US3541088A - Carbazole derivatives - Google Patents
Carbazole derivatives Download PDFInfo
- Publication number
- US3541088A US3541088A US682637A US3541088DA US3541088A US 3541088 A US3541088 A US 3541088A US 682637 A US682637 A US 682637A US 3541088D A US3541088D A US 3541088DA US 3541088 A US3541088 A US 3541088A
- Authority
- US
- United States
- Prior art keywords
- carbazolyl
- piperazinyl
- cis
- butene
- ether
- 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.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
Definitions
- R2 (:1) wherein R and R are the same or diflerent and denote lower alkyl, aminoalkyl, monoalkylated aminoalkyl or dialkylated aminoalkyl or R and R together with N form pyrrolidinyl (1), piperidino, morpholino, piperazinyl (1), 4-(1ower alkyl)-piperazinyl (1), 4-(lower hydroxyalkyl)-piperazinyl (1), 4-(acylated lower hydroxyalkyl)-piperaziny1 (1); or 4-(alkoxy lower alky1)-piperazinyl (1) having at most 6 carbon atoms in the alkoxyalkyl radical; and (b) the acid addition salts of (a).
- These compounds exhibit strong anti-convulsant activity, and the free base and the non-toxic acid addition salts are adapted for use as antiepileptic drugs.
- This invention is concerned with new carbazole derivatives of the formula:
- R and R are the same or dilfercht and denote lower alkyl, aminoalkyl, monoalkylated aminoalkyl or dialkylated aminoalkyl, or R and R together with N form pyrrolidinyl (1), piperidino, morpholino, piperazinyl (l), 4-(lower alkyl)-piperazinyl -(1), 4- (lower hydroxyalkyl)-piperazinyl (1), 4- (acylated lower hydroxyalkyl)-piperazinyl (1); or 4-(alkoxy lower alkyl)-piperazinyl (1) having at most 6 carbon atoms in the alkoxyalkyl radical.
- Lower alkyl or 3,541,088 Patented Nov. 17, 1970 hydroxyalkyl is intended to indicate, throughout the specification and claims, an alkyl or hydroxyalkyl group having at most 3 carbon atoms.
- A denotes a straight or branched saturated hydrocarbon chain having 2 to 6 carbon atoms
- R represents hydrogen, alkyl having at most 6 carbon atoms, aryl or an arylaliphatic radical, and derivatives thereof which are substituted by halogen, alkyl or alkoxy having at most 6 carbon atoms, aryl or aryloxy in the nuclei and/or methylated in the piperazine ring.
- Table I shows a comparison of activities between carbazole derivatives according to the invention and 1 (4-ethyl-piperazinyl-1-)-2-(carbazolyl-9-)-ethane which is given as the most active of the compounds according to Belgian patent specification No. 539,438.
- the anticonvulsant action was determined by the electro-shock test [method of Goodman et al., J. pharmacol. 108, 168 (1953)].
- ED 50 denotes that dose of known product or of a product according to the invention at which 50% of the test animals are protected against tonic extensor seizure of the hind extremities.
- LD 50 denotes the dose at which 50% of the mice die whereas ED 50 is the dose at which 50% of the rats show first neurological abnormalities (e.g. ataxia).
- the pharmaceutical preparations may be, for instance, in the form of tablets, dragees, or solutions for injection, one dosage tlnit containing from to 60 mg. of active substance, depending on its nature, on the route of administration and on the physicians prescription, the effective daily dose amounting from to 180 mg. of active substance.
- R and R have the meaning stated above, or an acid addition salt thereof.
- the reduction is performed, for instance, by treatment with hydrogen in the presence of a catalyst, e.g. Raney iron, Raney nickel or palladium, preferably however, in the presence of a deactivated palladium catalyst; by electrolysis; by treatment with complex hydrides, especially lithium aluminium hydride; or by treatment with metals, such as sodium, potassium or lithium in ammonia.
- a catalyst e.g. Raney iron, Raney nickel or palladium, preferably however, in the presence of a deactivated palladium catalyst
- electrolysis by treatment with complex hydrides, especially lithium aluminium hydride
- metals such as sodium, potassium or lithium in ammonia.
- the compounds of Formula II used as starting materials are obtained, for example, by reacting 9-(2-propynyl)-carbazole with amines of the formula HNR R in the presence of formaldehyde according to the Mannich reaction.
- the desired compounds (I) are also obtained by reacting amines of the formula Z-H, if desired, after prior or during simultaneous action by a condensing agent, with reactive esters of alcohols of the formula Y-CH CH CH-CH OH
- Z and Y are mutually interchangeable and denote on the one hand the carbazolyl(9) group and on the other hand the basic group
- reactive esters of alcohols of the formula Y-CH CH CHCH OH those of hydrohalic acids are especially suitable.
- a condensing agent is indicated when 9-unsubstituted carbazole is used as starting material.
- Suitable condensing agents are alkali metals, their hydrides or amides or other alkali metal compounds. Especially suitable is lithium amide.
- the compounds of Formula I may be obtained and used either as free bases or in the form of their addition salts with suitable acids, eg hydrohalic acids, toluene-sulphonic acids, sulphuric, nitric, phosphoric, acetic, oxalic, malonic, succinic, malic, maleic, or tartaric acid.
- suitable acids eg hydrohalic acids, toluene-sulphonic acids, sulphuric, nitric, phosphoric, acetic, oxalic, malonic, succinic, malic, maleic, or tartaric acid.
- EXAMPLE 1 5.0 g. of 1-morpholino-4-(carbazolyl-9-)-butyne(2) are dissolved in ml. of absolute ethanol, treated with 1.6 g. of a palladium catalyst which has been inactivated with lead salts, and hydrogenated with hydrogen under normal pressure at 20 C. Hydrogenation is stopped when 520 ml. of gaseous hydrogen have been taken up. The reaction mixture is then filtered and concentrated by evaporation in vacuo. The residue is crystallised from ether/ hexane, whereby 2.7 g. of 1-morpholino-4-(carbazolyl- 9)-cis-butene(2) of melting point 67-70 C. are obtained. The oxalate of this base melts at l85-188 C.
- the starting material used in this example is obtained as follows:
- aqueous solutions are then made alkaline with ammonia and extracted by shaking three times with chloroform/ether.
- the chloroform/ether extracts washed with water and dried with sodium sulphate, yield after concentration by evaporation 13.0 g. of l-morpholino 4 (earbazolyl-9)-butyne(2), which after crystallisation from ether/hexane forms colourless crystals of melting point -98 C.
- EXAMPLE 2 3.4 g. of 1-dimethylamino-4-(carbazolyl-9)-butyne(2) in 180 m1. of absolute tetrahydrofuran are heated together with 2.0 g. of lithium aluminium hydride under reflux with exclusion of moisture for three days. The excess lithium aluminium hydride is then destroyed by adding ethyl acetate. The residue obtained after evaporation of the solution in vacuo is taken up in ether and separated in a usual manner into neutral and basic constituents, whereby 2.7 g. of crude 1-dimethylamino-4- carbazoly1-9)-butene(2) are obtained. The oxalate obtained by reacting this base with oxalic acid has after crystallisation from methanol/ether a melting point of 136137 C.
- EXAMPLE 3 5.0 g. of 1-(4-5-hydroxyethyl-piperazinyl-1-)-4-(carba zolyl-9-)-butyne(2) are dissolved in ml. absolute ethanol, treated with 1.5 g. of a palladium catalyst, which has been inactivated with lead salts, and hydrogenated with hydrogen under normal pressure at 20 C. The hydrogenation ceases when 310 ml. of gaseous hydrogen have been taken up. The reaction mixture is then filtered to remove the catalyst and concentrated by evaporation in vacuo. The residue obtained is crystallised from methanol/ether and yields 3.0 g.
- reaction mixture After cooling, the reaction mixture is diluted with ether and separated in a usual manner into neutral and basic constituents, whereby 4.3 g. of crude 1 piperidino-4- (carbazoly1-9-)-trans-butene(2) are obtained.
- the oxalate obtained by reacting this base with oxalic acid shows after crystallisation from methanol/ether the form of colourless platelets of melting point 169-172 C.
- the products of this invention can, for instance, be mixed with lactose and granulated with water, parafiin oil, 0.5% sodium alginate or 5% gelatine solution.
- the dried granulate is compressed into tablets in the presence of the usual auxiliary agents for tabletting, such as talcum, corn starch, colloidal silicic acid, or magnesium stearate.
- auxiliary agents for tabletting such as talcum, corn starch, colloidal silicic acid, or magnesium stearate.
- These 110 mg. tablets which are provided with a crackline, can be administered orally in a dosage of half a tablet to one tablet two to six times per day in the treatment of subjects suffering from any type of epilepsy.
- R and R are members of the class consisting of lower alkyl, aminoalkyl, monoalkylated aminoalkyl and dialkylated aminoalkyl, or R and R together with N form a member of the class consisting of pyrrolidinyl(1), piperidino, morpholino, piperazinyl(l), 4-(lower alkyl)- piperazinyl(l), 4 (lower hydroxyalkyl) piperazinyl(l and 4-(alkoxy lower alkyl)-piperazinyl(l); each of the alkyl and alkoxy moieties in any of the above-mentioned substituents containing from 1 to 3 carbon atoms; and (B): acid addition salts of (A).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1646166A CH475982A (de) | 1966-11-16 | 1966-11-16 | Verfahren zur Herstellung von Carbazolderivaten |
CH786567A CH477439A (de) | 1966-11-16 | 1967-06-02 | Verfahren zur Herstellung von Carbazolderivaten |
Publications (1)
Publication Number | Publication Date |
---|---|
US3541088A true US3541088A (en) | 1970-11-17 |
Family
ID=25702363
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US682637A Expired - Lifetime US3541088A (en) | 1966-11-16 | 1967-11-13 | Carbazole derivatives |
Country Status (13)
Country | Link |
---|---|
US (1) | US3541088A (da) |
AT (1) | AT277998B (da) |
BE (1) | BE706600A (da) |
CH (2) | CH475982A (da) |
DE (1) | DE1720028A1 (da) |
DK (1) | DK114774B (da) |
ES (1) | ES347146A1 (da) |
FR (1) | FR7181M (da) |
GB (1) | GB1170468A (da) |
GR (1) | GR38358B (da) |
IL (1) | IL28917A (da) |
NL (1) | NL6715370A (da) |
SE (1) | SE312557B (da) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4868190A (en) * | 1988-12-27 | 1989-09-19 | Hoechst-Roussel Pharmaceuticals, Inc. | N-pyridinyl-9H-carbazol-9-amines |
-
0
- FR FR127918A patent/FR7181M/fr not_active Expired
-
1966
- 1966-11-16 CH CH1646166A patent/CH475982A/de not_active IP Right Cessation
-
1967
- 1967-06-02 CH CH786567A patent/CH477439A/de not_active IP Right Cessation
- 1967-10-25 DE DE19671720028 patent/DE1720028A1/de active Pending
- 1967-11-10 SE SE15470/67A patent/SE312557B/xx unknown
- 1967-11-10 IL IL28917A patent/IL28917A/xx unknown
- 1967-11-13 NL NL6715370A patent/NL6715370A/xx unknown
- 1967-11-13 US US682637A patent/US3541088A/en not_active Expired - Lifetime
- 1967-11-14 ES ES347146A patent/ES347146A1/es not_active Expired
- 1967-11-14 GR GR670138358A patent/GR38358B/el unknown
- 1967-11-15 AT AT1029867A patent/AT277998B/de not_active IP Right Cessation
- 1967-11-15 GB GB51911/67A patent/GB1170468A/en not_active Expired
- 1967-11-15 DK DK571067AA patent/DK114774B/da unknown
- 1967-11-16 BE BE706600D patent/BE706600A/xx unknown
Non-Patent Citations (1)
Title |
---|
None * |
Also Published As
Publication number | Publication date |
---|---|
ES347146A1 (es) | 1969-05-16 |
NL6715370A (da) | 1968-05-17 |
CH475982A (de) | 1969-07-31 |
DK114774B (da) | 1969-08-04 |
IL28917A (en) | 1971-05-26 |
BE706600A (da) | 1968-05-16 |
GB1170468A (en) | 1969-11-12 |
FR7181M (da) | 1969-08-11 |
DE1720028A1 (de) | 1971-07-01 |
AT277998B (de) | 1970-01-12 |
CH477439A (de) | 1969-08-31 |
GR38358B (el) | 1969-10-30 |
SE312557B (da) | 1969-07-21 |
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