CA1199919A - Eburnane oxime derivatives and process for preparing same - Google Patents
Eburnane oxime derivatives and process for preparing sameInfo
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- CA1199919A CA1199919A CA000431474A CA431474A CA1199919A CA 1199919 A CA1199919 A CA 1199919A CA 000431474 A CA000431474 A CA 000431474A CA 431474 A CA431474 A CA 431474A CA 1199919 A CA1199919 A CA 1199919A
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- alpha
- beta
- eburnane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
-
- 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
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- Heart & Thoracic Surgery (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract
ABSTRACT
Eburnane-oxime derivatives, process for their preparation, and pharmaceutical compositions containing these compounds The invention relates to racemic or optically active eburnane-oxime derivatives of the formulae (Ia) and/or (Ib) (Ia)
Eburnane-oxime derivatives, process for their preparation, and pharmaceutical compositions containing these compounds The invention relates to racemic or optically active eburnane-oxime derivatives of the formulae (Ia) and/or (Ib) (Ia)
Description
Eburnane-oxime derivatives, process for -their prepara-tion, and pharmaceutical compositions containing these compounds This invention relates to new eburnane-oxime derivatives and pharmaceutical co~positions containin~
them as active ingredient, furthermore the invention relates to a process for preparing same active ingredient.
More particul&rly, the invention concerns new racemic or optically active eburnane-oxime derivatives of the formulae (Ia) ard/or (Ib), ~
(1 1 ",~ (Ia) ~ (Ib) N X
6~ ~OlJ
~: :
,.
, -- 2 ~
wherein R represents an alkyl group having 1 to 6 carbon atoms, and the configuration of the hydrogen atom in the 3-posi~
tion and R is ~,~ and/or 137~ or ~ and/or B,~, ard acid addition salts thereof.
Accordi~g to a further aspect of the invention there i~ provided a process for the preparation of racemic or optically active eburnane-oxime derivatives of the ~ormulae (Ia) and/or (Ib) (wherein R and the configuration of the 3-hydrogen and ~ are as defined above), and acid addition salts thereof, which p~ocess comprises oximating a racemic or optically active eburnamonine derivative of the formula (II) 20 ~ (II) (wherein R and its configuration related tc the 3--hydrogen are the same as defined above) a~d, if desired~ separating the ZE-isomeric mixture of the eburnane-oxime~derivatives of the formulae (Ia) and/or (Ib~ obtained or, if desired, converting a Z-isomer of ~ ~9 ~ 9 ~
the formula (Ia) into an E-isomer of the formula (Ib) and/or, if desired, resolving a raGemic eburnane oxime derivative of the formula tIa) or (Ib) and/or~ if de-sired~ treating a racemic or optically active eburnane--oxime derivative of the formula (Ia) or (Ib) with an acid.
~ he new compounds of the ~ormula (Ia) possess valuable antihypo~ial activityO
~ he term "alkyl group having 1 to 6 carbon atoms" as u~ed herein means straight or branched chained ~liphatic hydrocarbon groups having 1 to 6 carbon atoms (e.g. methyl, ethyl, n~propyl, isopropyl, n-butyl, sec.~butyl, tertO-butyl, n-pentyl 9 i~opentyl, _-hexyl or isohexyl, etc.).
~he starting compounds o~ the formula (II) are prepared ~or examp]e according to the ~elgian patent specifications NosO 776,337 or 802,387 or as - described in the French patent specification No.
" - 2,2~8,016.
~he oximation o~ the compounds of the ~ormula tII) is generally carried out with a tertiary C~_8-alkyl nitrite, such as tert.-butyl nibrite, tert.--amyl nitrite or iæoamyl nitrite, in the presence of a strong base, such as an alkali metal alcoholate, eOgO potassium or sodium tert.-butylate, sodium or potassium isoamylate, potassium tert.-amylate, an `alkali metal amide, eOg~. lithium diisopropyl amide~ or organic metal compounds, e.g. butyl-lithiumO ~he oxima-~r~
.
., ~ 3 ~ ~
tion is preferably performed in an apolar organic solvent inert lmder the reaction conditions, pre~
ferably in an aromatic hydrocarbon, such as benzene, toluene or xylene.
~he oximation affords a mixture of the Z--isomer of the formula (Ia) and of the E-isomer of the formula (Ib), in which mi2ture the Z-isomer is the major component, if the reaction temperatule is moderate, preferably between 15 and 50 C, and the pH of the reaction mixture is neutral or slightly acidic and preferably is between 3 and 7. ~or example, if the reaction mixture of oximation is decomposed with an aqueous ammonium chloride solution at room temperature, essentially the Z-isomer of the for-mula (Ia) is obtained, while if a dilute aqueoussulfuric acid solution is used for the decomposi-tion, the two isomers are obtained in about equal proportion. ~he Z-isomer of the formula (Ia) is a kinetic product, which can be partially transiso-merized into the thermodinamically more stable E--isomer of the formula tIb) by heating, especially ~n the presence of protones.
