CA1329808C - Piperidine ring modified phencyclidine analogs as anticonvulsants - Google Patents
Piperidine ring modified phencyclidine analogs as anticonvulsantsInfo
- Publication number
- CA1329808C CA1329808C CA000594589A CA594589A CA1329808C CA 1329808 C CA1329808 C CA 1329808C CA 000594589 A CA000594589 A CA 000594589A CA 594589 A CA594589 A CA 594589A CA 1329808 C CA1329808 C CA 1329808C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Compounds of the formula
Compounds of the formula
Description
- ~ .
. .
PIPERIDINE RING MODIFIED PHENCYCLIDINF 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.
BACRGROUND 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 disabllng and can have potentially serlous c~nsequences, although generalized seizures are more often associated with injury. Most patients are treated by chronic drug therapy and, in certain lntractable cases, by surglcal removal of the affected brain tissue. Drug treatment of epllepsy is intended to prevent thc occurrence of selzures, but does not cure the underlying brain dysfunction. In practice, some ", :, . .
, ~ ,.
. ~
. . ..
.7 .;:
`- 1 329808 patients ~btain 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 ti~ be approximately 360,000 Americans whose seizures are not controlled by presently available medications. ~loreover, 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 idissyncratic 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, glngival hyperplasia, and hirsutism.
Carbamazepine may cause ataxia, nausea and vomiting, and dr~wginess. Primidone i9 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 ,'": .' F.~ " ;j , , . j .~ i;".
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.5. Patent 3,097,136, disclose l-phenylcyclohexylamine compounds of the formula /C~-CH~
C Ml C
--C~ N
R~ .:
' wherein Rl and R2 are hydrogen or alkyl radicals, the sum of the carbon atoms in the alkyl groups being less than 5, or wherein Rl and R2 together represent a polymethylene group containing 4 to 6 carbon atoms. ; ;
These compounds are said to be useful for producing vflrying degrees of depression on the central nervous sy~tem, such as euphoria, sedation, analgesia, and ane~thesia~ There is no disclosure that these compounds can be used as anticonvulsants.
' '','' ,:,:
,: ':
.-', .:, ; , Hack et al., in U.S. Patent 3,405,139, disclose phenylcyclohexylalkylamine co~pounds of the fermula ~ R, ~
wherein Rl is hydrogen or lower alkyl, R2, R3, R4, Rs, 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, dlsclose substituted phenyl piperidines of the formula:
~ N
(C~2.~,. .
wherein N is l or 3, Y i8 OH, RlCOO-, R2~3NCOO-, or R40, whoreby Rl i9 ~n alkyl group or a possibly substituted ph~nyl 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 ': .' Rl R2 .... .
wherein Rl 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; Rs 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 i~ of from 2 to 4 carbon atoms. The compounds are said to be useful in relieving pain in human~ and animals.
Vlgnon et al., in European Journal of PharmacoloaY~ 81: 531-542 ~1982), disclose compo~nds in the phencyclidine series which were used to study the :: ' .
''." ,: .
- 5 - ~
.. .... .
,:, .
method of binding of phencyclidine to receptors in the brain. However, there was no indication that any ~f 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 be used with little or no neurotoxicity.
It has now been discovered that structural modification of phencyclidine [1-(1-phenylcyclohexyl)piperidine, alternatively known as PCPl, a dissociative anesthetic compound, results in compounds that provide protection from seizures with little neurotoxicity.
The compounds of the ~resent invention are modifications of PCP wherein the piperidine ring is modified, and have the following formulae:
~N~,~
\~ , wherein Rl and R2 may be hydrogen or lower alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl or (unsaturated) lower alkylene, or Rl 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 d~ses, 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.
.. ,: ;-:....:
... .
1 329~08 Thus the present invention provides a pharmaceutical composition for treating epilepsy, said composition comprising-a compound having the formula /~ R3 :
R~, <O~
~ ~ J
~ .
wherein R " and R2 are independently H, C1 - C4 alkyl . ~
or C1 ~ C4 alkylene or taken together form a ring with ~-nitrogen having from three to seven members;
R3 i8 H, C~ - C4 alkyl or C1 ~ C4 alkylene; and :
R4 is H, C1 - C4 alkyl or C1 ~ C4 alkylene; or pharma¢euti¢ally a¢ceptable salts thereof;
with the provisos that at least one o~ Ri3 and R4 i3 not H, and that i~ R4 is H, then R1 and R2 muet also be H, together with a pharmaceutically acceptable carrier : :
or excipient.
