WO1994009007A1

WO1994009007A1 - 3a,6-bridged octahydroisoindoles and related hydroisoquinolines and hydrobenzazepines and their use as pharmaceutical and radioimaging agents

Info

Publication number: WO1994009007A1
Application number: PCT/US1993/009162
Authority: WO
Inventors: Engelbert Ciganek
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1992-10-09
Filing date: 1993-10-01
Publication date: 1994-04-28
Anticipated expiration: 1995-04-09

Abstract

This invention provides novel nitrogen-containing tricyclic compounds of formula (I) pharmaceutical compositions containing said compounds and methods of using said compounds to treat physiological and/or druginduced psychosis and as antidyskinetic agents.

Description

TITLE

3A, 6-BRIDGED OCTAHYDROISOINDOLES AND RELATED HYDROISOQUINOLINES AND

HYDROBENZAZEPINES AND THEIR USE AS PHARMACEUTICAL AND RADIOIMAGING AGENTS

FIELD OF THE INVENTION

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 .

BACKGROUND OF THE INVENTION

United States Patent No . 4 , 508 , 723 discloses compounds of formula :

The disclosed compounds are an antimicrobial agent and

intermediates used in the synthesis of the antimicrobial.

Gschwend et al., J. Org. Chem., 41, 104 (1976) disclose a compound of formula:

The compound is an intermediate used in the preparation of analgesics.

United States Patents 4,855,430, 4,927,934, and 4,937,347 disclose compounds of formula:

These compounds are disclosed as being 5-HT_1a agonists having utility as anxiolytics/antipsychotics, antidepressants and in the treatment of sexual dysfunction. Traditionally, antipsychotic agents have been potent dopamine receptor antagonists. For example, phenothiazines such as chlorpromazine and most butyrophenones such as haloperidol are potent dopamine receptor antagonists. These dopamine receptor antagonists are associated with a high incidence of side effects, particularly Parkinson-like motor effects or extra-pyramidal side-effects (EPS), and dyskinesias including tardive dyskinesias at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.

There is a need for effective antipsychotic agents that do not cause such side effects.

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. Towards this, 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

associated with the traditional dopamine antagonist antipsychotic agents. Compounds of the present invention demonstrate sigma receptor affinity. It is this sigma receptor affinity of the compounds of the present invention which makes them so

advantageous over the compounds in the prior art.

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). Another object of the present invention is to provide radiopharmaceuticals and compositions containing them useful for imaging with SPECT and PET. SUMMARY OF THE INVENTION

This invention provides compounds of formula:

or pharmaceutically acceptable salts thereof,

wherein:

R¹ is C₁-C₆ alkyl substituted with 1-3 R⁵, C₃-C₆ alkenyl substituted with 1-3 R⁵, C₃-C₆ alkynyl substituted with 1-3 R⁵,

(C₁-C₄ alkyl)CO(C₁-C₄ alkyl) R⁵,

(C₁-C₄ alkyl)COR⁵,

(C₁-C₄ alkyl)CHR⁵OR⁸, or

(C₁-C₄ alkyl)CHOR⁸(C₁-C₄ alkyl) R⁵;

R², R³, and R⁴ are independently selected from the group H, halogen, OR⁸, (=O), CO₂R⁷, CN, R⁵, and C₁-C₁₂ alkyl optionally substituted with 1-2 OR⁷, 1-6 halogen atoms or 1-2 R⁵; or R² and R³ may be taken together to form a saturated or unsaturated monocyclic or bicyclic ring system containing 3-10 carbon atoms and optionally 1 0 or 1 NR⁷;

R⁵ is C₃-C₈ cycloalkyl, aryl optionally substituted with 1- 3 R⁶, or heterocycle optionally substituted with 1-3 R⁶;

R⁶ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl, C₁-C₆ perfluoroalkyl, halogen, NO₂, OR⁷, OCOR⁷, N(R⁷)₂, SR⁷, S(O)R⁷, SO₂R⁷, CO₂R⁷ or CN;

R⁷ is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, or aryl;

R⁸ is H, C₁-C₈ alkyl, or C₁-C₈ acyl;

X is O or (CH₂)_p;

m = 1 to 3;

n = 1 to 3; and

p = 1 to 3;

provided that m + n is 2 to 4. Preferred Embodiments

Preferred are those compounds of formula (I) wherein m = 1 and n = 1.

