied continuously throughout the day and night, and scheduled randomly. Control animals were housed in a separate room and had no contract with the stressed animals.
• Results were analyzed by multiple analysis of variance, followed by Fisher's LSD test for post hoc comparisons of means.
• sucrose intake was approximately 13 gram in both groups. Following three weeks of stress (Week 0), intakes remained at 12.4 ( ⁇ 0.4) grams in controls but fell to 7.2 ( ⁇ 0.2) grams in stressed animals (pO.OOl). Such a difference between control and stressed animals treated with vehicle, persisted at similar level for the remainder of the experiment.

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