US3867536A - New diazepine derivatives for producing anticonvulsant effects - Google Patents

New diazepine derivatives for producing anticonvulsant effects Download PDF

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Publication number
US3867536A
US3867536A US239780A US23978072A US3867536A US 3867536 A US3867536 A US 3867536A US 239780 A US239780 A US 239780A US 23978072 A US23978072 A US 23978072A US 3867536 A US3867536 A US 3867536A
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Prior art keywords
benzodiazepine
chloro
triazolo
phenyl
diethylacetal
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US239780A
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English (en)
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Hans Allgeier
Andre Gagneux
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes

Definitions

  • the new diazepine derivatives correspond to the general formula I:
  • R represents a hydrogen atom of an alkyl group having from 1 to 3 carbon atoms, and either each of the symbols R represents an alkyl group having from 1 to 4 carbon atoms, or
  • R together represent a bivalent, saturated aliphatic hydrocarbon radical having from 2 to 5 carbon atoms, and wherein each of the rings A and B, independently of the other, may be substituted by one or more bromine, chlorine and/or fluorine atoms and/or trifluoromethyl groups, nitro groups, alkyl groups containing from 1 to 6 carbon atoms and/or alkoxy groups containing from 1 to 6 carbon atoms.
  • the invention also relates to the 5-oxides of the compounds of the general formula I, and to the addition salts of the compounds of the general formula I with inorganic and organic acids.
  • R is, e.g. the methyl, ethyl or propyl group.
  • R as an alkyl group is, e.g. the propyl, isopropyl, butyl, isobutyl or sec.butyl group, and particularly the methyl or ethyl group; or -R R-;
  • a saturated aliphatic hydrocarbon radical having 2 to 5 carbon atoms is, e.g. the ethylene, propylene, ethyl-ethylene, trimethylene, tetramethylene, 2,2-dimethyl-trimethylene, or the 2- ethyl-trimethylene group.
  • Halogen atoms as substituents of the rings A and B are fluorine, chlorine or bromine atoms; whilst as alkyl groups or alkoxy groups having 1 to 6 carbon atoms, the following are, for example, suitable: methyl, ethyl,
  • Ring B is preferably unsubstituted, or substituted by fluorine, chlorine or bromine in any desired position, especially, however, by fluorine or chlorine in the 0- position.
  • the anticonvulsive effectiveness can be determined, e.g. in the pentetrazole convulsion test on the mouse with oral doses from ca. 0.02 mg/kg, as well as in the strychnin convulsion test, in the electric shock test, and in the psychomotor electric shock test on the mouse after oral administration.
  • the central-depressant activity is shown, for example, from the anaestheticpotentiating effectiveness on the mouse after oral administration; this is, however, less pronounced compared with the anticonvulsive activity.
  • the musclerelaxing activity is reflected, for example, in the inhibition of polysynaptic reflexes on the rabbit after intravenous administration.
  • the mentioned properties and others which can be determined by selected standard tests [cp. W. Theobald and H. A. Kunz, Arzneistoffforsch. 13, 122 (1963), and W. Theobald et al., Arzneistoffforsch. 17, 561 (1967)], characterise the compounds of the general formula I, their 5-oxides, as well as their physiologically tolerable addition salts with inorganic and organic acids, as active substances for tranquillisers, sedatives, muscle-relaxants-and antiepileptics which are applicable, e.g. for the treatment of states of tension and agitation, for the lowering of the tension of the striated muscular system, as well as for the treatment of epilepsy.
