EP0610192A1 - Etherderivate von alkylpiperidin und -pyrrolidine und ihre verwendung als psychotrope wirkstoffe - Google Patents

Etherderivate von alkylpiperidin und -pyrrolidine und ihre verwendung als psychotrope wirkstoffe

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Publication number
EP0610192A1
EP0610192A1 EP92905089A EP92905089A EP0610192A1 EP 0610192 A1 EP0610192 A1 EP 0610192A1 EP 92905089 A EP92905089 A EP 92905089A EP 92905089 A EP92905089 A EP 92905089A EP 0610192 A1 EP0610192 A1 EP 0610192A1
Authority
EP
European Patent Office
Prior art keywords
compound
mammal
phenyl
inhibiting
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92905089A
Other languages
English (en)
French (fr)
Inventor
Gary Avonn Cain
Thomas Eugene Christos
Sang William Tam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DuPont Merck Pharmaceutical Co filed Critical DuPont Merck Pharmaceutical Co
Priority claimed from PCT/US1991/007842 external-priority patent/WO1993009094A1/en
Publication of EP0610192A1 publication Critical patent/EP0610192A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • This invention relates to novel unsaturated ether derivatives of alkyl piperidine and pyrrolidine
  • phenothiazines e.g., chlorpromazine, and most
  • butyrophenones e.g., haloperidol
  • haloperidol are potent dopamine receptor antagonists which produce a number of
  • Parkinson-like motor effects or extra-pyramidal side-effects (EPS), and dyskinesias including tardive motor effects EPS
  • dyskinesias including tardive motor effects
  • JA 065641 Abstract, August 26, 1971 describes propenylamine derivatives useful as antipsychotic, analgesic, antihypertensive and antiinflammatory agents
  • JA 061710 Abstract, August 6, 1969, describes 4-amino-2-butynyloxy beta-nitro-styrenes useful as antitumor agents which can be prepared from 2-propionyl-beta-nitro-styrenes.
  • n 0, 1, or 2;
  • p is 0 or 1;
  • n 1, 2, or 3;
  • R 1 and R 2 independently are H, alkyl of 1-4 carbon
  • Ar is naphthyl or phenyl, optionally substituted with 1- 5 substituents individually selected from N0 2 , halogen, CF 3 , SH, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, hydroxy alkyl of 1-4 carbon atoms, , -NR 3 R 4 , , , or
  • R 3 and R 4 independently are H, alkyl of 1-4 carbon
  • R 5 is alkyl of 1-4 carbon atoms or phenyl
  • R is H, alkyl of 1-5 carbon atoms, cycloalkyl of 3-6
  • R 6 and R 7 independently are H or alkyl of 1-4 carbon
  • This invention also includes pharmaceutical
  • compositions containing these compounds in another embodiment, this invention includes a method of using these compounds as antipsychotic agents.
  • this invention includes processes for making the compounds of this invention.
  • antipsychotic agents which are selective sigma receptor antagonists rather than the traditional dopamine
  • the compounds of this invention antagonize aggressive behavior and hallucinogenic-induced behavior without exhibiting any substantial movement disorder side-effects typically associated with dopamine antagonist antipsychotic agents.
  • n 0, 1, or 2;
  • p is 0 or 1;
  • n 1, 2, or 3;
  • R 1 and R 2 independently are H, alkyl of 1-4 carbon
  • Ar is naphthyl or phenyl, optionally substituted with 1- 5 substituents individually selected from NO 2 , halogen, CF3, SH, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, hydroxy alkyl of 1-4 carbon atoms, , -NR 3 R 4 , , , or
  • R 3 and R 4 independently are H, alkyl of 1-4 carbon
  • R 5 is alkyl of 1-4 carbon atoms or phenyl
  • R is H, alkyl of 1-5 carbon atoms, cycloalkyl of 3-6
  • R 6 and R 7 independently are H or alkyl of 1-4 carbon
  • Preferred compounds are those of formula (I) where:
  • n and p are 1;
  • R is phenyl
  • Ar is phenyl, p-F-phenyl, or p-CF 3 -phenyl; and/or
  • the side chain is attached at the 4-position of the piperidine ring.
  • Specifically preferred compounds of the present invention include:
  • Suitable bases which can be used include, alkali metal hydrides, preferably sodium hydride, alkali metal dialkylamides, preferably lithium diisopropylamide, alkali metal bis (trialkylsilyl) amides, preferably sodium bis (trimethylsilyl) amide, alkyl alkali metal compounds, such as n-butyl lithium, or alkyl alkaline earth metal halides, such as methyl magnesium bromide.
  • the inert solvent selected should be compatible with the base selected. Suitable solvents include dialkyl ethers of 4 to 10 carbon atoms, cyclic ethers of 4 to 10 carbon atoms, preferably tetrahydrofuran, dialkylformamides,
  • N,N-dimethylformamide preferably N,N-dimethylformamide, cyclic amides, such as N-methylpyrrolidinone, or cyclic dialkylureas, such as N,N 1 -dimethylpropyleneurea.
  • Y can be a halide, arylsulfonyloxy, preferably p-toluenesulfonyloxy, alkylsulfonyloxy, such as methanesulfonyloxy, or haloalkylsulfonyloxy, such as trifluoromethylsulfonyloxy.
  • Suitable reducing agents include alkali metal aluminum hydrides, preferably lithium aluminum hydride, or alkali metal alkoxy-aluminum hydrides, such as lithium tri-t-butoxyaluminum hydride.
