WO1994009005A1 - 4,7-bridged isoindoles as antipsycchotic and antidyskinetic agents - Google Patents

Abstract

This invention provides novel nitrogen-containing compounds such as compounds 1 - 4 pharmaceutical compositions containing said compounds and methods of using said compounds to treat physiological and/or drug induced psychosis and as antidyskinetic agents.

Description

TITLE

4 ,7-BRIDGED ISOINDOLES AS ANTIPSYCHOTIC AND ANTIDYSKINETIC AGENTS

FIELD OF THE INVENTION

This invention relates to novel nitrogen-containing tricyclic compounds , to pharmaceutical compositions containing them, to methods of using them in mammals to treat physiological or drug induced psychosis and to methods of using them in mammals as antidyskinetic agents .

BACKGROUND OF THE INVENTION

Gray et al . , J . Org . Chem . , 34, 3253 ( 1969) report a compound of formula :

They do not disclose biological activity.

Rehse et al., Arch. Pharm. , 312, 982 (1979), disclose compounds of Formula:

wherein R² is H or Ph, a is a single or double bond, and

Y is OCH₃ or O₂CCH₃.

They teach that these compounds have no central

depressant activity.

Casagrande et al., Farmaco Ed. Sci., 27, 445

(1972), disclose compounds of formula:

These compounds are reported to be alpha blockers.

Anderson et al., J. Org. Chem. 34, 5423 (1969;

disclose corrroounds of formula:

No biological activity is reported for these compounds,

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. Compounds of the present invention are disclosed in these patents; however, the compounds of the present invention are neither exemplified nor specifically claimed in any of the cited patents.

Furthermore, applicants have found that the compounds claimed herein are not 5-HT_1a agonists as taught by United States Patents 4,855,430, 4,927,934, and

4,937,347, but rather that the compounds claimed herein are sigma antagonists. Furthermore, all compounds exemplified in United States Patents 4,855,430,

4,927,934, and 4,937,347 posssess some affinity for the D2 receptor, whereas the compounds claimed herein do not possess such activity.

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 tarcive dyskinesias at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.

The 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.

SUMMARY OF THE INVENTION

The present invention provides the following compounds and their pharmaceutically acceptable salts:

;

;

;

;

;

;

;

;

The present invention also provides pharmaceutical compositions containing the compounds of this invention and it 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 this invention.

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.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention may be prepared by methods disclosed in United States Patents 4,855,430, 4,927,934, and 4,937,347 which is incorporated by reference herein, or by methods disclosed below.

Scheme 1 shows a general method for the

preparation of compounds of this invention from

appropriately substituted anhydrides such as 2 by reaction with an amine R¹NH₂ either without a solvent at temperatures of 100-200° or in a solvent such as dimethylformamide at 100-200° to give imides 3. The latter are converted into the compound of this invention 4 by reduction with standard imide reducing agents such as lithium aluminum hydride or sodium bis(methoxyethoxy) aluminum hydride. Scheme 1

Compounds 7 of this invention are prepared by catalytic hydrogenation of the anhydrides 2 to give anhydrides 5 which are treated with amines R¹NH₂ as described above to give imides 6; the latter on reduction furnish

compounds 7. Imides 6 may also be obtained by catalytic hydrogenation of imides 3 , and the compounds of this invention 7 may also be obtained by catalytic

hydrogenation of amines 4.

Scheme 2 shows an alternate general method, which is particularly preferred for compounds of this

invention containing a double bond and wherein X is O. The method consists of subjecting appropriately

substituted maleimides 8 to a Diels-Alder reaction with appropriately substituted dienes 9 followed by reduction. The maleimides such as 8 are prepared by known methods from maleic anhydrides and amines R¹NH₂. This reaction sequence was used by Anderson, et al., J. Qrg, Chem., 50, 5423 (1985) to prepare compounds 4 where R¹ is Me or Ph, and X = O.

