GB2060639A - Novel oxayohimbane derivatives useful in therapy - Google Patents
Novel oxayohimbane derivatives useful in therapy Download PDFInfo
- Publication number
- GB2060639A GB2060639A GB8032835A GB8032835A GB2060639A GB 2060639 A GB2060639 A GB 2060639A GB 8032835 A GB8032835 A GB 8032835A GB 8032835 A GB8032835 A GB 8032835A GB 2060639 A GB2060639 A GB 2060639A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- radical
- compound
- oxayohimbane
- hydrogen
- 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.)
- Withdrawn
Links
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
- C07D491/22—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 four or more hetero rings
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
Oxayohimbane derivatives of the formula <IMAGE> in which R1 is a hydrogen, alkoxycarbonyl, alkoxycarbonylalkyl or alkylcarbonyl or a phenoxycarbonyl radical in which the phenyl radical thereof is unsubstituted or is substituted by a halogen atom or a nitro radical and R2 is a hydroxyl or OM radical, M representing an alkali metal or alkaline earth metal, or is an alkoxy, cycloalkylalkoxy, cycloalkoxy, -NH2, alkylamino, dialkylamino or cycloalkylamino radical, with the exception of the compounds in which simultaneously R1 is H and R2 is CH3O or OH, in which definitions alkoxy and alkyl have from 1 to 4 carbon atoms, and cycloalkyl has from 3 to 6 carbon atoms, and their pharmaceutically acceptable acid addition salts, which are useful in therapy for combatting behavioural disorders and epileptic vertigo, can be prepared from raubasine by known methods.
Description
SPECIFICATION
Oxayohimbane derivatives useful in therapy and their preparation
The present invention relates to oxayohimbane derivatives useful in therapy and their preparation.
The present invention provides oxayohimbane derivatives which are compounds of general formula (I)
in which R1 is a hydrogen atom, or an alkoxycarbonyl, alkoxycarbonylalkyl or alkylcarbonyl radical or a phenoxycarbonyl radical in which the phenyl radical thereof is unsubstituted or is substituted by a halogen atom or a nitro radical and R2 is a hydroxyl or OM radical, M representing an alkali metal or alkaline earth metal, or is an alkoxy, cycloalkylalkoxy, cycloalkoxy, -NH2, alkylamino, dialkylamino or cycloalkylamino radical, with the exception of the compounds in which simultaneously R1 is H and R2 is OH3O or OH, in which definitions the R2 alkoxy radical and the alkyl and alkoxy parts of said radicals R and R2 have from 1 to 4 carbon atoms, and the cycloalkyl part of said radicals has from 3 to 6 carbon atoms, and their pharmaceutically acceptable acid addition salts.
In the above compounds the alkyl and alkoxy radicals and parts of radicals can have a straight or branched chain, the straight chain being preferred. The preferred compounds of the invention are those in which P1 is an alkoxycarbonyl radical or an alkoxycarbonylalkyl radical. Methoxycarbonyl is the most preferred.
The oxayohimbane derivatives can be prepared by a process which comprises (i) subjecting raubasine or its corresponding acid or a reactive derivative of such an acid, of formula:
in which R3 is methoxy to transesterification or in which R3 is hydroxy or a reactive radical to esterification, respectively, with an alcohol of formula R2H (Ill) where R2 is ethoxy, propoxy or butoxy, or cycloalkylalkoxy or cycloaikoxy as defined in formula (I), to produce a compound of formula (I) in which P1 is hydrogen and R2 is as defined in formula (Ill), (ii) amidifying a compound of formula (II) in which R3 is hydroxy or a reactive radical with ammonia, an alkylamine, dialkylamine or cycloalkylamine, the alkyl and cycloalkyl radicals thereof being as defined in formula (I) to give a compound of formula (I) in which P1 is hydrogen and R2 is NH2, alkylamino, dialkylamino or cycloalkylamino, respectively, or (iii) reacting a compound of formula (I) in which R, is hydrogen or a compound of formula (II) in which R3 is hydroxy or methoxy with a strong base and a halide of formula R,X, RX being as defined in formula (I), other than hydrogen, and X being a halogen atom, to produce a compound of formula (I) in which RX is other than hydrogen, and if desired forming a pharmaceutically acceptable acid addition salt of a compound of formula (I) thus prepared, or a free base of formula (I) from a said pharmaceutically acceptable salt thereof thus prepared.