The invention also comprises the use o~ such compound~ ~or treatment Or epilepsy, and ~or preparing medicaments there~or. . .
7a ~B ~
.
. . .
DETAILED DESCRIPTION OF THE INVENTION :~
The compounds of the present invention are modifications of phencyclidine, c~mp3und I, below, and involve changes in the piperidine ring.
~N~
O
The compounds of the present invention can generally be described as follows:
''' ~"' ~N~
f ~ A ' .; , . ' ~ '.. ,~', " .
~ ,, " , .
wherein Rl and R2 may be hydrogen or lower alkyl, such aR methyl, ethyl, propyl, isopropyl, or butyl, or ~unsaturated) lower alkylene, ~r Rl and R2 may form a three-to-seven membered ring with nitrogen. R3 and R4 can be hydrogen, lower alkyl, l~wer alkylene, hydroxy, methoxy, amino, alkylamino, thio, thioalkyl, or halogen (Cl, 3r, or F). Additionally, ring A may contain from 5 to 8 carbon atom~. For example, phenylcycloheptylamines have been ~ound to be particularly useful in treating epllepsy.
The compounds of the present invention may be in the form of any pharmaceutically acceptable acid addition sal~, i.e. any moiety which is non-toxic and makes the base compound soluble. Among these salts are hydr~chlorlc acid, phosphoric acid, sulfuric acid, methanesulfonic acid, fumaric acid, and the like.
Alternatively, the base compound may be used.
~N~ II
Compound II was prepared by the addition of phenylmagnesium bromide to l-(l-cyanocyclohexyl)-1,2,3,6-tetrahydropyridine. The l-(l-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 it~ utility, is known from ~1. R. Kazlowski, R. G. Browne and F. J. Vinick, Pharmac~loqY Biochemistry & Behavior 25: 1051-1058 (1986).
The hydrochloride salt of compound II is a free ~lowing white powder with a melting point of 217-218C. The molecular weight of the hydrochloride of compound II is 278.
_ ~ _ ' ,,:
' ' EXAMPLE 2-9 (Compounds III - X) ~ ~
~ H 3 NH~ NH~
CH 3"~ I V :
IV C1~13 N~ NH,~
CH 3 Vl CH3 :' '';
B
~3 NH2~,~ /~N2 O O ~''~'"~,' :,.
Vlll IX
~ H 2~,~) O ',"' Compound IlI was prepared in a three step synthesis from 3-~R)methylcyclohexanone.
Phenylm~gnesium bromide was condensed with 3-~R)-methylcyclohexanone to give a mixture of isomeric tertiary alcohol~. These alcohols were reacted with ~odlum azide in the pre~ence of trifluoroacetic acid to ~ive the corre~pondlng l-azido-l-phenyl-3-~R)-methylcyclohexanes. The azides were reduced to the tertlary amines, and compound III was separated from IV
by crystalllzation of fumarate qalt.
' ~. ', - 1 32q808 , ,:
The fumarate salt of compound III is a free -~
flowing white powder with a melting point of 230-231C
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 l-azido-l-(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. Ora. 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 contraRt 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 preRented in Table I.
.',, '. ' '. . , : .
:
. .
"",,~,,,"~ /,,,p, , "
Seizure Protectant Effect and Toxicity of Piperidine Ring Modified PCP Analogs and Related Compounds :
COMPOUND DOSESEIZURE PROTECTION l'OXICITY
(mg/kg) ~MES ) ~ rotorod ) III 3 1/4 0/4 `
DEXOXADROL* 10 2/4 3/4 LEVOXADROL*~ 30 0/1 0/4 X . . . l-phenylcycloheptylamine IX . . . 1-[1-(3-nitrophenylcyclohexyl]piperidine Mlce were in~ected intraperitoneally with the drugs indlcated ~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 exhlbit hind-limb extension. Toxic~ty indicates number of animals unable to maintain equilibrium for 1 mln when placed on a knurled rod rotating at 6 revolutions per min. Control animals are all able to maint~in equilibrium. Data is expressed as number ef animals showing effect/total number of animals tested.
~Dat~ ~or this compound which is pharmacologically simil~r to compound I ~phencyclidine) is shown for comparison.
~Thiis iiB the optical enantiomer of dexoxadrol which lacks PCP-like activity and serves as a control.
.
' t 1 ~29808 Table 2 sh~ws toxic doses and doses of :~
Compounds II, VI, and VIII.
