CA1262733A - Pharmaceutically active salt derivative of 3-hydroxy- 5-(hydroxymethyl)-2-methylisonicotinaldehyde phosphate - Google Patents
Pharmaceutically active salt derivative of 3-hydroxy- 5-(hydroxymethyl)-2-methylisonicotinaldehyde phosphateInfo
- Publication number
- CA1262733A CA1262733A CA000496746A CA496746A CA1262733A CA 1262733 A CA1262733 A CA 1262733A CA 000496746 A CA000496746 A CA 000496746A CA 496746 A CA496746 A CA 496746A CA 1262733 A CA1262733 A CA 1262733A
- Authority
- CA
- Canada
- Prior art keywords
- salt derivative
- hydroxy
- hydroxymethyl
- methylisonicotinaldehyde
- butanone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 salt derivative of 3-hydroxy- 5-(hydroxymethyl)-2-methylisonicotinaldehyde phosphate Chemical class 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- OWYLAEYXIQKAOL-UHFFFAOYSA-N 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone Chemical compound COC1=CC(OC)=CC(OC)=C1C(=O)CCCN1CCCC1 OWYLAEYXIQKAOL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical group C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 2
- TXQZTKXXMAKGCK-UHFFFAOYSA-N 3-hydroxy-5-(hydroxymethyl)-2-methylpyridine-4-carbaldehyde;phosphoric acid;4-pyrrolidin-1-yl-1-(2,4,6-trimethoxyphenyl)butan-1-one Chemical compound OP(O)(O)=O.CC1=NC=C(CO)C(C=O)=C1O.COC1=CC(OC)=CC(OC)=C1C(=O)CCCN1CCCC1 TXQZTKXXMAKGCK-UHFFFAOYSA-N 0.000 claims 2
- 230000036647 reaction Effects 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000000304 vasodilatating effect Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- ZQUJIOBCBGSBKS-UHFFFAOYSA-N 1-pyrrolidin-1-yl-4-(2,4,6-trimethoxyphenyl)butan-2-one Chemical compound COC1=CC(OC)=CC(OC)=C1CCC(=O)CN1CCCC1 ZQUJIOBCBGSBKS-UHFFFAOYSA-N 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229960004838 phosphoric acid Drugs 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 229960001415 buflomedil Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ZDPACSAHMZADFZ-UHFFFAOYSA-N 1-[3-(2,4,6-Trimethoxybenzoyl)propyl]pyrrolidinium chloride Chemical compound [Cl-].COC1=CC(OC)=CC(OC)=C1C(=O)CCC[NH+]1CCCC1 ZDPACSAHMZADFZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940057952 methanol Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure The present invention relates to a novel pharmacolog-ically active salt derivative,constituted by 4-(1-pyrrolidin-yl)-1-(2,4,6-trimethoxy-phenyl)-1-butanone 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphate, to the process for the production thereof, and to the relat-ed pharmaceutical compositions.
Said salt derivative is produced by reacting 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-3-butanone in an organic solvent and subsequently crystal-lizing the reaction product.
Said salt derivative carries out an important pharma-cological activity as inhibitor of platelet aggregation with vasodilative action.
Said salt derivative is produced by reacting 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-3-butanone in an organic solvent and subsequently crystal-lizing the reaction product.
Said salt derivative carries out an important pharma-cological activity as inhibitor of platelet aggregation with vasodilative action.
Description
27;~
.
J' Disclosure The present invention relates to a novel pharmaceutical ly active salt derivative, and namely to 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 3-hydroxy-5-(hydroxy-methyl)-2-methyl1sonicotinaldehyde-5-phosphate, naYing tne g following structural formula:~
~ 2 P03H H CH2-CH2-CH C ~ - OCH3 (I) The present invention relates also to the process for the production of the salt derivative (I) and to the relat ed pharmaceutical compositions.
The salt derivative (I) is obtained by means of the salifying of 3-hydroxy-5-(hydroxymethyl)-2-methylisonico-tinaldehyde-5-phosphoric acid with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone~
: 20 The pharmaceutical activity of the two starting prod-ucts is known. In particular, the pharmacological a'ctivity ~ . 9~ .