  • Particularly valuable compounds within this group are those having the general formula Ia wherein R represents a hydrogen atom or a methyl or ethyl group, each of the symbols R represents a methyl or ethyl group, and v R; and R independently of each other represent hydrogen, a chlorine, fluorine or bromine atom, or a nitro or trifluoro methyl group, at least one of the symbols R and R being other than hydrogen.
  • R is hydrogen
  • R is a methyl or ethyl group
  • R is hydrogen or a chlorine atom
  • R is hydrogen or a fluorine or chlorine atom
  • X is preferably the methylthio or ethylthio group, and as alkoxy groups the methoxy or ethoxy group. These groups can be activated by a substituent. Such activated groups are, e.g. the 0- or p-nitrobenzylthio group and the 0- or pnitrobenzyloxy group, respectively.
  • X is, in particular, a lower alkylamino group such as the methylamino group, or ant aralkylamino group such as the benzylamino group.
  • X is, in particular, a lower dialkylamino group such as the dimethylamino group.
  • the reaction according to the invention is preferably performed at a reaction temperature of ca. to C in an inert solvent.
  • Suitable inert solvents are, for example, hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as chlorobenzene, a lower alkanol, preferably one agreeing with that of the acetal grouping, such as, e.g. ethanol or butanol, ethereal liquids such as diethylene glycol dimethyl ether, diethylene glycol diethyl ether, or dioxane and amides, especially N,N,N')N,N",N"-hexamethyl-phosphoric acid triamide, or sulphoxides such as dimethylsulphoxide.
  • the reaction times are between ca. 1 hour and 24 hours.
  • Suitable oxidising agents for the subsequent conver sion of compounds of the general formula 1 into their S-oxides are preferably hydrogen peroxide or peroxy acids, at a temperature of ca. 0 to 70C.
  • Suitable peroxy acids are, e.g. peroxyacetic acid, or peroxybenzoic acids such as peroxybenzoic acid or, in particular, mchloroperoxybenzoic acid.
  • the oxidising agents are preferably used in a solvent, e.g. peroxyacetic acid in acetic acid, and peroxybenzoic acid in halogenated hydrocarbons such as methylene chloride or chloroform.
  • R OH (VI) wherein R or R .R has the meaning given under formula I; and, optionally the oxidation of the obtained reaction product to its -oxide, or the conversion of the said reaction product into an addition salt with an inorganic or organic acid.
  • the reaction according to the invention is preferably performed in a solvent, e.g. in an excess of the employed alkanol of the general formula V, or of an alkanediol of the general formula Vl, in the presence of a catalyst.
  • the catalyst used is, for example, a mineral acid, e.g. sulphuric acid or phosphoric acid, an aromatic sulphonic acid, e.g. the 0- or p-toluenesulphonic acid, or a Lewis acid, e.g. boron trifluoride.
  • the reaction is performed at a temperature of from ca. to 170C, particularly at the boiling temperature of the employed solvent.
  • the starting materials of the general formula IV can be obtained, for example, as follows: the starting compounds are compounds of the previously defined general formula II; these are reacted with benzyloxyacetic acid hydrazide to give corresponding lbenzyloxymethyl-4l-l-s-triazolo[4,3-a] [l,4]benzodiazepines, which are split with hydrobromic acid to corresponding 4H-s-triazolo[4,3-a] [l,4]benzodiazepine-l-methanols; the obtained alcohols are subsequently oxidised with dimethylsulphoxide in the presence of dicyclohexylcarbodiimide and phosphoric acid.
  • R or R .R has the meaning given under formula I; and, optionally, the oxidation of the obtained reaction product to its 5-oxide, or the conversion of the said reaction product into an addition salt with an inorganic or organic acid.
  • reactive esters of a compound of the general formula Vlll it is possible to use, e.g. lower alkyl esters, particularly the methyl or ethyl ester.
  • the reaction according to the invention is preferably carried out at a reaction temperature of ca. to C in an inert solvent.
  • suitable inert solvents are, e.g. hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as chlorobenzene, a lower alkanol, preferably one corresponding to the alkanol of the acetal grouping, such as, e.g. ethanol or butanol, ethereal liquids such as diethylene glycol methyl ether or dioxane, and amides, particularly N,N,N',N, N", N"-hexamethyl-phosphoric acid triamide.
  • the reaction times are between ca. 1 hour and 24 hours.
  • the compounds of the general formula I obtained by the processes according to the invention are optionally subsequently converted, in the usual manner, into their addition salts with inorganic and organic acids.
  • the acid desired as the salt component is added to a solution of a compound of the general formula I in an organic solvent.
  • the organic solvents preferred for the reaction are ones in which the formed salt is difficulty soluble, and can hence be separated by filtration.
  • solvents are, e.g. methanol, ether. acetone, methyl ethyl ketone, acetone/ether, acetone/ethanol, methanol/ether or ethanol/ether.
  • physiologically tolerable acid addition salts i.e. salts with such acids of which the anions are not toxic in the dosage amounts concerned.
  • the salts to be used as pharmaceutical compositions crystallise well, and are not, or only slightly, hygroscopic.
  • salt formation with compounds of the general formula I it is possible to use, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid 2-hydroxyethanesulphonic acid, or perchloric acid.
  • the new active substances are administered orally, rectally or parenterally.
  • the dosage depends on the manner of administration, on the age, and on the individual condition.
  • the daily dosages of the free bases, their -oxides, and of physiologically tolerable acid addition salts of the free bases vary between 0.02 and 4 mg/kg for warmblooded animals.
  • Suitable dosage units, such as dragees, tablets or suppositories, preferably contain 0.5 25 mg of an active substance according to the invention.
  • Dosage units for oral administration contain as active substance preferably between 1 and 50% of a compound of the general formula 1, of its 5-oxide or of a corresponding physiologically tolerable salt. They are produced by combining the active substance, e.g. with solid pulverulent carriers such as lactose, saccharose, sorhitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or dragee cores. The dragee cores are coated, e.g.
  • Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.
  • Further dosage units suitable for oral administration are hard gelatine capsules, as well as soft closed capsules made from gelatine and a softener, such as glycerin.
  • the hard capsules preferably contain the active substance as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and optionally stabilisers such as sodium metabisulphite (Na2S- O or ascorbic acid.
  • the active substance is preferably dissolved or suspended in suitable liquids such as polyethylene glycols, whereby stabilisers may also be added.
  • Suitable dosage units for rectal administration are, e.g. suppositories consisting of a combination of an active substance with a suppository base material.
  • Suitable suppository base materials are, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols, or higher alkanols.
  • gelatine rectal capsules consisting of a combination of the active substance with a base material.
  • Suitable as a base material are, e.g. liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Ampoules for parenteral administration especially intramuscular administration, preferably contain a water-soluble salt of an active substance in a concentration of preferably 0,] 1%, optionally together with suitable stabilisers and buffer substances, in aqueous solution.
  • prescriptions further illustrate the production of tablets, dragees, capsules, suppositories and ampoules.
  • a granulate is produced from 50 g of 6-phenyl-8- chloro-4H-s-triazolo[4,3-a] ⁇ 1,4]benzodiazepine- 1 carboxaldehyde-diethylacetal, 175.90 g of lactose, and the alcoholic solution of 10 g of stearic acid. After drying of the granulate, it is mixed with 56.60 g of colloidal silicon dioxide, 165 g of talcum, 20 g of potato starch and 2.50 g of magnesium stearate; the mixture is then pressed into 10,000 dragee cores.