  • Inert solvents include, but are not limited to, ethereal solvents such as diethyl ether or tetrahydrofuran.
  • temperatures range from about -78°C to about 25°C.
  • the carbamate can be cleaved under standard conditions as described in the Greene reference to yield a compound of formula (VI).
  • the amines of formula (VI) can then be alkylated by treatment with a compound of formula (VII) in the presence of a base in an inert solvent to yield the desired compounds of formula (I).
  • trialkylamines such as triethylamine or diisopropylethylamine
  • polycyclic diamines such as 1,4-diazabicyclo-[2.2.2]-octane or
  • 1,8-diazabicyclo-[5.4.0]-undecene 1,8-diazabicyclo-[5.4.0]-undecene.
  • Appropriate solvents include those described above for Scheme I as well as lower alkyl alcohols of 1 to 6 carbons, or halocarbons, such as chloroform or dichloromethane.
  • Suitable reaction temperatures range from about -78°C to about 100°C, preferably -78°C to 25°C.
  • the type of leaving group Y includes those described above for Scheme I. The choice of Y, base, solvent, and reaction temperature will be readily apparent to those skilled in the art.
  • the intermediate of formula (V) can alternately be prepared according to Scheme III by treating an alcohol of formula (VIII) with base in an inert
  • Y is methane sulfonyloxy or p-toluenesulfonyloxy
  • Z is phenyl or O-t-butyl
  • the base is sodium hydride
  • the solvent is N,N 1 - dimethylformamide
  • the reaction temperature is from 0°C to reflux.
  • Scheme IV is via partial reduction of the acetylenic intermediates of formula (Va) to provide the cis allylie ethers of formula (Vb), followed by conversion of the group to N- ⁇ CH2)mR as described earlier.
  • Va acetylenic intermediates of formula (Va)
  • Vb cis allylie ethers of formula (Vb)
  • N- ⁇ CH2mR N- ⁇ CH2mR
  • the alkylamino alcohol intermediates of formula (II) can be prepared via one of the two routes shown in Scheme V.
  • a hydroxyamine of formula (X) which is either available commercially or can be
  • the choice of reducing agent includes alkali metal aluminum hydrides, preferably lithium aluminum hydride, alkali metal alkoxyaluminum hydrides, such as lithium tri-t-butoxyaluminum hydride, alkali metal borohydrides, preferably lithium borohydride, dialkyaluminum hydrides, such as diisobutylaluminum hydrides, alkali metal trialkylboron hydrides, such as lithium tri-s-butylboron hydride.
  • Appropriate solvents include ethers such as diethyl ether or tetrahydrofuran. Reaction temperatures range from about -78°C to about 100°C, preferably from about 0°C to about 25°C.
  • the protected amino alcohol intermediates of formula (IV) can be prepared by one of the routes shown in Scheme VI.
  • An aminoalcohol of formula (X) is treated with an acylating agent of formula (XIII) in the presence of a base in an inert solvent to produce the protected amine of formula (IV).
  • the conditions for acylation of amines to form amides and carbamates are quite varied; the above cited Green reference (Chapter 7) provides a multitude of procedures and examples.
  • the ester group of compound (XIV) is then selectively reduced to an alcohol in the presence of 'the acyl amine using the lithium borohydride/methyl borate conditions reported by H. C. Brown (J. Org. Chem. (1982), 47, 1604; (1984), 49, 3891) to yield the desired product (IV).
  • the alcohol intermediates of formula (VIII) can be converted into the alkylating reagents of formula (III), with leaving groups Y as described earlier, via a number of standard methods as reported in the March reference cited above (pp. 357-358, 381-384)
  • Examples 1-16 describe the preparation of reagents of formula (II).
  • Protected amino alcohol reagents of formula (IV) are prepared as described in Examples 17-18.
  • Intermediates of formula (IX) are synthesized as described in Examples 19-20.
  • Compounds of formula (I) can be prepared as described in Examples 21-42.
  • Table 1 sets forth additional examples which can be prepared according to the procedure described in
  • Table 2 sets forth additional examples which can be prepared according to the procedure described in Example 8 above.
  • Methanesulfonyl chloride (4.0 mL, 52 mmol) was added slowly to a 0°C solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (10.0 g, 43.7 mmol) and
  • Table 3 sets forth additional examples which can be prepared according to the procedure described in Example 21 above.
  • N-t-BOC intermediate 500 mg, 1.46 mmol was stirred with 3 M hydrogen chloride in ethyl acetate (10 mL) at room temperature for 2 hours, then concentrated in vacuo.
  • the crude product was purified by
  • the amine salt (0.34 g, 1.4 mmol), phenethyl bromide (0.26 g, 1.4 mmol), and potassium carbonate (0.50 g) were heated at reflux in absolute ethanol (50 mL) for 48 hours. After cooling, the mixture was filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with 10% methanol in chloroform, and concentrated in vacuo to yield a colorless oil (0.25 g, 51%).
