CA1117939A - Derivatives of eburnamomine and related method of manufacturing - Google Patents
Derivatives of eburnamomine and related method of manufacturingInfo
- Publication number
- CA1117939A CA1117939A CA000321006A CA321006A CA1117939A CA 1117939 A CA1117939 A CA 1117939A CA 000321006 A CA000321006 A CA 000321006A CA 321006 A CA321006 A CA 321006A CA 1117939 A CA1117939 A CA 1117939A
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- Prior art keywords
- acid
- vincamone
- ethanol
- glucose
- phosphate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
- C07H11/04—Phosphates; Phosphites; Polyphosphates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/126—Acids containing more than four carbon atoms
- C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
- C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
- C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
-
- 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
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Abstract
Abstract The invention relates to a group of compounds having therapeuti-cal activity at the cerebrovascular level, more particularly having vasodilating activity comprising derivatives of eburnamonine having the general formula :
wherein X is the radical of an acid of the group comprising glucose--1-phosphate acid, acetylsalicylic acid, pamoic acid, 2,4-dihydro xybenzoic acid, 3,5-dihydroxybenzoic acid pivalic acid and clofibric acid.
The process of the invention comprise reacting a suspension or so-lution of the eburnamonine, depending on the desired derivative, in a stechiometrical ratio andat a temperature controlled by the boiling point of the reaction solvent, with the acid, preferably in form of a solution and under stirring until be reaction is completed, the reaction product being thereafter separated.
wherein X is the radical of an acid of the group comprising glucose--1-phosphate acid, acetylsalicylic acid, pamoic acid, 2,4-dihydro xybenzoic acid, 3,5-dihydroxybenzoic acid pivalic acid and clofibric acid.
The process of the invention comprise reacting a suspension or so-lution of the eburnamonine, depending on the desired derivative, in a stechiometrical ratio andat a temperature controlled by the boiling point of the reaction solvent, with the acid, preferably in form of a solution and under stirring until be reaction is completed, the reaction product being thereafter separated.
Description
3~
NOVEL DERlVATlVES OF EBURNAMONINE ANV RELATED ME-THOD OF MAI`IUFA.CTU RING "
O O O O O O
The present invention relates to novel derivatives of eburnamonine having interesting therapeutical properties at the cerebrovascular level, and more particularly having cerebral vasodilating action, u seful for the prevention and the treatment of the cerebro-vascular diseases .
The eburnamomine (the laevorotatory form of which is known as vin camone) having the formula (I):
~ ' (I) is a compound already known and used in the therapy of the cerebro-vascular diseases, due to the efficacious vasoregulating action thereof at the cerebral level and also due to its capability of activating the metabolism of the nervous cells.
The eburnamonine in the dextro-~aevo-rotatory and racemic forms has been the subject of rather intense studies as regards the structu-re and characterization, as well the preparation thereof. In this con-nection there are known and reported in the literat~re:
1. processes for its extraction and isolation from several vegetable spe cies, belonging to the family of Apocinaceae (for instance, Hunteria e-burnea, Amsonia tabernaemontana, Vinca m~ etc.)~~DT-OS
1,933,110; DT-PS 1,187,031; Doepke et al., Pharmazia, 21 (7), ~i/l/l (1966) etc.)
NOVEL DERlVATlVES OF EBURNAMONINE ANV RELATED ME-THOD OF MAI`IUFA.CTU RING "
O O O O O O
The present invention relates to novel derivatives of eburnamonine having interesting therapeutical properties at the cerebrovascular level, and more particularly having cerebral vasodilating action, u seful for the prevention and the treatment of the cerebro-vascular diseases .
The eburnamomine (the laevorotatory form of which is known as vin camone) having the formula (I):
~ ' (I) is a compound already known and used in the therapy of the cerebro-vascular diseases, due to the efficacious vasoregulating action thereof at the cerebral level and also due to its capability of activating the metabolism of the nervous cells.
The eburnamonine in the dextro-~aevo-rotatory and racemic forms has been the subject of rather intense studies as regards the structu-re and characterization, as well the preparation thereof. In this con-nection there are known and reported in the literat~re:
1. processes for its extraction and isolation from several vegetable spe cies, belonging to the family of Apocinaceae (for instance, Hunteria e-burnea, Amsonia tabernaemontana, Vinca m~ etc.)~~DT-OS
1,933,110; DT-PS 1,187,031; Doepke et al., Pharmazia, 21 (7), ~i/l/l (1966) etc.)