  • a suppository base mixture is prepared from 1.0 g 6-phenyl-8-chloro-4H-s-triazolo[4,3-a] [1,4]benzodiazepine-1-carboxaldehyde-diethylacetal and 169.0 g of adeps solidus; the mixture is then filled into 100 suppositories each containing 10 mg of active substance.
  • active substances for the above described or other dosage units e.g. the identical amounts of 6-(0- fluorophenyl )-8-chloro-4H-s-triazolo[4,3-a] 1,4]benzodiazepine-1-carboxaldehyde-diethylacetal, 6-(0- chlorophenyl)-8-chloro-4l-l-s-triazolo[4,3-a] [l,4]benzodiazepine-l-carbox'aldehyde-diethylacetal, 6-(0- chlorophenyl)-4H-s-triazolo[4,3-a] [1,4]benzodiazepine-l-carboxaldehyde-diethylacetal or 6-phenyl-8- chloro-4l-l-s-triazolo[4, 3-a] 1,4]benzodiazepine-1- carboxaldehyde-dimethylacetal can be used as well.
  • the diethoxyacetic acid hydrazide used as starting material is prepared as follows:
  • substituted Z-(methylthio)-5-phenyl-3l-l-1,4- benzodiazepines required as starting materials for the aforementioned final materials are obtainable from the corresponding substituted 1,3-dihydro-5-phenyl-2H- 1,4-benzodiazepine-Z-thiones described in J.Org.- Chem. 29, 231 (1964) analogously to the process described therein for 2-(methylthio)-5-phenyl-7-chloro- 3H-1 ,4-benzodiazepine.
  • EXAMPLE 6 a A solution of 200 mg of 2-(dimethylamino)-5- phenyl-7-chloro-3H-1,4-benzodiazepine [cp. J. Farber et al., J.Med.Chem. 7, 235 (1964)] and 150 mg of diethoxyacetic acid hydrazide in 3 ml of abs. hexamethyl phosphoric acid triamide is heated for hours at 140.
  • the three aforementioned starting materials can be produced, for example, by the process of the German Offenlegungsschrift No. 1,933,986, Chemical Abstracts 72, 100772 h (1970), or analogously to the previously mentioned 2-amino compound.
  • EXAMPLE 7 i A mixture of 300 mg of 6-phenyl-8-chloro-4H-striazolo[4,3-a][ l ,4]benzodiazepine-1-methanol, 0.57 g of dicyclohexyl-carbodiimide, 45 mg of phosphoric acid and 3 ml of abs. dimethylsulphoxide is stirred for 6 days at 250 and for a further 2 days at -80. Methylene chloride is then added, the organic phase washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation.
  • the starting compound is produced as follows:
  • EXAMPLE 8 A solution of 2-hydrazino-5-phenyl-7-chloro-3H-l ,4- benzodiazepine [cp. Kanji Meguro and Yutaka Kuwada, Tetrahedron Letters 1970, 4039 (1970)] and 5 g of diethoxyacetic acid ethyl ester in 50 ml of N,N.- N',N',N",N"-hexamethylphosphoric acid triamide is heated for 5 hours at 100. The reaction mixture is then concentrated in vacuo, and the residue distributed between methylene chloride and water. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulphate, and concentrated by evaporation.
  • R represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms
  • each of the symbols R represents a methyl or ethyl group
  • R and R independently of each other, represents hydrogen, methyl, methoxy, a chlorine, fluorine or bromine atom, a nitro or trifluoromethyl group, at least one of the symbols R and R being other than hydrogen, a
  • R represents hydrogen, each of the symbols R represents the methyl or ethyl group, R represents hydrogen or a chlorine atom and R represents hydrogen or a fluorine or chlorine atom, at least one of the symbols R and R being other than hydrogen, together with a pharmaceutically acceptable carrier.
  • the method of producing an anticonvulsant effect in a warm-blooded animal comprises administering to said animal an anticonvulsive amount of a compound of the formula defined in claim 1, wherein R R R and R have the meanings given in claim 1 and rings A and B are unsubstituted or substituted as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Plural Heterocyclic Compounds (AREA)
US239780A 1971-04-08 1972-03-30 New diazepine derivatives for producing anticonvulsant effects Expired - Lifetime US3867536A (en)

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US05/406,060 US3946032A (en) 1971-04-08 1973-10-12 Acetal derivatives of 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde

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JP (1) JPS5614671B1 (enrdf_load_stackoverflow)
AR (3) AR193382A1 (enrdf_load_stackoverflow)
AT (2) AT317222B (enrdf_load_stackoverflow)
AU (1) AU472767B2 (enrdf_load_stackoverflow)
BE (1) BE781816A (enrdf_load_stackoverflow)
CA (1) CA991639A (enrdf_load_stackoverflow)
CH (1) CH545302A (enrdf_load_stackoverflow)
CS (3) CS178449B2 (enrdf_load_stackoverflow)
DD (1) DD97655A5 (enrdf_load_stackoverflow)
DE (1) DE2215939A1 (enrdf_load_stackoverflow)
DK (1) DK141965B (enrdf_load_stackoverflow)
FI (1) FI52583C (enrdf_load_stackoverflow)
FR (1) FR2132767B1 (enrdf_load_stackoverflow)
GB (1) GB1392327A (enrdf_load_stackoverflow)
HU (1) HU165318B (enrdf_load_stackoverflow)
IE (1) IE36231B1 (enrdf_load_stackoverflow)
IL (1) IL39051A (enrdf_load_stackoverflow)
NL (1) NL7204700A (enrdf_load_stackoverflow)
NO (1) NO134839C (enrdf_load_stackoverflow)
PL (1) PL83566B1 (enrdf_load_stackoverflow)
SE (1) SE413408B (enrdf_load_stackoverflow)
SU (3) SU499808A3 (enrdf_load_stackoverflow)
ZA (1) ZA721896B (enrdf_load_stackoverflow)

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US3681343A (en) * 1971-05-11 1972-08-01 Upjohn Co 6-phenyl-s-triazolo{8 4,3-a{9 {8 1,4{9 {0 benzodiazepines

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US3987052A (en) * 1969-03-17 1976-10-19 The Upjohn Company 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines
BE759099A (fr) * 1969-11-18 1971-04-30 Takeda Chemical Industries Ltd Procede de fabrication de composes heterocycliques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3681343A (en) * 1971-05-11 1972-08-01 Upjohn Co 6-phenyl-s-triazolo{8 4,3-a{9 {8 1,4{9 {0 benzodiazepines

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DK141965B (da) 1980-07-28
IE36231B1 (en) 1976-09-15
IL39051A0 (en) 1972-05-30
CA991639A (en) 1976-06-22
HU165318B (enrdf_load_stackoverflow) 1974-08-28
DE2215939A1 (de) 1972-10-19
AU4082072A (en) 1973-10-11
DK141965C (enrdf_load_stackoverflow) 1980-12-08
AT317230B (de) 1974-08-26
AR193382A1 (es) 1973-04-23
ZA721896B (en) 1972-12-27
DD97655A5 (enrdf_load_stackoverflow) 1973-05-12
FR2132767B1 (enrdf_load_stackoverflow) 1975-06-20
NO134839C (enrdf_load_stackoverflow) 1976-12-21
PL83566B1 (en) 1975-12-31
SE413408B (sv) 1980-05-27
SU489332A3 (ru) 1975-10-25
IE36231L (en) 1972-10-08
AT317222B (de) 1974-08-26
CS178406B2 (enrdf_load_stackoverflow) 1977-09-15
AR194991A1 (es) 1973-08-30
AU472767B2 (en) 1973-10-11
FR2132767A1 (enrdf_load_stackoverflow) 1972-11-24
SU482045A3 (ru) 1975-08-25
CS178448B2 (enrdf_load_stackoverflow) 1977-09-15
CH545302A (de) 1974-01-13
FI52583C (fi) 1977-10-10
CS178449B2 (enrdf_load_stackoverflow) 1977-09-15
NO134839B (enrdf_load_stackoverflow) 1976-09-13
AR193942A1 (es) 1973-05-31
JPS5614671B1 (enrdf_load_stackoverflow) 1981-04-06
GB1392327A (en) 1975-04-30
BE781816A (fr) 1972-10-09
IL39051A (en) 1975-02-10
FI52583B (enrdf_load_stackoverflow) 1977-06-30
NL7204700A (enrdf_load_stackoverflow) 1972-10-10
SU499808A3 (ru) 1976-01-15

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