Scheme 2

2-[2-(4-Fluorophenyl)ethyl]-4.7-epoxy- 1,2,3,4,7,7a-hexahydro-1H-isoindole A solution of 4.9 g of maleic anhydride in 20 mL of acetic acid was treated with 7.0 g of 2-(4-fluorophenyl)ethylamine and the mixture was heated unde: reflux for 3 hours. The solvent was removed under vacuum, the residue was taken up in methylene chloride and washed with 10% aqueous sodium carbonate. Removal of the solvent from the dried organic phase and

crystallization from ethyl acetate gave 2.71 g of N-[2- (4-fluorophenyl)ethyl]maleimide. An additional 1.08 g, mp 116° was obtained by short-path distillation of the mother liquor at 160° bath temperature/0.003mm followed by crystallization from ethyl acetate.

Anal. Calcd. for C₁₂H₁₀FNO₂:C, 65.75; H, 4.60; N, 6.39. Found: C, 65.51; H, 4.44; N, 6.36.

A solution of 1.00 g of the above imide in 5mL of furan was allowed to stand at room temperature

overnight, the solvent was removed under reduced pressure at room temperature and the residue was dissolved immediately in 5mL of dry THF. The solution was added to 20mL of 1M lithium aluminum hydride in ether, keeping the temperature below 20°. Water (0.8mL) followed by 15% aqueous sodium hydroxide solution

(0.8mL) and water (2.4mL) were added with cooling after 4 hours, and the mixture was filtered. Removal of the solvent from the filtrate and short-path distillation of the residue (170° bath temperature, 0.005mm) gave 0.56 g of the title compound. The fumarate had mp 162-165° (dec.) after crystallization from ethanol.

Anal. Calcd. for C₂₀H₂₂FNO₅: C, 63.99; H, 5.91; N, 3.75. Found: 63.93; H, 5.99; N, 3.67.

Example 2

2-[2-(4-Fluorophenyl)ethyl-4,7- epoxvoctahydro-1H-ifioindole

A mixture of 1.5 g of 3,4-epoxy-1,2-cyclohexanedicarboxylic anhydride, 1.30 g of 2-(4-fluorophenyl)ethylamine and 4mL of dimethylformamide was heated under reflux for 3 hours, the solvent was removed under vacuum, and the residue was dissolved in toluene and washed with 10% aqueous sodium carbonate. Removal of the solvent and crystallization of the residue from ethyl acetate gave 1.67 g of

2-[2-(4-fluorophenyl)ethyl]-4,7-epoxy-3a,4,5,6,7,7a- hexahydro-1H-isoindole-1,3-dione.

To a solution of this product (1.5g) in 10mL of dry THF was added with cooling 10 mL of 1M lithium aluminum hydride in THF and the mixture was heated under reflux for 6 hours. Sequential addition of 0.4mL of water, 0.4mL of 15% aqueous sodium hydride, and 1.2mL of water, filtration, and concentration of the filtrate gave 1.34 g of crude title compound. Short-path

distillation (160° bath temperature, 0.002mm) gave 1.26 g of purified product. ¹HNMR spectrum: (δ 7.2 (m, 2H);

7.0(m,2H); 4.3 (t, J=2.6Hz, 2H) ; 3.2 (m, 2H); 2.8(m,2H);

2.6(m,2H); 2.4(m,2H); 2.0(m,2H)l 2.7(m,2H); 1.4(m,2H).

The fumarate had mp 192-193° (dec.) after

crystallization from ethanol.

Anal. Calcd. for C₂₀H₂₄FNO₄: C, 63.65; H, 6.41; N, 3.71, Found: C, 63.54; H, 6.34; N, 3.59.

Table 1 shows data for other examples of this invention prepared by the disclosed methods.

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 HCl (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 HCl, 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 KiS 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 2 under the heading SIGMA.

Dopamine Recept or 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 KiS 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 2 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 2 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. Isolate mice failing to consistently attack an intruder were eliminated from the colony.

Drug testing was carried out by treating the isolate mice with test drugs or standards. Thirty minutes after dosing with test drugs by the oral route, one isolate 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 5 day washout period between treatments. The data are shown in Table 2 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 2 under the heading RAT CAT.

indicates ED50 (mg/kg) = 21-70

indicates ED50 (mg/kg) > 70

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:

1. The compounds of formulae:

;

;

;

;

;

;

;

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

3. 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.