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WO1994009007A1 - 3a,6-octahydroisoindoles pontes et hydroisoquinolines et hydrobenzazepines apparentees et leur utilisation comme agents pharmaceutiques et de radio-imagerie - Google Patents

3a,6-octahydroisoindoles pontes et hydroisoquinolines et hydrobenzazepines apparentees et leur utilisation comme agents pharmaceutiques et de radio-imagerie Download PDF

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Publication number
WO1994009007A1
WO1994009007A1 PCT/US1993/009162 US9309162W WO9409007A1 WO 1994009007 A1 WO1994009007 A1 WO 1994009007A1 US 9309162 W US9309162 W US 9309162W WO 9409007 A1 WO9409007 A1 WO 9409007A1
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Prior art keywords
compound
mammal
alkyl
compounds
antipsychotic
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PCT/US1993/009162
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English (en)
Inventor
Engelbert Ciganek
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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Publication of WO1994009007A1 publication Critical patent/WO1994009007A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K51/047—Benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates to novel nitrogen-containing tricyclic compounds , to pharmaceutical compositions thereof and to methods of use to treat physiological or drug-induced psychosis and as antidyskinetic agents .
  • the disclosed compounds are an antimicrobial agent and
  • the compound is an intermediate used in the preparation of analgesics.
  • 5-HT 1a agonists having utility as anxiolytics/antipsychotics, antidepressants and in the treatment of sexual dysfunction.
  • antipsychotic agents have been potent dopamine receptor antagonists.
  • phenothiazines such as chlorpromazine and most butyrophenones such as haloperidol are potent dopamine receptor antagonists.
  • EPS extra-pyramidal side-effects
  • dyskinesias including tardive dyskinesias at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.
  • An object of the present invention is to provide compounds, compositions and methods useful for the treatment of physiological and/or drug-induced psychosis and dyskinesia.
  • the present invention provides antipsychotic agents which are sigma receptor antagonists, not traditional dopamine receptor blockers known in the art; and therefore, the compounds of the present invention maintain the ability to antagonize aggressive behavior and antagonize hallucinogenic-induced behavior while having low potential for the typical movement disorder side-effects
  • Radiopharmaceutical compounds have been in use for diagnostic purposes for many years. Such compounds are useful for imaging organs such as the heart, brain, liver, kidneys, spleen, lungs, etc. Two important imaging modalities that utilize
  • radiopharmaceutical imaging agents are Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography
  • PET PET
  • Another object of the present invention is to provide radiopharmaceuticals and compositions containing them useful for imaging with SPECT and PET.
  • This invention provides compounds of formula:
  • R 1 is C 1 -C 6 alkyl substituted with 1-3 R 5 , C 3 -C 6 alkenyl substituted with 1-3 R 5 , C 3 -C 6 alkynyl substituted with 1-3 R 5 ,
  • R 5 is C 3 -C 8 cycloalkyl, aryl optionally substituted with 1- 3 R 6 , or heterocycle optionally substituted with 1-3 R 6 ;
  • R 6 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 6 perfluoroalkyl, halogen, NO 2 , OR 7 , OCOR 7 , N(R 7 ) 2 , SR 7 , S(O)R 7 , SO 2 R 7 , CO 2 R 7 or CN;
  • R 7 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or aryl;
  • R 8 is H, C 1 -C 8 alkyl, or C 1 -C 8 acyl
  • X is O or (CH 2 ) p ;
  • n 1 to 3;
  • X is O
  • R 5 is aryl optionally substituted with 1-3 R 6 .
  • the present invention also provides pharmaceutical compositions containing compounds of formula (I).
  • the present invention also provides methods for the treatment of physiological or drug-induced psychosis or dyskinesia by administering to a host suffering from such physiological or drug-induced psychosis or dyskinesia a pharmaceutically effective amount of a compound of formula (I).
  • the present invention also provides
  • the provided radiopharmaceuticals are especially useful for imaging the brain in mammals.
  • the compounds herein described may have asymmetric centers . All chiral, enantiomeric, diastereomeric, and racemic forms are included in the present invention.
  • the compounds of formula (I) may be provided in the form of an individual stereoisomer, individual enantiomers, a non-racemic stereoisomer mixture, or a racemic mixture.
  • substitutents R 2 , R 3 and R 4 may be attached to any of carbon atoms 2-6 of formula (I).
  • any variable occurs more than one time in any constituent or in formula (I), or any other formula herein, its definition on each occurrence is independent of its definition at every other
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. The number of carbon atoms in a group is specified herein, for example, as C 1 -C 5 to indicate 1-5 carbon atoms.
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge;
  • cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and
  • biycloalkyl is intended to include saturated bicyclic ring groups such as
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like; and "alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • Cycloalkyl-alkyl is intended to include cycloalkyl attached to alkyl.
  • Counteririon is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo. This term also includes isotopes of halogen atoms including 18 F and 123 I .
  • aryl or “aromatic residue” is intended to mean phenyl or naphthyl;
  • carbocyclic is intended to mean any stable 5- to 7- membered monocyclic or bicyclic or 7- to 14- membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic, for example, indanyl or tetrahydronaphthyl (tetralin).
  • heterocycle is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10- membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,
  • substituted means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • stable compound or “stable structure” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • salts refer to derivatives of the disclosed compounds that are modified by making acid or base salts. Examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids .
  • compositions of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • the compounds of this invention are prepared by saturation of the double bond in compounds 1 as shown in Scheme 1.
  • the preferred method is hydrogenation in the presence of catalysts such as platinum or palladium in solvents such as alcohols or ethers at temperatures of 0-200°, preferably at 25° and at
  • the double bond in lactam or cyclic imide derivatives of compounds 1 may be saturated by the methods given above followed by removal of the carbonyl groups in the lactams and cyclic imides by standard methods such as reduction with borane, lithium aluminum hydride, or sodium
  • the precursors 1 are prepared by intramolecular Diels-Alder reaction of suitably substituted furan, cyclopentadiene, 1,3-cyclohexadiene or 1,3-cycloheptadiene derivatives of type 2.
  • Diels-Alder reaction see E.
  • R 2 , R 3 and R 4 are H.
  • the cyclization is effected by heating the free base of 2 or, preferrably, salts of the amines 2 either neat or, preferably, in solvents such as alcohols, aromatic hydrocarbons,
  • dimethylformamide or water at temperatures of 50-300°.
  • Precursors of compounds of formula 2 are prepared by standard amine-forming reactions well known to those skilled in the art of organic synthesis.
  • amides of formulae 2., A, and 5, and imides of formula &. may be subjected to the intramolecular Diels-Alder reaction to afford compounds of formulae 3a-6a, respectively, which are useful for the synthesis of compounds of the present invention.
  • This method is shown in Scheme 4 which illustrates the preparation of a compounds of formula 3a-6a therein substitutents R 2 , R 3 and R 4 are H.
  • substitutents R 2 , R 3 and R 4 are not all H may be prepared via the method of Scheme 4 by using as starting material compounds of formulae 2-3. bearing substitutents R 2 , R 3 and R 4 which are other than H.
  • the substitutents R 2 , R 3 and R 4 may be on the ring of 3-6 or the pendant olefin group of 3-6 or they may be divided between both the ring and the pendant olefin of 3-6.
  • R 2 , R 3 and R 4 are H, and A is R 1 less one CH 2 group.
  • the cyclizations of substrates 3-6 may, in some cases, be catalyzed by Lewis acids such as diethylaluminum chloride, methylaluminum dichloride, or aluminum chloride.
  • Compounds of formulae 3a-6a may then be converted into compounds of formula (I) using techniques disclosed above.
  • the double bond created during the cyclization may be removed by hydrogenation in the presence of catalysts such as platinum or palladium in solvents such as alcohols or ethers at temperatures of 0-200°, preferably at 25° and at hydrogen
  • the carbonyl group (s) in the lactams and cyclic imides may be reduced to methylene by standard methods such as reduction with borane, lithium aluminum hydride, or sodium
  • R 2 , R 3 and R 4 are H.
  • the diene component may be activated by a carbonyl group in conjugation with the diene system.
  • This method is shown in Scheme 8 which illustrates the preparation of a compound of formula 1 wherein substitutents R 2 , R 3 and R 4 are H from cyclization of a compound of formula 8 which possesses an activating carbonyl group in conjugation with the diene.
  • substitutents R 2 , R 3 and R 4 are not all H may be prepared via the method of Scheme 8 by using as starting material compounds of formula 8 bearing substitutents R 2 , R 3 and R 4 which are other than H.
  • the substitutents R 2 , R 3 and R 4 may be on the ring of 8 or the pendant olefin group of 8 or they may be divided between both the ring and the pendant olefin of 8.
  • R 2 , R 3 and R 4 are H.
  • the activations shown in Schemes 7 and 8 are known to facilitate the intramolecular Diels-Alder reaction [E. Ciganek, Qrg. React, 32, 1-374 (1984)].
  • the carbonyl groups used to activate the diene or olefin may then be removed by standard methods such as reduction to the alcohol, conversion of the alcohol into the p-toluenesulfonate, and reduction of the latter with lithium aluminum hydride.
  • the secondary amines are best obtained by carrying out any of the reaction sequences disclosed in Schemes 1-8 with compounds having protecting groups R! that are then removed at the end.
  • An example of such a protecting group R 1 is the benzyl group which may be removed by hydrogenation in the presence of a palladium catalyst.
  • Compounds of this invention that are radiopharmaceuticals suitable for imaging with SPECT are those compounds wherein R ⁇ is 123 I.
  • Compounds of this invention that are radiopharmaceuticals suitable for imaging with PET are those containing at least one lie atom and those wherein R 6 is 18 F.
  • Compounds of this invention wherein R 6 is 123 I or 18 F can be prepared using techniques known to those skilled in the art.
  • Scheme 10 shows a method for the synthesis of compounds of this invention wherein R 6 is 123 I.
  • MS mass spectra
  • HRMS high resolution mass spectra
  • Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general
  • N-(4-fluorophenethyl)-2-furanmethylamine (30g), 20g of allyl bromide, 75mL of methylene chloride, and 150mL of 15% aqueous sodium hydroxide solution was stirred at room temperature overnight. The layers were separated and the aqueous phase was extracted twice with methylene chloride. The solvent was removed, the residue was partitioned between ether and water, and the product obtained from the dried ether layer was short-path distilled (130° bath temperature, 0.004 mm) to give 27.6g (79%) of N-allyl-N-(4-fluorophenethyl)-2-furanmethylamine.
  • the free base was separated into the two optical isomers by chromatography on a column packed with the 3, 5-dimethylcarbamate of cellulose (solvent: 89.5: 10: 0.5 hexane/2-propanol methylene chloride).
  • the fumarate of the (-) isomer had mp 160-161° after
  • (+) and (-) isomers were prepared in the same manner from the (+) and (-) isomers of 2-[2-(4-fluorophenyl)ethyl]-1,2,3,6,7,7a-hexahydro-3a,6-epoxy-3aH-isoindole.
  • the fumarate has a mp 147-149° after crystallization from 90% ethanol.
  • the fumarate had mp 177-178° after crystallization from 90% 2-propanol.
  • the compounds of this invention and their pharmaceutically acceptable salts 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 may also be useful as antidotes for certain psychotomimetic agents such as phencyclidine (PCP), and as antidyskinetic agents.
  • PCP phencyclidine
  • Brain membranes were prepared by the method of Tam (Proc. Natl. Acad. Sci. USA 80: 6703-6707, 1983).
  • Whole brains were homogenized (20 seconds) in 10 vol (wt/vol) of ice-cold 0.34 M sucrose with a Brinkmann Polytron (setting 8). The homogenate was centrifuged at 920 ⁇ g for 10 minutes. The supernatant was centrifuged at 47,000 ⁇ g for 20 minutes.
  • the 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 HC1 (50 mL per brain).
  • K i IC 50 /[1 + (L/K d )] (4), where L is the concentration of radioligand and K d is its
  • 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).
  • IC 50 s were calculated from log-logit plots.
  • mice Male CF1 Mice (Charles River) were injected orally with test compound and placed singly into square (13 cm) Plexiglass observation chambers. Twenty minutes later mice were injected orally with mescaline (25 mg/kg).
  • a scratching episode is defined as a brief (1-2 sec) burst of scratching either the head or the ear with the hind foot.
  • the mean number of scratching episodes is expressed as a percentage of the corresponding Drug Vehicle (control) value. The percent antagonism is used to calculate ED 50 values when
  • mice Male Balb/c mice (Charles River) were used. After 4-6 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. Thirty 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. Selection of home cage and intruder mice was randomized for each test. Mice were treated and tested once a week with at least a 6 day washout period between
  • the intensity of catalepsy is measured by the length of time it takes the animal to move both forelegs to the table. A time of 20 seconds is considered maximal catalepsy.
  • the data are shown in Table 3 under the heading RAT CAT.
  • antipsychotics that are dopamine receptor antagonists.
  • Dosage forms (compositions) suitable for 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.
  • 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 unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are.
  • suitable stabilizing agents are also used.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

