CA1248101A - Aminoalkoxybenzopyranones as antipsychotic and anxiolytic agents - Google Patents

Abstract

ABSTRACT

Aminoalkoxybenzopyranones of the formula

Description

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BACKGROUND OF THE INVENTION
Various aminoalkoxybenzopyranones have been described in the literature. Compounds of the formula:

o ~ r ~ o(cu)n _ N~ R3 wherein R is lower alkyl have been described in US Patent 3,810,898 as having antioedematous act:lvity and the ability to reduce increased caplllary permeability.
Commonly assigned, copending Canadian appli-cation 490,241 filed September 9, 1985 discloses and claims benzopyranones which have valuable neuroleptic propertles and as such are useful as antipsychotic agents and as anxiolytic agents. The compounds of application 490,24l. are of the formula O (Cl~2) n-R

- ~2~10~

wherein n is an integer from 2-5; R is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy; R is a radical of the formula:

-~ ~ N-Ar , _~3 He~, or ~N3Ar, in which --- represents a single or double bond, Ar is phenyl or phenyl substituted by lower alkyl, lower alkoxy, lower thioalkoxy, halogen, or trifluoromethyl, and Het is 2-, 3- or 4-pyridinyl or 2-, 3- or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen; 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen; 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen; 2- or 3-thienyl or 2-or 3-thienyl substituted by lower alkyl or halogen; 2-or 3-furanyl or 2- or 3-furanyl substituted b~ lower alkyl or halogen, or 2- or 5-thiazolyl or 2- or 5-thiazolyl substituted by lower alkyl or halogen, or a pharmaceutically acceptable acid addition salt thereof, with the exclusion of the compound wherein n is 3, R is methyl, and R is a radical of the formula:

-~ N-~r /

in which Ar is phenyl.

SUMMARY OF THE INVENTION
The present invention relates to compounds of the above formula wherein R is a radical of the formula ~ 1 -N ~ Het, wherein Het is as defined above. That is, the present invention relates to antipsychotic or anxiolytic compounds of formula ~ (CH2)n - N 3 Het (I) wherein ---, n, R and Het are as defined above.
The present invention also relates to a pharmaceutical composition comprising an antipsychotic effective am3unt or an anxiolytically effective amount of a compound of Formula I as a pharmaceutically acceptable acid addition salt thereof with a pharmaceutically acceptable carrier.
The present invention further relates to a method of treating psychoses, e.g., schizophrenia, or to a method of treating anxiety, in a subject suffering therefrom comprising administering to said subject an effective amount of a compound of the Formula Io DETAILED DESCRIPTION
In the compounds of the Formula I, the term "lower alkyl" is meant to include a straight or branched ~-z~

alkyl group having from one to six carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, amyl, isoamyl, neopentyl, hexyl, and the like.
Halogen includes particularly fluorine, chlorine, or bromine.
Lower alkoxy and thioalkoxy are ~-alkyl or S-alkyl of from one to six carbon atoms as defined above for "lower alkyl."
A preferred embodiment of the present invention is a compound of the Formula II

o ~ O(CU2) - N ~ Uee wherein ---, n, R, and Het are as defined above, or a pharmaceutically acceptable acid addition salt thereof.
Another preferred embodiment of the present invention is a compound of ~he Formula II, wherein R is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment is a compound of the Formula II, wherein R is hydrogen, and Het is 2-, 3-, or 4-pyridinyl; 2-, 3-, or 4-pyridinyl substituted by methyl, chloro, or bromo; 2-, 4- or 5-pyrimidinyl; 2-~2'~0~

pyrazinyl, or 2-thiazolyl.
Still another preferred embodiment is a compound of the Formula ~I, wherein n is 2-5, but more preferably 3 or 4; R is hydrogen, and Het is 2-, 3-, or 4-pyridinyl; 2-, 4-, or 5-pyrimidinyl; 2-pyrazinyl or 2-thia~olyl.
A particularly preferred embodiment of the present invention is 7-~3-[3,6-dihydro-~-(2-thienyl)-1(2H)-pyridinyl]-propoxy-2H-l-benzopyran-2-one.
The compounds of the invention form pharmaceutically acceptable acid addition salts with organic and inorganic acids. Examples of suitable acids for salt formulation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid in the conventional manner.
The free base forms may be regenerated by treating the salt form with a base. For example, dilute aqueous base solutions may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose.
The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are ~2~

