GB1593598A – Tetranicotinic ester of papaveroline and process for the production thereof
– Google Patents
GB1593598A – Tetranicotinic ester of papaveroline and process for the production thereof
– Google Patents
Tetranicotinic ester of papaveroline and process for the production thereof
Download PDF
Info
Publication number
GB1593598A
GB1593598A
GB21857/78A
GB2185778A
GB1593598A
GB 1593598 A
GB1593598 A
GB 1593598A
GB 21857/78 A
GB21857/78 A
GB 21857/78A
GB 2185778 A
GB2185778 A
GB 2185778A
GB 1593598 A
GB1593598 A
GB 1593598A
Authority
GB
United Kingdom
Prior art keywords
papaveroline
ester
nicotinic
characteristic
compound
Prior art date
1977-05-30
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
Application number
GB21857/78A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scharper SpA Per L’industria Farmaceutica
SCHARPER SpA
Original Assignee
Scharper SpA Per L’industria Farmaceutica
SCHARPER SpA
Priority date (The priority date 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 date listed.)
1977-05-30
Filing date
1978-05-24
Publication date
1981-07-22
1978-05-24
Application filed by Scharper SpA Per L’industria Farmaceutica, SCHARPER SpA
filed
Critical
Scharper SpA Per L’industria Farmaceutica
1981-07-22
Publication of GB1593598A
publication
Critical
patent/GB1593598A/en
Status
Expired
legal-status
Critical
Current
Links
Espacenet
Global Dossier
Discuss
Classifications
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P9/00—Drugs for disorders of the cardiovascular system
A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
Paperveroline derivative for the treatment of arteriopathies, which is easily soluble in water and having the formula:
Description
(54) TETRA-NICOTINIC ESTER OF PAPAVEROLINE AND PROCESS
FOR THE PRODUCTION THEREOF
(71) We, SCHARPER S.p.A. PER L’INDUSTRIA FARMACEUTICA, an Italian
Joint-Stock Company, of Via Montenapoleone, 27, 20121 Milan, Italy, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:
The present invention concerns a novel derivative of papaveroline, having effective and long lasting pharmacological properties, and a process for preparing same.
Papaveroline is a known tetraphenol consisting of an isoquinoline nucleus and a benzene nucleus, condensed through a methylene bridge. Papaveroline can be easily prepared by the total demethylization of papaverine.
The therapeutic use of papaveroline is also known although such use is limited by its low solubility in water and other pharmaceutically acceptable solvents.
To overcome this disadvantage, it has been proposed to introduce a sulfonic acid group into the benzene ring and the sulfonated product thus obtained has been effectively used in the treatment of particular arteriopathic conditions.
A continuing object, in medicine, is to provide pharmaceutical compounds suitable for selective therapy, and having a controlled period of activity, commonly known as a ‘fast-delayed’ action.
Various suggestions have been made, for example, involving the use of metallic derivatives of low solubility or using particular excipients which permit the slow release of the active substance but these do not always give satisfactory results.
In accordance with the present invention it has been found that the tetra-nicotinic ester of papaveroline, i.e. the compound of the formula:
provides a ‘fast-delayed’ pharmaceutical action which is believed to be due to the fact that the esterified phenolic groups of the nicotinic acid belong to different nuclei, i.e. the isoquinoline nucleus and the benzene nucleus. Therefore their hydrolysis will take place at different rates and is dependent on the pH value of the hydrolysis medium.
It has been further discovered that, in the therapy of arteriopathic forms, the tetra-nicotinic acid of papaveroline combines the action of papaveroline with the action of nicotinic acid, with the advantage of operating not only upon the deep stratus, as is the case with papaveroline, but also upon the superficial and cutaneous ‘status, which is characteristic of nicotinic acid.
The tetra-nicotinic ester of papaveroline can be obtained by the reaction of nicotyl chloride hydrochloride with papaveroline. The reaction is slightly exothermic and takes place preferably at 20-300C by the direct addition of the nicotyl chloride hydrochloride to a solution of papaveroline in pyridine.
The ester may be separated from the reaction mixture by dilution with water and ice followed by neutralization with sodium bicarbonate.
The precipitate, after separation, is washed with acetone and dried.
The raw product thus obtained may be purified by dissolving it in dioxane, filtering while hot, and allowing it to precipitate.
The ester, separated, washed and dried, has been identified by means of tests for papaveroline and nicotinic acid and, quantitatively, by spectrophotometric means.
The composition and the structure of the ester thus obtained have been confirmed by elemental analysis, N.M.R., I.R. and U.V. spectra, determination of the nicotinic groups, thin layer chromatography and melting point, as reported in detail in the following example.
Pharmacological tests, such as LD50, total and partial vascular resistances, central and partial vascular resistances, central and peripheric, deep level fluximetry, medial and superficial, cutaneous thermometry and acute and chronic toxicity, have shown that:
a) the tetra-nicotine ester of papaveroline maintains unaltered, quantitatively, the pharmacodynamic characteristics of the components of the ester, i.e., papaveroline and nicotinic acid;
b) the nicotinic activity shows itself as soon as the ester is administered and continues for 6-12 hours;
c) the cutaneous hyperemia, due to the nicotinic action, is less pronounced, as compared to those compounds in which the nicotinic acid is in a free state or in the form of a salt, but, as compared to the latter, presents a more prolonged action (fast-delayed action):
d) on an equal weight basis, the ester shows a lower toxicity than that of the two components administered separately.
As can be seen above, it is evident that the nicotinic radicals are not hydrolysed and therefore freed at the same moment but rather at separate times, thus obtaining the desired “fast-delayed” action.