Most preferred are preferred compounds of formula (I) wherein:

X is O; and

R⁵ is aryl optionally substituted with 1-3 R⁶.

Specifically preferred are those compounds of formula (I) which are:

2-[2-(4-Fluorophenyl)ethyl]-octahydro-3a,6-epoxy-3aH- isoindole;

2-[2-(4-Fluorophenyl)ethyl]-octahydro-3a,6-epoxy-3aH- isoindole-7-methanol;

2-(2-Phenylethyl)octahydro-3a,6-methano-3aH-isoindole;

2-[2-(4-chlorophenyl)ethyl]-octahydro-3a,6-epoxy-3aH- isoindole.

In the present invention it has been discovered that

compounds of formula (I) are useful as agents to treat

physiological or drug-induced psychosis and as antidyskenetic agents. 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

radiopharmaceuticals useful for imaging with Single Photon

Emission Computed Tomagraphy (SPECT) and Positron Emission

Tomograpy (PET). 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. Thus, 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.

Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention.

It is understood that substitutents R², R³ and R⁴ may be attached to any of carbon atoms 2-6 of formula (I). When 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

occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable

compounds.

As used herein, "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 C₁-C₅ to indicate 1-5 carbon atoms. As used herein "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

[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "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. "Counterion" 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 ¹⁸F and ¹²³I .

As used herein, "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).

As used herein, the term "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. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such 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,

tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, pyrazinyl, quinazolyl, phthalazinyl,

naphthyridinyl or octahydroisoquinolinyl.

The term "substituted", as used herein, 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.

By "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.

As used herein, "pharmaceutically acceptable 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 .

Pharmaceutically acceptable salts 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.

The term "pharmacologically 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.

DETAILED DESCRIPTION

The compounds of this invention are prepared by saturation of the double bond in compounds 1 as shown in Scheme 1.

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

hydrogen pressures of

1-100 atmospheres. Other methods include reduction with diimide.

Alternatively, 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

bis (methoxyethoxy) aluminum hydride. This is shown in Scheme 2 wherein the substrate is a lactam derivative and the reducing agent is borane.

Scheme 2

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. For a review of the intramolecular Diels-Alder reaction see E.

Ciganek, Org. React. 32, 1-374 (1984). This method is shown in Scheme 3 which illustrates the preparation of a compound of formula 1 wherein substitutents R², R³ and R⁴ are H. Compounds of formula 1 wherein substitutents R², R³ and R⁴ are not all H may be prepared via the method of Scheme 3 by using as starting material compounds of formula 2 bearing substitutents R², R³ and R⁴ which are other than H. The substitutents R², R³ and R⁴ may be on the ring of 2 or the pendant olefin group of 2 or they may be divided between both the ring and the pendant olefin of 2 .

Scheme 3

Wherein R², R³ and R⁴ 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.

Alternatively, 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 R², R³ and R⁴ are H. Compounds of formulae 3a-6a wherein

substitutents R², R³ and R⁴ 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 R², R³ and R⁴ which are other than H. The substitutents R², R³ and R⁴ 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.

Scheme 4

Wherein R², R³ and R⁴ are H, and A is R¹ less one CH₂ group. The cyclization of amides 4 (R¹ = Me; X = 0; m = 1; n = 1 to 3) has been reported by Parker and Adamchuk, Tetrahedron Lett., 1978, 1689 which is herein incorporated by reference. It is expected that the conditions reported by Parker and Adamchuk for the cyclization of compounds of formula A will also convert compounds of formulae 2, 4 and 5 into the corresponding compounds of formulae 3a, 4a and 5a. Imides of type 3 also undergo the intramolecular Diels-Alder reaction to give compounds of formula 6a which are useful for the preparation of compounds of formula (I). This method was disclosed by Ciganek and Wong in U.S.

4,751,306 which is herein incorporated by reference.

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. For example, 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

pressures of 1-100 atmospheres. Another method is reduction with diimide. 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

bis(methoxyethoxy)aluminum hydride.

