WO1994006758A1 - Anticonvulsifs a base de semicarbazone aryle - Google Patents

Anticonvulsifs a base de semicarbazone aryle Download PDF

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WO1994006758A1
WO1994006758A1 PCT/CA1993/000386 CA9300386W WO9406758A1 WO 1994006758 A1 WO1994006758 A1 WO 1994006758A1 CA 9300386 W CA9300386 W CA 9300386W WO 9406758 A1 WO9406758 A1 WO 9406758A1
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alkylamino
group
aryl
halogen
amino
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PCT/CA1993/000386
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English (en)
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Jonathan R. Dimmock
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University Of Saskatchewan
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
    • C07C281/14—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
    • C07C281/10—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to an acyclic carbon atom or to a carbon atom of a ring other than a six-membered aromatic ring

Definitions

  • This invention relates to a novel class of semicarbazone compounds and their use on central nervous system activity.
  • the compounds are particularly useful as anticonvulsants.
  • epilepsy The cause of epilepsy is only poorly understood, but it is thought to be due to the activity of faulty neurons in the brain which give sudden and excessive bursts of electrical activity. These aberrant neutrons in turn can affect neurons far from the original site which then behave in a similar way to the original abnormal neurons.
  • the five major classification types of epilepsy are: 1° generalized seizures which involve the entire brain, 2° unilateral seizures which involve one side of the body, 3° focal seizures originating at one place in the body, 4° seizures of the new born, and 5° unclassified seizures, which are severe and often fatal.
  • Two principal types of generalized seizures are grand mal and petit mal.
  • Medication is available to treat generalized tonic-clonic (GTC) seizures (grand mal).
  • GTC generalized tonic-clonic
  • An example of such medication is phenytoin.
  • An experimental model to uncover drugs useful against this type of epilepsy is the maximal electroshock (MES) screen.
  • ethosuximide which are ineffective against GTC seizures, are useful in treating absence seizures (petit mal).
  • Compounds with this activity may be detected in the subcutaneous pentylenetetrazol seizure threshold (scPTZ) test.
  • scPTZ subcutaneous pentylenetetrazol seizure threshold
  • Synthetic anticonvulsants which incorporated the molecular features referred to in the previous paragraphs and yet were structurally dissimilar from many common monocyclic anticonvulsants containing the dicarboximide function which may contribute to toxic side effects have been prepared.
  • a series of thiosemicarbazones and semicarbazones of arylidene methyl ketones were synthesized and evaluated in the MES, scPTZ and neurotoxicity screens. Approximately 75% of the compounds were active in the MES and/or scPTZ screens when given by the intraperitoneal route in mice. Although neurotoxicity and lethality in mice were higher in the thiosemicarbazones than the semicarbazones, the two most active compounds were both thiosemicarbazones. Hence, developments of this series of compounds rather than the corresponding semicarbazones were considered more likely to produce potent anticonvulsants.
  • a novel class of anticonvulsant semicarbazones is provided.
  • the invention therefore relates to a compound having the following formula
  • R 1 is or
  • a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N,
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 2 and R 3 are the same or different and are selected from hydrogen, halogen, lower alkylamino, dilower alkylamino, amino, straight chain or branched, lower alkyl, lower alkoxy, lower alkylidene and lower arylidene,
  • lower alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino,
  • lower alkoxy, lower alkylidene and lower arylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 4 is hydrogen, strai.ght chai.n or branched alkyl or alkylidene,
  • alkyl or alkylidene having between 1 and 10 carbon atoms and being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl.