2) partial synthesis processes, starting from natural alkaloids, su-ch as for example those described in the Hungarian patent No. 151,2957 in the French patent No. 2,209,757, in the paper by Hugel G. et al., Bull. Soc. Chim. Franc. 1965, 2497, etc.
3) total synthesis processes; such as for example -those described in:
- Bartlett M.E. et al., Tetrahedron Lett., 1959, 20;
- Werkert E. e-t al., J. Am. Chem. Soc., 87, 1580, 1965;
- Belgian patents Nos . 776 ,337 and 802 ,913 .
However the therapeutical effec-t thereof, through the several admi-nistration routes, is characterized by a short duration, as caused by the quick elimination thereof, whereby several administrations are needed in the 24 hour period.
It has been now found, and it is the object of the present invention, that some salts of the vincamone are e~dowed with a like therapeutical activity together with a time delayed effect, namely- have the so-cal-led long-acting effect, these salts having the following general formu-la (II):
~ N X
0//~ - 2 -Et ~ 7 ~
wherein X represents the radical of a compound selected in the class comprising glucose-l-phosphate acid, clo~ibric acid, acetylsalicy-lic acid, pamoic acid, 2,4-dihydroxyben~oic acid, 3,5-dihydroxy-benzoic acid and pivalic acid. Among the above compounds, -the e-quimolar association of vincamone and glucose-l-phosphate sodium salt is furthermore of interest.
The general process for the preparation of the compounds of the in-stOc~, 0,~ ,ca/
vention comprises reacting, in stechio~nctrical ratio, the-vincamone, which according to the desired derivative is in form of a solution or suspension in lower aliphatic alcohol, chloroform or their mixtures, with the acid, preferably in form of a solution in a lower aliphatic al ,o~c~ v~
cohol or water, the reaction being effected,~rhot ~at a tempe-- rature controlled by the boiling point of the solvent mixture and under stirring, until the reaction is completed, the reaction product being thereafter separated by filtration or by concentration to a residue of the reaction mixture.
The following examples detailedly illustrate the presen-t invention.
Vincamone glucose-l-phosphate bisodium salt This compound is in fact an equimolar association, the raw formula being ClgH22N20. C6HllNa209P, whereas -the structural formula is as follows:
~ P_Olla 0~
~-2 ~inca~o~ e _~ 5.9 g (2.10 moles) of ~-~Pws~ are disso]ved in a mi~ture of '~ ethanol and chloroform, the solution being prepared uncler heaciny in a water bath and under stirring.
Then a solution of 6.9 g of glucose-l-phosphate bisod-ium salt tetrahydrate in the minimurn amount of water is added dropwise and the mixture is maintained at 70C ancl under stirrin~
for 30 minutes and then concentrated at the-- ~ pres-sure to a small volume. Then 80-lO0 mls OL ethanol are added and the solvent is distilled to a residue. This ste~ is repeated two times, the reaction mixture being finally brouht to a vol- -' ume of a~out l5 to 20 mls.
The precipitation of the reaction product is completed ;`
by maintaining the reac-tion mixture on standing in an ice bath.
After filtration and drying of the product in an air circulation oven at 60C, about ll g are obtained of a white crystalline substance, which is not soluble in water and alcohol, having total melting point of about l80C.
T~e content of vincarnone in this adduct is 49QO.
E~IPI.E 2 ~eutral vincamone ~lucose-l~phosphate --O H OH OH
, iL$~
5.9 g (2.10 mol- s) of vincamone are suspended in a mixture of 250 mls of ethanol and 40 mls of chloroforrrl.
The suspension is heated to 70C i a water bath, under stirring,and is dropwise added with a water solution of 2.6 g (10 moles) of gluco-se-1-phosphate acid.
The mixture is main-tained under stirring and at the boiling point for 30 minutes and then concentrated to a small volurne under reduced pressu-re .
The r~sidue is taken with 2 x 200 mls ethanol and finally concentrated to 80 mls.
The product is crystallized by putting the reactor in an ice bath.Af-ter filtration and drying in an air circulating oven at 70C, there a-re obtained about 7 g of a white, crystalline, solid product, which is insoluble in water and alcohol.
m.p.: about 170C (with decomposition).
The vincamone dosage in the salt is 66%.