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Abstract

Cette invention se rapporte à des nouveaux composés tricycliques contenant de l'azote, répondant à la formule (I), à des compositions pharmaceutiques contenant lesdits composés et à des procédés d'utilisation desdits composés pour traiter des psychoses physiologiques et/ou induites par médicament ainsi que comme agents antidyskinétiques.
PCT/US1993/009162 1992-10-09 1993-10-01 3a,6-octahydroisoindoles pontes et hydroisoquinolines et hydrobenzazepines apparentees et leur utilisation comme agents pharmaceutiques et de radio-imagerie Ceased WO1994009007A1 (fr)

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US95913692A 1992-10-09 1992-10-09
US07/959,136 1992-10-09

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WO1994009007A1 true WO1994009007A1 (fr) 1994-04-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106588772A (zh) * 2016-12-19 2017-04-26 广西中医药大学 重松节油长叶烯衍生物及其制备和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4508723A (en) * 1977-05-17 1985-04-02 Ciba Geigy Corporation 6-Azaoligocycloalkylmethyleneaminopenam compounds
US4855430A (en) * 1987-11-12 1989-08-08 American Home Products Corporation Polycyclicamine with psychotropic activity
US5216018A (en) * 1992-02-14 1993-06-01 Du Pont Merck Pharmaceutical Company Hydroisoindolines and hydroisoquinolines as psychotropic

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4508723A (en) * 1977-05-17 1985-04-02 Ciba Geigy Corporation 6-Azaoligocycloalkylmethyleneaminopenam compounds
US4855430A (en) * 1987-11-12 1989-08-08 American Home Products Corporation Polycyclicamine with psychotropic activity
US5216018A (en) * 1992-02-14 1993-06-01 Du Pont Merck Pharmaceutical Company Hydroisoindolines and hydroisoquinolines as psychotropic

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 68, no. 23, 1968, Columbus, Ohio, US; abstract no. 105055d, D. BILOVIC ET AL: "On the preparation of some tertiary amines containing the 2-furfuryl group. Isomerization of allyl aryl(2-furfuryl)-amines to N-aryl-4H-5,7alpha-epoxyisoindolines" page 10139; *
CROAT. CHEM. ACTA, vol. 39, 1967, pages 189 - 197 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106588772A (zh) * 2016-12-19 2017-04-26 广西中医药大学 重松节油长叶烯衍生物及其制备和应用

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