TA~LE 2 .
.:
COM POUND ED50 TD50 : .
(mg/kg) (mg/kg) , II 5 6 : :
VIII 12 34 . ..
': " ' . ':
The toxic dose (TDso) for 50% of animals at the peak of the toxic effect, and the MES protective dose (EDso) 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 admini~tered as the bases, or may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" i~ intended to include salts with pharmaceutically acceptable acids such as hydrochloric, sulfuric, acetic, phosphoric, methane~ulfonic, fumaric, and the like.
Pharmaceutical compositions for treating epilepsy or other convulsions within the scope of the present invention include compoqitions wherein the actlve ingredient compound i~ contained in an effective amount to achieve its intended purpo~e. 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 ~eizures when administered in dosages 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, eontain from about 0.1 to about 99 percent by weight of aetive ingredient, together with the excipient.
The pharmaeeutieal preparations of the present invention are manufactured in a eonventional manner, for example, by means of eonventional mixing, granulating, dra~ee-maklnq, or dissolving proeesses. Thus, pharmaeeutieal preparations for oral use can be obtained by eombining the aetive compounds with solid excipients, optionally grindlng the resulting mixture, and proces3ing the mixture of granules, after adding 5uitable auxllLaries if desired or necessary to obtain tablets or dragee cores.
Suitable exeipient9 are, in partieular, fillers sueh as sugars, for example, laetose or suerose, mannitol or sorbltol, eellulose preparations and/or ealeium phosphates, sueh as triealcium phosphate or ;~
ealeium hydrogen phosphate, as well as binders sueh as stareh paste, using for example maize starch, wheat stareh, riee starch, potato starch, gelatin, gum :
- 15 - .:
tragacanth, methyl cellulose, hydroxypropylmethylcellul~se, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone.
If desired, disintegrating agents may be added, such as the ab~ve-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. Dragée 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 pyrrolldone, polyethylene glycol and/or titanium dioxide, lacquer solutions, and ~uitable organic solvents or solvent mixtures. In order to produce coatings resistant to ga~tric 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 dragée 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 cap~ule~ 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 a~ talc or magnesium stearate and, optionally, stabllizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid para~fin, 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 triclyeerides, 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 compoundR 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 Ruspension may also contain Rtabilizers.
Alternatively, the active ingredient may be contained in liposomes, pharmaceutical compositions in which the active ingredient is contained either disper~ed or variou~ly present in corpuscles consisting of aqueou~ concentrlc 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 material~ of a hydrophobic nature. The diameters of the liposomes generally range from about 15 nm to 5 microns.
I~hile 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 80 fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt Eor 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 i9 to be understood that the phra~eology or terminology herein i~ for the purpose of description and not of limitation.
' ' '
. .
PIPERIDINE RING MODIFIED PHENCYCLIDINF 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.
BACRGROUND 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 disabllng and can have potentially serlous c~nsequences, although generalized seizures are more often associated with injury. Most patients are treated by chronic drug therapy and, in certain lntractable cases, by surglcal removal of the affected brain tissue. Drug treatment of epllepsy is intended to prevent thc occurrence of selzures, but does not cure the underlying brain dysfunction. In practice, some ", :, . .
, ~ ,.
. ~
. . ..
.7 .;:
`- 1 329808 patients ~btain 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 ti~ be approximately 360,000 Americans whose seizures are not controlled by presently available medications. ~loreover, 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 idissyncratic 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, glngival hyperplasia, and hirsutism.
Carbamazepine may cause ataxia, nausea and vomiting, and dr~wginess. Primidone i9 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 ,'": .' F.~ " ;j , , . j .~ i;".
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.5. Patent 3,097,136, disclose l-phenylcyclohexylamine compounds of the formula /C~-CH~
C Ml C
--C~ N
R~ .:
' wherein Rl and R2 are hydrogen or alkyl radicals, the sum of the carbon atoms in the alkyl groups being less than 5, or wherein Rl and R2 together represent a polymethylene group containing 4 to 6 carbon atoms. ; ;
These compounds are said to be useful for producing vflrying degrees of depression on the central nervous sy~tem, such as euphoria, sedation, analgesia, and ane~thesia~ There is no disclosure that these compounds can be used as anticonvulsants.
' '','' ,:,:
,: ':
.-', .:, ; , Hack et al., in U.S. Patent 3,405,139, disclose phenylcyclohexylalkylamine co~pounds of the fermula ~ R, ~
wherein Rl is hydrogen or lower alkyl, R2, R3, R4, Rs, 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, dlsclose substituted phenyl piperidines of the formula:
~ N
(C~2.~,. .
wherein N is l or 3, Y i8 OH, RlCOO-, R2~3NCOO-, or R40, whoreby Rl i9 ~n alkyl group or a possibly substituted ph~nyl 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 ': .' Rl R2 .... .
wherein Rl 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; Rs 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 i~ of from 2 to 4 carbon atoms. The compounds are said to be useful in relieving pain in human~ and animals.
Vlgnon et al., in European Journal of PharmacoloaY~ 81: 531-542 ~1982), disclose compo~nds in the phencyclidine series which were used to study the :: ' .
''." ,: .
- 5 - ~
.. .... .
,:, .
method of binding of phencyclidine to receptors in the brain. However, there was no indication that any ~f 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 be used with little or no neurotoxicity.
It has now been discovered that structural modification of phencyclidine [1-(1-phenylcyclohexyl)piperidine, alternatively known as PCPl, a dissociative anesthetic compound, results in compounds that provide protection from seizures with little neurotoxicity.
The compounds of the ~resent invention are modifications of PCP wherein the piperidine ring is modified, and have the following formulae:
~N~,~
\~ , wherein Rl and R2 may be hydrogen or lower alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl or (unsaturated) lower alkylene, or Rl 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 d~ses, 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.
.. ,: ;-:....:
... .
1 329~08 Thus the present invention provides a pharmaceutical composition for treating epilepsy, said composition comprising-a compound having the formula /~ R3 :
R~, <O~
~ ~ J
~ .
wherein R " and R2 are independently H, C1 - C4 alkyl . ~
or C1 ~ C4 alkylene or taken together form a ring with ~-nitrogen having from three to seven members;
R3 i8 H, C~ - C4 alkyl or C1 ~ C4 alkylene; and :
R4 is H, C1 - C4 alkyl or C1 ~ C4 alkylene; or pharma¢euti¢ally a¢ceptable salts thereof;
with the provisos that at least one o~ Ri3 and R4 i3 not H, and that i~ R4 is H, then R1 and R2 muet also be H, together with a pharmaceutically acceptable carrier : :
or excipient.
The invention also comprises the use o~ such compound~ ~or treatment Or epilepsy, and ~or preparing medicaments there~or. . .
7a ~B ~
.
. . .
DETAILED DESCRIPTION OF THE INVENTION :~
The compounds of the present invention are modifications of phencyclidine, c~mp3und I, below, and involve changes in the piperidine ring.
~N~
O
The compounds of the present invention can generally be described as follows:
''' ~"' ~N~
f ~ A ' .; , . ' ~ '.. ,~', " .
~ ,, " , .
wherein Rl and R2 may be hydrogen or lower alkyl, such aR methyl, ethyl, propyl, isopropyl, or butyl, or ~unsaturated) lower alkylene, ~r Rl and R2 may form a three-to-seven membered ring with nitrogen. R3 and R4 can be hydrogen, lower alkyl, l~wer alkylene, hydroxy, methoxy, amino, alkylamino, thio, thioalkyl, or halogen (Cl, 3r, or F). Additionally, ring A may contain from 5 to 8 carbon atom~. For example, phenylcycloheptylamines have been ~ound to be particularly useful in treating epllepsy.
The compounds of the present invention may be in the form of any pharmaceutically acceptable acid addition sal~, i.e. any moiety which is non-toxic and makes the base compound soluble. Among these salts are hydr~chlorlc acid, phosphoric acid, sulfuric acid, methanesulfonic acid, fumaric acid, and the like.
Alternatively, the base compound may be used.
~N~ II
Compound II was prepared by the addition of phenylmagnesium bromide to l-(l-cyanocyclohexyl)-1,2,3,6-tetrahydropyridine. The l-(l-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 it~ utility, is known from ~1. R. Kazlowski, R. G. Browne and F. J. Vinick, Pharmac~loqY Biochemistry & Behavior 25: 1051-1058 (1986).
The hydrochloride salt of compound II is a free ~lowing white powder with a melting point of 217-218C. The molecular weight of the hydrochloride of compound II is 278.
_ ~ _ ' ,,:
' ' EXAMPLE 2-9 (Compounds III - X) ~ ~
~ H 3 NH~ NH~
CH 3"~ I V :
IV C1~13 N~ NH,~
CH 3 Vl CH3 :' '';
B
~3 NH2~,~ /~N2 O O ~''~'"~,' :,.