Vincamone glucose - 1-phosphate, acid salt ~ /\ CH20H
\N~/ H~O--1~
\ H 01-1 ~ \/
Et ~7~ ~
25 35N210P - M W- = 554.5 The example 2 is repeated, except that 5.9 g (2.10 moles) o~-vi-n camone and 5.2 g of glucose-1-phosphate acid are used.
There are obtained about 10 g of a white, crystalline product, so-luble in water and having melting point of abou-t 175C with decom-position .
The vincamone content of the salt is 50%.
Vincamone 2,4-dihydroxy-benzoate ~) \\
lS Et C26H28N205 - M.W.= 448.5 A suspension comprising 5.9 g ( 2.10 moles) of vincamone and 100 mls of ethanol is heated to boiling and then gradually added with a solution of 3.1 g (2.10 moles) of 2,4-dihydroxybenzoic acid in ethanol.
The boiling condition is maintained for about one hour, possibly adding chloroform so as to obtain a homogeneous solution. The reaction mixture is then concentrated under reduced pressure to a small volume and the precipitation of the salt is completed by .
, . , . ~
.. .
diluting with ethyl ether. Af-ter filtra-tion and drying in an air circu-lating oven at 60C, there are obtained about 8 g of a salt, water insoluble and poorly so~uble in alcohol, having melting point of 183--185C .
The vincamone content of the salt is 65.5%.
Vincamone 3,5-dihydrox~ben7Oate COOH
0 ~N HOJ~\OH
The preparation is carried out according to the precise conditions of the preceding example.
There are obtained about 8.5 g of a white, crystalline product,inso-luble in water and poorly soluble in alcohol, having melting point of 185-187C. In this case the vincamone content of the salt is slightly lower than that found in the preceding example Vincamone acetylsalicylate C 8H30N205- M.W.= 474.6 A solution of 3.6. g (2.10 moles) of acetylsalicyclic acid in 30 mls of ethanol is added -to a solution of 5.9 g (2.10 moles) of vincamone ,:
.
~7~
in a mixture of ethanol and chloroform.
The mixture is maintained to boiling under stirring for 10 minutes, concentrated to a small volume, taken with ethanol and then the sol-10 vent is evaporated until a final volume of 10 mls is attained. The saltprecipitation is completed by adding ether, the mixture being cooled in an ice bath.
After filtration and drying in an oven under vacuum at 40C, about 8 g of a product insoluble in water, poorly soluble in al-cohol and having total melting point of about 150C.
The vincamone content is about 59.1%
Vincamone pivalate ~ CH3--C--COOH
25C24H32N203- M.W.= 396.75 11 g of this salt are prepared, according to the conditions of the , , . ,, : ~. ~ , i. ..
preceding examples, starting from 8.83 g (3.10 moles) of vincamo-ne and 3.06 g (3.10 2moles) of piva~c acid. The resulting product is insoluble in water, poorly soluble in alcohol and does totally melt at 168C.
The vincamone content of the salt is 74.6%.
EXAMPLE 8 Cl Vincamone clofibra~e ~ ~3 C29H33Cl N204 - M.W.= 509 CH3 The procedure of the examples 5,6 and 7 is repeated starting from 5.9 g ( 2 .10 2moles) of vincamone and 4.3 g (2 .10 moles) of clofi~
bric acid.
15 The final product (about 9 g) is a low melting solid (at 65C), with a total melting occurring at 135C, which is insoluble in water and poorly soluble ir: alcohol, the vincamone content being 50 . 3%
r O~ ~ CH2 L ~ 2 ~ COOH
? ~
S.9 g (2.10 moles) o:F vincamone are dissolved in 20 mls of N HCl;
possibly adding a small amount of methanol to prom ,te the solving of the substance.
A solution comprising 3.88 g (10 moles) of pamoic acid in 20 mls of N NaOH is separatedly prepared and dropwise added under stir-ring to the vincamone solution.
Upon the addition is completed, the stirring is continuated for 10 minutes further, the precipitate is filtered, washed with water in-to the filter and then dried in an oven under reduced pressure at 80C .
There are obtained about 8 g of a product, insoluble in water and alcohol, ha~-ring total melting point of 175C.
The vincamone content of the salt is 60.9%.
The novel derivatives according to the invention have been tested from the pharmacological point of view, and the following prope:r-ties have been particularly examined:
- acute toxicity by intraperitoneal route;
- hematic levels and urinary recovery;
- variations of the hematic flow in the cerebral ar-teria as well as of the cerebro-vascular resistances.
A-acute toxicity The acute toxicity has been determined in the mouse, type COBS
CD-1 (Charles River), having an average body weight of 20-25 g and of male sex., groups of three animals being used and evaluated on the basis of the average lethal dose (observation time: 8 days) The compounds were administered as a suspension in 1% car~oxyme-thylcellulose .
-The results of the tests of acute toxicity confirmed that the compounds of the invention, when administered by the parenteral route are scar-cel y toxic .
B- Absorption All the compounds have been orally administered a-t the dosage of 1OO mg/kg, expressed as vincamone, in form of a suspension in 1% carboxymethylcellulose, to albine male rats, G~` the COBS type and of average body weight of 250 g.
The absorption was determined by evaluating the hematic levels at the following times (minutes):O, 30,60, 120,240,360, and 480.
There was also assessed the urinary elimination at the following times (hours): 8, 24 and 48.
The vincamone concentrations were determined by the chromato-graphic me-thod.
All the tested compounds show a good absorption followed by a quick elimination. More particularly, from the abs~orptio~ data, as reported in Table 1, it can be appreciated that the compound of example 3 shows a relevant " deiayecl", effect. A greater bio--availability with respect to the vincamone is also shown by the compounds of the examples 5, 7 and 9.
C- Hematic flow The cerebral vasodilating activity was studied in Beagle dogs, f average body weight of 15 kg, the animals being anestetized with sodium Thiopental (30 mg/kg i p.) . The right vertebral ar-, - ., ~ . ~ , .
,; ..~ .
tery of the animals was isolated and the hematic flow was recorded by means of a flow transducer connect~d to an electromagnetic flow-meter Statham SP 2201, in turn connec-tcd -to a Med.ium Gain Ampli-fier Hewlett Packard 8802A.
Hematic levels (as/ug/ml) of vincamone after administration per os in the rat of the deri~ati.ves of the invention Compound Time from the administration, hours 0.5 1 2 4 6 8 Example 1 1,07 1.69 0.94 0,65 0.18 ----Example 2 1~62 2.63 1.06 traces ---- ------Example 3 traces 0.13 0.79 0.82 1.69 1.28 Example 4 0.15 1.34 1.30 traces ----- ----~--Example 5 0.13 1.78 2.37 1.39 0.68 traces Example 6 N.D. N.D. N.D. N.D.N.D. N.D.
Example 7 0.18 3.01 2.95 1~05traces ------Example 8 N.D. N.D. N.D. N.D. N.D. N.D.
Example 9 1.191.27 1.55 1.32 traces ----Vincamone 1.372.20 1 .04 0.42 traces -----N.D. not determined The arterial pressure in the right femoral artery was also recorded by means of a Hewlett Packard l280C transducer, in turn connected to a Carrier Amplifier Hawlett Packard 8805B.
. .
The compounds ~vere administered by intravenous route in the right femoral vein at doses corresponding to 4 mg/kg of vincamone.
For the evalu-tazion ~f the vasodilating effect of the vincamone deri-vatives, both the percent variations of the cerebral flow as caused by the compounds of the invention and the maximum percen-t variation of the cerebrovascular resistance were compared.
The results confirmed that all the tested compounds have vasodilating action at the level of the right vertebral artery which controls the cerebral circulation.
o O o o o ', ;
- Bartlett M.E. et al., Tetrahedron Lett., 1959, 20;
- Werkert E. e-t al., J. Am. Chem. Soc., 87, 1580, 1965;
- Belgian patents Nos . 776 ,337 and 802 ,913 .
However the therapeutical effec-t thereof, through the several admi-nistration routes, is characterized by a short duration, as caused by the quick elimination thereof, whereby several administrations are needed in the 24 hour period.
It has been now found, and it is the object of the present invention, that some salts of the vincamone are e~dowed with a like therapeutical activity together with a time delayed effect, namely- have the so-cal-led long-acting effect, these salts having the following general formu-la (II):
~ N X
0//~ - 2 -Et ~ 7 ~
wherein X represents the radical of a compound selected in the class comprising glucose-l-phosphate acid, clo~ibric acid, acetylsalicy-lic acid, pamoic acid, 2,4-dihydroxyben~oic acid, 3,5-dihydroxy-benzoic acid and pivalic acid. Among the above compounds, -the e-quimolar association of vincamone and glucose-l-phosphate sodium salt is furthermore of interest.
The general process for the preparation of the compounds of the in-stOc~, 0,~ ,ca/
vention comprises reacting, in stechio~nctrical ratio, the-vincamone, which according to the desired derivative is in form of a solution or suspension in lower aliphatic alcohol, chloroform or their mixtures, with the acid, preferably in form of a solution in a lower aliphatic al ,o~c~ v~
cohol or water, the reaction being effected,~rhot ~at a tempe-- rature controlled by the boiling point of the solvent mixture and under stirring, until the reaction is completed, the reaction product being thereafter separated by filtration or by concentration to a residue of the reaction mixture.
The following examples detailedly illustrate the presen-t invention.
Vincamone glucose-l-phosphate bisodium salt This compound is in fact an equimolar association, the raw formula being ClgH22N20. C6HllNa209P, whereas -the structural formula is as follows:
~ P_Olla 0~
~-2 ~inca~o~ e _~ 5.9 g (2.10 moles) of ~-~Pws~ are disso]ved in a mi~ture of '~ ethanol and chloroform, the solution being prepared uncler heaciny in a water bath and under stirring.
Then a solution of 6.9 g of glucose-l-phosphate bisod-ium salt tetrahydrate in the minimurn amount of water is added dropwise and the mixture is maintained at 70C ancl under stirrin~
for 30 minutes and then concentrated at the-- ~ pres-sure to a small volume. Then 80-lO0 mls OL ethanol are added and the solvent is distilled to a residue. This ste~ is repeated two times, the reaction mixture being finally brouht to a vol- -' ume of a~out l5 to 20 mls.
The precipitation of the reaction product is completed ;`
by maintaining the reac-tion mixture on standing in an ice bath.
After filtration and drying of the product in an air circulation oven at 60C, about ll g are obtained of a white crystalline substance, which is not soluble in water and alcohol, having total melting point of about l80C.
T~e content of vincarnone in this adduct is 49QO.
E~IPI.E 2 ~eutral vincamone ~lucose-l~phosphate --O H OH OH
, iL$~
5.9 g (2.10 mol- s) of vincamone are suspended in a mixture of 250 mls of ethanol and 40 mls of chloroforrrl.
The suspension is heated to 70C i a water bath, under stirring,and is dropwise added with a water solution of 2.6 g (10 moles) of gluco-se-1-phosphate acid.
The mixture is main-tained under stirring and at the boiling point for 30 minutes and then concentrated to a small volurne under reduced pressu-re .
The r~sidue is taken with 2 x 200 mls ethanol and finally concentrated to 80 mls.
The product is crystallized by putting the reactor in an ice bath.Af-ter filtration and drying in an air circulating oven at 70C, there a-re obtained about 7 g of a white, crystalline, solid product, which is insoluble in water and alcohol.
m.p.: about 170C (with decomposition).
The vincamone dosage in the salt is 66%.
Vincamone glucose - 1-phosphate, acid salt ~ /\ CH20H
\N~/ H~O--1~
\ H 01-1 ~ \/
Et ~7~ ~
25 35N210P - M W- = 554.5 The example 2 is repeated, except that 5.9 g (2.10 moles) o~-vi-n camone and 5.2 g of glucose-1-phosphate acid are used.
There are obtained about 10 g of a white, crystalline product, so-luble in water and having melting point of abou-t 175C with decom-position .
The vincamone content of the salt is 50%.
Vincamone 2,4-dihydroxy-benzoate ~) \\
lS Et C26H28N205 - M.W.= 448.5 A suspension comprising 5.9 g ( 2.10 moles) of vincamone and 100 mls of ethanol is heated to boiling and then gradually added with a solution of 3.1 g (2.10 moles) of 2,4-dihydroxybenzoic acid in ethanol.
The boiling condition is maintained for about one hour, possibly adding chloroform so as to obtain a homogeneous solution. The reaction mixture is then concentrated under reduced pressure to a small volume and the precipitation of the salt is completed by .
, . , . ~
.. .
diluting with ethyl ether. Af-ter filtra-tion and drying in an air circu-lating oven at 60C, there are obtained about 8 g of a salt, water insoluble and poorly so~uble in alcohol, having melting point of 183--185C .
The vincamone content of the salt is 65.5%.
Vincamone 3,5-dihydrox~ben7Oate COOH
0 ~N HOJ~\OH
The preparation is carried out according to the precise conditions of the preceding example.
There are obtained about 8.5 g of a white, crystalline product,inso-luble in water and poorly soluble in alcohol, having melting point of 185-187C. In this case the vincamone content of the salt is slightly lower than that found in the preceding example Vincamone acetylsalicylate C 8H30N205- M.W.= 474.6 A solution of 3.6. g (2.10 moles) of acetylsalicyclic acid in 30 mls of ethanol is added -to a solution of 5.9 g (2.10 moles) of vincamone ,:
.
~7~
in a mixture of ethanol and chloroform.
The mixture is maintained to boiling under stirring for 10 minutes, concentrated to a small volume, taken with ethanol and then the sol-10 vent is evaporated until a final volume of 10 mls is attained. The saltprecipitation is completed by adding ether, the mixture being cooled in an ice bath.
After filtration and drying in an oven under vacuum at 40C, about 8 g of a product insoluble in water, poorly soluble in al-cohol and having total melting point of about 150C.
The vincamone content is about 59.1%
Vincamone pivalate ~ CH3--C--COOH
25C24H32N203- M.W.= 396.75 11 g of this salt are prepared, according to the conditions of the , , . ,, : ~. ~ , i. ..
preceding examples, starting from 8.83 g (3.10 moles) of vincamo-ne and 3.06 g (3.10 2moles) of piva~c acid. The resulting product is insoluble in water, poorly soluble in alcohol and does totally melt at 168C.
The vincamone content of the salt is 74.6%.
EXAMPLE 8 Cl Vincamone clofibra~e ~ ~3 C29H33Cl N204 - M.W.= 509 CH3 The procedure of the examples 5,6 and 7 is repeated starting from 5.9 g ( 2 .10 2moles) of vincamone and 4.3 g (2 .10 moles) of clofi~
bric acid.
15 The final product (about 9 g) is a low melting solid (at 65C), with a total melting occurring at 135C, which is insoluble in water and poorly soluble ir: alcohol, the vincamone content being 50 . 3%
r O~ ~ CH2 L ~ 2 ~ COOH
? ~
S.9 g (2.10 moles) o:F vincamone are dissolved in 20 mls of N HCl;
possibly adding a small amount of methanol to prom ,te the solving of the substance.
A solution comprising 3.88 g (10 moles) of pamoic acid in 20 mls of N NaOH is separatedly prepared and dropwise added under stir-ring to the vincamone solution.
Upon the addition is completed, the stirring is continuated for 10 minutes further, the precipitate is filtered, washed with water in-to the filter and then dried in an oven under reduced pressure at 80C .
There are obtained about 8 g of a product, insoluble in water and alcohol, ha~-ring total melting point of 175C.
The vincamone content of the salt is 60.9%.
The novel derivatives according to the invention have been tested from the pharmacological point of view, and the following prope:r-ties have been particularly examined:
- acute toxicity by intraperitoneal route;
- hematic levels and urinary recovery;
- variations of the hematic flow in the cerebral ar-teria as well as of the cerebro-vascular resistances.
A-acute toxicity The acute toxicity has been determined in the mouse, type COBS
CD-1 (Charles River), having an average body weight of 20-25 g and of male sex., groups of three animals being used and evaluated on the basis of the average lethal dose (observation time: 8 days) The compounds were administered as a suspension in 1% car~oxyme-thylcellulose .
-The results of the tests of acute toxicity confirmed that the compounds of the invention, when administered by the parenteral route are scar-cel y toxic .
B- Absorption All the compounds have been orally administered a-t the dosage of 1OO mg/kg, expressed as vincamone, in form of a suspension in 1% carboxymethylcellulose, to albine male rats, G~` the COBS type and of average body weight of 250 g.
The absorption was determined by evaluating the hematic levels at the following times (minutes):O, 30,60, 120,240,360, and 480.
There was also assessed the urinary elimination at the following times (hours): 8, 24 and 48.
The vincamone concentrations were determined by the chromato-graphic me-thod.
All the tested compounds show a good absorption followed by a quick elimination. More particularly, from the abs~orptio~ data, as reported in Table 1, it can be appreciated that the compound of example 3 shows a relevant " deiayecl", effect. A greater bio--availability with respect to the vincamone is also shown by the compounds of the examples 5, 7 and 9.
C- Hematic flow The cerebral vasodilating activity was studied in Beagle dogs, f average body weight of 15 kg, the animals being anestetized with sodium Thiopental (30 mg/kg i p.) . The right vertebral ar-, - ., ~ . ~ , .
,; ..~ .
tery of the animals was isolated and the hematic flow was recorded by means of a flow transducer connect~d to an electromagnetic flow-meter Statham SP 2201, in turn connec-tcd -to a Med.ium Gain Ampli-fier Hewlett Packard 8802A.