In the starting compounds of the formula tII) the mutual configuration of the 3-hydrogen and the R ~ubstituent is not changed during the process of the present in~ention. Therefore, the configuration of the 3-hydrogen and R in the starting compounds of the for-mula (II) and the enl rrod-ots of the formulae (Ia) :
~;g9~3 and/or (Ib) is the same.
~ or the preparation of salts of the com-pounds of the formula (I) for example the following acids can be usecl: inorganic acids, such as hydrogen 5 halides~ e~g. hydrochloric acid, hydrogen bromide;
sul~uric acid; phosphoric acid; nitric acid; or per-haloic acids, such as perchloric acid; or organic acids, such as formic acid9 acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, 10 f~aric acid, malic acid, citric acid3 ascorbic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, P-amino~benzoic acid, ~-~hydro-benzoic acid, ~amino-benzoic acid, ~-amino--salicylic acid, etc.; alkylsulfonic acids, such as 15 methanesulfonic acid, ethanesulfonic acid, etc~;
cycloaliphatic sulfonic acids, such as cyclohexane-sul~onic acid; arylsulfonic acids, such as ~-toluene--sul~onic acidg naphthylsulfonic acid, sulfanilic acid, etc.; amino acids, such as asparaginic acid, glutaminic acid, etc~
~ he salts are prèpared in an inert organic ~olvent, ~or example an aliphatic alcohol having 1 to 6 carbon atoms, for example by dissolving a racemic or optioally active compound of the formula (Ia) or ~Ib) in said solvent, and adding a corresponding acid ; to the solution obtained as such or ln the form of a solution with the above solvent until the mixture be~
comes slightly acididc (about pH 5-6)o ~he precipitated ~ ~ 9 acid addition salt can thereafter be separated from-the reaction mixture by conventional technique, e.gO
by filtration.
The racemic compounds of the formula (Ia) or (Ib) can be resolved in a known manner but optical-ly active starting materials of the formula (II) may also be employed when optically active end products are desired. Preferably racemic compounds of the for-mula (Ia) or (Ib) are prepared from racemic compounds of the formula (II), while optically active compounds of the formula (Ia) or ~b) are obtained starting from optically active compounds of the formula (II).
If desired, the optically active or racemic compounds of the formula (Iaj or (Ib) or acid addition salts thereof may be subjected to further purification, e.gO recrystallization. ~he solvents used for re-crystallization are selected depending on the solubility and crystallizability of the compounds to be crystallized.
According to a still further aspect of the present invention there are provided pharmaceutical compositions which comprise as an active ingredient at least one racemic or optically active compound of the formula (Ia) or (Ib) or a pharmaceutically accept-able salt thereof, in admi~ture with inert solîd or liquid pharmaceutical carriers and/or additives~
~ he pharmaceutical compositions can be for-mulated in forms suitable for parenteral or enteral administrationl As carriers for e~ample water, gelatine, ~ 7 --lactose, milk sugar, s-tarch, pectine, magnesium stearate, stearic acid, talc, vegetable oils, such as peanut oil, oiive oil, etc~ can be used. The composi~tior.s may be fi-^lshed in thQ form of solid, 5 e.g. tablets, lozenges, dragQes, capsules, such as hard gelatine capsules, suppositories9 etc g or liquid, e.gO oily or aqucous solu~ions, suspen-sions, emulsions, syrups, soft gelatine capsules ?
injectable oily or aqueous solutions or suspensions, 10 etc. formulations. ~he quantity of the solid carrier can be varied within a wide range but preferably is about between 25 mg. a-nd 1 gO ~he pharmaceutical compositions optionally can contain also conventional pharmaceutical additives, such as preservatives, stabiliz-15 ing, wetting, emulsifying agen-ts, salts capable of adjusting the osmotic pressure, buffers, flavouring agents, aroma agents, etc. Optionally further pharma-ceutically active compounds can also be present in the formulations.
~he pharmaceutical compositions are prefer-ably manufactured in dosage units, suitable for the desired route of administration. ~he pharmaceutical compositions may be prepared b~ conventional techniquesg which comprise for example screening~ admixing~
25 granulating, pressing or~dissolving of the componentsO
~he compositions obtained can be subjected to further operations con~entionally used in the pharmaceutical industry, for example sterilization.