  • R 2 and R 3 being the same or different and representing H, Cl, CH 3 , OCH 3 or OH, R 4 is not methyl;
  • R 5 is a single bond between R 1 and R 6 , a straight chain or branched alkyl having between 1 and 10 carbon atoms or an alkylidene having between 2 and 20 carbon atoms, said alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy, said alkylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino, with the proviso that when R 1 is
  • R 2 and R 3 are independently selected from the same or different and representing hydrogen, halogen or alkyl having 1 to 3 carbon atoms, R 5 is not alkylidene having between 2 and
  • R 6 is carbon
  • R 2 and R 3 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, iodine, lower alkoxy and straight chain or branched lower alkyl;
  • R 4 is hydrogen
  • R 5 is a single bond between R 1 and R 6 , a straight chain or branched lower alkyl or a substituted or unsubstituted alkylidene having between 2 and 20 carbon atoms;
  • R 6 is carbcon
  • compositions having anticonvulsant activity in mammals comprising as an active ingredient an effective amount of a compound having the following formula
  • R 1 is or
  • a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 2 and R 3 are the same or different and are selected from hydrogen, halogen, straight chain or branched. substituted or unsubstituted lower alkyl, amino, nitro, lower alkoxy, lower alkylidene and lower arylidene; said lower alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino,
  • lower alkoxy, lower alkylidene and lower arylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 4 is aryl or a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N, hydrogen, straight chain or branched alkyl or alkylidene,
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl, wherein said aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • alkyl or alkylidene having between 1 and 10 carbon atoms and being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy,
  • R 2 and R 3 being the same or different and representing H, Cl, CH 3 , OCH 3 or OH, R 4 is not methyl;
  • R 5 is a single bond between R 1 and R 6 , a straight chain or branched alkyl having between 1 and 10 carbon atoms or an alkylidene having between 2 and 20 carbon atoms, said alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy, said alkylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino; and
  • R 6 is carbon
  • R 2 and R 3 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, iodine, lower alkoxy and straight chain or branched lower alkyl;
  • R 4 is hydrogen
  • R 5 is a single bond between R 1 and R 6 , a straight chain or branched lower alkyl having between 1 and 10 carbon atoms or an alkylidene having between 2 and 20 carbon atoms;
  • R 2 is carbcon
  • the present invention also relates to a method for the treatment or prevention of convulsions in mammals.
  • the method comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound having the following formula:
  • a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 2 and R 3 are the same or different and are selected from hydrogen, halogen, straight chain or branched, substituted or unsubstituted lower alkyl, amino, nitro, lower alkoxy, lower alkylidene and lower arylidene; said lower alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino,
  • lower alkoxy, lower alkylidene and lower arylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 4 is aryl or a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N, hydrogen, straight chain or branched alkyl or alkylidene,
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • alkyl or alkylidene having between 1 and 10 carbon atoms and being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy,
  • R 2 and R 3 being the same or different and representing H, Cl, CH 3 , OCH 3 or OH, R 4 is not methyl;
  • R 5 is a single bond between R 1 and R 6 , a straight chain or branched alkyl having between 1 and 10 carbon atoms or an alkylidene having between 2 and 20 carbon atoms, said alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl.
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy, said alkylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino; and
  • R is carbon
  • a commercial package for the treatment or prevention of convulsions in mammals comprising a pharmaceutical agent therapeutically effective for the treatment of convulsions in mammals, together with instructions to use this pharmaceutical agent in the treatment or prevention of convulsions.
  • the pharmaceutical agent used in the commercial package of the present invention is an effective amount of a compound of the following formula:
  • a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 2 and R 3 are the same or different and are selected from hydrogen, halogen, straight chain or branched, substituted or unsubstituted lower alkyl, amino, nitro, lower alkoxy, lower alkylidene and lower arylidene; said lower alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino,
  • lower alkoxy, lower alkylidene and lower arylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 4 is aryl or a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N, hydrogen, straight chain or branched alkyl or alkylidene,
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • alkyl or alkylidene having between 1 and 10 carbon atoms and being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy,
  • R 4 is not methyl;
  • R 4 is a single bond between R 1 and R 6 , a straight chain or branched alkyl having between 1 and 10 carbon atoms or an alkylidene having between 2 and 20 carbon atoms, said alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy, said alkylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino; and
  • R 6 is carbon
  • Figure 1 represents the numbering scheme of semicarbazones used in molecular modelling and X-ray studies.
  • Figure 2 represents the ORTEP diagram of compound 2b.
  • Figure 3 represents the ORTEP diagram of compound 2d.
  • the invention relates to a novel class of semicarbazone compounds useful as anticonvulsants.
  • a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 2 and R 3 are the same or different and are selected from hydrogen, halogen, straight chain or branched, substituted or unsubstituted lower alkyl, amino, nitro, lower alkoxy, lower alkylidene and lower arylidene; said lower alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino,
  • lower alkoxy, lower alkylidene and lower arylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • R 4 is aryl or a 5 to 7 member heterocycle having between 1 and 3 heteroatoms selected from the group consisting of O, S and N, hydrogen, straight chain or branched alkyl or alkylidene,
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • heterocycle being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy;
  • alkyl or alkylidene having between 1 and 10 carbon atoms and being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy,
  • R 2 and R 3 being the same or different and representing H, Cl, CH 3 , OCH 3 or OH, R 4 is not methyl;
  • R 5 is a single bond between R 1 and R 6 , a strai.ght chain or branched alkyl having between 1 and 10 carbon atoms or an alkylidene having between 2 and 20 carbon atoms, said alkyl being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino, lower alkoxy and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and lower alkoxy, said alkylidene being unsubstituted or substituted with at least one substituant selected from the group consisting of halogen, amino, lower alkylamino, dilower alkylamino and aryl,
  • aryl is unsubstituted or substituted with at least one substituant selected from the group consisting of hydrogen, halogen, straight chain or branched lower alkyl, lower alkoxy, amino, lower alkylamino and dilower alkylamino; and
  • R 6 is carbon
  • R 2 and R 3 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, iodine, lower alkoxy and straight chain or branched lower alkyl;
  • R 4 is hydrogen
  • R 5 is a single bond between R 1 and R 6 , a straight chain or branched lower alkyl having between 1 and 10 carbon atoms or an alkylidene having between 2 and 20 carbon atoms;
  • R 6 is carbon
  • the compounds of the present invention can be prepared by condensation of the appropriate aryl aldehyde, aryl alkyl ketone or aralkyl aldehyde or ketone with semi-carbazide in a suitable solvent.
  • the product of the reaction is collected, recrystallized from appropriate solvents and identified by elemental analysis and NMR spectroscopy. After syntheses, the compounds are assayed for anticonvulsant properties.
  • the anticonvulsant properties of the compounds of the present invention have been measured by evaluating their ability to prevent the spread of seizures and/or increase the minimal seizure threshold.
  • the procedures used to perform initial testing of candidate anticonvulsants are well-established procedures. Essentially, the testing was three-fold. It included the maximal electroshock seizure test (MES), the subcutaneous pentylenetetrazol test (scPTZ) as well as a toxicity screen used to detect minimal neurological deficit.
  • MES maximal electroshock seizure test
  • scPTZ subcutaneous pentylenetetrazol test
  • Another important property of at least one of the preferred compounds of the present invention is their potential of maintained efficiency as anticonvulsants even when administered orally. This is important in the development of efficient and practical medication that, in the case of epilepsy for example, has to be taken daily by patients suffering from this ailment. In comparison, a wide variety of thiosemicarbazones and related compounds afford no protection against seizures induced in the scPTZ screen when given orally to rats.
  • the compounds of the present invention appear to be stable in vivo.
  • a stability study whereby the compounds were incubated at 37°C in deuterated dimethylsulfoxide, revealed that, at the time of peak effects of oral dosage in rats, no decomposition occurred. This is important and provides an advantage over most existing anticonvulsants compounds that tend to decompose relatively quickly after having been administered to mammals.
  • the activity of the semicarbazone anticonvulsants of the present invention is dependent on both pharmacokinetic and pharmacodynamic considerations.
  • First the molecule must reach the receptor microenvironment (significance of log P); next, it must interact with its receptor.
  • the receptor may have a lipophilic pocket and a hydrogen bonding surface to interact with the lipophilic and hydrogen bonding moieties of the semicarbazone, respectively.
  • the separation and orientation of the lipophilic pocket and hydrogen bonding surface can both influence activity.
  • the semicarbazones disclosed and claimed in the present application have significant activity in protecting convulsions in the MES screen when administered orally to rats. High protection indices were found in the majority of compounds tested. In fact, no neurotoxicity was displayed at the maximum doses administered in many compounds.
  • the presence of a large hydrophobic group (aryl ring) near four electron donor atoms (in the semicarbazo group) fulfills the structural requirements for activity in the MES screen which may account for the selective protection in this test in contrast to the scPTZ screen when the compounds were given orally.
  • these semicarbazones are rapidly acting compounds and the most common mechanism of action is by interaction with chloride channels.
  • the fragments of the semicarbazone molecules associated with oral activity in rats in the MES screen were obtained using empirical and semi- empirical conformational calculations which also suggest that the lipophilicity of the molecules was an important feature.
  • compositions comprising at least one of the semicarbazones described above, information is provided on appropriate formulation and dosage requirements.
  • any suitable carrier known in the art can be used.
  • the choice of the carrier, which should be a non-toxic carrier, is within the knowledge of the person skilled in the art.
  • the carrier may be a solid, a liquid or mixture of a solid and a liquid.
  • Solid form compositions include powders, tablets and capsules. If a liquid composition is prepared, a suspension of an aqueous material is necessary, due to the lack of aqueous solubility of the semicarbazones used as one of the pharmaceutical agents of the composition.
  • the choice of the aqueous material is within the realm of the skilled artisan.
  • the pharmaceutical composition is preferably provided in unit dosage form.
  • the composition is subdivided in unit doses containing appropriate quantities of the pharmaceutical agent.
  • the quantity of pharmaceutical agent in a unit dose of composition can be varied or adjusted according to the particular need of the patient and the anticonvulsant activity of the particular compound used.
  • the compositions of the present invention are to be administered orally 4 times daily and have a pharmaceutical agent concentration ranging from 10 to 25 mg/kg.
  • H NMR spectra of 10mM solutions of 2a- h, 3a-d in deuterated dimethylsulfoxide at 37°C were also obtained. Acquisition of the spectra was obtained with 16K TD and 16K SI and the resolution was 0.513 Hz/Pt. The pulse angle was about 30° giving 1.95 sec acquisition and the relaxation delay was 2 sec. The total number of scans were 128. Chemical shifts were reported in ppm using tetramethylsilane as the internal standard.
  • the absorption of the methine protons were as follows: 2a : 7.84; 2b:: 8.24; 2c: 7.89; 2d: 7.82; 2e: 8.25; 2f: 8.18; 2g: 8.09 and 2h: 7.80.
  • Phase I screening consisted of administering doses of 30, 100 and 300 mg/kg of the compounds in series 1-4 to mice by the intraperitoneal route and at the end of 0.5 and 4 hours evaluating whether protection in the MES and scPTZ screens occurred and also whether neurotoxicity was demonstrated.
  • Compounds 1a-d. 2a,c,d,h, 3a-f, 4a-c were active in the MES screen while compounds 1a-c, 2a,c,d, 3a,c,e, 4c afforded protection in the scPTZ test.
  • the semicarbazones 2-4 displayed anticonvulsant activity and toxicity in 72 and 61% of the compounds respectively; however in contrast to the thiosemicarbazones, no other neurotoxic symptoms were noted except in the cases of 4a, b. In general therefore, anticonvulsant activity is retained in the semicarbazones while toxicity is diminished relative to the related thiosemicarbazones.
  • the Phase II screening is carried out by first injecting compounds by the intraperitoneal route into mice.
  • the first experiment is to determine the time of peak effect for both the neurotoxicity and MES screens. After this has been accomplished, four to five doses are administered to eight mice to obtain the TD 50 and ED 50 values.
  • the scPTZ screen is undertaken at the time of peak effect found in the MES screen.
  • mice were given to mice at a dose of 100 mg/kg by both the intraperitoneal and oral routes. No protection in the MES screen was observed by these two compounds except that half of the mice were protected when 2f was given intraperitoneally.
  • the ED 50 values for compounds 2a, 2b and 4c in the MES test were 40.27, 57.74 and 77.85 mg/kg respectively and 54.86, 68.67 and 147.22 mg/kg in the scPTZ screen.
  • the TD 50 figures for 2a, 2d and 4c were 87.67, 252.66 and 377.18 mg/kg respectively.
  • the times of peak effect were initially determined by oral dosage of various quantities of the compounds into 4 to 8 rats and examining them at one or more of the following time periods, namely 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. Quantification of the response was achieved at the times of peak effect using a minimum of 4 doses and 4 to 8 animals per dose were employed.
  • TPE time of peak effect
  • Table II reveals that in series 1 , 1a-c have the same potency and are clearly superior to id while the thiosemicarbazone derived from an aryl aldehyde namely 1a had the highest P.I.
  • Series 2 comprising a number of semicarbazones of various aryl aldehydes revealed that high potency was retained in this group of compounds and in general, protection indices comparable to or greater than 1a were obtained.
  • Compounds 2c.d.h were equipotent with .la while 2j had a considerably higher P.I. than 1a but in the case of these four semicarbazones, no neurotoxicity was noted at a dose of 500 mg/kg.
  • alkyl groups attached to the azomethine group are disadvantageous.
  • the most promising lead compound in series 3 is 3e with a P.I. of greater than 15.
  • intraperitoneal injection of 1c, 3a and 4c to rats produced neurotoxicity at lower doses than when the compounds were given orally and the ED 5 value in the MES screen of 1c was reduced.
  • a dose of 100 mg/kg of 2e given intraperitoneally into rats gave protection in half of the animals in the MES screen.
  • the ED 50 values (95% C.I.) of phenobarbital, phenytoin and ethosuximide in the MES test when administered by the intraperitoneal route to mice are as follows: 21.8(15.0-25.5), 9.50(8.13-10.4) and > 1000 mg/kg respectively.
  • the figures in the scPTZ screen are 13.2(5.87-15.9), inactive and 130(111-150) mg/kg respectively.
  • the figures for these three drugs are 69.0(62.8-72.9), 65.5(52.5- 72.1) and 441(383-485) mg/kg respectively.
  • the ED 50 values for phenobarbital and mephenytoin in the MES screen are 9.1(7.58-11.86) and 18.1(14.07-24.91) mg/kg respectively and the TD 50 figures for these two compounds are 61.1(43.72-95.85) and 85.7(69.88-93.70) mg/kg respectively.
  • the 95% confidence intervals for a number of derivatives mentioned in the text are as follows namely compound (route of administration and animals), screen, ED 50 or TD 50 values (mg/kg); 1c (intraperitoneal injections to mice): MES, 7.46(4.14-13.58); TD 50 , 20.45(11.57-33.41); 2a (oral administration to mice): MES, 40.27(31.04-53.08); SCPTZ, 54.86(39.50-87.10); TD 50 , 87.67(72.00-101.92); 2d (oral administration to mice): MES, 57.74(52.16-65.79); scPTZ, 68.67(54.61-94.96); TD 50 , 252.66(95% C.I.
  • adenosine is thought to be involved in the central actions of benzodiazepines, a number of compounds binding at the benzodiazepine receptor inhibit the uptake of adenosine into synaptosomes.
  • the compounds in methylcellulose solution were administered by the intraperitoneal route to mice using ten animals per dose (nine animals for the 135 mg/kg dose of 2d). After 0.25 h, a solution of 0.5% pentylenetetrazol in heparinized 0.9% sodium chloride solution was infused into the tail veins of mice and the times of the first appearance of both the focal seizure and also clonic seizure were recorded. These times were compared to values obtained using ten control animals (nine in the case of 2d).
  • the times of the first focal seizures were as follows: 2a: 50 , 33.9 , 0.10; 100 , 38.4 , 0. 0004 ; 2 d: 75 , 37.4 , 0.04 ; 135 , 42.6 , 0. 002 ; 3b: 50 , 38. 1 , 0. 003 ; 100 , 37.7 , 0. 03 ; 3e : 50,33.1,0.33;100, 35.8, 0.02.
  • the times of the clonic seizures were as follows: 2a: 50,47.3,0.008;100,53.5,0.0002; 2d: 75 , 62.4 , 0.004 ; 135 , 60.5 , 0.001; 3b: 50, 46.8 , 0.008 ; 100, 50.5 , 0. 002 ; 3e: 50,40.5,0.26;100,45.7,0.005.
  • the semicarbazones 2a,d, 3b, e increased the times prior to the first focal seizures and also chronic convulsions induced by the intravenous administration of pentylenetrazol.
  • Certain anticonvulsants have proconvulsant properties.
  • pentylenetetrazol was infused into the tail veins of mice and the time taken for the appearances of the first local seizures and also clonic seizures were recorded. The experiment was repeated using varying concentrations of 2a,d, 3b, e and in each case the times prior to seizures occurring were increased and hence they appear to be bereft of proconvulsant properties.
  • the protection afforded by 2d at doses of 5, 10, 20, 40 and 80 mg/kg was 1/5, 2/6, 3/10, 4/6 and 6/10 animals and an ED 50 was unable to be calculated.
  • the experiment was repeated using a concentration of 3.0 ⁇ g/5 ⁇ l of N-methyl-D-aspartate and protection against forelimb tonic extensions in mice by 2a,d, 3e expressed as ED 50 values (95% C.I., slope, SE) was as follows: 2a: 28.62 mg/kg (17.92- 44.68,2.20,0.51); 2d: 12.9 mg/kg (8.6-18.4,4.65,1.36); 3e: 59.67 (30.5-172.08), 1.38, 0.42.
  • the ED 50 values (95% C.I.) of phenobarbitone, phenytoin and ethosuximide in protecting against clonic seizures in this test are 2.75(0.17-4.90), 8.59(6.64-14.10) and 408.09(341.68-487.96) mg/kg respectively.
  • the same drugs have ED 50 values in protecting against forelimb tonic extension of 3.09 (1.44-4.67), 0.60 (0.34-0.95) and 82.58(30.94-131.87) mg/kg respectively.
  • Table III indicates that a site of action of 2a
  • 3e, 4a is GABA receptors while six of the ten compounds acted on chloride channels. No significant protection was noted by any of the compounds listed in Table III against seizures induced by strychnine. Thus the most common site of action of the anticonvulsant semicarbazones appears to be chloride channels.
  • ED S0 values for mephenytoin, valproic acid and phenobarbital in the bicuculline test are 124.1, 360.0 and 37.7 mg/kg respectively and in the sc picrotoxin screen the figures are 101.0, 387.2 and 27.5 mg/kg respectively.
  • anticonvulsant potency was significantly correlated with f and r values (p ⁇ 0.05) as well as the g constants (p ⁇ 0.10) but not with the MR figures (p>0.10).
  • the following calculational strategy was used. First, for each analog, fifty different starting conformations were fully optimized using the Dreiding force field and a first derivative minimization procedure. These analogs were selected by varying dihedral angles. Next, the ten lowest energy conformations from the Dreiding calculations were optimized using the MM2(85) force field and a second- derivative Newton-Raphson minimization procedure. The lowest energy conformer from the MM2 calculations was then mimized using the AMI semi-empirical molecular orbital Hamiltonian. The AMI optimized conformation and geometries were used for the structure-activity relationship studies.
  • each analog was described by four series of descriptors: (i) geometric descriptors to represent three-dimensional properties and to reflect aspects of molecular size and shape (e.g. bond lengths, torsional angles, interatomic distances, substituent volumes); (ii) electronic descriptors to represent variable electron distribution throughout the molecular framework (e.g. atomic charge densities, molecular dipole); (iii) topological descriptors encoding aspects of molecular composition and connectivity (e.g. Randic Indices, Keir-Hall Indices); and (iv) physicochemical descriptors describing molecular lipophilicity (e.g. log P).
  • topological descriptors were divided into two groups: graph theory descriptors and ad hoc.
  • the graph theory topological descriptors were determined from graph theory calculations.
  • the physicochemical descriptor was calculated using the approach of Ghose and Crippen. Descriptors are listed in Table IV.
  • Each compound was described by thirty-nine descriptors. Regression and discriminant statistical analyses were performed to establish a relationship between the molecular descriptors and biological activity and to ascertain the minimal number of descriptors for identifying optimal bioactivity.
  • the semicarbazone anticonvulsants of the present invention may be considered as bifunctional molecules, possessing a lipophilic moiety (substituted phenyl ring) and a hydrogen bonding moiety (the semicarbazono portion, N1-N2-C8 (O)-N3).
  • Figure 1 indicates the numbering of these molecules. All analogues from series 2 , 3 and 4 were studied. Each analogue was described by 39 descriptors which are listed in Table IV.

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Abstract

Une certaine quantité de semicarbabazone aryle a été préparée comme possibles agents anticonvulsifs. Lorsqu'ils ont été administrés oralement à des rats, une activité significative a été remarquée sur l'écran d'électrochoc maximal (MES) et comme la neurotoxicité était soit absente soit réduite (en comparaison aux injections intrapéritonéales chez les souris), des indices de protection élevés ont été trouvés dans la majorité des composés. Les semicarbazones on montré peu ou pas d'activité sur l'écran pentylène tétrazol sous-cutané. Ces observations confirment la théorie selon laquelle les composés d'un groupe hydrophobe important (dans ce cas la chaîne aryle) sont nécessaires pour la protection dans l'écran MES. En général, les semicarbazones ont un début d'action rapide et le mécanisme de fonctionnement le plus commun est l'interaction avec les canaux de chlorure. Des calculs de conformité empiriques et semi-empiriques ont indiqué que certains fragments moléculaires et l'hydrophobicité de ces molécules affectent l'activité biologique.
PCT/CA1993/000386 1992-09-21 1993-09-21 Anticonvulsifs a base de semicarbazone aryle WO1994006758A1 (fr)

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WO1996040628A1 (fr) * 1995-06-07 1996-12-19 The University Of Saskatchewan Semicarbazones ayant une activite sur le systeme nerveux central et compositions pharmaceutiques les contenant
US5608109A (en) * 1993-12-08 1997-03-04 Nihon Nohyaku Co., Ltd. Insecticidal hydrazine derivatives
EP0986540A1 (fr) * 1997-04-22 2000-03-22 Cocensys, Inc. Semicarbazones et thiosemicarbazones carbocycliques et heterocycliques substitues et leur utilisation
EP1568690A1 (fr) * 1997-04-22 2005-08-31 Euro-Celtique S.A. Semicarbazones et thiosemicarbazones carbocycliques et heterocycliques substitues utiles comme agents bloquants du canal sodique
CN103880711A (zh) * 2014-03-06 2014-06-25 陕西科技大学 一种制备醛缩氨基脲Schiff碱的方法

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5608109A (en) * 1993-12-08 1997-03-04 Nihon Nohyaku Co., Ltd. Insecticidal hydrazine derivatives
WO1996040628A1 (fr) * 1995-06-07 1996-12-19 The University Of Saskatchewan Semicarbazones ayant une activite sur le systeme nerveux central et compositions pharmaceutiques les contenant
US5741818A (en) * 1995-06-07 1998-04-21 University Of Saskatchewan Semicarbazones having CNS activity and pharmaceutical preparations containing same
CN1062263C (zh) * 1995-06-07 2001-02-21 萨斯喀彻温大学 具有中枢神经系统活性的缩氨基脲及含有它们的药物制剂
USRE38425E1 (en) 1995-06-07 2004-02-10 University Of Saskatchewan Technologies, Inc. Semicarbazones having CNS activity and pharmaceutical preparations containing same
EP0986540A1 (fr) * 1997-04-22 2000-03-22 Cocensys, Inc. Semicarbazones et thiosemicarbazones carbocycliques et heterocycliques substitues et leur utilisation
EP0986540A4 (fr) * 1997-04-22 2001-07-11 Cocensys Inc Semicarbazones et thiosemicarbazones carbocycliques et heterocycliques substitues et leur utilisation
US6613803B1 (en) 1997-04-22 2003-09-02 Euro-Celtique S.A. Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
US6638947B2 (en) 1997-04-22 2003-10-28 Euro-Celtique S.A. Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
US6696442B2 (en) 1997-04-22 2004-02-24 Euro-Celtique S.A. Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
EP1568690A1 (fr) * 1997-04-22 2005-08-31 Euro-Celtique S.A. Semicarbazones et thiosemicarbazones carbocycliques et heterocycliques substitues utiles comme agents bloquants du canal sodique
CN103880711A (zh) * 2014-03-06 2014-06-25 陕西科技大学 一种制备醛缩氨基脲Schiff碱的方法

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