otherwise equivalent to their respective free base forms for purposes of the invention.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for purposes of the invention.
The compounds of the present invention and of the Formula I may be prepared by first reacting a hydroxy-2H-l-benzopyran-2-one of the fGrmula ~ (III) wherein ~ is as defined previously, with a compound of the formula X-(CH ) -Y (IIIa)

2 n wherein n is an interger of 2-5; X and Y are the same or different and are a leaving group such as halogen or a sulfonyloxy group, for example, methanesulfonyloxy or p-toluenesulfon~loxy; and secondly, reacting the resultingproduct of the Formula IV

~ ~5~1 0 ~ (CH2)n--X(Y) (IV) with an amine of the formula HN ~ Het wherein Het is as defined previously, and, if desired, converting the resulting free base by known methods to a pharmaceutically acceptable acid addition salt.
The reaction of the benzopyran-2-one of Formula III with a compound of Formula IIIa is carried out in an inert solvent, preferably a polar solvent such as a ketone, for example, acetone or methyl isobutyl ketone, in the presence of an acid scavenger, such as, for example, sodium or preferably, potassium carbonate in anhydrous form, at the reflux temperature of the solvent.

The intermediate product of Formula IV is then reacted with the amine in a polar aprotic solvent such as, for example, dimethylfor~amide and in the presence of a neutralizing agent such as, for example, sodium ., ~L%i~O~

bicarbonate. The reaction is carried out at elevated ternperatures, e.g , from about 50 to 150C.
An alternate method for the preparation of a compound of Formula I is to first prepare a compound of the formula /~ (V) X(CH2)n N Het wherein n, Het and ~ are as defined above, according to a method described in Ind. J. Chem. 435 ~1982), and react said compound of Formula V directly with a benzopyran-2-one of Formula III. This reaction is also best carried out at elevated temperatures, e.g., 50-150C, in a solvent such as dimethylformamide and in the presence of an acid neutralizing agent such as sodium bicarbonate.
The appropriate hydroxy-coumarin derivatives, compounds of Formula III, and amine derivatives are available commercially or may be prepared by well-known methods. For example, 4-substituted-7-hydroxy-coumarins are prepared by slight variations on the method described in Organic Syn~hesis, Coll Vol 3, p 282, for preparing 4-methyl-7-hydroxy-coumarin.

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The compounds of the present invention are new chemical substances which are also useful as pharma-ceutical agents for the treatment of anxiety, i.e., anxiolytic agents. The antianxiety activity of a representative compound showing such activity for the compounds of the Formula I of the present invention is established by the use of an animal model of anxiety based on the Geller-Seifter conflict test described in Psychopharmacologia 1:482 (1960). Particularlg the test follows initial snaping of response, an experimental conflict is induced, with animals trained until stable performance is established. Each animal serves as his own control. A description of the test is as follows:
Subjects: Mature male hooded rats (Long-Evans strain) 300-350 g body weight.
Apparatus: The experimental chamber consists of an inner test compartment with a lever mounted in one wall, a grid floor, an automatic feeding device, and a speaker. This chamber is enclosed by a sound insulated cubicle. Shock is provided by a LVE Model 1531 Constant Current Shocker. White ~masking) noise is supplied by a LVE Model 1524 Noise Generator. A tone is produced by a LVE Model 1664 4.5 KC Tone Generator. All events and recordings are automatic and are programmed with appropriate electric timers and relay devices.
Procedure: Variable interval (VI) = two-minute; trial periods = four; shock = 0.6 to 0.8 ma;