Where it is necessary to carry out an esterification, transesterification or amidation to produce the desired radical R2 and it is also necessary to produce a compound in which RX is other than hydrogen, the reactions can be carried out in either order (provided, of course, that reasonable reagents and conditions are chosen, e.g. to avoid hydrolysis of an ester when reacting the compound of formula (I) wi'th a strong base in introducing the radical R1).
The esterification reactions can be carried out by a conventional method, in particular either by direct esterification of the acid or a functional derivative preferably the acid chloride, with the alcohol
R2H (as such or as an alkali metal salt) or by transesterification of raubasine. The amides can be obtained from the corresponding acid or from one of its functional derivatives, by conventional amidification. The compounds carrying a radical R, other than hydrogen can be obtained from the compounds in which R, is H by abstracting a proton at the 1- position N-atom (forming an anion of the compound of formula (I)) for example by reacting the-starting compound, in solution in e.g.
dimethylformamide, with sodium hydride, and then adding the halide R1X (X is preferably chlorine or bromine).
The reaction can be carried out at a temperature of O to 200C. The starting compounds of formula (II) are raubasine (ajmalicine) its corresponding acid, or a reactive derivative thereof effective for ester or amide formation. Raubasine can be obtained by reduction of the quanternary base serpentine, e.g. by catalytic hydrogenation or an alkyli metal borohydride, to give the tetrahydrogenated compound, raubasine, which is a methyl ester. The corresponding acid can then be obtained by saponification of raubasine.
The following Examples illustrate the invention. The analyses and the IR and NMR spectra confirm the structure of the compounds.
EXAMPLE 1
Methyl 1 -ethoxycarbonylmethyl- 1 6,1 7-didehydro-1 9-methyl-oxayohimbane-1 6-carboxylate, formula l: Rr = CH2COOCH2CH3, P2=CO3O,compound6 1.8 g of sodium hydride are added, whilst stirring and under argon, to 6 g of raubasine (ajmalicine), dissolved in 100 ml-of dry dimethylformamide. After 50 minutes, 3.7 ml of ethyl chloroacetate are added in the course of 10 minutes with the aid of a dropping funnel, whilst stirring, under argon and at a temperature in the region of +100C. After 20 minutes, a precipitate is formed. 500
ml of water are then added and the precipitate is filtered off. The precipitate is dissolved in 200 ml of
methylene chloride. The solution is washed with water, dried over sodium sulphate and evaporated to dryness.The title compound crystallises from methanol, m.p. = 2O30O[aJ25 = 116.60 (c = I; CHC13).
EXAMPLE 2
Oxayohimbane derivatives which have been prepared similarly are summarised in the following
Table, which also includes the derivative prepared in Example 1.
TABLE fital
Melting point Compound R1 R2 Form ( C) [α]25 1 COCH3 CH3O HCl 276 -176.8 (c=0.2 ; pyridine-CH3OH 1:1) 2 COOCH3 CH3O HCl 228 -155.4 (c=0.3 ; CHCl3) 3 COOC2H5 CH3O HCl 260 4 COOC3H7(n) CH3O HCl 251 -155 (c=0.6 ; CHCl3-CH3OH 1:1) 5 # CH3O HCl 279 -145 (c=0.2 ; CHCl3-CH3OH 1:1) 6 CH2COOC2H5 CH3O Base 203 -116.6 (c=1 ; CHCl3) 7 H C4H9O HCl 300 -9.5 (c=0.8 ; CH3OH) 8 COOCH3 C4H9O 9 H NHC2H5 HCl 267-8 -28.7 (c=1.7 ; CH3OH) 10 COOCH3 NHC2H5 Base 168-9 -192.7 (c=0.7 ; CH3OH) 11 H N(CH3)2 12 COOCH3 N(CH3)2 13 COOC4H9 (n) N(CH3)2 The above salts are converted to corresponding free bases and vice-versa, in manner known per se
The oxayohimbane derivatives were subjected to pharmacological experiments.
The toxicity of the compounds was determined by intraperitioneal administration to mice. The LD 50 varies from 300 to 1,000 mg/kg.