.
J' Disclosure The present invention relates to a novel pharmaceutical ly active salt derivative, and namely to 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 3-hydroxy-5-(hydroxy-methyl)-2-methyl1sonicotinaldehyde-5-phosphate, naYing tne g following structural formula:~
~ 2 P03H H CH2-CH2-CH C ~ - OCH3 (I) The present invention relates also to the process for the production of the salt derivative (I) and to the relat ed pharmaceutical compositions.
The salt derivative (I) is obtained by means of the salifying of 3-hydroxy-5-(hydroxymethyl)-2-methylisonico-tinaldehyde-5-phosphoric acid with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone~
: 20 The pharmaceutical activity of the two starting prod-ucts is known. In particular, the pharmacological a'ctivity ~ . 9~ .
2. ~.~6Z73~
is known of 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-l-butanone hydrochloride (8uflomedil) on the cere`oral circle for the treat~ent of disturbances of consciousness, and of states consequent to cerebral traumata, and its peripheral vasodilative properties are known too.
As for 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotin-aldehyde-5-phosphoric acid (Piridoxal phosphate), it is known as an enzyme co-factor vitamin.
From the reaction of these two products, the obtaining could be expected of a drug having vasodilating activity and, at the same time, vitaminic activity, useful for the handLing of pathological forms in old people.
On the contrary, we have unespectedly found that from such a reaction a drug is obtained with antithrombotic ac-tivity, which is to be added to the vasodilative action of Buflomedil, which is not modified.
It is to be noted that no one of the presently used drugs shows a combination of antithrombotic action and of peripheral vasodilative action.
The salt derivative (I) according to the present in-vention shows hence a platelet aggregation inhibitor and a vasodilator activity in one single molecule and is hence directed to the treatment of clinical patterns characteriz-ed by peripheral failure, clinical patterns to be found with particular frequency in old people, with a wider and more complete efficacy than 8uflomedil.
The salt derivative (I) according to the invention shows moreover, relatively to Buflomedil, the further ad-vantage of a high solubility in water, which favours its bioavailability and allows it to be administered by the parenteral and the rectal way.
The salt derivative (I) according to the present in
is known of 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-l-butanone hydrochloride (8uflomedil) on the cere`oral circle for the treat~ent of disturbances of consciousness, and of states consequent to cerebral traumata, and its peripheral vasodilative properties are known too.
As for 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotin-aldehyde-5-phosphoric acid (Piridoxal phosphate), it is known as an enzyme co-factor vitamin.
From the reaction of these two products, the obtaining could be expected of a drug having vasodilating activity and, at the same time, vitaminic activity, useful for the handLing of pathological forms in old people.
On the contrary, we have unespectedly found that from such a reaction a drug is obtained with antithrombotic ac-tivity, which is to be added to the vasodilative action of Buflomedil, which is not modified.
It is to be noted that no one of the presently used drugs shows a combination of antithrombotic action and of peripheral vasodilative action.
The salt derivative (I) according to the present in-vention shows hence a platelet aggregation inhibitor and a vasodilator activity in one single molecule and is hence directed to the treatment of clinical patterns characteriz-ed by peripheral failure, clinical patterns to be found with particular frequency in old people, with a wider and more complete efficacy than 8uflomedil.
The salt derivative (I) according to the invention shows moreover, relatively to Buflomedil, the further ad-vantage of a high solubility in water, which favours its bioavailability and allows it to be administered by the parenteral and the rectal way.
The salt derivative (I) according to the present in
3 ~l26;;~73;3 vention is prepared by means of a process characterized in that 3-hydroxy-5-(hydroxymethyl)-Z-methyl-isonicotinalde-hyde-5-phosphoric acid is reacted with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone in a reaction medium constituted-by an organic solvent in which (I) is soluble, and the reaction product (I) i~ crystallized from an organ-ic solvent wher0in it is insoluble. The characteristics and the advantages of the salt derivative (I) and of the relat-ed production process shall be better evidenced by the fol-lowing disclosure, which relates to a preferred embodiment~
Fo~ the preparation of the salt derivative (I), 3-hy-droxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phos phoric acid is previously liberated from its monosodium salt in a column with strongly basic ion exchange resin ac-tivated as chloride. The aqueous solution of 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric ac-id so obtained is concentrated to dryness, a yellow oily re sidue being obtained, which is redispersed three times with small portions of absolute ethanol, to remove water. The residue is finally treated with anhydrous ethyl acetate, a product being obtained which is filtered and dried in a vacuum desiccator.
3-Hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid so obtained is dispersed in methanol, in which it is not soluble, and solid 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone is added under stir-ring. The reaction mass is then heated to a temperature com prised within the range of from 400C to the solvent reflux ing temperature, Ind, preferably, to a temperature comprised within the range of from 45 to 55C, a clear yellow solu-tion being obtaine~, which even after cooling, does not yield any precipitates. The solution is concentrated up to :, 62~3~
co~plete removal of methanol, is then redispersed with ethyl ether, and after shalcing the salt derivative (I) is obtained as crystals, which is filtered, wasned with ethyl ether and dried in a vacuum desiccator.
The salt derivative (I) obtained is a crystalline pow-der of yellow colour, very soluble in water and aliphatic alcohols, whilst it is insoluble in ethyl ether. The crys-tallization of t~e raw product is carried out from a blend of aliphatic alcohols and ethyl ether, up to the required purity degree. The yield of each crystallization is of a-bout 90cto.
The characterization of said product was carried out by: X-ray diffractometry, I.R., U.V., and NMR spectrography and by means of the determination of the melting tempera-ture and of pH.
The crystallographic analysis by X-ray diffractometry demonstrates that the product is a single substance deriv-ing from the formation of a ionic bond between the two reac tants.
In the following Table 1 the characteristic peaks (dif fraction angles ~ and interplanar distances d), ~C
1~5418 A, and the intensity on relative scale I are re-, rel ported for the salt derivative (I) according to the inven-tion, and, for comparison purposes, for the two reactants (auflomedil an~ ~yridoxal phosphate).
2~Cu rel . . _ 1. BUFLOMEDIL Base a 19-7 4-51 (9.0) b 16.3 5.44(7.o) c 15.9 5.57(7-5) d 23.9 3-72(7.0) e 25.7 3.47(5.8) 2. SODIUM PYRIDOXAL
~6273~
(Table cont.'d)~
2~Cu rel PHOSPHATE (acid) a4.2 21.04 (1.6) . b17.6 5.04 (1.1) 53. SALT DE2IVATIVE (I) a 24.2 3.68 (2.9) b20.5 4.33 (2.0) c24.7 3.60 (1.8) d15.3 5~79 (1.6) e12.4 7.14 (1.5) It results from this Table that no characteristic peaks of the reactants are present in the salt derivative (I), and vice-versa; in the salifying of the reactants a new crys-talline phase has hence been obtained.
The I.R. absorption spectrum carried out in Nujol shows characteristic absorption peaks at the following wave-lengths:
- at .. ..2720 cm absorption band of aldehydic -CH
- at .. ..1695 cm absorption band of ketonic carbonyl at .. ..1665 cm band of the aldehydic carbonyl - at .. ..1460 and 1375 cm bands of the aromatic double bond.
The absorption spectrum of a solution in ethanol shows an absorption peak at Z83 ~ 1 nm.
At the NMR spectrum the following signals are detected:
- at 2.1 s 3 H (CH3) Pyr Z5 - at 3.7 5 9 H (OCH3) B
_ at 3.9 5 3 H (lCH3) _ at 5.95 5 2 H (Aromatics) B
- at 4.16 q 1 H (lCH) - at 7.22 s 1 H (Aromatics) P
3o _ at 7-95 s 1 H (Aromatics) P
- from 7.16 to 8.23 m 10 H (Aromatics) at 10.4 s 1 H (aldehydic -CH) P
6. ~ 7~3~
_ at 10.5 s 1 H (lNH) The melting temperature, as measured on Kofler block, is well defined at ,70-800C.
pH, as determined in a 2% aqueous solutio~,is of 7Ø
As for the pharmaceutical compositions, wherein the salt derivative (I) according to the present invention may enter as the active principle, it can be observed that, due to its high solubility in water, with it all the pharmaceutical forms can be prepared, both for oral and rectal ad~inister-ing, and for the injectable and topic way, in comblnationwith the usual excipients and with the co~ventional phar-maceutical media.
To the purpose of illustrating, without limiting, ~he ;
process according to the present invention, the following Example is reported.
Example 1 In a column about 700 ml of (moist) strongly basic ion exchange resins are activated with a 5~0 HCl solution, and the resin is washed up to the removal of the excess of hy-drochloric acid. After that, through the column a 20% so-lution of 50 g of monosodium 3-hydroxy-5-(hydroxy-methyl) 2-methyl-isonicotinaldehyde-5-phosphate is passed. The mass inside the column is finally washed with water up to neutral pH. The so-obtained aqueous solution of 3-hydroxy-5-(hy-droxymethyl)-2-methyl-isonicotinaldehyde-5-phosphoric ac-id is concentrated to an oil which is radispersed three times in an amount of absolute ethanol which is nearly threefold relatively to the weight of the residue. After the removal of water, the residue is redispersed in 200 ml of anhydrous ethyl acetate, within which a yellow precipitate is formed under shaking, which is vacuum filtered.
The filtrate is washed with anhydrous ethyl acetate .
~2~
and vacuum dried.
An amount of 42.5 g of 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid (C8H1oN06P, m.
w. = 247.156) ready for the salifying is obtained (yield 85%). In 380 ml of methanol 40 g of 3-hydroxy-5-(hydroxy-methyl)-2-methylisonicotinaldehyde-5-phosphoric acid are dis persed and, always at room temperature and under stirring, 56 g are introduced of 4-(1-pyrrolidinyl) -1-(2,4,6-trimeth-yphenyl)-l-butanone (C17H26 4, The system is heated at 50~C until a single phase is obtained. One is so sure that the salifying has taken place, on considering the insolubility of 3-hydroxy-5-(hy-droxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid even at high temperature.
'rhe solution obtained is cooled, is concentrated in và`-cuo until the methanol, solvent wherein the solubility of the salt derivative (I) is such as to prevent the crystal-lizing, has been completely removed. After that the meth-anol has been rPmoved, the residue-is dispersed in 480 ml of ethyl ether, and is then fi~te~ed and dried in a desic-cator in vacuo at room temperature.
An amount of 76.8 g of 4-(1-pyrrolidinyl)-1-(2,4,6)-tri-methoxyphenyl)-l-butanone 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphate (C25H36N201o, m.w. =
554.576) is obtained, with an active salifying yield of 80~o. The salt derivative (I) obtained has a melting point of 77-800C~
The subsequent crystallizations from methanol-ethyl ether yield the product with the desired purity level.
.
Fo~ the preparation of the salt derivative (I), 3-hy-droxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phos phoric acid is previously liberated from its monosodium salt in a column with strongly basic ion exchange resin ac-tivated as chloride. The aqueous solution of 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric ac-id so obtained is concentrated to dryness, a yellow oily re sidue being obtained, which is redispersed three times with small portions of absolute ethanol, to remove water. The residue is finally treated with anhydrous ethyl acetate, a product being obtained which is filtered and dried in a vacuum desiccator.
3-Hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid so obtained is dispersed in methanol, in which it is not soluble, and solid 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone is added under stir-ring. The reaction mass is then heated to a temperature com prised within the range of from 400C to the solvent reflux ing temperature, Ind, preferably, to a temperature comprised within the range of from 45 to 55C, a clear yellow solu-tion being obtaine~, which even after cooling, does not yield any precipitates. The solution is concentrated up to :, 62~3~
co~plete removal of methanol, is then redispersed with ethyl ether, and after shalcing the salt derivative (I) is obtained as crystals, which is filtered, wasned with ethyl ether and dried in a vacuum desiccator.
The salt derivative (I) obtained is a crystalline pow-der of yellow colour, very soluble in water and aliphatic alcohols, whilst it is insoluble in ethyl ether. The crys-tallization of t~e raw product is carried out from a blend of aliphatic alcohols and ethyl ether, up to the required purity degree. The yield of each crystallization is of a-bout 90cto.
The characterization of said product was carried out by: X-ray diffractometry, I.R., U.V., and NMR spectrography and by means of the determination of the melting tempera-ture and of pH.
The crystallographic analysis by X-ray diffractometry demonstrates that the product is a single substance deriv-ing from the formation of a ionic bond between the two reac tants.
In the following Table 1 the characteristic peaks (dif fraction angles ~ and interplanar distances d), ~C
1~5418 A, and the intensity on relative scale I are re-, rel ported for the salt derivative (I) according to the inven-tion, and, for comparison purposes, for the two reactants (auflomedil an~ ~yridoxal phosphate).
2~Cu rel . . _ 1. BUFLOMEDIL Base a 19-7 4-51 (9.0) b 16.3 5.44(7.o) c 15.9 5.57(7-5) d 23.9 3-72(7.0) e 25.7 3.47(5.8) 2. SODIUM PYRIDOXAL
~6273~
(Table cont.'d)~
2~Cu rel PHOSPHATE (acid) a4.2 21.04 (1.6) . b17.6 5.04 (1.1) 53. SALT DE2IVATIVE (I) a 24.2 3.68 (2.9) b20.5 4.33 (2.0) c24.7 3.60 (1.8) d15.3 5~79 (1.6) e12.4 7.14 (1.5) It results from this Table that no characteristic peaks of the reactants are present in the salt derivative (I), and vice-versa; in the salifying of the reactants a new crys-talline phase has hence been obtained.
The I.R. absorption spectrum carried out in Nujol shows characteristic absorption peaks at the following wave-lengths:
- at .. ..2720 cm absorption band of aldehydic -CH
- at .. ..1695 cm absorption band of ketonic carbonyl at .. ..1665 cm band of the aldehydic carbonyl - at .. ..1460 and 1375 cm bands of the aromatic double bond.
The absorption spectrum of a solution in ethanol shows an absorption peak at Z83 ~ 1 nm.
At the NMR spectrum the following signals are detected:
- at 2.1 s 3 H (CH3) Pyr Z5 - at 3.7 5 9 H (OCH3) B
_ at 3.9 5 3 H (lCH3) _ at 5.95 5 2 H (Aromatics) B
- at 4.16 q 1 H (lCH) - at 7.22 s 1 H (Aromatics) P
3o _ at 7-95 s 1 H (Aromatics) P
- from 7.16 to 8.23 m 10 H (Aromatics) at 10.4 s 1 H (aldehydic -CH) P
6. ~ 7~3~
_ at 10.5 s 1 H (lNH) The melting temperature, as measured on Kofler block, is well defined at ,70-800C.
pH, as determined in a 2% aqueous solutio~,is of 7Ø
As for the pharmaceutical compositions, wherein the salt derivative (I) according to the present invention may enter as the active principle, it can be observed that, due to its high solubility in water, with it all the pharmaceutical forms can be prepared, both for oral and rectal ad~inister-ing, and for the injectable and topic way, in comblnationwith the usual excipients and with the co~ventional phar-maceutical media.
To the purpose of illustrating, without limiting, ~he ;
process according to the present invention, the following Example is reported.
Example 1 In a column about 700 ml of (moist) strongly basic ion exchange resins are activated with a 5~0 HCl solution, and the resin is washed up to the removal of the excess of hy-drochloric acid. After that, through the column a 20% so-lution of 50 g of monosodium 3-hydroxy-5-(hydroxy-methyl) 2-methyl-isonicotinaldehyde-5-phosphate is passed. The mass inside the column is finally washed with water up to neutral pH. The so-obtained aqueous solution of 3-hydroxy-5-(hy-droxymethyl)-2-methyl-isonicotinaldehyde-5-phosphoric ac-id is concentrated to an oil which is radispersed three times in an amount of absolute ethanol which is nearly threefold relatively to the weight of the residue. After the removal of water, the residue is redispersed in 200 ml of anhydrous ethyl acetate, within which a yellow precipitate is formed under shaking, which is vacuum filtered.
The filtrate is washed with anhydrous ethyl acetate .
~2~
and vacuum dried.
An amount of 42.5 g of 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid (C8H1oN06P, m.
w. = 247.156) ready for the salifying is obtained (yield 85%). In 380 ml of methanol 40 g of 3-hydroxy-5-(hydroxy-methyl)-2-methylisonicotinaldehyde-5-phosphoric acid are dis persed and, always at room temperature and under stirring, 56 g are introduced of 4-(1-pyrrolidinyl) -1-(2,4,6-trimeth-yphenyl)-l-butanone (C17H26 4, The system is heated at 50~C until a single phase is obtained. One is so sure that the salifying has taken place, on considering the insolubility of 3-hydroxy-5-(hy-droxymethyl)-2-methylisonicotinaldehyde-5-phosphoric acid even at high temperature.
'rhe solution obtained is cooled, is concentrated in và`-cuo until the methanol, solvent wherein the solubility of the salt derivative (I) is such as to prevent the crystal-lizing, has been completely removed. After that the meth-anol has been rPmoved, the residue-is dispersed in 480 ml of ethyl ether, and is then fi~te~ed and dried in a desic-cator in vacuo at room temperature.
An amount of 76.8 g of 4-(1-pyrrolidinyl)-1-(2,4,6)-tri-methoxyphenyl)-l-butanone 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-5-phosphate (C25H36N201o, m.w. =
554.576) is obtained, with an active salifying yield of 80~o. The salt derivative (I) obtained has a melting point of 77-800C~
The subsequent crystallizations from methanol-ethyl ether yield the product with the desired purity level.
.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmacologically active salt derivative consti-tuted by 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde-phosphate, having the following structural formula:
(I)
(I)
2. A process for the preparation of the pharmacologi-cally active salt derivative constituted by 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone 3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinaldehyde phosphate having the following struc-tural formula:
which comprises reacting 3-hydroxy-5-(hydroxymethyl)-2-methyliso-nicotinaldehyde-phosphoric acid with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone in an organic solvent in which the salt derivative is highly soluble, and crystallizing the salt derivative from an organic solvent in which its solubility is low.
which comprises reacting 3-hydroxy-5-(hydroxymethyl)-2-methyliso-nicotinaldehyde-phosphoric acid with 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone in an organic solvent in which the salt derivative is highly soluble, and crystallizing the salt derivative from an organic solvent in which its solubility is low.
3. A process according to claim 2, in which said reac-tion is carried out at a temperature from 40°C to the refluxing temperature of the solvent.
4. A process according to claim 2, in which said reac-tion is carried out at a temperature from 45°C to 55°C.
5. A process according to claim 2, 3 or 4, in which the organic solvent is an aliphatic alcohol containing from 1 to 4 carbon atoms.
6. A process according to claim 2, 3 or 4, in which the reactants are reacted in a substantially stoichiometric molar ratio.
7. A process according to claim 2, 3 or 4, in which the crystallization solvent is a mixture of an aliphatic alcohol and ethyl ether.
8. A therapeutical composition for oral and rectal administration, and for the injectable or topic administration comprising the salt derivative as claimed in claim 1 as active principle together with conventional pharmaceutical excipients and carriers.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000496746A CA1262733A (en) | 1985-12-03 | 1985-12-03 | Pharmaceutically active salt derivative of 3-hydroxy- 5-(hydroxymethyl)-2-methylisonicotinaldehyde phosphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000496746A CA1262733A (en) | 1985-12-03 | 1985-12-03 | Pharmaceutically active salt derivative of 3-hydroxy- 5-(hydroxymethyl)-2-methylisonicotinaldehyde phosphate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1262733A true CA1262733A (en) | 1989-11-07 |
Family
ID=4132002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000496746A Expired CA1262733A (en) | 1985-12-03 | 1985-12-03 | Pharmaceutically active salt derivative of 3-hydroxy- 5-(hydroxymethyl)-2-methylisonicotinaldehyde phosphate |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1262733A (en) |
-
1985
- 1985-12-03 CA CA000496746A patent/CA1262733A/en not_active Expired
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