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food reward = Borden's Sweetened Condensed Milk diluted two parts water to one part milk; animals are deprived to 70% of their free feeding weight and are 23 hours starved; session length = one hour and 12 minutes.
The conflict is induced in the following manner: hungry rats are conditioned to press a lever to obtain a food reward. Reinforcement is contingent upon a lever press and occurs at variable intervals on the average of once every two minutes - VI two-minute (See Ferster; C. B., and Skinner, B. F., "In Schedules of Reinforcement," Appleton-Century-Crofts, New York, 1957).
Spaced at regular intervals throughout the experimental session are four three-minute periods.
During these trial periods a tone signals that every lever press will be food reinforced (CRF) and simul-taneously punished by a painful electric foot shock.
In other words, food-deprived rats are trained to depress a lever in order to obtain food (sweetened condensed milk). Normally, the rats perform on a variable interval (VI) schedule on which a lever press results in food delivery on the average of once every two minutes; the time between successive periods of food availability is varied continuously such that animals respond at low but steady rates to obtain occasional access to food. After animals perform for 12 minutes on this schedule the house lights are extinguished and two small stimulus lights are illuminated, signaling the 1~L~

availability of food for each depression of the lever during a three minute trial period. During the t}ial, each depression of the lever also results in the delivery of mild electric shock (0.8 ma, 0.25 second duration) delivered through the grid floor (punishment~.
Thus, an approach-avoidance conflict is established with associated anxiety: food is readily available for each response, but each response is punished (see Miller, N.
E., "Some Recent Studies of Conflict Behavior and Drugs," Am. Pharmacologist, 16:12, 1961). The scheduled used in our test employed four successive trials, each preceded by a 12-minute period during which the food-reinforced VI was in effect.
During sessions in which no drug is administered, rats normally respond at steady rates on the VI component but emit very few responses during the punished trial period.
7-[3-[4-(2-pyrimidinyl)-1-piperazinyl]propo~y]-2H-benzopyran-2-one increased responding during trial periods at doses to the rat of 55 and 80 mg/kg P0, but not at 27.5 mg/kg P0. This effect was selective in that it was not accompanied by decreased responding during the VI
component. In other words, there is a notable absence of gross sedation. This compound produced increases in punished responding in three of four rats tes~ed with 55 mg/g and in four of four rats tested with 80 mg/kg~ The total number of punished responses made by the four ~z~

subjects in the pretest and test sessions for the noted compound are as follows.

Compound Dose (mg/ Total Punished Responses kg P0) Pretest Test .
7-~3-~4-(2-pyrimi- 27.5 39 44 dinyl)-i-pipera-æinyl]propoxy]-2H- 55 78 147 benzopyran-2-one 80 23 77 :

The pretest responses are cummulative responses emitted during the three minute tests from a previous nondrug session.
An increase in responses during the trial periods (attenuation of conflict) indicates minor tranquilizer activity. This is shown by an increase in the trial/pretrial ratio. Total response rate is a measure of debilitating side effects. A decrease in total responses indicates side effect.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I, a corresponding pharmaceutically acceptable salt of a compound of Formula I, or a mixture of such compounds and/or salts.

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For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, and sup-positories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like. The term "preparation"
is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier~ which is thus in association with it. Similarly, cachets are included.
Tablets, powders, cachets, and capsules can be used as .,~ .

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solid dosage forms suitable for oral administration.
Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg , ~z~o~ ~

according to the particular application and the potency of the active ingredient.
In therapeutic use as antipsychotic agents, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.1 mg to about 100 mg per kilogram daily. A daily dose range of about 1.0 mg to about 10 mg per kilogram is preferred.
In therapeutic use as anxiolytic agents. the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.1 mg/kg to about 20 mg/kg daily. A daily dose range of about 1 mg/kg to about 3 mg/kg is preferred.
The dosages, however, may be varied depending upon the requirements of the patient, the severity of -the condition being treated, and the compound being employed.
Determination of the proper dosage for a particulàr situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are le-ss than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The following nonlimiting example illustrates the inventor's preferred method for preparing the compounds of the invention.