Vlll IX
~ H 2~,~) O ',"' Compound IlI was prepared in a three step synthesis from 3-~R)methylcyclohexanone.
Phenylm~gnesium bromide was condensed with 3-~R)-methylcyclohexanone to give a mixture of isomeric tertiary alcohol~. These alcohols were reacted with ~odlum azide in the pre~ence of trifluoroacetic acid to ~ive the corre~pondlng l-azido-l-phenyl-3-~R)-methylcyclohexanes. The azides were reduced to the tertlary amines, and compound III was separated from IV
by crystalllzation of fumarate qalt.
' ~. ', - 1 32q808 , ,:
The fumarate salt of compound III is a free -~
flowing white powder with a melting point of 230-231C
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 l-azido-l-(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. Ora. 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 contraRt 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 preRented in Table I.
.',, '. ' '. . , : .
:
. .
"",,~,,,"~ /,,,p, , "
Seizure Protectant Effect and Toxicity of Piperidine Ring Modified PCP Analogs and Related Compounds :
COMPOUND DOSESEIZURE PROTECTION l'OXICITY
(mg/kg) ~MES ) ~ rotorod ) III 3 1/4 0/4 `
DEXOXADROL* 10 2/4 3/4 LEVOXADROL*~ 30 0/1 0/4 X . . . l-phenylcycloheptylamine IX . . . 1-[1-(3-nitrophenylcyclohexyl]piperidine Mlce were in~ected intraperitoneally with the drugs indlcated ~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 exhlbit hind-limb extension. Toxic~ty indicates number of animals unable to maintain equilibrium for 1 mln when placed on a knurled rod rotating at 6 revolutions per min. Control animals are all able to maint~in equilibrium. Data is expressed as number ef animals showing effect/total number of animals tested.
~Dat~ ~or this compound which is pharmacologically simil~r to compound I ~phencyclidine) is shown for comparison.
~Thiis iiB the optical enantiomer of dexoxadrol which lacks PCP-like activity and serves as a control.
.
' t 1 ~29808 Table 2 sh~ws toxic doses and doses of :~
Compounds II, VI, and VIII.
TA~LE 2 .
.:
COM POUND ED50 TD50 : .
(mg/kg) (mg/kg) , II 5 6 : :
VIII 12 34 . ..
': " ' . ':
The toxic dose (TDso) for 50% of animals at the peak of the toxic effect, and the MES protective dose (EDso) 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 admini~tered as the bases, or may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" i~ intended to include salts with pharmaceutically acceptable acids such as hydrochloric, sulfuric, acetic, phosphoric, methane~ulfonic, fumaric, and the like.
Pharmaceutical compositions for treating epilepsy or other convulsions within the scope of the present invention include compoqitions wherein the actlve ingredient compound i~ contained in an effective amount to achieve its intended purpo~e. 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 ~eizures when administered in dosages 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, eontain from about 0.1 to about 99 percent by weight of aetive ingredient, together with the excipient.
The pharmaeeutieal preparations of the present invention are manufactured in a eonventional manner, for example, by means of eonventional mixing, granulating, dra~ee-maklnq, or dissolving proeesses. Thus, pharmaeeutieal preparations for oral use can be obtained by eombining the aetive compounds with solid excipients, optionally grindlng the resulting mixture, and proces3ing the mixture of granules, after adding 5uitable auxllLaries if desired or necessary to obtain tablets or dragee cores.
Suitable exeipient9 are, in partieular, fillers sueh as sugars, for example, laetose or suerose, mannitol or sorbltol, eellulose preparations and/or ealeium phosphates, sueh as triealcium phosphate or ;~
ealeium hydrogen phosphate, as well as binders sueh as stareh paste, using for example maize starch, wheat stareh, riee starch, potato starch, gelatin, gum :
- 15 - .:
tragacanth, methyl cellulose, hydroxypropylmethylcellul~se, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone.
If desired, disintegrating agents may be added, such as the ab~ve-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. Dragée 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 pyrrolldone, polyethylene glycol and/or titanium dioxide, lacquer solutions, and ~uitable organic solvents or solvent mixtures. In order to produce coatings resistant to ga~tric 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 dragée 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 cap~ule~ 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 a~ talc or magnesium stearate and, optionally, stabllizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid para~fin, 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 triclyeerides, 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 compoundR 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 Ruspension may also contain Rtabilizers.