Hematic levels (as/ug/ml) of vincamone after administration per os in the rat of the deri~ati.ves of the invention Compound Time from the administration, hours 0.5 1 2 4 6 8 Example 1 1,07 1.69 0.94 0,65 0.18 ----Example 2 1~62 2.63 1.06 traces ---- ------Example 3 traces 0.13 0.79 0.82 1.69 1.28 Example 4 0.15 1.34 1.30 traces ----- ----~--Example 5 0.13 1.78 2.37 1.39 0.68 traces Example 6 N.D. N.D. N.D. N.D.N.D. N.D.
Example 7 0.18 3.01 2.95 1~05traces ------Example 8 N.D. N.D. N.D. N.D. N.D. N.D.
Example 9 1.191.27 1.55 1.32 traces ----Vincamone 1.372.20 1 .04 0.42 traces -----N.D. not determined The arterial pressure in the right femoral artery was also recorded by means of a Hewlett Packard l280C transducer, in turn connected to a Carrier Amplifier Hawlett Packard 8805B.
. .
The compounds ~vere administered by intravenous route in the right femoral vein at doses corresponding to 4 mg/kg of vincamone.
For the evalu-tazion ~f the vasodilating effect of the vincamone deri-vatives, both the percent variations of the cerebral flow as caused by the compounds of the invention and the maximum percen-t variation of the cerebrovascular resistance were compared.
The results confirmed that all the tested compounds have vasodilating action at the level of the right vertebral artery which controls the cerebral circulation.
o O o o o ', ;
Claims (22)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a derivative of vincamone having therapeutical activity of vincamone as well as a time delayed effect, having the following general formula (I) (I) wherein X is the radical of an acid of the group comprising glucose l-phosphate acid or an alkali metal salt thereof, 2,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, acetyl-salicyclic acid, pivalic acid, clofibric acid and pamoic acid comprising reacting vincamone in a stoichiometrical ratio with the acid.
2. A process according to claim 1, in which the vincamone is in the form of a solution or suspension in a lower aliphatic alcohol; chloroform or a mixture thereof and the acid is in the form of a solution or suspension in a lower aliphatic alcohol or water, the reaction being conducted at a temperature depending on the boiling point of the solvent mixture and under stirring, until the reaction is completed, the reaction product being thereafter separated from the reaction mixture.
3. A derivative of vincamone having therapeutical activity of vincamone as well as a time delayed effect, having the following general formula (I) (I) wherein X is the radical of an acid of the group comprising glucose l-phosphate acid or an alkali metal salt thereof, 2,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, acetylsalicyclic acid, pivalic acid, clofibric acid and pamoic acid whenever prepared or produced by the process as claimed in claim 1 or 2 or an obvious chemical equivalent thereof.
4. A process according to claim 1, which comprises the equimolar reaction of vincamone and bisodium glucose-l-phosphate.
5. A process according to claim 1, which comprises reacting vincamone in a mixture of ethanol and chloroform with glucose l-phosphate bisodium salt tetrahydrate in water.
6. Vincamone glucose-l-phosphate bisodium salt when-ever prepared or produced by the process as claimed in claim 4 or 5 or an obvious chemical equivalent thereof.
7. A process according to claim 1, which comprises reacting vincamone in a mixture of ethanol and chloroform with heating with an aqueous solution of glucose-l-phosphate acid in a molar ratio of 2:1.
8. Vincamone glucose-l-phosphate neutral salt when-ever prepared or produced by the process as claimed in claim 7 or an obvious chemical equivalent thereof.
9. A process according to claim 1, which comprises reacting vincamone in a mixture of ethanol and chloroform with heating with an aqueous solution of glucose-l-phosphate acid in a molar ratio of 1:1.
10. Vincamone glucose-l-phosphate acid salt when-ever prepared or produced by the process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process according to claim 1, which comprises reacting vincamone in ethanol at boiling with 2,4-dihydroxy -benzoic acid in ethanol.
12. Vincamone 2,4-dihydroxybenzoate whenever pre-pared or produced by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process according to claim 1, which comprises reacting vincamone in ethanol at boiling with 3,5-dihydroxy-benzoic acid in ethanol.
14. A derivative according to claim 1, which is vincamone 3,5-dihydroxybenzoate whenever prepared or produced by the process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process according to claim 1, which comprises reacting acetylsalicyclic acid in ethanol with vincamone in a mixture of ethanol and chloroform with boiling.
16. Vincamone acetylsalicylate whenever prepared or produced by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process according to claim 1, which comprises reacting pivolic acid in ethanol with vincamone in a mixture of ethanol and chloroform with boiling.
18. Vincamone pivalate whenever prepared or produced by the process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. A process according to claim 1, which comprises reacting clofibric acid in ethanol with vincamone in a mixture of ethanol and chloroform with boiling.
20. Vincamone clofibrate whenever prepared or produced by the process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. A process according to claim 1, which comprises reacting vincamone in hydrochloric acid with pamoic acid in sodium hydroxide solution.
22. Vincamone pamoate whenever prepared or produced by the process as claimed in claim 21 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1674/78-7 | 1978-02-15 | ||
| CH167478 | 1978-02-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1117939A true CA1117939A (en) | 1982-02-09 |
Family
ID=4215945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000321006A Expired CA1117939A (en) | 1978-02-15 | 1979-02-07 | Derivatives of eburnamomine and related method of manufacturing |
Country Status (12)
| Country | Link |
|---|---|
| AT (1) | AT368155B (en) |
| AU (1) | AU523984B2 (en) |
| BE (1) | BE874154A (en) |
| CA (1) | CA1117939A (en) |
| DE (1) | DE2905329A1 (en) |
| ES (1) | ES477754A1 (en) |
| FR (1) | FR2417511A1 (en) |
| GB (1) | GB2017088B (en) |
| IT (1) | IT1207171B (en) |
| NL (1) | NL7901107A (en) |
| NZ (1) | NZ189650A (en) |
| ZA (1) | ZA79564B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU187139B (en) * | 1982-06-30 | 1985-11-28 | Richter Gedeon Vegyeszet | Process for preparing new eburnan derivatives |
| ES8507140A1 (en) * | 1984-05-10 | 1985-09-01 | Covex Sa | Citric-acid salt of (-)vinburnine and process for its preparation. |
| US8198292B2 (en) * | 2008-07-03 | 2012-06-12 | Osteogenex, Inc. | Vinpocetine and eburnamonine derivatives for promoting bone growth, treating renal damage and cancer, and devices thereof |
Family Cites Families (3)
| 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 |
| FR2228471A2 (en) * | 1973-05-09 | 1974-12-06 | Synthelabo | Medicaments contg aneburnan-type base and ascorbic acid - - with rapid resorption on oral administration |
| GB1549501A (en) * | 1976-06-03 | 1979-08-08 | Mora E | Adducts of vincamine and apovincamine |
-
1979
- 1979-02-07 CA CA000321006A patent/CA1117939A/en not_active Expired
- 1979-02-09 ZA ZA79564A patent/ZA79564B/en unknown
- 1979-02-12 NL NL7901107A patent/NL7901107A/en not_active Application Discontinuation
- 1979-02-13 DE DE19792905329 patent/DE2905329A1/en not_active Withdrawn
- 1979-02-14 FR FR7903737A patent/FR2417511A1/en not_active Withdrawn
- 1979-02-14 GB GB7905197A patent/GB2017088B/en not_active Expired
- 1979-02-14 AU AU44246/79A patent/AU523984B2/en not_active Ceased
- 1979-02-14 NZ NZ189650A patent/NZ189650A/en unknown
- 1979-02-14 BE BE193449A patent/BE874154A/en unknown
- 1979-02-15 IT IT7920203A patent/IT1207171B/en active
- 1979-02-15 AT AT0114679A patent/AT368155B/en not_active IP Right Cessation
- 1979-02-15 ES ES477754A patent/ES477754A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NZ189650A (en) | 1981-07-13 |
| DE2905329A1 (en) | 1979-08-16 |
| NL7901107A (en) | 1979-08-17 |
| GB2017088A (en) | 1979-10-03 |
| AU4424679A (en) | 1979-08-23 |
| IT7920203A0 (en) | 1979-02-15 |
| ES477754A1 (en) | 1979-07-16 |
| GB2017088B (en) | 1982-10-20 |
| IT1207171B (en) | 1989-05-17 |
| AU523984B2 (en) | 1982-08-26 |
| ATA114679A (en) | 1982-01-15 |
| ZA79564B (en) | 1980-02-27 |
| BE874154A (en) | 1979-05-29 |
| AT368155B (en) | 1982-09-27 |
| FR2417511A1 (en) | 1979-09-14 |
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