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EXAMPLE

7-[3-[3,6-dihydro-4-(2-thienyl)-1(2H)-pyridinyll-propox~-2H-l-benzopyran-2-one, 4-(2-thienvl)tetrahydropyridine A solution under nitrogen of 1.3 g (0.01 mole) AlCl in 40 ml ether is added to a stirred suspension of 1.2 g (0.03 mole) LAH in 100 ml ether and 75 ml tetrahydrofuran at 15 C, then stirred for 15 minutes. To the stirred suspension is added slowly a solution of 3 g (0.018 mole) 4-(2-(thienyl)-pyridine in 30 ml of tetrahydrofuran. The mixture is stirred at room temperature for about five hours, then decomposed by cautious addition of 2 ml H 0, 3 ml 40% NaOH, 2 ml H 0.
The mixture is filtered, and evaporated in vacuo. The residue is partitioned in 1 N HCl-ether. The aqueous portion is mixed with methylene dichloride and made basic with concentrated NaOH. The methylene dichloride layer is dried (MgSO ) and evaporated in vacuo to obtain 2 g of 4-(2-thienyl)-tetrahydropyridine.
Mass spec. calcd. 165.25 Found: 165 A 2.9 g (0.012 mole) sample of 7-(3-chloropropoxy)-2H-l-benzopyran-2-one as prepared above, ~ g (0.012 mole) 4-(2-thienyl)~etrahydropyridine, and 5 g NaHCO in 80 ml DMF is stirred at 80-90C for seven hours at room temperature overnight then filtered and evaporated in vacuo. The residue in methylene dichloride is washed with NaHCO , dried (MgSO ) and

3 4 , ~L2~8~L0~

evaporated in vacuo. 7-[3-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]propoxy-2H-l-benzopyran-2-one as 4.3 g of dark oil was obtained. The oil was dissolved in 20 ml of 2-propanol and treated with 3 ml of 20% 2-propanolic hydrogen chloride solution to give 2.4 ~ of the monhydrochloride sal~, mp 235-7 C. Anal. calcd. as:
C H N0 S HCl 0 5H 0 C, 60.99; H, 5.62; N, 3.39 Found: C, 61.06; H, 5.6Q; N. 3.27

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula wherein ? is a single or double bond; n is an integer from 2-5; R is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy; and Het is 2-, 3-, or 4-pyridinyl or 2-3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen 2-, 4-, or 5-pyrimidinyl, or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen; 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen; 2-or 3-thienyl, or 2- or 3-thienyl substituted by lower alkyl or halogen; 2- or 3 furanyl, or 2- or 3-furanyl substituted by lower alkyl or halogen, or 2- or 5-thiazolyl or 2- or 5-thiazolyl substituted by lower alkyl or halogen, or a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to Claim 1 and of the formula

3. A compound according to Claim 2, wherein R is hydrogen.

4. A compound according to Claim 3, wherein Het is 2-, 3-, or 4-pyridinyl, 2-, 3-, or 4-pyridinyl substituted by methyl, chloro, or bromo; 2-, 4-, or 5-pyrimidinyl; 2-pyrazinyl, or 2- or 5-thiazolyl.

5. A compound according to Claim 4, wherein Het is 2-, 3-, or 4-pyridinyl; 2-, 4-, or 5-pyrimidinyl; 2-pyrazinyl, or 2- or 5-thiazolyl.

6. A compound according to Claim 5, wherein n is 3 or 4.

7. 7-[3-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-propoxy]-2H-1-benzopyran-2-one.

8. A process for the preparation of a compound as claimed in Claim 1, which comprises reacting a compound of the formula wherein X is a leaving group, with an amine of the formula in an inert solvent and in the presence of a neutralizing agent at elevated temperatures.

9. A pharmaceutical composition comprising an anti-psychotic effective amount of a compound as claimed in Claim 1 or a pharmaceutically acceptable acid addition salt thereof with a pharmaceutically acceptable carrier.