WO1989009209A1

WO1989009209A1 - Piperidine ring modified phencyclidine analogs as anticonvulsants

Info

Publication number: WO1989009209A1
Application number: PCT/US1989/001229
Authority: WO
Inventors: Michael A. Rogawski; Kenner Rice; Arthur E. Jacobson; Andrew Thurkauf
Original assignee: Marion Laboratories, Inc.
Priority date: 1988-03-25
Filing date: 1989-03-22
Publication date: 1989-10-05
Also published as: AU3366389A; CA1329808C

Abstract

Compounds of formula (I), wherein R1, and R2 are selected from the group consisting of hydrogen, lower alkyl, and lower alkylene, and R1 and R2 together with nitrogen can form a ring having from three to seven members; R3 and R4 are selected from the group consisting of hydrogen, lower alkyl, lower alkylene, hydroxy, methoxy, amino, alkylamino, thio, thioalkyl, and halogen; ring A has from 5 to 8 carbon atoms; and pharmaceutically acceptable salts thereof, are useful as anticonvulsant agents for treating epilepsy.

Description

PIPERIDINE RING MODIFIED PHENCYCLIDINE ANALOGS AS

ANTICONVULSANTS

FIELD OF THE INVENTION The present invention relates to improvements in epilepsy therapy, and more particularly to compounds useful in the treatment of epilepsy and control of epileptic seizures.

BACKGROUND OF THE INVENTION Epilepsy is a disorder characterized by recurrent seizures, each of which consists of a sudden, excessive discharge of cerebral neurons resulting in transient neurological impairment. Seizures can affect a localized area of cerebral tissues, i.e. a partial seizure, or may involve wide areas of both cerebral hemispheres, i.e. a generalized seizure. Both types of seizures may be disabling and can have potentially serious consequences, although generalized seizures are more often associated with injury. Most patients are treated by chronic drug therapy and, in certain intractable cases, by surgical removal of the affected brain tissue. Drug treatment of epilepsy is intended to prevent the occurrence of seizures, but does not cure the underlying brain dysfunction. In practice, some patients obtain a complete relief from seizures, others experience a diminution in the frequency or severity of seizures, and some patients do not respond.

Approximately one percent of the general population is afflicted with epilepsy, and there are estimated to be approximately 360,000 Americans whose seizures are not controlled by presently available medications. Moreover, all currently used medications have undesirable side effects. Thus, there is a need for more effective and less toxic antiepileptic drugs.

Several drugs are currently in use for chronic prophylaxis against epileptic seizures. These compounds include phenobarbital, phenytoin, carbamazepine, primidone, valproic acid, ethosuximide, and clonazepam. Of these compounds, only the first four are effective and widely in use in the treatment of partial seizures. Valproic acid may be effective in treating partial seizures, although it is not approved or in widespread use for this treatment. All currently available antiepileptic drugs fail to control seizures in some patients. In those patients who respond, adverse drug effects may limit the patient to a suboptimal dose, or may prevent use of the drug. These adverse effects include dose dependent side effects and rare allergic or idiosyncratic reactions.

Each commonly used compound has a distinct profile of adverse effects. Phenobarbital may cause motor impairment including ataxia (unsteadiness), drowsiness, fatigue, and cognitive impairment. Phenytoin may cause ataxia, coarsening of the facial features, gingival hyperplasia, and hirsutism. Carbamazepine may cause ataxia, nausea and vomiting, and drowsiness. Primidone is metabolized to phenobarbital and phenylethylmalonamide, and has similar side effects to phenobarbital. In addition to these common side effects, all anticonvulsant drugs may cause rare idiosyncratic reactions, including serious blood and liver disorders, serious skin or integumentary disorders, or nerve damage (peripheral neuropathy).

Phencyclidine, commonly known as PCP, is currently a major drug of abuse in the United States. In recent years, it has received widespread attention because of the violent, homicidal and suicidal behavior of some of its users. Moreover, phencyclidine is one of the most fascinating psychotropic drugs, as the psychosis it elicits may provide the best available drug model of schizophrenia.