Alternatively, the active ingredient may be contained in liposomes, pharmaceutical compositions in which the active ingredient is contained either disper~ed or variou~ly present in corpuscles consisting of aqueou~ concentrlc 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 material~ of a hydrophobic nature. The diameters of the liposomes generally range from about 15 nm to 5 microns.
I~hile 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 80 fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt Eor 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 i9 to be understood that the phra~eology or terminology herein i~ for the purpose of description and not of limitation.
' ' '
Claims (5)
1. A pharmaceutical composition for treating epilepsy, said composition comprising a compound having the formula wherein R1, and R2 are independently H, C1 - C4 alkyl or C1 - C4 alkylene or taken together form a ring with nitrogen having from three to seven members;
R3 is H, C1 - C4 alkyl or C1 - C4 alkylene; and R4 is H, C1 - C4 alkyl or C1 - C4 alkylene; or pharmaceutically acceptable saltsthereof;
with the provisos that at least one of R3 and R4 is not H, and that if R4 is H, then R1 and R2 must also be H, together with a pharmaceutically acceptable carrier or excipient.
R3 is H, C1 - C4 alkyl or C1 - C4 alkylene; and R4 is H, C1 - C4 alkyl or C1 - C4 alkylene; or pharmaceutically acceptable saltsthereof;
with the provisos that at least one of R3 and R4 is not H, and that if R4 is H, then R1 and R2 must also be H, together with a pharmaceutically acceptable carrier or excipient.
2. A composition as in claim 1 wherein the compound has the formula
3. A composition as in claim 1 wherein the compound has a formula
4. The use of a compound as set out in any one of claims 1, 2, or 3, for treating epilepsy.
5. The use of a compound as set out in any one of claims 1, 2, or 3, for preparing a medicament for treating epilepsy.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17292288A | 1988-03-25 | 1988-03-25 | |
| US07/172,922 | 1988-03-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1329808C true CA1329808C (en) | 1994-05-24 |
Family
ID=22629762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000594589A Expired - Fee Related CA1329808C (en) | 1988-03-25 | 1989-03-23 | Piperidine ring modified phencyclidine analogs as anticonvulsants |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3366389A (en) |
| CA (1) | CA1329808C (en) |
| WO (1) | WO1989009209A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260286A (en) * | 1992-10-16 | 1993-11-09 | Japan Tobacco, Inc. | 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB853775A (en) * | 1957-09-19 | 1960-11-09 | Parke Davis & Co | Pharmaceutical compositions and methods for producing phenylcyclohexane compounds |
| BE565262A (en) * | 1957-09-19 | |||
| US3097207A (en) * | 1958-03-06 | 1963-07-09 | Parke Davis & Co | 1-halophenyl and 1-alkoxyphenyl cyclohexylamines |
| GB948071A (en) * | 1959-05-01 | 1964-01-29 | May & Baker Ltd | New heterocyclic compounds |
| US3145229A (en) * | 1960-04-04 | 1964-08-18 | Parke Davis & Co | Process for the production of nu-substituted-1-phenylcyclohexylamines |
| US3097136A (en) * | 1960-04-04 | 1963-07-09 | Parke Davis & Co | Process for producing a depressant-like effect on the central nervous system |
| US3192219A (en) * | 1960-04-04 | 1965-06-29 | Parke Davis & Co | Process for producing certain new 1-phenylcyclohexylamine compounds |
| GB1207731A (en) * | 1968-05-14 | 1970-10-07 | Reckitt & Sons Ltd | Derivatives of pyrrolidine |
| US3652769A (en) * | 1969-10-01 | 1972-03-28 | Merck & Co Inc | Cycloalkylamines in the treatment of mental disorders involving depression and compositions therefor |
| US4460604A (en) * | 1976-06-03 | 1984-07-17 | The Upjohn Company | 4-Amino-4-aryl-cyclohexanones |
| US4113866A (en) * | 1977-04-01 | 1978-09-12 | The Upjohn Company | Analgetic compounds, compositions and process of treatment |
| ZA821577B (en) * | 1981-04-06 | 1983-03-30 | Boots Co Plc | Therapeutic agents |
-
1989
- 1989-03-22 AU AU33663/89A patent/AU3366389A/en not_active Abandoned
- 1989-03-22 WO PCT/US1989/001229 patent/WO1989009209A1/en unknown
- 1989-03-23 CA CA000594589A patent/CA1329808C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU3366389A (en) | 1989-10-16 |
| WO1989009209A1 (en) | 1989-10-05 |
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