The cyclization of compounds of 2-6 wherein X is CH₂ may be difficult to effect because these compounds are derivatives of cyclopentadiene and such derivatives often dimerize. In these cases the dimer may be elaborated and the monomers 2-6 (X = CH₂) may then be regenerated from the dimers by heating. This pathway is shown in Scheme 5. The elaboration of the acid to the amide is accomplished using standard techniques for the preparation of amides from acids. Cf. Protective Groups in Organic Synthesis. Theodora Greene (John Wiley & Sons, New York, 1981). The

temperature required to crack the dimer is usually sufficient to effect the subsequent intramolecular Diels Alder reaction as well. Scheme 5

For intramolecular Diels-Alder reactions of substrates 2 to £ where n = 2 or 3 it may be advantageous to activate the

dienophilic component by introducing a carbonyl group α to the pendant olefin. This is shown in Scheme 6 which illustrates the preparation of a compound of formula 1 wherein substitutents R², R³ and R⁴ are H from cyclization of a compound of formula 2 which bears a carbonyl group a to the pendant olefin. Compounds of formula 1 wherein substitutents R², R³ and R⁴ are not all H may be prepared via the method of Scheme 7 by using as starting material compounds of formula 2 bearing substitutents R², R³ and R⁴ which are other than H. The substitutents R², R³ and R⁴ may be on the ring of 2 or the pendant olefin group of 7 or they may be divided between both the ring and the pendant olefin of 7.

Scheme 7

Wherein R², R³ and R⁴ are H.

Alternatively, 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 R², R³ and R⁴ are H from cyclization of a compound of formula 8 which possesses an activating carbonyl group in conjugation with the diene.

Compounds of formula 1 wherein substitutents R², R³ and R⁴ are not all H may be prepared via the method of Scheme 8 by using as starting material compounds of formula 8 bearing substitutents R², R³ and R⁴ which are other than H. The substitutents R², R³ and R⁴ 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.

Scheme 8

Wherein R², R³ and R⁴ 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.

Compounds of formula 1 and compounds of formula (I) with varying substituents R¹ may also be prepared from the secondary amines (R¹ = H) by standard methods for the preparation of tertiary amines such as alkylation with reagents R¹Y (wherein Y is a good leaving group, such as Cl, Br, I, methanesulfonyl or arenesulfonyl) in the presence of a base. 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 R¹ is the benzyl group which may be removed by hydrogenation in the presence of a palladium catalyst. Examples of other suitable protecting groups and methods for their removal have been disclosed. Protective Groups in Organic Synthesis, Theodora Greene (John Wiley & Sons, New York, 1981). This method is illustrated in Scheme 9. The preparation of a compound of formula 1 wherein R¹ to R⁴ = H, X = 0 and m, n = 1 utilizing this method is disclosed by Schaffner and Scartazzini in U.S. 4,508,723 which is herein incorporated by reference.

Scheme 9

Compounds of this invention that are radiopharmaceuticals suitable for imaging with SPECT are those compounds wherein R^ is ¹²³I. Compounds of this invention that are radiopharmaceuticals suitable for imaging with PET are those containing at least one lie atom and those wherein R⁶ is ¹⁸F. Compounds of this invention wherein R⁶ is ¹²³I or ¹⁸F 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 R⁶ is ¹²³I. In Scheme 10, a compound of formula (I) bearing a bromobenzene substituent, such as 9, is reacted with n-butyllithium to give the corresponding phenyllithium derivative of 9 which is then reacted with a trialkyltin chloride, such as trimethyltin chloride, to give the trialkyltin derivative 10. This type of reaction was disclosed by Kroth et al., J. Am. Chem. Soc., 97, 1754 (1975). In the next step, ¹²³I is introduced by reaction of 1 0. with Na¹²³I and iodogen to give 11 which is a compound of formula (I) wherein R⁶ is ¹²³I. This step was disclosed by McBride et al., Appl.

Radiat. Isot., 42, 173-175, which is herein incorporated by reference. If desired, 11 can be further purified prior to use as a radiopharmaceutical with SPECT.

Scheme 10

EXAMPLES

Preparations of representative compounds of this invention are described in detail in the examples which follow. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare the compounds of this invention.

Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on a Varian FT-NMR spectrometer (200 MHz or 300 MHz) ; chemical shifts were recorded in ppm (9) from an internal tetramethylsilane standard in deuterochloroform or

deuterodimethylsulfoxide and coupling constants (J) are reported in Hz. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on Finnegan MAT 8230 spectrometer or Hewlett Packard 5988A model spectrometer. Melting points are uncorrected.

Boiling points are uncorrected.

Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general

procedures outlined by D. D. Perrin and W. L. F. Armarego,

Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Parts and percentages are by weight unless otherwise specified. Common abbreviations include: THF (tetrahydrofuran), TBDMS (t-butyl-dimethylsilyl), DMF

(dimethylformamide), Hz (hertz) TLC (thin layer chromatography).

EXAMPLE 1

2- [2- (4-Fluorophenyl ) ethyl ] -octahydro-3a, 6-epoxy-3aH-isoindole

2- [2- (4-Fluorophenylethyl ] -1 , 2 , 3, 6 , 7 , 7a-hexahydro-3a, 6-epoxy-3aH-isoindole : A mixture of 84g of 4-fluorophenethylamine , 60g of 2-furaldehyde and 250mL of ethanol was heated under reflux for 1 hour. To the cooled (ice bath) mixture were added 250mL of ethanol and 50ml of water followed 24g of sodium borohydride in small portions. The mixture was stirred in an ice bath for 2 hours and at room temperature overnight. Water (500mL) was added and the mixture was extracted with 800 and 2 × 50mL of methylene chloride. Removal of the solvent from the dried extracts and distillation of the residue gave 118.7g (90%) of N-(4-fluorophenethyl)-2-furanmethylamine, bp 92° (0.015mm).

A mixture of 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.

A solution of N-allyl-N-(4-fluorophenethyl)-2-furanmethylamine in ethanol was treated with one equivalent of fumaric acid and the mixture was heated under reflux overnight. Removal of the solvent and crystallization of the residue from ethanol gave 2-[2-(4-fluorophenylethyl)]-1,2,3,6,7,7a-hexahydro-3a,6-epoxy-3aH-isoindole fumarate, mp 143-145°.

Anal. Calcd. for C₂₀H₂₂FNO₅: C, 63.99; H, 5.91; N, 3.73. Found: C, 63.89; H, 5.87; N, 3.80.

¹HNMR spectrum of the free base (in CDCI₃); δ 7.2 (m, 2H); 7.0 (m, 2H); 6.4 (d, J = 6Hz, 1H); 6.3 (d/d, J = 6/1.5Hz, 1H); 5.0 (d/d, J = 4.5/1.5HZ, 1H); 3.6 (d, J = 11.5Hz, 1H); 3.2 (d/d, J =

8.5/6.5HZ, 1H); 2.7-2.9 (m, 4H); 2.7 (d, J = 11.5 Hz, 1H);

2.2 (d/d, J = 10/8.5Hz, 1H); 2.0 (m, 1H); 1.7 (m, 1H), 1.4 (d/d, J=11.5/7Hz, 1H); ¹³C NMR spectrum of the free base (in CDCI₃); δ 28.998, 34.492, 43.464, 55.028, 57.838, 58.690, 79.830, 96.136, 114.813, 115.097, 129.764, 129.865, 135.670, 137.944, 159.639, 162.871. 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 161-162° after crystallization from ethanol; [a] _D + 16.11° (c = 0.602 in

ethanol).

Anal. Calcd. for C₂₀H₂₂FNO₅; C, 63.99; H, 5.91; N, 3.73.

Found: C, 63.87; H, 5.82; N, 3.67.

The fumarate of the (-) isomer had mp 160-161° after

crystallization from ethanol; [a]o -15.45° (c = 0.602 in ethanol).

Anal. Calcd. for C₂₀H₂₂FNO₅: C, 63.99; H, 5.91; N, 3.73. Found: C, 63.83; H, 5.72; N, 3.70.

A mixture of 1.09g of 2-[2-(4-fluorophenyl)ethyl]-1,2,3,6,7,7a-hexahydro-3a,6-epoxy-3aH-isoindole, 10 mL of ethanol and 0.12g of prereduced platinum oxide was stirred in the presence of hydrogen at atmospheric pressure at 25° for 2 hours. Removal of the solvent from the filtered solution and short-path

distillation of the residue (160° bath temperature, 0.001/mm) gave 1.01g of the title compound as an oil. ¹HNMR spectrum (in CDCI₃) δ 7.2 (m, 2H); 7.0 (m, 2H); 4.6 (t, J = 5.8Hz, 1H); 3.2 (d, J =

11Hz, 1H); 3.0 (m, 1H); 2.8 (d, J= 11Hz, 1H); 2.7-2.8 (m, 4H); 2.2 (m, 2H); 1.5-2.0 (m, 6H). The fumarate had a mp 142-144° after crystallization from 2-propanol.

Anal. Calcd. for C₂₀H₂₄FNO₅; C, 63.65; H, 6.41; N, 3.71.

Found: C, 63.59; H, 6.39; N, 3.63.

The (+) 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 of the (+) isomer had a mp 146-147° after crystallization from ethanol; [a]o + 23.75° (c = 0.602 in

ethanol).

Anal. Calcd. for C₂₀H₂₄FNO₅ :C, 63.65; H, 6.41; N, 3.71.

Found: C, 63.63; H, 6.42; N, 3.66.

The fumarate of the (-) isomer had a mp 146-147° after crystallization from ethanol; [a]_D = -23.92°, (c = 0.602 in

ethanol). Anal. Calcd. for C₂₀H₂₄FNO₅: C, 63.65; H, 6.41; N, 3.71 Found: C, 63.45; H, 6.41; N, 3.65.

2-[2-(4-Fluorophenyl)ethyl]-octahydro-3a,6-epoxy-3aH-isoindole-7- methanol

A mixture of 2.0g of maleic anhydride, 4.4 g of N-(2-furylmethyl)-2(4-fluorophenyl)ethylamine and 12 mL of dry THF was heated under reflux for 1 hour. Removal of the solvent and crystallization of the residue from ethyl acetate/acetonitrile gave 4.42g of 2-[2-(4-fluorophenyl)ethyl]-1,2,3,6,7,7a-hexahydro-1-oxo-3a,6-epoxy-3aH-isoindole-7-carboxylic acid. ¹HNMR spectrum (in CDCI₃) δ 7.2 (m, 2H); 7.0 (m, 2H) 4.6 (AB quartet, J = 6Hz,

2H); 5.3 (s,. IH) 3.8 (d, J = 11.7Hz, 1H); 3.7 (m+d, J = 11.7Hz, 2H); 3.5 (m, IH) and 2.8 (m, 4H).

A mixture of 2.70g of the above compound, 30 mL- of ethanol, and 0.20g of prereduced platinum oxide was stirred under hydrogen at atmospheric pressure and 25° for 5 hours. Removal of the solvent from the filtered mixture gave 2.65g of 2-[2-(4-fluorophenyl)ethyl]-octahydro-1-oxo-3a,6-epoxy-3aH-isoindole-7-carboxylic acid. ¹HNMR spectrum (in CDCI₃) δ 7,2 (m, 2H); 7.0 (m,

2H), 4.9 (d, J = 5.5Hz, 1H), 3.4-3.6 (m+ AB quartet, J = 11.5Hz, 4H; 3.0 (AB quartet, J = 10Hz, 2H); 2.8 (m, 2H); 2.0 (m, 1H); 1.6-1.8 (m, 3H).

To a mixture of 2.67g of the above compound and 25 mL of dry THF was added slowly with cooling 15 mL of IM lithium aluminum hydride in THF. The mixture was heated under reflux for 6 hours, cooled, treated sequentially with 0.6 mL of water, 0.6 mL of 15% aqueous sodium hydroxide, and 1.8 mL of water, and filtered.

Removal of the solvent from the filtrate and short-path distillation of the residue (180-200° bath temperature, 0.003mm) gave 1.69g of the title compound. ¹HNMR spectrum (in CDCI₃) δ 7.2

(m, 2H); 7.0 (m, 2H); 4.4 (d, J= 5.5Hz, 1H), 3.4-3.7 (m, + br, 3H), 3.2 (d, J = 11Hz, 1H); 2.6-2.9 (m, 5H); 2.3-2.5 (m, 2H); 2.1 (m, 1H); 1.9 (m, 1H), 1.6-1.8 (m, 4H).

The fumarate has a mp 147-149° after crystallization from 90% ethanol.

Anal. Calcd. for C₂₁H₂₆FNO₆; C, 61.91; H;6.43; N, 3.44.

Found: C, 61.99; H, 6.50; N, 3.41.

EXAMPLE 3

2-(2-Phenylethyl)octahydro-3a,6-methano-3aH-isoindole

To a mixture of 1.1g of cyclopentadienecarboxylic acid dimer (Pyasena et al., Tetrahedron Lett. 1988, 135) and 6 mL of dry THF was added 1.70g of 1,1'-carbonyldiimidazole. After stirring at room temperature for 30 minutes, a solution of 3.3g of N-allylphenethylamine in 8 mL of tetrahydrofuran was added slowly and stirring was continued overnight. Toluene (50 mL) and 20 mL of 5% hydrochloric were added, resulting in three layers. The two lower layers were extracted with 2 × 10 mL of toluene and the combined toluene layers were washed with 10% aqueous sodium carbonate solution and dried. Removal of the solvent gave 1.04g of the crude dimer of N-allyl-N-phenethylcyclopenta-dienecarboxamide. Short-path distillation (220° bath temperature, 0.003mm) gave 0.75g of 2-(2-phenylethyl)-1,6,7,7a-tetrahydro-3a,6-methano-3aH-isoindol-3(2H)-one as a solid. ¹HNMR spectrum in

(CDCI₃) δ 7.2-7.3 (m, 5H); 6.4 (d, J = 5.5Hz, 1H); 6.1 (d/d, J =

5.5/2.5HZ, 1H); 3.4-3.7 (m, 3H); 2.8-3.1 (m, 4H); 2.0 (m, 1H); 1.6

(m, 2H); 1.5 (d,

J = 8Hz, 1H); 1.3 (m, 1H). A mixture of 0.75 g of the above lactam, 5 mL of THF and 0.08g prereduced platinum oxide was stirred under hydrogen at atmospheric pressure and 25° for 3 hours. Removal of the solvent from the filtered mixture gave 0.75g of hexahydro-2-(2-phenylethyl)-3a,6-methano-3a,H-isoindol-3-(2H)-one.

A mixture of the above product, 10 mL of dry THF and 1 mL of borane-methylsulfide was heated under reflux for 8 hours.

Hydrochloric acid (10%, 10 mL) was added slowly with cooling, the mixture was stirred at room temperature for 30 minutes and made basic with 15% aqueous sodium hydroxide solution. Extraction with methylene chloride and removal of the solvent from the dried extracts gave 0.78g of a solid which was stirred with 10 mL of acetic acid at 100° for 2 hours. The acetic acid was removed under vacuum, and the residue was taken up in methylene chloride and washed with 15% aqueous sodium hydroxide solution. Removal of the solvent from the dried organic phase and short-path

distillation of the residue (170° bath temperature, 0.008mm) gave 0.46g of the title compound. ¹HNMR spectrum (in CDCI₃) δ 7.2 -

7.3 (m, 5H); 3.0 (m, 2H); 2.6 - 2.8 (m, 5H); 2.2 (m, 2H); 2.0 (m, 2H); 1.2 - 1.7 (m, 7H). ¹³CNMR spectrum (in CDCI₃) δ 28.989,

32.468, 35.636, 36.671, 38,758, 41,981, 46,449, 54,753, 56,419, 58,937, 60,539, 125,800, 128,190, 128,556, 140,540.

The fumarate had mp 177-178° after crystallization from 90% 2-propanol.

Anal. Calcd. for C₂₁H₂₇NO₄: C, 70.56; H, 7.61; N, 3.92.

Found: C, 70.63; H, 7.63; N, 3.89.