The compounds were also subjected to the test for the anoxia caused by pressure reduction. Mice of the CDI strain were kept in an oxygen-depleted atmosphere produced by creating a partial vacuum (190 mm of mercury, corresponding to 5.25% of oxygen). The survival time of the animals was noted.
This time is increased by agents which are capable of assisting the oxygenation of tissues and in particular of the brain. The compounds studied were administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control animals, were calculated. The mean active dose (MAD), that is to say the dose which increases the survival time by 100%, was determined graphically. The MAD of the compounds of the invention varies from 10 to 60 mg/kg, when administered intraperitoneally.
These pharmacological studies show that they are active in the test for the anoxia caused in mice by pressure reduction, whist being only slightly toxic.
The oxayohimbane derivatives possess an anti-anoxia action, and can therefore be used in therapy (especially human therapy) for the treatment of vigilance disorders, in particular for combatting behavioural disorders which can be attributed to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics, and also for the treatment of epileptic vertigo due to cranial traumatisms, and the treatment of depression.
The said oxayohimbane derivatives can be administered as a pharmaceutical composition containing the oxayohimbane derivative defined above as active principle, in asociation with any excipient which is suitable for its administration, in particular oral or parenteral administration.
The methods of administration can be oral and parenteral. The daily posology can range from 10 to 200 mg.
Claims (1)
- CLAIMS:1. Oxayohimbane derivatives which are compounds of general formula (I)in which R1 is a hydrogen atom, or an alkoxycarbonyl, alkoxycarbonylalkyl or alkylcarbonyl radical or a phenoxycarbonyl radical in which the phenyl radical thereof is unsubstituted or is substituted by a halogen atom or a nitro radical and R2 is a hydroxyl or OM radical, M representing an alkali metal or alkaline earth metal, or is an alkoxy, cycloalkylalkoxy, cycloalkoxy, -NH2, alkylamino, dialkylamino or cycloalkylamino radical, with the exception of the compounds in which simultaneously R1 is H and R2 is CH3O or OH, in which definitions the R2 alkoxy radical and the alkyl and alkoxy parts of said radicals R and R2 have from 1 to 4 carbon atoms, and the cycloalkyl part of said radicals has from 3 to 6 carbon atoms, and their pharmaceutically acceptable acid addition salts.2. Derivatives according to Claim 1, wherein R1 is a said alkoxycarbonyl or alkoxycarbonylalkyl radical.3. Derivatives according to Claim 1, wherein R1 is a hydrogen atom, a said phenoxycarbonyl radical or a said alkylcarbonyl radical.4. As oxayohimbane derivatives according to Claim 1, methyl 1-methoxycarbonyl-1 6,1 7-di- dehydro-1 9a:-methyl-1 6-carboxylate and its pharmaceutically acceptable acid addition salts.5. A process for the preparation of oxayohimbane derivatives claimed in Claim 1, which process comprises (i) subjecting raubasine or itsin which R3 is methoxy to trans-esterification or in which R3 is hydroxy or a reactive radical to esterification, respectively, with an alcohol of formula R2H (III) where R2 is ethoxy, propoxy or butoxy, or cycloalkylalkoxy or cycloalkoxy as defined in formula (I), to produce a compound of formula (I) in which P1 is hydrogen and R2 is as defined in formula (III), (ii) amidifying a compound of formula (II) in which R3 is hydroxy or a reactive radical with ammonia, an alkylamine, dialkylamine or cycloalkylamine, the alkyl and cycloalkyl radicals thereof being as defined in formula (I) to give a compound of formula (I) in which R, is hydrogen and R2 is NH2, alkylamino, dialkylamino or cycloalkylamino, respectively, or (iii) reacting a compound of formula (I) in which R1 is hydrogen or a compound of formula (Il) in which R3 is hydroxy or methoxy with a strong base and a halide of formula R X, P1 being as defined in formula (I), other than hydrogen, and X being a halogen atom, to produce a compound of formula (I) in which R1 is other than hydrogen, and if desired forming a pharmaceutically acceptable acid addition salt of a compound of formula (I) thus prepared, or a free base of formula (I) from a said pharmaceutically acceptable salt thereof thus prepared.7. Oxayohimbane derivatives according to claim 1 when prepared by a process claimed in Claim 68. A pharmaceutical composition comprising an oxayohimbane derivative claimed in any one of Claims 1 to 5 or in Claim 7, in association with a pharmaceutically acceptable excipient.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7925353A FR2467206A1 (en) | 1979-10-11 | 1979-10-11 | OXAYOHIMBANE-CARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
Publication Number | Publication Date |
---|---|
GB2060639A true GB2060639A (en) | 1981-05-07 |
Family
ID=9230588
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8032835A Withdrawn GB2060639A (en) | 1979-10-11 | 1980-10-10 | Novel oxayohimbane derivatives useful in therapy |
Country Status (17)
Country | Link |
---|---|
JP (1) | JPS5661382A (en) |
AU (1) | AU6316580A (en) |
BE (1) | BE885656A (en) |
DE (1) | DE3038401A1 (en) |
DK (1) | DK428780A (en) |
ES (1) | ES495797A0 (en) |
FR (1) | FR2467206A1 (en) |
GB (1) | GB2060639A (en) |
GR (1) | GR70751B (en) |
IL (1) | IL61246A0 (en) |
IT (1) | IT1195761B (en) |
LU (1) | LU82833A1 (en) |
NL (1) | NL8005609A (en) |
NO (1) | NO803038L (en) |
PT (1) | PT71901B (en) |
SE (1) | SE8007121L (en) |
ZA (1) | ZA806246B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4125137C2 (en) * | 1991-07-30 | 1995-06-14 | Icos Ges Fuer Ind Communicatio | Control panel for processing and measuring machines |
-
1979
- 1979-10-11 FR FR7925353A patent/FR2467206A1/en active Granted
-
1980
- 1980-10-09 ZA ZA00806246A patent/ZA806246B/en unknown
- 1980-10-09 JP JP14184380A patent/JPS5661382A/en active Pending
- 1980-10-09 IT IT25251/80A patent/IT1195761B/en active
- 1980-10-10 GR GR63108A patent/GR70751B/el unknown
- 1980-10-10 PT PT71901A patent/PT71901B/en unknown
- 1980-10-10 BE BE0/202429A patent/BE885656A/en unknown
- 1980-10-10 AU AU63165/80A patent/AU6316580A/en not_active Abandoned
- 1980-10-10 NO NO803038A patent/NO803038L/en unknown
- 1980-10-10 SE SE8007121A patent/SE8007121L/en not_active Application Discontinuation
- 1980-10-10 LU LU82833A patent/LU82833A1/en unknown
- 1980-10-10 DE DE19803038401 patent/DE3038401A1/en not_active Withdrawn
- 1980-10-10 NL NL8005609A patent/NL8005609A/en not_active Application Discontinuation
- 1980-10-10 GB GB8032835A patent/GB2060639A/en not_active Withdrawn
- 1980-10-10 DK DK428780A patent/DK428780A/en unknown
- 1980-10-10 IL IL61246A patent/IL61246A0/en unknown
- 1980-10-10 ES ES495797A patent/ES495797A0/en active Granted
Also Published As
Publication number | Publication date |
---|---|
LU82833A1 (en) | 1982-05-10 |
IT8025251A0 (en) | 1980-10-09 |
ES8206521A1 (en) | 1982-01-16 |
PT71901B (en) | 1981-08-31 |
FR2467206A1 (en) | 1981-04-17 |
DE3038401A1 (en) | 1981-04-23 |
SE8007121L (en) | 1981-04-12 |
FR2467206B1 (en) | 1983-01-28 |
NL8005609A (en) | 1981-04-14 |
NO803038L (en) | 1981-04-13 |
BE885656A (en) | 1981-04-10 |
ZA806246B (en) | 1981-10-28 |
IT1195761B (en) | 1988-10-27 |
JPS5661382A (en) | 1981-05-26 |
PT71901A (en) | 1980-11-01 |
IL61246A0 (en) | 1980-12-31 |
AU6316580A (en) | 1981-04-16 |
DK428780A (en) | 1981-04-12 |
ES495797A0 (en) | 1982-01-16 |
GR70751B (en) | 1983-03-14 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |