Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
  • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • 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
  • C07D211/72—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 hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• GABA gamma-aminobutyric acid
• CNS central nervous system
• muscimol of the formula (a substance found in fly amanita (Amanita muscaria)) has various interesting pharmacological properties and especially shows an inhibition of motoric functions. Later, it was reported that muscimol is a very potent GABA agonist with respect to bicuculline--sensitive postsynaptic receptors (Johnston et al., Biochem. Pharmacol.
• agents influencing the GABA system are therefore under consideration and research for the therapeutical treatment of such GABA system malfunction-related diseases. It is also under consideration to administer agents influencing the GABA system against diseases in which malfunctions of the pituitary hormones are involved, e.g. diseases where a decreased secretion of prolactin is involved, and it is, furthermore, contemplated that such agents may be useful against artereoschlerotic diseases in the brain where a vasodilatation is desired.
• muscimol has toxic effects, such as narcotic effects (derealisation and depersonalisation), and the difference between the effective dose and the toxic dose of muscimol is very small (Arzneiffenaba, 1968, 18, 311 - 315), which may limit or prevent the therapeutic use of muscimol.
• various muscimol-analogues or muscimol-like substances have been synthesized and tested (P.
• the present invention relates to novel compounds showing GABA--related activity, to salts thereof with acids or bases, and to pharmaceutical compositions containing the novel compounds or a salt thereof as an active ingredient. Moreover, the present invention relates to methods for the preparation of the novel compounds and salts thereof and to a method for the treatment of neurological and psychiatrical disorders, such as epilepsy, parkinsonism, schizophrenia and Huntington's chorea, or diseases in which malfunctions of the pituitary hormones are involved, or artereoschlerotic diseases in the brain where a vasodilatation is desired, by administering a therapeutically active amount of the novel compound or a non-toxic salt thereof to a living animal body including human beings.
• neurological and psychiatrical disorders such as epilepsy, parkinsonism, schizophrenia and Huntington's chorea, or diseases in which malfunctions of the pituitary hormones are involved, or artereoschlerotic diseases in the brain where a vasodilatation is desired, by administer
• the novel compound of the formula Ia (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol) is well tolerated and is a very potent GABA agonist having a very specific activity, being inactive as a GABA-uptake inhibitor. Particulars concerning the activity of this compound are given in the section "Test Results” below.
• the potent, specific GABA agonist activity of the compound Ia is especially remarkable on the background of the fact that the known very closely related compounds, that is, 5,6,7,8-tetrahydro-4H-isoxazolo-[4,5-c]-azepine-3-ol (P. Krogsgaard-Larsen, Acta Chem. Scand. B 31, 1977, 584 - 588, and P. Krogsgaard-Larsen and G.A.R. Johnston, J. Neurochem., 1978, 30, 1377 - 1382). 5,6,7,8-tetrahydro-4H-isoxazolo-[5,4-c]-azepine-3-ol (P.
• the present invention is not to be limited by any theory, it is believed that the remarkable selective activity of the compound Ia is ascribable to the particular position of the nitrogen atom in the 6-membered ring in relation to the acidic hydroxy group in the 5-membered ring.
• the present invention therefore relates to the novel compound Ia and to derivatives thereof which upon administration will be decomposed in situ to yield the parent compound Ia, in particular compounds of the general formula I wherein R" is hydrogen, acetyl or a group of the general formula VII wherein R 5 is C 1-8 alkyl; phenyl; phenyl substituted in the 4- position with halogen, lower alkoxy, or lower alkyl; or phenylalkyl such as benzyl or phenylethyl in which the phenyl group may be substituted in the 4-position with halogen, lower alkoxy, or lower alkyl; and salts thereof.
• R" is hydrogen, acetyl or a group of the general formula VII wherein R 5 is C 1-8 alkyl; phenyl; phenyl substituted in the 4- position with halogen, lower alkoxy, or lower alkyl; or phenylalkyl such as benzyl or phenylethyl in which
• the compounds I the only species showing pronounced GABA agonist activity in the brain is the compound Ia.
• the groups R" which are different from hydrogen may enhance the penetration of the compounds into the brain in that they may enhance the ability of the compounds to pass the blood- brain barrier, and will thereafter be split off in situ to yield the parent compound.
• a prolonged effect of Ia may be obtained via decomposition in situ of compounds wherein R" is different from hydrogen, to yield the parent compound.
• lower alkyl and “lower alkoxy” designate such groups containing 1 - 4 carbon atoms.
• the compounds of the general formula I may exist in a tautomeric form, as shown by the formula I' and in the present specification and claims, the formula I is to be understood as covering also this tautomeric form and mixtures of the two tautomeric forms.
• salts of the compound of the formula Ia are acid addition salts thereof, such as pharmaceutically acceptable salts with inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, or with organic acids, such as organic carboxylic acids, e.g. acetic, propionic, glycolic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, glucuronic, benzoic, pamoic acid and the like, or organic sulfonic acids, e.g.
• salts may be prepared by procedures known per se, e.g. by adding the acid in question to the base, preferably in a solvent.
• Compounds of formula I may form pharmaceutically acceptable salts with bases, such as metal salts, e.g. sodium, potassium, calcium or aluminium salts, and ammonium and substituted ammonium salts, e.g. salts of amines such as triethylamine, triethanolamine, ethylpiperidine, procaine, dibenzylamine and the like.
• the compound Ia was tested in microelectrophoretic experiments. Experiments were performed on lumbar dorsal horn interneurones and Renshaw cells of cats anaesthetized with pentobarbitone sodium. The approximate potency of the depressant actions of the compound was assessed relative to that of GABA on the basis of electrophoretic currents required to produce equal and submaximal inhibitions of the firin of the central neurones. The inhibitory action of Ia on central neurones was antagonized by the specific GABA antagonist bicu- culline methochloride (BMC).
• BMC bicu- culline methochloride
• the compound Ia did not interact with the GABA uptake system at concentrations of 5 x 10 4 M, and it did not interact with the GABA metabolizing enzymes GABA:2-oxo-glutarate aminotransferase and L-glutamate 1-carboxylase at concentrations of 10 -3 M.
• the compound Ia is a specific and very potent GABA agonist.
• compound Ia is considerably less toxic than muscimol.
• Ia was shown to be weaker than muscimol.
• I a was found to be weaker than muscimol.
• test compound is injected i.p. in the doses 0, 1/2, 1/8 and 1/32 of the determined “i.v. LD 50 ".
• doses 0, 1/4, 1/16 and 1/64 of the determined "i.p. LD 50 " are used.
• mice are used for each dose level.
• isoniazide 300 mg/kg is injected s.c. This dose of isoniazide induces intermittent tonic clonic seizures within 60 minutes.
• compound Ia has been shown to be a potent GABA agonist.
• Compound Ia is weaker than muscimol but considerably less toxic.
• the compounds of formula I may be prepared by
• Compound IVa in reaction scheme I is a key intermediate in the above synthesis and in other syntheses of the compounds of the present invention. Similar key intermediates may contain other hydrolysable N-protecting groups and other lower alkyl groups, and hence, in its broad concept, this novel key intermediate of the present invention has the general formula IV in which Alk is a lower alkyl group and Z is hydrogen or an amino--protecting group readily removable, e.g. by hydrolysis, suitably a group R" (as defined above) or a trityl or formyl group.
• Z are the following: hydrogen, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, tert.butyloxycarbonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, trityl, formyl, acetyl.
• novel intermediates according to the present invention are the compounds of the formulae VIIIa and IXa in reaction scheme I, and also the generic classes which they represent, which is, compounds of the general formula VIII' in which Z is as defined above, T is a group convertible, by hydrolysis, into an oxy group, e.g., an acetal group such as ethylene dioxy, and Q is a leaving group which, on reaction with hydroxylamine, forms a hydroxamic acid group, examples of Q being halogen, especially chlorine and bromine, hydroxy, the residue of an acid, the residue of an activated amide, the residue of an activated ester, lower alkoxy, and the like, and compounds of the general formula IX' in which Z and T are as defined above, and also, at the stage of compound Va (which is both a compound of the general formula I and an intermediate for the preparation of compounds of the general formula I), an intermediate may be used which in generalized form has the formula V above.
• T is a group convertible, by hydrolysis, into an oxy group,
• An interesting aspect of the present invention is the compound Ia as intermediate in the preparation of compounds of formula I in which R" is different from hydrogen.
• the present invention also relates to the total sequence of synthesis stages IV ⁇ VIII' ⁇ IX' ⁇ V ⁇ I and to the final stages thereof, i.e., VIII' ⁇ IX' ⁇ V ⁇ I and IX' ⁇ V ⁇ I.
• the conversion of ethyl l-benzyl-3-oxy-piperidine-4-carboxylate into the intermediate IV as exemplified by IVa is usually performed in lower alkanols, e.g. ethanol or ethanol/water.
• the removal of the N-benzyl group may be effected with gaseous hydrogen in the presence of a hydrogenation catalyst, e.g. platinum, palladium or Raney nickel.
• the alkyl 3-oxy-piperidine-4-carboxylate formed is dissolved, e.g. in water, and treated with an acid acceptor, e.g. alkali carbonate, and an ester of chloroformic acid, e.g. methyl chloroformate.
• the temperature is kept near 0°C during the reaction.
• the compound IV is isolated by extraction into an organic solvent followed by evaporation of the solvent.
• the formation of the compound of formula VIII' as exemplified by the ethylene acetal VIIIa is usually performed in a solvent, e.g. benzene, which forms an azeotropic mixture with water.
• a solvent e.g. benzene
• the reaction is preferably carried out at reflux temperature and with a strong acid, e.g. a sulfonic acid as catalyst.
• the hydroxamic acid IX' as exemplified by IXa is synthesized by reacting VIIIa with hydroxylamine, preferably in water or a lower alcohol, e.g. methanol and usually at a temperature between -20°C and room temperature, preferably at 0 - 10°C.
• the compound may be isolated and purified by a manner known per se, e.g. column chromatography.
• Q in formula VIII' is a halogen or the residue of an acid
• the reaction is effected in the presence of a base.
• a condensing agent e.g. dicyclohexyl carbodiimide or carbonyldiimidazole.
• solvent an iner
• the hydrolysis of the acetal group of IXa or, quite generally, the conversion of T in compounds of formula IX' into an oxo group, followed by cyclization to a compound of formula V as exemplified by Va may be effected by an aqueous solution of a strong acid optionally also containing acetic acid, e.g. concentrated hydrochloric acid or 70% perchloric acid at a temperature between 0°C and 100°C, preferably at 50 - 80°C.
• the compound V may be isolated by extraction with an organic solvent or by evaporation of the water.
• the compound can be purified by column chromatography or by crystallization.
• Removal of the protecting group Z and/or W in compound V may be effected with a strong inorganic acid, e.g. hydrochloric or hydrobromic acid, in a solvent, e.g. glacial acetic acid or water, or a mixture of water and glacial acetic acid.
• a strong inorganic acid e.g. hydrochloric or hydrobromic acid
• the temperature may be kept between room temperature and the boiling point of the solvent.
• the reaction time is usually short, e.g. less than 1 hour.
• the Ia salt may be isolated by evaporation of the solvent.
• the Ia salt may be transformed into Ia by treatment with a base, e.g. a tertiary amine, in a solvent, usually a mixture of water and a lower alkanol.
• Compound Ia may be transformed into another salt as described above.
• reaction of a compound of the general formula IV as exemplified by IVa with hydroxylamine may give a mixture of a compound of the general formula V and the corresponding isomeric compound V as exemplified by Va and VIa.
• the reaction may be effected at a temperature between -30°C and 50°C, preferably between -30 and -lO o C.
• the solvent is usually water or a lower alkanol or mixtures thereof.
• reaction scheme II although yielding a mixture of two isomers, is nevertheless advantageous. It is very time-saving in that it avoids the protection of the oxo group in compounds of the general formula IV and the subsequent hydroxamic acid formation.
• the compounds formed in the reaction of IV with hydroxylamine, as exemplified by Va and VIa, are easily separated by manners known per se, e.g. by column chromatography.
• the introduction of the group R" may be performed by manners known per se.
• R" is a group of the above formula VII
• the introduction may be performed by treatment of compound Ia with the appropriate. formic acid ester of the general formula X'- -OR 5 wherein X' is a leaving group, especially halogen, azido, etc., in the presence of an acid acceptor, for example an alkali carbonate.
• an acid acceptor for example an alkali carbonate.
• the BOC-derivative can be made by means of tert.butyl azidoformate.
• R" is acetyl
• a reactive derivative of acetic acid e.g. acetyl chloride or acetanhydride may be used for the introduction of the group R".
• the compounds of the formula I, and salts thereof may be formulated for administration in any convenient way by analogy with other pharmaceuticals.
• compositions comprising the compounds of the invention may be in the form of pharmaceutical preparations, e.g. in solid, semisolid or liquid form, which contain the active compound of the invention in admixture with a pharmaceutical organic or inorganic carrier or excipient suitable for enteral or parenteral application.
• the active ingredient may, e.g., be formulated with the usual carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, aqueous suspensions and other suitable administration forms.
• Examples of carriers are glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and other carriers suitable for use in manufacturing compositions in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, colouring, flavouring, and preservative agents can be contained in the composition of this invention.
• the active compound is included in the compositions of the invention in an amount sufficient to produce the desired therapeutical effect upon administration.
• the dosage or therapeutically effective quantity of the compound varies and also depends upon the age and condition of each individual patient being treated.
• a preferred tablet or capsule formulation for oral administration contains 0.1 - 200 mg, preferably 1 - 100, especially 5 - 50, mg of a compound of the formula I or a salt thereof per unit dosage which may be administeret 1 - 4 times per day or as a sustained release composition.
• Injection preparations preferably contain 0.1 - 200 mg, preferably 1 - 100, especially 5 - 50, mg of a compound of the formula I or a salt thereof per unit dosage.
• a preferred injected dose is about 0.5 to 2 ml.
• the invention also relates to the use of the compounds of the general formula I and salts thereof in medicaments for treating GABA system malfunction-related diseases, and a process of treating GABA system malfunction-related diseases in human beings by administering, to the human being, an effective dose of a compound of the general formula I, or a salt thereof.
• compositions and the above-mentioned uses it may be suitable or preferred to combine the compounds of the general formula I or a salt thereof with minor tranquillizers such as benzodiazepines or neuroleptics, for example butyrophenones such as haloperidol, phenothiazines such as chloropromazine, thioxanthene, and the like.
• minor tranquillizers such as benzodiazepines or neuroleptics, for example butyrophenones such as haloperidol, phenothiazines such as chloropromazine, thioxanthene, and the like.
• the neuroleptics are suitably administered in their effective amounts or, in a preferred embodiment in lower amounts than the amounts in which they would be effective when used alone.
• IXa (1.9 g; 29%) as a crystalline and TLC-pure substance [R F : 0.23; eluent: ethyl acetate-methanol-formic acid (90:9:1)].
• An analytical sample was recrystallized (ethanol-benzene) to give IXa as colourless crystals, m.p. 150.0--152.0°C.

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