Godefroi et al., in U.S. Patent 3,097,136, disclose 1-phenylcyclohexylamine compounds of the formula

wherein R₁ and R₂ are hydrogen or alkyl radicals, the sura of the carbon atoms in the alkyl groups being less than 5, or wherein R₁ and R₂ together represent a polymethylene group containing 4 to 6 carbon atoms. These compounds are said to be useful for producing varying degrees of depression on the central nervous sys tem , such as euphoria , sedat ion , analges ia , and anesthesia. There is no disclosure that these compounds can be used as anticonvulsants. Hack et al . , in U .S . Patent 3 , 405 , 139 , disclose phenylcyclohexylalkylamine compounds of the formula

wherein R₁ is hydrogen or lower alkyl, R₂, R₃, R₄, R₅, and R₆ are hydrogen, halogen, hydroxyl, lower alkyl, aralkoxy, or alkoxy, and wherein two adjacent groups R₂- R₆ may together form a methylenedioxy group, X is lower alkylene which may be substituted by hydroxyl and/or keto groups and/or interrupted by a hetero atom, R₇ is hydrogen or lower alkyl, and n is 2 or 3. The compounds are said to be coronary artery dilating agents.

Arvidsson et al., in U.S. Patent 4,426,386, disclose substituted phenyl piperidines of the formula:

wherein N is 1 or 3, Y is OH, R₁COO-, R₂R₃NCOO-, or R4O, whereby R₁ is an alkyl group or a possibly substituted phenyl group, R₂ is an alkyl, phenethyl, benzyl, or phenyl group, R₃ is H or an alkyl group, and R₄ is an allyl or benzyl group, and R is an alkyl, hydroxyalkyl, dimethylaminoalkyl, or methylthioalkyl group or alkenyl group. The compounds are said to be useful for treatment of disorders in the central nervous system, and are said to have dopaminergic properties.

Lednicer, in U.S. Patents 4,113,866 and 4,447,454, discloses analgetic compounds of the formula

wherein R₁ is a variable consisting of hydrogen, alkyl of from 1 to 8 carbon atoms, CH₂-alkenyl wherein alkenyl is from 2 to 4 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms, cycloalkylmethyl of from 3 to 6 carbon atoms; R₂ is a variable consisting of hydrogen, alkyl of from 1 to 8 carbon atoms; Y is a variable consisting of alkyl of from 1 to 4 carbon atoms; R₅ is a variable consisting of hydrogen and alkyl of from 1 to 4 carbon atoms; R₄ is a variable consisting of alkyl of from 1 to 4 carbon atoms, CH₂-alkenyl wherein alkenyl is of from 2 to 4 carbon atoms. The compounds are said to be useful in relieving pain in humans and animals.

Vignon et al., in European Journal of Pharmacology, 81 : 531-542 (1982), disclose compounds in the phencyclidine series which were used to study the method of binding of phencyclidine to receptors in the brain. However, there was no indication that any of the compounds disclosed could be used as anticonvulsants.

SUMMARY OF THE INVENTION

It is an object of the present invention to overcome deficiencies in the prior art, such as indicated above.

It is another object of the present invention to provide compounds which are effective anticonvulsants.

It is yet another object of the present invention to provide improvements in the treatment of epilepsy.

It is a further object of the present invention to provide anticonvulsant drugs that can beused with little or no neurotoxicity.

It has now been discovered that structural modification of phencyclidine [1-(1-phenylcyclohexyl)piperidine, alternatively known as PCP], a dissociative anesthetic compound, results in compounds that provide protection from seizures with little neurotoxicity.

The compounds of the present invention are modifications of PCP wherein the piperidine ring is modified, and have the following formulae:

wherein R₁ and R₂ may be hydrogen or lower alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl or ( unsaturated) lower alkylene, or R₁ and R₂ may form with the nitrogen a three- to seven-membered ring with or without unsaturation, and R₃ and R₄ can be selected from the group consisting of hydrogen, lower alkyl, lower alkylene, hydroxy, methoxy, amino, alkylamino, thio, thioalkyl, and halogen, i.e. chlorine, bromine or fluorine. In addition, ring A may be a ring of from 5 to 8 carbon atoms.

The compounds of the present invention have anticonvulsant activity and, at effective doses, no toxicity (ataxia) has been observed. The compounds of the present invention thus are superior to the presently available compounds for seizure prophylaxis in patients who fail to respond or who have unacceptable adverse reactions to presently available drugs.

The compounds of the present invention have been found to protect laboratory animals from seizures with little neurotoxicity. The compounds were active in the maximal electroshock (MES) test, which determines the ability of a compound to prevent the spread of seizures, and is therefore a test for efficacy against partial seizures, i.e. those that begin locally in an area of abnormal cerebral cortex and subsequently spread to adjacent areas, often resulting in a generalized seizure. Partial seizures are believed to be the most common type of seizure and to be responsible for many generalized seizures.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are modifications of phencyclidine, compound I, below, and involve changes in the piperidine ring.