EXAMPLE 4

Dodecahydro-2-[2-(4-fluorophenyl)ethyl]-5,9b-epoxy-6,9-methano- 9bH-benz[e]isoindole A mixture of 1.30g of 2-[2-(4-fluorophenyl)ethyl]-1,2,3,6,7,7a-hexahydro-3a,6-epoxy-3aH-isoindole, prepared as described in Example 1, 2 mL of methylene chloride, and 2 mL of freshly distilled cyclopentadiene was stirred at room temperature for 10 days; additional 1-mL portions of cyclopentadiene were added after 1, 2, 4, and 7 days. Concentration under reduced pressure gave 2.28g of a mixture of unreacted starting material and 1,2 , 3,3a,4,5,5a,6,9,9a-decahydro-2-[2-(4-fluorophenyl)ethyl]-5,9b-epoxy-6,9-methano-9bH-benz[e]isoindole in a ratio of 34:66 in addition to cyclopentadiene dimer. It was dissolved in 10 mL of ethanol and stirred with 0.12g of prereduced platinum oxide under hydrogen until hydrogen uptake stopped. Removal of the solvent from the filtered mixture and fractional short-path distillation of the residue gave 0.78g of an 88:12 mixture of two isomers of the title compound, distilling at a bath temperature of 130-220°/0.003mm. High-resolution mass spectrum: calcd. for

C₂₁H₂₇FNO[(m+H)⁺]:328.207668: measured : 328 .207286 . Additional examples of compounds of this invention which were prepared or which may be prepared by methods disclosed herein are shown in Tables 1 and 2.

Utility Section

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.

In vitro

Sigma Receptor Binding Assay

Male Hartley guinea pigs (250-300 g, Charles River) were sacrificed by decapitation. 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).

Aliquots (0.5 mL) of the membrane preparation were incubated with unlabeled drugs, 1 nM (+)-[³H]SKF 10,047 in 50 mM Tris HC1, pH 7.4, in a final volume of 1 mL. Nonspecific binding was measured in the presence of 10 μM (+)-SKF 10,047. The apparent dissociation constant (Kd) for (+)-[³H]SKF 10,047 is 50 nM. After 45 minutes of incubation at room temperature, samples were filtered rapidly through Whatman GF/C glass filters under negative pressure, and washed 3 times with

ice-cold Tris buffer (5 mL).

IC₅₀s were calculated from log-logit plots. Apparent K_is were calculated from the equation, K_i = IC₅₀/[1 + (L/K_d)] (4), where L is the concentration of radioligand and K_d is its

dissociation constant. The data are shown in Table 3 under the heading SIGMA.

Dopamine Receptor Binding

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).

0.5 mL aliquots of the membrane preparation were incubated with unlabeled drugs, and 0.15 nM [³H] spiperone in a final volume of 1 mL containing 50 mM Tris HCl, 120 mM NaCl and 1 mM MgCl2 (pH

7.7). 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. Apparent K_is were calculated from the equation K_i=IC₅₀ [1+ (L/K_d)] (4), where L is the concentration of radioligand and K_d is its dissociation constant.

The data are shown in Table 3 under the heading D2.

In Vivo

Mescaline-Induced Scratching in Mice

This is a modification of the procedure of Fellows and Cook

(Psychotropic Drugs, ed. by S. Garrattini and V. Ghatti, pp. 397- 404, Elsevier, Amsterdam, 1957). 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).

Beginning 25 minutes after treatment with mescaline (45 minutes after treatment with test compound), scratching episodes were counted during a 5 minute observation period. A scratching episode is defined as a brief (1-2 sec) burst of scratching either the head or the ear with the hind foot. For each dose of test compound, 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 ED₅₀ values when

appropriate. The data are shown in Table 3 under the heading MUR MESC. Isolation-Induced Aggression in Mice

This is a modification of the method of Yen et al. (Arch. Int. Pharmacodyn. 123: 179-185, 1959) and Jannsen et al. (J.

Pharmacol. Exp. Ther. 129: 471-475, 1960). 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

treatments .

The data are shown in Table 3 under the heading MUR MIIA.

Induction of Catalepsy

This is a modification of the method of Costall and Naylor (Psychopharmacologia (Berl.), 43, 69-74, 1975). Male CD rats (Charles River) weighing 250-300 g were treated with test drugs and standards by the oral route and tested for the presence of catalepsy 30-360 minutes after treatment. To test for catalepsy, each rat is placed with its front paws over a 10 cm high

horizontal bar. 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.

The data demonstrate that 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. Therefore, these compounds are not expected to produce the extrapyramidal symptoms associated with use of haloperidol and other typical

antipsychotics that are dopamine receptor antagonists.

Dosage Forms

Daily dosage ranges from 1 mg to 2000 mg. 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.

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.

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. Also used are citric acid and its salts and sodium EDTA. In addition, 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.

Claims

WHAT IS CLAIMED IS

A compound of formula :

or pharmaceutically acceptable salts thereof,

wherein:

R¹ is C₁-C₆ alkyl substituted with 1-3 R⁵, C₃-C₆ alkenyl substituted with 1-3 R⁵, C₃-C₆ alkynyl substituted with

1-3 R⁵,

(C₁-C₄ alkyl) CO (C₁-C₄ alkyl) R⁵,

(C₁-C₄ alkyl) COR⁵,

(C₁-C₄ alkyl) CHR⁵OR⁸, or

(C₁-C₄ alkyl) CHOR⁸ (C₁-C₄ alkyl) R⁵;

R⁵ is C₃-C₈ cycloalkyl, aryl optionally substituted with 1-3 R6, or heterocycle optionally substituted with 1-3 R⁶; R⁶ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl, C₁-C₆ perfluoroalkyl, halogen, NO₂, OR⁷, OCOR⁷, N(R⁷)₂, SR⁷, S(O)R⁷, SO₂R⁷, CO₂R⁷ or CN;

R⁷ is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, or aryl;

R⁸ is H, C₁-C₈ alkyl, or C₁-C₈ acyl;

X is O or (CH₂)_p;

m = 1 to 3;

n = 1 to 3; and p = 1 to 3;

provided that m + n is 2 to 4.

2. A compound of Claim 1 wherein m = 1 and n = 1.

3. A compound of Claim 2 wherein:

X is O; and

R⁵ is aryl optionally substituted with 1-3 R⁶.

4. The compounds of Claim 1 which are :

2-[2-(4-Fluorophenyl)ethyl]-octahydro-3a,6-epoxy-3aH- isoindole;

2-[2-(4-Fluorophenyl)ethyl]-octahydro-3a,6-epoxy-3aH- isoindole-7-methanol;

2-(2-Phenylethyl)octahydro-3a,6-methano-3aH-isoindole;

2-[2-(4,-chlorophenyl)ethyl]-octahydro-3a,6-epoxy-3aH- isoindole.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antipsychotic and/or antidyskinetic effective amount of a compound of Claim 1.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antipsychotic and/or antidyskinetic effective amount of a compound of Claim 2.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antipsychotic and/or antidyskinetic effective amount of a compound of Claim 3.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antipsychotic and/or antidyskinetic effective amount of a compound of Claim 4.

9. A method for treatment of physiological or drug induced

psychosis or dyskinesia in a mammal comprising administering to a mammal in need of such treatment an antipsychotic or antidyskinetic effective amount of a compound of Claim 1.

10. A method for treatment of physiological or drug induced

psychosis or dyskinesia in a mammal comprising administering to a mammal in need of such treatment an antipsychotic or antidyskinetic effective amount of a compound of Claim 2.

11. A method for treatment of physiological or drug induced

psychosis or dyskinesia in a mammal comprising administering to a mammal in need of such treatment an antipsychotic or antidyskinetic effective amount of a compound of Claim 3.

12. A method for treatment of physiological or drug induced

psychosis or dyskinesia in a mammal comprising administering to a mammal in need of such treatment an antipsychotic or antidyskinetic effective amount of a compound of Claim 4.

13. A compound of Claim 1 wherein R⁶ is ¹²³I .

14. A compound of Claim 13 wherein m = 1 and n = 1.

15. A compound of Claim 14 wherein:

X is 0; and

R⁵ is aryl substituted with 1 R⁶.

16. A process of radioimaging comprising (i) administering

parenterally to a mammal a compound of Claim 13 in a

pharmaceutically acceptable carrier, and (ii) radioimaging the brain of said mammal after allowing sufficient time for said compound to localize in the brain.

17. A process of radioimaging comprising (i) administering parenterally to a mammal a compound of Claim 14 in a pharmaceutically acceptable carrier, and (ii) radioimaging the brain of said mammal after allowing sufficient time for said compound to localize in the brain.

18. A process of radioimaging comprising (i) administering

parenterally to a mammal a compound of Claim 15 in a pharmaceutically acceptable carrier, and (ii) radioimaging the brain of said mammal after allowing sufficient time for said compound to localize in the brain.