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
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- United Kingdom
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- formula
- radical
- compound
- oxayohimbane
- hydrogen
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- 238000002560 therapeutic procedure Methods 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 12
- GRTOGORTSDXSFK-XJTZBENFSA-N ajmalicine Chemical compound C1=CC=C2C(CCN3C[C@@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 GRTOGORTSDXSFK-XJTZBENFSA-N 0.000 claims abstract description 11
- ZLQMRLSBXKQKMG-UHFFFAOYSA-N rauniticine Natural products COC(=O)C1=CC2CC3N(CCc4c3[nH]c5ccccc45)CC2C(C)O1 ZLQMRLSBXKQKMG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims abstract description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract description 3
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 claims abstract description 3
- 239000002585 base Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005809 transesterification reaction Methods 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- -1 ethoxy, propoxy Chemical group 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
- 125000005265 dialkylamine group Chemical group 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 206010000117 Abnormal behaviour Diseases 0.000 abstract description 2
- 208000012886 Vertigo Diseases 0.000 abstract description 2
- 230000001037 epileptic effect Effects 0.000 abstract description 2
- 231100000889 vertigo Toxicity 0.000 abstract description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 206010002660 Anoxia Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- CZJDUZOWQVAEEV-XIEZEKGWSA-N (+)-19-epi-Ajmalicine Natural products O=C(OC)C=1[C@@H]2[C@@H]([C@@H](C)OC=1)C[N+]1[C@H](c3[nH]c4c(c3CC1)cccc4)C2 CZJDUZOWQVAEEV-XIEZEKGWSA-N 0.000 description 2
- 241000976983 Anoxia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229940007897 ajmalicine Drugs 0.000 description 2
- 230000007953 anoxia Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Chemical group 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000003970 cerebral vascular damage Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
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
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preventing Corrosion Or Incrustation Of Metals (AREA)
- Polyesters Or Polycarbonates (AREA)
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 IT IT25251/80A patent/IT1195761B/en active
- 1980-10-09 JP JP14184380A patent/JPS5661382A/en active Pending
- 1980-10-09 ZA ZA00806246A patent/ZA806246B/en unknown
- 1980-10-10 SE SE8007121A patent/SE8007121L/en not_active Application Discontinuation
- 1980-10-10 IL IL61246A patent/IL61246A0/en unknown
- 1980-10-10 ES ES495797A patent/ES495797A0/en active Granted
- 1980-10-10 NL NL8005609A patent/NL8005609A/en not_active Application Discontinuation
- 1980-10-10 NO NO803038A patent/NO803038L/en unknown
- 1980-10-10 GB GB8032835A patent/GB2060639A/en not_active Withdrawn
- 1980-10-10 LU LU82833A patent/LU82833A1/en unknown
- 1980-10-10 DE DE19803038401 patent/DE3038401A1/en not_active Withdrawn
- 1980-10-10 BE BE0/202429A patent/BE885656A/en unknown
- 1980-10-10 PT PT71901A patent/PT71901B/en unknown
- 1980-10-10 DK DK428780A patent/DK428780A/en unknown
- 1980-10-10 GR GR63108A patent/GR70751B/el unknown
- 1980-10-10 AU AU63165/80A patent/AU6316580A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| SE8007121L (en) | 1981-04-12 |
| ZA806246B (en) | 1981-10-28 |
| IT1195761B (en) | 1988-10-27 |
| IT8025251A0 (en) | 1980-10-09 |
| JPS5661382A (en) | 1981-05-26 |
| FR2467206A1 (en) | 1981-04-17 |
| PT71901A (en) | 1980-11-01 |
| PT71901B (en) | 1981-08-31 |
| AU6316580A (en) | 1981-04-16 |
| ES8206521A1 (en) | 1982-01-16 |
| NL8005609A (en) | 1981-04-14 |
| NO803038L (en) | 1981-04-13 |
| DK428780A (en) | 1981-04-12 |
| GR70751B (en) | 1983-03-14 |
| DE3038401A1 (en) | 1981-04-23 |
| IL61246A0 (en) | 1980-12-31 |
| FR2467206B1 (en) | 1983-01-28 |
| ES495797A0 (en) | 1982-01-16 |
| LU82833A1 (en) | 1982-05-10 |
| BE885656A (en) | 1981-04-10 |
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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) |