9~
I~'urther details of the present invention ~ e to be fcund i-n the following Examples which are, however, by no means intended to limit the scope of the protection soughtO
E~am~le 1 (+)-14-Oxo-15-hydro~yimino-eburnane(3~,1~) ~Z-isomer) and its hydrochloride ~o a solution of 4-0 gO ~13.6 mmoles) of (-)-vincamone (3~16~) in 80 mlO of absolute benzene 13.6 ml. (148 mmoles) of freshly distilled tert~-butyl nitrite and some minutes later 3.8 gO (34 mmoles) of potassium tert.-butylate are added, lhe solution is stirred at room;temperature under nitrogen atmosphere for 1 to 1.5 hoursO ~he reaction mixture is decomposed with a solution of 15 g. of ammonium chloxide in 150 ml o~ water, under ice cooling. lhe organic phase is separated, and the aqueous phase is shaken with three 30-ml. portions of dichloromethane. ~he organic ph~ses are combinedg dried over,solid, anhydrous magnesium sulfate, filtered and from the Piltrate the solvent is eliminated by distillation in vacuo. ~he residual oil is or~stallized from methanol. 2.05 g~ of the ~ aimed compound are obtained.
Yield: 47 %.
According to thin layer chromatography the Rf-value of the end product is hi~her than that of the starting compound (~KG-G, dlohlorom-thane/methanol)~
8a Melting point: 158 to 159 C (methanol)O
~3D = ~7804 ~c = 1 15, chloroform)O
Anal~-sis for C19~21N32 (3 calculated: C 70057 ~ H 6.54 %, M 12.99 %9 found: C 70060 %~ H 6060 %a N 12,92 %0 LR spectrum (KBr): 3200-2600 (broadg chelate OH), 1710 (CO) 5 1630 cm 1 ~C=N).
Mass spectrum ~m/e, %): 324 (M+1,24), 323 (M+,100), 306 (15), 294 (40)~ 277 (53~, 276 (42), 264 (10), 253 (12) O--.
H-NMR spectrum (CDC13, cr ): 14.47 (lH3s,N-OH), 8.40-7~27 (4H,m,aromatic), 4.26 (lH,s,3-H), 1.03 (3H,t,j~3Hz~CH2-C_3).
C-NMR spectrum (CDC13~ 158.0 ~CO), 148.0 (C=N), 134.0 (C-13), 130.7 (C-2)~ 129.9 (C-8), 125.3-125.0 (C-10/C-11), 118.6 (C-9)~ 116.8 (C-12), 115-1 (C-7), 53.5 (C-3), 50.7 ~C-5), 44.8 (C-l9), 44.2 (C-16), 31.0 (C-20), 23.5 (C-17), 20.6 (C-18), 16.3 (C-6), 9.0 (C-21).
To the mother liquor of the methanolic crystallization hydrochloric acid in methanol is added until pH=3 to yield a further 0.9 g. batch (18.3%) of the aimed compound as a hydrochloride.
Total yield: 65.3%.
Example 2 (~)-14-Oxo-15-hydroxyimino-eburnane (3a,16a) (Z-isomer) and (-)-14-oxo-15-hydroxyimino-eburnane (3a,16a) (E-isomer) The procedure described in Example 1 is followed until the decompo-sition of the reaction mixture with ammonium chloride. Instead of decomposi-tion Witil ammonium chloride the separated benzene phase is extracted with three 15-ml. portions of a 2.5% aqueous sulfuric acid solution, the extract is alkalized until pH 9 with a concentrated aqueous ammonium hydroxide ~n solution ~mder coolin~ with ice, whereupon it is extracted with three 30-ml.
portions of dichloromethane. The or~anic , ~a: .l _ g _ ;
9~L~
pha3es are com~ine d, dried over solid, anhydrous m~gnesium sulfate, filtered ~nd ~rom the filtrate the solvent is distilled off in vacuo~ 204 g. of an oily product (55 %) are obtained. ~he product 5 is separated by thin layer chromato~;raphy into two ~25"-~366' dichloromethane:methanol _ 20:2, elution with ~oetone, the Rf-value of the Z--isomer is higher ~han that of the E-isomer)~
By crystallization of the components having 10 a higher Rf-value fro:~ rnethanol 1.04 g. of the Z--isomer given in the title are obtained.
Yield: 24 %~
'rhe material havin~5 a lower Rf-~-alue is brought into a filterable state wi~h pe roleum ether, filtered and driedO 009 g. of the ~-isomer given in the title are obtained.
Yield 20.5 %.
Melting point: 202-203 C ~petroleu~rn ether)~
~oc] 546 = -198~ (c - 1, chloroform).
Analysi~ for ClgH21N302 ~323-38~:
caloulal;ed; ~ 12.99 ~, found: N 12.80 %, lH-~ speGtrum ~aDcl3~ DMS0-d63 ~): 8.38-7.27 t4H~ m, aromatic)~ 4.30 tlH~s,3-H3, 0.98 t3HIt,J-8Hz~CH2CH3)0 25 13C-NMR(CDC13J DMSO-d6, d~) 156.8 ~C0), 150.7 (C~7), 134c6 ~13-C~ 13009 (C-2), 130.3 (C~ 24,0 (C-10), 123.9 (C-ll)g 118~2 ~Ç-9)1 116..(;) tc-~2), 11~D4 ~C-7), 52.0 tC 3)~ 51~4 ~C-5)~ 45.3 (C-l9)a 45"1 (C-16)t :: :
~, :
3~3~
~ 11 --28~3 (C-20), 25.7 (C-17), 2003 (C-18), 16.0 (C-6), 10.2 (C-21) 0 IR spectrum ~3r): 3250 (OH, broad), 1700 (GO), 1630 cm 1 (C=M).
5 Mass spectr~i (m/e, %): 324 (M~1.24)~ 323 ~M+, 100)5 306 (27), 29~ (46), 277 (66), 276 (62), 264 (16)~
253 (13) . .
them as active ingredient, furthermore the invention relates to a process for preparing same active ingredient.
More particul&rly, the invention concerns new racemic or optically active eburnane-oxime derivatives of the formulae (Ia) ard/or (Ib), ~
(1 1 ",~ (Ia) ~ (Ib) N X
6~ ~OlJ
~: :
,.
, -- 2 ~
wherein R represents an alkyl group having 1 to 6 carbon atoms, and the configuration of the hydrogen atom in the 3-posi~
tion and R is ~,~ and/or 137~ or ~ and/or B,~, ard acid addition salts thereof.
Accordi~g to a further aspect of the invention there i~ provided a process for the preparation of racemic or optically active eburnane-oxime derivatives of the ~ormulae (Ia) and/or (Ib) (wherein R and the configuration of the 3-hydrogen and ~ are as defined above), and acid addition salts thereof, which p~ocess comprises oximating a racemic or optically active eburnamonine derivative of the formula (II) 20 ~ (II) (wherein R and its configuration related tc the 3--hydrogen are the same as defined above) a~d, if desired~ separating the ZE-isomeric mixture of the eburnane-oxime~derivatives of the formulae (Ia) and/or (Ib~ obtained or, if desired, converting a Z-isomer of ~ ~9 ~ 9 ~
the formula (Ia) into an E-isomer of the formula (Ib) and/or, if desired, resolving a raGemic eburnane oxime derivative of the formula tIa) or (Ib) and/or~ if de-sired~ treating a racemic or optically active eburnane--oxime derivative of the formula (Ia) or (Ib) with an acid.
~ he new compounds of the ~ormula (Ia) possess valuable antihypo~ial activityO
~ he term "alkyl group having 1 to 6 carbon atoms" as u~ed herein means straight or branched chained ~liphatic hydrocarbon groups having 1 to 6 carbon atoms (e.g. methyl, ethyl, n~propyl, isopropyl, n-butyl, sec.~butyl, tertO-butyl, n-pentyl 9 i~opentyl, _-hexyl or isohexyl, etc.).
~he starting compounds o~ the formula (II) are prepared ~or examp]e according to the ~elgian patent specifications NosO 776,337 or 802,387 or as - described in the French patent specification No.
" - 2,2~8,016.
~he oximation o~ the compounds of the ~ormula tII) is generally carried out with a tertiary C~_8-alkyl nitrite, such as tert.-butyl nibrite, tert.--amyl nitrite or iæoamyl nitrite, in the presence of a strong base, such as an alkali metal alcoholate, eOgO potassium or sodium tert.-butylate, sodium or potassium isoamylate, potassium tert.-amylate, an `alkali metal amide, eOg~. lithium diisopropyl amide~ or organic metal compounds, e.g. butyl-lithiumO ~he oxima-~r~
.
., ~ 3 ~ ~
tion is preferably performed in an apolar organic solvent inert lmder the reaction conditions, pre~
ferably in an aromatic hydrocarbon, such as benzene, toluene or xylene.
~he oximation affords a mixture of the Z--isomer of the formula (Ia) and of the E-isomer of the formula (Ib), in which mi2ture the Z-isomer is the major component, if the reaction temperatule is moderate, preferably between 15 and 50 C, and the pH of the reaction mixture is neutral or slightly acidic and preferably is between 3 and 7. ~or example, if the reaction mixture of oximation is decomposed with an aqueous ammonium chloride solution at room temperature, essentially the Z-isomer of the for-mula (Ia) is obtained, while if a dilute aqueoussulfuric acid solution is used for the decomposi-tion, the two isomers are obtained in about equal proportion. ~he Z-isomer of the formula (Ia) is a kinetic product, which can be partially transiso-merized into the thermodinamically more stable E--isomer of the formula tIb) by heating, especially ~n the presence of protones.
In the starting compounds of the formula tII) the mutual configuration of the 3-hydrogen and the R ~ubstituent is not changed during the process of the present in~ention. Therefore, the configuration of the 3-hydrogen and R in the starting compounds of the for-mula (II) and the enl rrod-ots of the formulae (Ia) :
~;g9~3 and/or (Ib) is the same.
~ or the preparation of salts of the com-pounds of the formula (I) for example the following acids can be usecl: inorganic acids, such as hydrogen 5 halides~ e~g. hydrochloric acid, hydrogen bromide;
sul~uric acid; phosphoric acid; nitric acid; or per-haloic acids, such as perchloric acid; or organic acids, such as formic acid9 acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, 10 f~aric acid, malic acid, citric acid3 ascorbic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, P-amino~benzoic acid, ~-~hydro-benzoic acid, ~amino-benzoic acid, ~-amino--salicylic acid, etc.; alkylsulfonic acids, such as 15 methanesulfonic acid, ethanesulfonic acid, etc~;
cycloaliphatic sulfonic acids, such as cyclohexane-sul~onic acid; arylsulfonic acids, such as ~-toluene--sul~onic acidg naphthylsulfonic acid, sulfanilic acid, etc.; amino acids, such as asparaginic acid, glutaminic acid, etc~
~ he salts are prèpared in an inert organic ~olvent, ~or example an aliphatic alcohol having 1 to 6 carbon atoms, for example by dissolving a racemic or optioally active compound of the formula (Ia) or ~Ib) in said solvent, and adding a corresponding acid ; to the solution obtained as such or ln the form of a solution with the above solvent until the mixture be~
comes slightly acididc (about pH 5-6)o ~he precipitated ~ ~ 9 acid addition salt can thereafter be separated from-the reaction mixture by conventional technique, e.gO
by filtration.
The racemic compounds of the formula (Ia) or (Ib) can be resolved in a known manner but optical-ly active starting materials of the formula (II) may also be employed when optically active end products are desired. Preferably racemic compounds of the for-mula (Ia) or (Ib) are prepared from racemic compounds of the formula (II), while optically active compounds of the formula (Ia) or ~b) are obtained starting from optically active compounds of the formula (II).
If desired, the optically active or racemic compounds of the formula (Iaj or (Ib) or acid addition salts thereof may be subjected to further purification, e.gO recrystallization. ~he solvents used for re-crystallization are selected depending on the solubility and crystallizability of the compounds to be crystallized.
According to a still further aspect of the present invention there are provided pharmaceutical compositions which comprise as an active ingredient at least one racemic or optically active compound of the formula (Ia) or (Ib) or a pharmaceutically accept-able salt thereof, in admi~ture with inert solîd or liquid pharmaceutical carriers and/or additives~
~ he pharmaceutical compositions can be for-mulated in forms suitable for parenteral or enteral administrationl As carriers for e~ample water, gelatine, ~ 7 --lactose, milk sugar, s-tarch, pectine, magnesium stearate, stearic acid, talc, vegetable oils, such as peanut oil, oiive oil, etc~ can be used. The composi~tior.s may be fi-^lshed in thQ form of solid, 5 e.g. tablets, lozenges, dragQes, capsules, such as hard gelatine capsules, suppositories9 etc g or liquid, e.gO oily or aqucous solu~ions, suspen-sions, emulsions, syrups, soft gelatine capsules ?
injectable oily or aqueous solutions or suspensions, 10 etc. formulations. ~he quantity of the solid carrier can be varied within a wide range but preferably is about between 25 mg. a-nd 1 gO ~he pharmaceutical compositions optionally can contain also conventional pharmaceutical additives, such as preservatives, stabiliz-15 ing, wetting, emulsifying agen-ts, salts capable of adjusting the osmotic pressure, buffers, flavouring agents, aroma agents, etc. Optionally further pharma-ceutically active compounds can also be present in the formulations.
~he pharmaceutical compositions are prefer-ably manufactured in dosage units, suitable for the desired route of administration. ~he pharmaceutical compositions may be prepared b~ conventional techniquesg which comprise for example screening~ admixing~
25 granulating, pressing or~dissolving of the componentsO
~he compositions obtained can be subjected to further operations con~entionally used in the pharmaceutical industry, for example sterilization.
9~
I~'urther details of the present invention ~ e to be fcund i-n the following Examples which are, however, by no means intended to limit the scope of the protection soughtO
E~am~le 1 (+)-14-Oxo-15-hydro~yimino-eburnane(3~,1~) ~Z-isomer) and its hydrochloride ~o a solution of 4-0 gO ~13.6 mmoles) of (-)-vincamone (3~16~) in 80 mlO of absolute benzene 13.6 ml. (148 mmoles) of freshly distilled tert~-butyl nitrite and some minutes later 3.8 gO (34 mmoles) of potassium tert.-butylate are added, lhe solution is stirred at room;temperature under nitrogen atmosphere for 1 to 1.5 hoursO ~he reaction mixture is decomposed with a solution of 15 g. of ammonium chloxide in 150 ml o~ water, under ice cooling. lhe organic phase is separated, and the aqueous phase is shaken with three 30-ml. portions of dichloromethane. ~he organic ph~ses are combinedg dried over,solid, anhydrous magnesium sulfate, filtered and from the Piltrate the solvent is eliminated by distillation in vacuo. ~he residual oil is or~stallized from methanol. 2.05 g~ of the ~ aimed compound are obtained.
Yield: 47 %.
According to thin layer chromatography the Rf-value of the end product is hi~her than that of the starting compound (~KG-G, dlohlorom-thane/methanol)~
8a Melting point: 158 to 159 C (methanol)O
~3D = ~7804 ~c = 1 15, chloroform)O
Anal~-sis for C19~21N32 (3 calculated: C 70057 ~ H 6.54 %, M 12.99 %9 found: C 70060 %~ H 6060 %a N 12,92 %0 LR spectrum (KBr): 3200-2600 (broadg chelate OH), 1710 (CO) 5 1630 cm 1 ~C=N).
Mass spectrum ~m/e, %): 324 (M+1,24), 323 (M+,100), 306 (15), 294 (40)~ 277 (53~, 276 (42), 264 (10), 253 (12) O--.
H-NMR spectrum (CDC13, cr ): 14.47 (lH3s,N-OH), 8.40-7~27 (4H,m,aromatic), 4.26 (lH,s,3-H), 1.03 (3H,t,j~3Hz~CH2-C_3).
C-NMR spectrum (CDC13~ 158.0 ~CO), 148.0 (C=N), 134.0 (C-13), 130.7 (C-2)~ 129.9 (C-8), 125.3-125.0 (C-10/C-11), 118.6 (C-9)~ 116.8 (C-12), 115-1 (C-7), 53.5 (C-3), 50.7 ~C-5), 44.8 (C-l9), 44.2 (C-16), 31.0 (C-20), 23.5 (C-17), 20.6 (C-18), 16.3 (C-6), 9.0 (C-21).
To the mother liquor of the methanolic crystallization hydrochloric acid in methanol is added until pH=3 to yield a further 0.9 g. batch (18.3%) of the aimed compound as a hydrochloride.
Total yield: 65.3%.
Example 2 (~)-14-Oxo-15-hydroxyimino-eburnane (3a,16a) (Z-isomer) and (-)-14-oxo-15-hydroxyimino-eburnane (3a,16a) (E-isomer) The procedure described in Example 1 is followed until the decompo-sition of the reaction mixture with ammonium chloride. Instead of decomposi-tion Witil ammonium chloride the separated benzene phase is extracted with three 15-ml. portions of a 2.5% aqueous sulfuric acid solution, the extract is alkalized until pH 9 with a concentrated aqueous ammonium hydroxide ~n solution ~mder coolin~ with ice, whereupon it is extracted with three 30-ml.
portions of dichloromethane. The or~anic , ~a: .l _ g _ ;
9~L~
pha3es are com~ine d, dried over solid, anhydrous m~gnesium sulfate, filtered ~nd ~rom the filtrate the solvent is distilled off in vacuo~ 204 g. of an oily product (55 %) are obtained. ~he product 5 is separated by thin layer chromato~;raphy into two ~25"-~366' dichloromethane:methanol _ 20:2, elution with ~oetone, the Rf-value of the Z--isomer is higher ~han that of the E-isomer)~
By crystallization of the components having 10 a higher Rf-value fro:~ rnethanol 1.04 g. of the Z--isomer given in the title are obtained.
Yield: 24 %~
'rhe material havin~5 a lower Rf-~-alue is brought into a filterable state wi~h pe roleum ether, filtered and driedO 009 g. of the ~-isomer given in the title are obtained.
Yield 20.5 %.
Melting point: 202-203 C ~petroleu~rn ether)~
~oc] 546 = -198~ (c - 1, chloroform).