The compounds of the present invention can generally be described as follows:

wherein R₁ and R₂ may be hydrogen or lower alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl, or (unsaturated) lower alkylene, or R₁ and R₂ may form a three-to-seven membered ring with nitrogen. R₃ and R₄ can be hydrogen, lower alkyl, lower alkylene, hydroxy, methoxy, amino, alkylamino, thio, thioalkyl, or halogen (Cl, Br, or F). Additionally, ring A may contain from 5 to 8 carbon atoms. For example, phenylcycloheptylamines have been found to be particularly useful in treating epilepsy. The compounds of the present invention may be in the form of any pharmaceutically acceptable acid addition salt, i.e. any moiety which is non-toxic and makes the base compound soluble. Among these salts are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, fumaric acid, and the like.

Alternatively, the base compound may be used.

EXAMPLE 1

Compound II was prepared by the addition of phenylmagnesium bromide to 1-(1-cyanocyclohexyl)-1,2,3,6-tetrahydropyridine. The 1-(1-cyanocyclohexyl)-1,2,3,6-tetrahydropyridine was prepared by the acid catalyzed condensation of cyclohexanone, 1,2,3,6-tetrahydropyridine and potassium cyanide. Compound II, but not its utility, is known from M. R. Kazlowski, R. G. Browne and F. J. Vinick, Pharmacology Biochemistry & Behavior 25: 1051-1058 (1986).

The hydrochloride salt of compound II is a free flowing white powder with a melting point of 217- 218ºC. The molecular weight of the hydrochloride of compound II is 278. EXAMPLE 2-9 (Compounds III - X)

Compound III was prepared in a three step synthesis from 3-(R)methylcyclohexanone. Phenylmagnesium bromide was condensed with 3-(R)- methylcyclohexanone to give a mixture of isomeric tertiary alcohols. These alcohols were reacted with sodium azide in the presence of trifluoroacetic acid to give the corresponding 1-azido-1-phenyl-3-(R)- methylcyclohexanes. The azides were reduced to the tertiary amines, and compound III was separated from IV by crystallization of fumarate salt. The fumarate salt of compound III is a free flowing white powder with a melting point of 230-231°C and a molecular weight of 305.

Compounds V, VI and VII were prepared in a similar manner to that used for the preparation of compounds III and IV except that the appropriately substituted cyclohexanones were used as starting materials.

Compound VIII was prepared in a three step synthesis from cyclohexanone. 3-Methylphenylmagnesium bromide was condensed with cyclohexanone to give 1-(3-methylphenyl)cyclohexanol which in turn was reacted with sodium azide in the presence of trifluoroacetic acid to give the corresponding 1-azido-1-(3-methylphenyl)cyclohexane. The azide was then reduced to the tertiary amine VIII.

Compound IX was prepared by nitration of compound I with nitric acid according to the method of P. Y. Johnson, R. Pan, J. Q. Wen and C. J. Halfman, J. Org. Chem. 46: 2049-2054 (1981).

Compound X was prepared in the same manner as III except that cycloheptanone was used as the starting material instead of 3-(R)-methylcyclohexanone.

The above compounds prevented maximal electroshock (MES) seizures in mice. However, in contrast to phencyclidine, which causes neurotoxicity as determined by the mouse rotorod ataxia test, compounds II and III did not cause measurable toxicity at the effective anticonvulsant doses. These data are presented in Table I. TABLE 1

Seizure Protectant Effect and Toxicity of Piperidine Ring Modified PCP Analogs and Related Compounds

COMPOUND DOSE SEIZURE PROTECTION TOXICITY

(mg/kg) (MES) (rotorod)

II 10 2/4 0/4

III 3 1/4 0/4

III 10 4/4 0/4

IV 100 3/3 4/8

V 30 1/1 2/4

VI 30 1/1 1/4

VII 100 3/3 2/8

VIII 10 1/4 0/4

IX 30 1/1 0/4

X 10 1/4 0/4

30 1/4 0/4

DEXOXADROL* 10 2/4 3/4

LEVOXADROL** 30 0/1 0/4

X . . . 1-phenylcycloheptylamine

IX . . . 1- [1-(3-nitrophenylcyclohexyl]piperidine Mice were injected intraperitoneally with the drugs indicated (dissolved in aqueous 0.9% sodium chloride solution) and tested 30 min later. Seizure protection indicates number of animals failing to exhibit hind-limb tonic extension in response to a 200 msec electrical stimulus (50 mA; 60 Hz) applied via corneal electrodes primed with 0.9% sodium chloride solution. Animals not treated with the vehicle solution ("control animals") all exhibit hind-limb extension. Toxicity indicates number of animals unable to maintain equilibrium for 1 min when placed on a knurled rod rotating at 6 revolutions per min. Control animals are all able to maintain equilibrium. Data is expressed as number of animals showing effect/total number of animals tested.

*Data for this compound which is pharmacologically similar to compound I (phencyclidine) is shown for comparison.

**This is the optical enantiomer of dexoxadrol which lacks PCP-like activity and serves as a control. Table 2 shows toxic doses and doses of Compounds II, VI, and VIII.

TABLE 2

COMPOUND ED₅₀ TD₅₀

(mg/kg) (mg/kg)

II 5 6 VI 15 80 VIII 12 34

The toxic dose (TD₅₀) for 50% of animals at the peak of the toxic effect, and the MES protective dose (ED₅₀) for 50% of the animals at the peak of the seizure protective effect were determined by probit analysis. The date are reported in mg/kg.

The compounds of the present invention may be administered as the bases, or may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" is intended to include salts with pharmaceutically acceptable acids such as hydrochloric, sulfuric, acetic, phosphoric, methanesulfonic, fumaric, and the like.

Pharmaceutical compositions for treating epilepsy or other convulsions within the scope of the present invention include compositions wherein the active ingredient compound is contained in an effective amount to achieve its intended purpose. Determination of the effective amount is, of course, within the skill of the art. However, the compounds of the present invention are generally effective in preventing seizures when administered in dosaσes of from about 1 mg/kg of body weight to about 100 mg/kg of body weight, it being understood that individual dosages will vary with the individual response of the patient.

In addition to the phencyclidine derivatives of the present invention, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Preferably, the preparations, particularly those which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.1 to about 99 percent ,by weight of active ingredient, together with the excipient.

The pharmaceutical preparations of the present invention are manufactured in a conventional manner, for example, by means of conventional mixing, granulating, dragee-making, or dissolving processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired or necessary to obtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as sugars, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using for example maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone.

If desired, disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Slow or extended release compositions may also be formulated.

Auxiliaries include flow-regulating agents and lubricants, such as silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, may be resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum Arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize different combinations of active compound doses.

Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

Pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triclycerides, paraffin hydrocarbons, polyethylene glycols, and higher alkanols. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.

Alternatively, the active ingredient may be contained in liposomes, pharmaceutical compositions in which the active ingredient is contained either dispersed or variously present in corpuscles consisting of aqueous concentric layers adherent to lipidic layers (hydrophobic). The drug may be present both in the aqueous layer and in the lipidic layer (inside or outside) or, in any event, in the non-homogeneous system generally known as a liposomic suspension.

The hydrophobic layer, generally but not exclusively, comprises phospholipids such as lecithin and sphingomycelin, steroids such as cholesterol, more or less ionic surface active substances such as dicetylphosphate, stearylamine or phosphatidic acid, and/or other materials of a hydrophobic nature. The diameters of the liposomes generally range from about 15 nm to 5 microns.

While the invention is described above in relation to certain specific embodiments, it will be understood that many variations are possible, and that alternative materials and reagents can be used without departing from the invention. In some cases such variations and substitutions may require some experimentation, but such will only involve routine testing.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and therefore such adaptations and modifications are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula

wherein R₁ and R₂ are selected from the group consisting of hydrogen, lower alkyl and lower alkylene, or R₁ and R₂ together with nitrogen form a ring having from three to seven members; R₃ and R₄ are selected from the group consisting of hydrogen, lower alkyl, lower alkylene, hydroxy, methoxy, amino, alkylamino, thio, thioalkyl, chlorine, bromine, or fluorine; ring A has from 5 to 8 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that R₂-N-R, is not a 3,4-dehydro piperidine ring.

2. A compound according to claim 1 having the formula:

3. A method for treating epilepsy comprising administering to a patient afflicted with epilepsy an effective amount for at least partially controlling seizures of a compound according to claim 1.

4. The method of claim 3 wherein the compound has the formula:

5. The method of claim 3 wherein the compound has the formula:

6. A composition for treating epilepsy comprising an effective amount for at least partially controlling seizures of a compound according to claim 1 and a pharmaceutically acceptable carrier.

7. The composition of claim 6 wherein the compound has the formula

8. The composition of claim 7 wherein the compound has the formula: