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WO1997038978A1 - (10,11-dihydro)10-oxy-5h-dibenz(b,f)azepine-5-carboxamides anticonvulsivants - Google Patents

(10,11-dihydro)10-oxy-5h-dibenz(b,f)azepine-5-carboxamides anticonvulsivants Download PDF

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Publication number
WO1997038978A1
WO1997038978A1 PCT/EP1997/001742 EP9701742W WO9738978A1 WO 1997038978 A1 WO1997038978 A1 WO 1997038978A1 EP 9701742 W EP9701742 W EP 9701742W WO 9738978 A1 WO9738978 A1 WO 9738978A1
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WO
WIPO (PCT)
Prior art keywords
compounds
positions
linked
formula
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1997/001742
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English (en)
Inventor
Alberto Milanese
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Trifarma Srl
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Trifarma Srl
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Filing date
Publication date
Application filed by Trifarma Srl filed Critical Trifarma Srl
Priority to AU26942/97A priority Critical patent/AU2694297A/en
Publication of WO1997038978A1 publication Critical patent/WO1997038978A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines

Definitions

  • the present invention relates to compounds of formula ( I )
  • R is straight or branched c 2 ⁇ c 6 alk Y 1 ' c 3 -c 7 cycloalkyl, aryl, arylalkyl, with the proviso that, when the 10- and 11- positions are linked by a double bond, R is different from methyl, and, when the 10- and 11- positions are linked by a simple bond, R is different from methyl and ethyl.
  • the invention further relates to the use of the compounds of formula (I), as well as of the compounds (I) in which R is methyl or ethyl, a ⁇ therapeutical agents.
  • a C2 -c 6 alkyl group is preferably ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-hexyl;
  • a C 3 -C 6 cycloalkyl group is preferably cyclopropyl, cyclopentyl or cyclohexyl;
  • an aryl group is preferably phenyl, optionally substituted with c ⁇ c ⁇ a lko*Y groups, halogen atoms, cyano, nitro, C ⁇ -C ⁇ alkyl, C ⁇ -Cg haloalkoxy groups;
  • an aralkyl group is preferably benzyl, optionally substituted as indicated for the phenyl group.
  • Preferred compounds of formula (I), whan the 10- and 11- positions are linked by a single bond are par ⁇ ticularly those in which R is n-propyl, isopropyl, n-bu ⁇ tyl, isobutyl, t-butyl, n-hexyl, cyclohexyl or benzyl.
  • 5H-dibenz- [b,f]-azepine derivatives on the central nervous system has been knovm for a long time, in particular that of 5H-dibenz-[b,f]-azepine-5-carboxamide or CARBAMAZEPINE (IT) and of 10-oxo-10,ll-dihydro-5Hdibenz-[b,f]-azepine- 5-carboxamide or OXCARBAZEPINE (III).
  • oxcarbazepine (III) is a tautomer, in equilibrium between a keto form (III) and an enol one (III bis ).
  • the desired 10-alkoxy-iminostilbene (VI) is first prepared, according to the scheme:
  • the dihalo acetyliminostilbene (V), prepared according to what disclosed in Belgian Patent 597,796 and USA Re 27,622 is treated with an alkoxide R0 ⁇ excess (R having the same meanings as in formula (I)), in a ROH alcohol, optionally diluted con inert solvents such a ⁇ benzene, toluene, xylene, monoglyme, diglyme or analogues .
  • Alkoxy iminostilbene is recovered by concentration of the reaction mixture and dilution with water. After drying, this is reacted with isocyanic acid, prepared in situ from metal cyanates and acids, for example alkali or alkaline-earth cyanates and mineral acids such as sulfuric, hydrochloric or hydrobromic acids dry or in an acetic acid solution, or in acetic, formic, monochloroacetic, monobromoacetic, dichloroacetic, trichloroacetic, 2-chloropropionic acids, in solvents such as benzene, toluene, chlorobenzene, chloroform, di ⁇ chloromethane, 1,2-dichloroethane, 1,1,1-tricloroethane, trichloroethylene at temperatures from 20 ⁇ C to 60 ⁇ C, optionally in the presence of water traces (Scheme B).
  • isocyanic acid prepared in situ from metal cyanates and acids, for example alkali or alkaline-e
  • the resulting alkoxy carbamazepine (I) is recovered after washing the reaction mixture with water, concentrating the solvent and crystallizing from solvents such as benzene, toluene, cyclohexane, ethyl or isopropyl ether alone or in a mixture.
  • the compounds (I) having a single bond between the 10- and 11- positions are prepared starting from oxcarbazepine (III), by reduction of the keto group at the 10- position with sodium borohydride in solvents such as methanol, ethanol tetrahydrofuran, dimethyl ⁇ formamide or diglyme (possibly aqueous), without recovering the intermediate, and subsequent alkylation in the same reaction medium by means of R - X compounds wherein R has the above mentioned meanings and X is Cl, Br, I, OTs, OMs.
  • the crude 10-alkoxy-dihydrocarbamazepine is recovered by dilution with water, after neutralization of the sodium borohydride excess and concentration of the reaction solvent.
  • the product is crystallized from solvents such as alcohols (even aqueous), benzene, toluene, xylene, cyclohexane, petroleum ethers with various boiling points, ethers or mixtures thereof.
  • solvents such as alcohols (even aqueous), benzene, toluene, xylene, cyclohexane, petroleum ethers with various boiling points, ethers or mixtures thereof.
  • the reaction scheme is the following :
  • the compounds described above are useful in the analgesic, antidepressive and anticonvulsant therapies.
  • Bioavailability, tolerability and effectiveness are very good, better than those of other products used in therapy for the same purposes, such as carbamazepine and oxcarbazepine.
  • the dosages for humans can range from 1 to 1000 mg for the single administration, with doses repeated 1 to 3 times a day.
  • the administration can be carried out by the oral, rectal, intramuscular or transdermal routes, in formulations such as hard-gelatin capsules with a solid content, soft-gelatin capsules with a liquid content, optionally coated or gastric-coated tablets, sugar- coated pills, suppositories, vials for injectable solutions, plasters for a protracted transdermal absorption, mixing the active ingredient with suitable excipients according to known procedures of pharmaceutical technique.
  • formulations such as hard-gelatin capsules with a solid content, soft-gelatin capsules with a liquid content, optionally coated or gastric-coated tablets, sugar- coated pills, suppositories, vials for injectable solutions, plasters for a protracted transdermal absorption, mixing the active ingredient with suitable excipients according to known procedures of pharmaceutical technique.
  • N-acetyliminostilbene (23.52 g, 0.1 moles) is dissolved in 100 ml of chloroform. The mixture i ⁇ cooled at O'C to - 5"C. Bromine (15.98 g, 5.14 ml, 0.1 moles) is dropped without exceeding + 5"C, stirring between - 5 * C and + 5 * C overnight. Chloroform is distilled off under vacuum to dryness, the solid residue is taken up with absolute ethyl alcohol (200 ml); a solution of sodium ethoxide (100 g) in absolute ethanol (300 ml) is added carefully, heating slowly until reflux. A strong reaction takes place which i ⁇ controlled by cooling on a cold water bath.
  • example 1 The procedure of example 1 is followed, replacing sodium ethoxide with an equimolecular amount of sodium butoxide, prepared from n-butanol (500 ml) and 60% sodium hydride (60 g), added in portions to butanol diluted with toluene (200 ml), then refluxing until effervescence ceases.
  • Oxcarbazepine (III) (25.23 g, 0.1 moles) is dissolved partially in 70% aqueous tetrahydrofuran (500 ml), at room temperature.
  • sodium borohydride (1.1 g, 0.029 moles - 0.116 equivalents) is added in portions, stirring at r.t. until an analytic control evidences the disappearance of the starting oxcarbazepine.
  • n-Butyl-bromide (27.4 g, 21.52 ml, 0.2 moles) is added, refluxing for 4 h.
  • the solvent is distilled off to dryness under vacuum, taking up the residue with water (250 ml), pH i ⁇ adjusted at ⁇ 7, and the mixture is stirred strongly and filtered, washing thoroughly the solid with water, then recrystallizing from ethanol/water.
  • Example 4 10-ISOPROPOXY-DIHYDRO-CARBAMAZEPINE The procedure of example 1 is followed, but carrying out the reaction in diglyme (250 ml), and using an equimolar amount of isopropyl tosylate instead of n- butylbromide, at 50° - 60°C.
  • Bromides or iodides can indifferently be used, or the chlorides in the presence of catalytic amounts of sodium iodide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

On décrit des composés de la formule (I) dans laquelle R représente alkyle C1-C6 droit ou ramifié, cycloalkyle C3-C7, aryle ou arylalkyle éventuellement substitué par des groupes alcoxy C1-C3, des atomes d'halogène, cyano, nitro, des groupes alkyle C1-C3 ou haloalcoxy C1-C3. Ces composés sont utiles dans des thérapies analgésiques, antidépressives et anticonvulsivantes. Ces composés de la formule (I) sont nouveaux, à condition que, lorsque les positions 10- et 11- sont liées par une liaison double, R soit différent de méthyle, et que, lorsque les positions 10- et 11- sont liées par une liaison simple, R soit différent de méthyle et d'éthyle.
PCT/EP1997/001742 1996-04-12 1997-04-08 (10,11-dihydro)10-oxy-5h-dibenz(b,f)azepine-5-carboxamides anticonvulsivants Ceased WO1997038978A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26942/97A AU2694297A (en) 1996-04-12 1997-04-08 Anticonvulsant (10,11-dihydro) 10-oxy-5h-dibenz{b,f}azepine-5-carboxamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT96MI000709A IT1283594B1 (it) 1996-04-12 1996-04-12 Derivati della 5h-dibenz- (b,f)-azepin-5-carbossiammide, loro preparazione e uso come sostanze ad azione medicinale
ITMI96A000709 1996-04-12

Publications (1)

Publication Number Publication Date
WO1997038978A1 true WO1997038978A1 (fr) 1997-10-23

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Application Number Title Priority Date Filing Date
PCT/EP1997/001742 Ceased WO1997038978A1 (fr) 1996-04-12 1997-04-08 (10,11-dihydro)10-oxy-5h-dibenz(b,f)azepine-5-carboxamides anticonvulsivants

Country Status (3)

Country Link
AU (1) AU2694297A (fr)
IT (1) IT1283594B1 (fr)
WO (1) WO1997038978A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2377440B (en) * 2001-05-11 2003-07-16 Portela & Ca Sa Method for preparation of (s)-(+)-and(r)-(-)-10,11-dihydro-10-hydroxy-5h-di benz/b.f/azepine-5-carboxamide
WO2003106414A3 (fr) * 2002-06-14 2004-07-01 Taro Pharmaceuticals Usa Inc Procede d'elaboration de 5h-dibenz[b,f]azepine-5-carboxamide
US7112673B2 (en) 2000-02-07 2006-09-26 Novartis Ag Dibenzo [b,f]azepine intermediates
US7834177B2 (en) 2005-01-14 2010-11-16 Bial - Portela & Ca, S.A. Method for preparation of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide
US9763954B2 (en) 2007-01-15 2017-09-19 Bial—Portela & Ca, S.A. Therapeutical uses of eslicarbazepine
US10675287B2 (en) 2005-05-06 2020-06-09 Bial-Portela & Ca S.A. Methods of treatment of partial onset seizures using eslicarbazepine acetate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2128996A (en) * 1982-10-15 1984-05-10 Ciba Geigy Ag 5H-dibenz[b,f]azopine-5- carboxamides
DD218889A1 (de) * 1983-11-09 1985-02-20 Dresden Arzneimittel Verfahren zur herstellung neuer 5-carbamyl-10,11-dihydro-5h-dibenz (b,f) azepine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2128996A (en) * 1982-10-15 1984-05-10 Ciba Geigy Ag 5H-dibenz[b,f]azopine-5- carboxamides
DD218889A1 (de) * 1983-11-09 1985-02-20 Dresden Arzneimittel Verfahren zur herstellung neuer 5-carbamyl-10,11-dihydro-5h-dibenz (b,f) azepine

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7112673B2 (en) 2000-02-07 2006-09-26 Novartis Ag Dibenzo [b,f]azepine intermediates
CZ301572B6 (cs) * 2000-02-07 2010-04-21 Novartis Ag Zpusob prípravy dibenzo[b,f]azepinového derivátu
US7820813B2 (en) 2001-05-11 2010-10-26 Portela & C.A., S.A. Method for preparation of (S)-(+)- and (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide
GB2377440B (en) * 2001-05-11 2003-07-16 Portela & Ca Sa Method for preparation of (s)-(+)-and(r)-(-)-10,11-dihydro-10-hydroxy-5h-di benz/b.f/azepine-5-carboxamide
US7091339B2 (en) 2002-06-14 2006-08-15 Taro Pharmaceuticals Usa, Inc. Method of preparing a 5H-dibenz(b,f)azepine-5-carboxamide
WO2003106414A3 (fr) * 2002-06-14 2004-07-01 Taro Pharmaceuticals Usa Inc Procede d'elaboration de 5h-dibenz[b,f]azepine-5-carboxamide
US7723514B2 (en) 2002-06-14 2010-05-25 Taro Pharmaceuticals U.S.A., Inc. Method of preparing a 5H-dibenz(b,f)azepine-5-carboxamide
US7834177B2 (en) 2005-01-14 2010-11-16 Bial - Portela & Ca, S.A. Method for preparation of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide
US10675287B2 (en) 2005-05-06 2020-06-09 Bial-Portela & Ca S.A. Methods of treatment of partial onset seizures using eslicarbazepine acetate
US10695354B2 (en) 2005-05-06 2020-06-30 Bial-Portela & Ca S.A. Methods of treatment of partial onset seizures using eslicarbazepine acetate
US10702536B2 (en) 2005-05-06 2020-07-07 Bial-Portela & Ca S.A. Methods of treatment of partial onset seizures using eslicarbazepine acetate
US11364247B2 (en) 2005-05-06 2022-06-21 Bial-Portela & Ca S.A. Methods of treatment of partial onset seizures using eslicarbazepine acetate
US9763954B2 (en) 2007-01-15 2017-09-19 Bial—Portela & Ca, S.A. Therapeutical uses of eslicarbazepine

Also Published As

Publication number Publication date
IT1283594B1 (it) 1998-04-22
ITMI960709A0 (fr) 1996-04-12
ITMI960709A1 (it) 1997-10-12
AU2694297A (en) 1997-11-07

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