Analysi~ for ClgH21N302 ~323-38~:
caloulal;ed; ~ 12.99 ~, found: N 12.80 %, lH-~ speGtrum ~aDcl3~ DMS0-d63 ~): 8.38-7.27 t4H~ m, aromatic)~ 4.30 tlH~s,3-H3, 0.98 t3HIt,J-8Hz~CH2CH3)0 25 13C-NMR(CDC13J DMSO-d6, d~) 156.8 ~C0), 150.7 (C~7), 134c6 ~13-C~ 13009 (C-2), 130.3 (C~ 24,0 (C-10), 123.9 (C-ll)g 118~2 ~Ç-9)1 116..(;) tc-~2), 11~D4 ~C-7), 52.0 tC 3)~ 51~4 ~C-5)~ 45.3 (C-l9)a 45"1 (C-16)t :: :
~, :
3~3~
~ 11 --28~3 (C-20), 25.7 (C-17), 2003 (C-18), 16.0 (C-6), 10.2 (C-21) 0 IR spectrum ~3r): 3250 (OH, broad), 1700 (GO), 1630 cm 1 (C=M).
5 Mass spectr~i (m/e, %): 324 (M~1.24)~ 323 ~M+, 100)5 306 (27), 29~ (46), 277 (66), 276 (62), 264 (16)~
253 (13) . .
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a racemic mixture or an optically active eburnane-oxime derivative of the formulae (Ia) or (Ib) or a pharma-ceutically acceptable acid addition salt thereof (Ib) wherein R represents an alkyl group having 1 to 6 carbon atoms, and the configuration of the hydrogen atom in the 3-position and R is .alpha.,.alpha. or .beta.,.beta. or .alpha.,.beta. or .beta.,.alpha.,which process comprises oximating a racemic or optically active eburn-amonine derivative of the formula (II) and R is .alpha..alpha.,.alpha..alpha. and/or .beta.,.beta. or .alpha..alpha.,.beta. and/or .beta.,.alpha..alpha. and acid addition salts thereof.
2. Pharmaceutical compositions, which com-prise as an active ingredient at least one racemie or optically active compound of the formula (Ia) or (Ib) (as defined in claim 1) or a pharmaceutically accept-able acid addition salt thereof, in admixture with inert solid or liquid pharmaceutical carriers and/or additives.
3. Pharmaceutical compositions as claimed in claim 2 in forms suitable for parenteral or enteral administration.
4. A process according to claim 1 wherein in the starting materials R is hydrogen.
5. A process for preparing (+)-14-Oxo-15-hydroxyimino-eburnane (3cX , 16cx) which comprises reacting (-)-vincamone (3cX,16cX) with tert.-butyl nitrite and potassium tert.-butylate.
6. A process according to claim 5 wherein the reaction mixture is decomposed with ammonium chloride to obtain the z-isomer.
7. A process according to claim 6 further comprising treating the z-isomer product so obtained with hydrogen chloride to obtain a hydrochloride salt thereof.
8. A process according to claim 5 further comprising treating the reaction mixture with aqueous sulfuric acid and separating the E-isomer product so obtained.
9. The compound (+)-14-Oxo-15-hydroxyimino-eburnane (3cX, 16cX) or a pharmaceutically acceptable salt thereof whenever prepared by a process according to claim 4 or 5 or by an obvious chemical equivalent thereof.
10. The compound (+)-14-Oxo-15-hydroxyimino-eburnane (3cX, 16CX) (z-isomer) or a pharmaceutically acceptable salt thereof whenever prepared by a process according to claim 4 or 5, or by an obvious chemical equivalent thereof .
11. The compound (+)-14-Oxo-15-hydroxyimino-eburnane (3CX, 16cX) (z-isomer) or a pharmaceutically acceptable salt thereof whenever prepared by a process according to claim 6 or 7 or by an obvious chemical equivalent thereof.