  • Cinnamyl alcohol (1.52 g, 11.3 mmol) and sodium hydride (0.56 g, 14 mmol, 60% oil disp.) were stirred in dry N,N-dimethylformamide (15 mL) at room temperature under a nitrogen atmosphere for 45 minutes. After the hydrogen gas evolution had ceased, a solution of 1-benzoyl-4[(p-toluene sulfonyl)oxyethyl]piperidine (3.93 g, 11.3 mmol) in dry DMF (40 mL) was added, and the mixture was stirred for 18 hours. Additional sodium hydride (0.53 g) was added, and the reaction was further stirred for 24 hours.
  • Lithium aluminum hydride (1.0 M. in tetrahydrofuran, 2.1 mL, 2.1 mmol) was added dropwise over 4 minutes to a -78°C solution of the above amide (0.72 g, 2.1 mmol) in dry THF with stirring under nitrogen. After 3 hours, the reaction was allowed to slowly warm to room
  • compositions possess psychotropic properties, particularly antipsychotic activity of good duration with selective sigma receptor antagonist activities while lacking the typical movement disorder side-effects of standard dopamine receptor antagonist antipsychotic agents.
  • These compounds can also be useful as antidotes for certain psychotomimetic agents such as phencyclidine (PCP), and as antidyskinetic agents.
  • resulting membrane pellet was resuspended in 10 vol (original wt/vol) of 50 mM Tris HCl (pH 7.4) and incubated at 37°C for 45 minutes to degrade and dissociate bound endogenous ligands. The membranes were then centrifuged at 47,000 ⁇ g for 20 minutes and resuspended in 50 mM Tris HCl (50 mL per brain).
  • IC 50 s were calculated from log-logit plots.
  • K i IC 50 /[1 + (L/K d )] (4), where L is the concentration of radio ligand and K d is its dissociation constant.
  • Membranes were prepared from guinea pig striatum by the method described for sigma receptor binding. The membranes were then resuspended in 50 mM Tris HCl (9 mL per brain).
  • Nonspecific binding was measured in the presence of 100 nM (+)-butaclamol. After 15 minutes of incubation at 37°C, samples were filtered rapidly through Whatman GF/C glass filters under negative pressure, and washed three times with ice-cold binding buffer (5 mL).
  • IC50S were calculated from log-logit plots.
  • K i IC 50 [1+(L/K d )] (4), where L is the concentration of radio ligand and K d is its dissociation constant.
  • mice Male Balb/c mice (Charles River) were used. After 2 weeks of isolation in plastic cages (11.5 ⁇ 5.75 ⁇ 6 in) the mice were selected for aggression by placing a normal group-housed mouse in the cage with the isolate for a maximum of 3 minutes. Isolated mice failing to consistently attack an intruder were eliminated from the colony.
  • Drug testing was carried out by treating the isolated mice with test drugs or standards. Fifteen minutes after dosing with test drugs by the oral route, one isolated mouse was removed from its home cage and placed in the home cage of another isolate. Scoring was a yes or no response for each pair. A maximum of 3 minutes was allowed for an attack and the pair was separated immediately upon an attack.
  • mice were treated and tested twice a week with at least a 2 day washout period between treatments.
  • Daily dosage ranges from 1 mg to 2000 mg.
  • administration ordinarily will contain 0.5-95% by weight of the active ingredient based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar
  • diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • glycols such as propylene glycol or polyethylene glycols are suitable carriers for
  • parenteral solutions preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • suitable stabilizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are suitable stabilizing agents.
  • parenteral solutions can contain preservatives, such as
  • benzalkonium chloride methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
EP92905089A 1991-10-30 1991-10-30 Etherderivate von alkylpiperidin und -pyrrolidine und ihre verwendung als psychotrope wirkstoffe Withdrawn EP0610192A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US1991/007842 WO1993009094A1 (en) 1991-10-30 1991-10-30 Ether derivatives of alkyl piperidines and pyrrolidines as antipsychotic agents
CA002122599A CA2122599A1 (en) 1991-10-30 1991-10-30 Ether derivatives of alkyl piperidines and pyrrolidines as antipsychotic agents

Publications (1)

Publication Number Publication Date
EP0610192A1 true EP0610192A1 (de) 1994-08-17

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP92905089A Withdrawn EP0610192A1 (de) 1991-10-30 1991-10-30 Etherderivate von alkylpiperidin und -pyrrolidine und ihre verwendung als psychotrope wirkstoffe

Country Status (3)

Country Link
EP (1) EP0610192A1 (de)
JP (1) JPH07502008A (de)
CA (1) CA2122599A1 (de)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9309094A1 *

Also Published As

Publication number Publication date
JPH07502008A (ja) 1995-03-02
CA2122599A1 (en) 1993-05-13

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