12. The compound (+)-14-Oxo-15-hydroxyimino-eburnane (3cX, 16cX) (E-isomer) or a pharmaceutically acceptable salt thereof whenever prepared by a process according to claim 4, 5 or 8 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU2131/82 | 1982-06-30 | ||
| HU822131A HU190400B (en) | 1982-06-30 | 1982-06-30 | Process for preparing new eburnan-oxime derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1199919A true CA1199919A (en) | 1986-01-28 |
Family
ID=10957920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000431474A Expired CA1199919A (en) | 1982-06-30 | 1983-06-29 | Eburnane oxime derivatives and process for preparing same |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5962591A (en) |
| AT (1) | AT385990B (en) |
| AU (1) | AU554196B2 (en) |
| BE (1) | BE897148A (en) |
| CA (1) | CA1199919A (en) |
| CH (1) | CH656881A5 (en) |
| DE (1) | DE3323606A1 (en) |
| DK (1) | DK300583A (en) |
| ES (1) | ES523695A0 (en) |
| FR (1) | FR2529551B1 (en) |
| GB (1) | GB2124215B (en) |
| GR (1) | GR77525B (en) |
| HU (1) | HU190400B (en) |
| IL (1) | IL69107A (en) |
| NL (1) | NL8302298A (en) |
| NZ (1) | NZ204754A (en) |
| PT (1) | PT76951B (en) |
| SE (1) | SE457641B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU191403B (en) * | 1984-04-02 | 1987-02-27 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for preparing new, raceme and optically active 14-hydroxyimino-eburnane |
| US4735943A (en) * | 1984-06-29 | 1988-04-05 | Sanwa Kagaku Kenkyusho Co., Ltd. | Eburnamonine oxime derivatives, salts thereof, and pharmaceutical agents containing the same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2085630A1 (en) * | 1970-04-07 | 1971-12-31 | Le Men Georges | Vincamone compsn - having vasodilator ganglioplegic and antihistamine activity |
| FR2206090A1 (en) * | 1972-11-16 | 1974-06-07 | Omnium Chimique Sa | Homovincamone-contg. medicaments - with vasodilating, spasmolytic anti-arrhythmic and anti-ischaemic properties |
| US4315011A (en) * | 1978-07-12 | 1982-02-09 | Richter Gedeon Vegyeszeti Gyar Rt. | 1-Alkyl-9-bromohexahydroindolo quinolizium salts and use thereof to increase blood flow |
| FR2454808A1 (en) * | 1979-04-26 | 1980-11-21 | Roussel Uclaf | Syn. and anti E homo eburnane oxime - having cerebral circulation regulating activity |
-
1982
- 1982-06-30 HU HU822131A patent/HU190400B/en not_active IP Right Cessation
-
1983
- 1983-06-28 CH CH3529/83A patent/CH656881A5/en not_active IP Right Cessation
- 1983-06-28 BE BE1/10823A patent/BE897148A/en not_active IP Right Cessation
- 1983-06-29 CA CA000431474A patent/CA1199919A/en not_active Expired
- 1983-06-29 GR GR71804A patent/GR77525B/el unknown
- 1983-06-29 GB GB08317612A patent/GB2124215B/en not_active Expired
- 1983-06-29 NL NL8302298A patent/NL8302298A/en not_active Application Discontinuation
- 1983-06-29 NZ NZ204754A patent/NZ204754A/en unknown
- 1983-06-29 JP JP58116245A patent/JPS5962591A/en active Pending
- 1983-06-29 DK DK300583A patent/DK300583A/en not_active Application Discontinuation
- 1983-06-29 AU AU16396/83A patent/AU554196B2/en not_active Ceased
- 1983-06-29 SE SE8303719A patent/SE457641B/en not_active IP Right Cessation
- 1983-06-29 FR FR8310734A patent/FR2529551B1/en not_active Expired
- 1983-06-29 IL IL69107A patent/IL69107A/en unknown
- 1983-06-29 AT AT0239083A patent/AT385990B/en not_active IP Right Cessation
- 1983-06-29 ES ES523695A patent/ES523695A0/en active Granted
- 1983-06-29 PT PT76951A patent/PT76951B/en unknown
- 1983-06-30 DE DE19833323606 patent/DE3323606A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| PT76951A (en) | 1983-07-01 |
| ES8500619A1 (en) | 1984-11-01 |
| SE457641B (en) | 1989-01-16 |
| GR77525B (en) | 1984-09-24 |
| JPS5962591A (en) | 1984-04-10 |
| IL69107A0 (en) | 1983-10-31 |
| PT76951B (en) | 1986-01-24 |
| NL8302298A (en) | 1984-01-16 |
| DK300583D0 (en) | 1983-06-29 |
| DE3323606A1 (en) | 1984-01-12 |
| NZ204754A (en) | 1985-11-08 |
| DK300583A (en) | 1983-12-31 |
| IL69107A (en) | 1986-03-31 |
| SE8303719L (en) | 1983-12-31 |
| ATA239083A (en) | 1987-11-15 |
| AU1639683A (en) | 1984-01-05 |
| SE8303719D0 (en) | 1983-06-29 |
| HU190400B (en) | 1986-08-28 |
| AU554196B2 (en) | 1986-08-14 |
| GB2124215A (en) | 1984-02-15 |
| GB2124215B (en) | 1985-08-29 |
| FR2529551A1 (en) | 1984-01-06 |
| ES523695A0 (en) | 1984-11-01 |
| FR2529551B1 (en) | 1985-10-18 |
| BE897148A (en) | 1983-12-28 |
| CH656881A5 (en) | 1986-07-31 |
| GB8317612D0 (en) | 1983-08-03 |
| AT385990B (en) | 1988-06-10 |
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