The present invention is further illustrated by the following example.
EXAMPLE
A) – Preparation of the nicotyl chloride hydrochloride
In a 500cc round-bottom flask, equipped with a reflux condenser, there is heated under reflux conditions and under anhydrous conditions for 3 hours 60.5g (0.5 mol) of nicotinic acid with 300g (2.5 mol) of SOC12.
The acid dissolves rapidly and, when the solution is complete, the hydrochloride acid addition salt of nicotyl chloride begins to precipitate. After allowing the reaction mixture to stand for one hour, the excess of SOCK2 is removed by distillation under reduced pressure and the solid residue is washed repeatedly with petroleum ether and placed in a desiccator.
B) – Preparation of the tetranicotinic ester of papaveroline
In a 500cc three-necked round-bottom flask, equipped with stirrer, reflux condenser and thermometer, there is dissolved 15g (0.078 mol of papaveroline in 500cc of pyridine.
Maintaining the temperature between 20-30″C, there is slowly added 43g (0.2415 mol) of the nicotyl chloride hydrochloride prepared in part A).
As the latter dissolves only slowly it is necessary to maintain a strong stirring action.
The mixture is allowed to react for 8 hours at ambient temperature and it is then heated for one hour at 600C to complete the reaction.
After cooling, the reaction mixture is poured into water and ice and the solution is neutralized with sodium bicarbonate.
After filtration, the precipitate is washed with acetone and dried. There is thus obtained 23g of product.
The 23g of the raw product are then dissolved under reflux conditions in 200cc of
dioxane, filtered while hot and the solution allowed to stand for a long period to obtain a precipitate.
There is obtained 18.5g of crystallized product with a yield of 50%.
Reaction scheme
The product thus obtained is a white crystalline powder, insoluble in water, methanol, ethanol and soluble in dioxane.
Its characteristics change after prolonged treatment with acid and alkaline solutions.
The ester hydrolyzes in acid and alkaline environments; the hydrolytic reaction involves the reaction of 4 molecules of water; from one mole of tetranicotinate there are obtained 4 mols of nicotinic acid and one mole of papaveroline.
Such process permits the qualitative and quantitative determination of the components of the ester.
The ester, after recrystallization from dioxane, shows a melting point of 214-215″C.
The compound, dried to constant weight in an oven at 110 C, gave the following analytical values:
Found: C : 67.97%; H : 3.68%; N : 10.12.% corresponding to an empirical formula: C40H25O8N5.
The calculated values are: C : 68.28%; H : 3.55%; N : 9.96% which agree fully with the experimental values.
Thin-layer chromatography was performed on a glass plate 5×20 coated with a 0.2mm layer of silica gel : GF 254 Merck (Registered Trade Mark). Activation was at 1200C for 1 hour with a development time 180 min. Travel was 10 cm. The eluent was a mixture of:
60% n-butanol
20% acetic acid (96%)
20% water
The determination was made under U.V. light of 360 mll while 0.1-0.2 cc of a 0.2% solution in dioxane of the tetranicotylpapaveroline obtained above is deposited as a spot on the above-described glass plate.
After development, on the plate there is observed an oblong spot of blue/purplish color having an Rf of 0.62.
Leaving the plate exposed to the air at ambient temperature, the spot assumes a yellow-brown coloration.
To confirm the pressure of 4 nicotinic groups, the following procedure was followed.
In a 250cc round-bottom flask equipped with a stopcock-controlled funnel, reflux condenser and thermometer there was introduced 0.12-0.15g of the product.
In the reaction flask there are introduced 150 ml. of 85% phosphoric acid (equivalent to 155g) and 20 ml. of water.
It is then heated over a direct flame controlling initially the rate of heating: when the temperature inside the flask reaches 1600C, there is added through the funnel 50 ml. of water at the rate of 6 drops per minute. The mixture is then heated to the boiling point for 30 minutes.
The mixture is allowed to cool and it is titered potentiometrically with 0.1 N NaOH, 1 ml of 0.1 N NaOH corresponding to 0.01231g of CsH4N-COOH.
We have used 0.1246g of tetranicotinic ester; there have been utilized 7.05 ml of 0.1N
NaOH. Found: 0.08678g; theorical: 0.08678; error: minus 0.14%.
The ester has therefore been assigned the following structure: 6,7-dinicotinoxy-1-(3′ ,-4′-dinicotinoxybenzyl) isoquinoline, i.e.
Empirical formula: C40H250sN5 M.W.: 705.708
Papaveroline base: 39.57%
Nicotinic acid: 60.33%
U.V. Spectrum
The compound presents, in dioxane, two significative maxima: at 231 mF ( = 57000 + 1%) characteristic of the nicotinic nucleus, at 258 mF ( E =28000 + 1%). practically referrable to the papaverolinic nucleus (papaveroline base max. ass. 250 m,u in 1 N HC1).
The drop in the maximum is probably due to the different solvents employed.
The presence of maximum absorptions in the U.V. permits determination of the concentration of the compound by spectrophotometric methods.
The l.R. spectrum of the ester in suspension in Nujol (Registered Trade Mark) presents zones of absorption at 1740 cm-lm characteristic of the ester group C=O; at 1590 cm-l, characteristic of the groups C=C and C=N; and at 1225-1070 cm- , characteristic of the 1,2,3,4 substituted nucleus.
The NMR spectrum (in chloroform) is very complex: in fact, since the ester, unlike papaveroline, is insoluble in dimethylsulfoxide it is difficult to make an exact evaluation of the NMR data. However, the ratio of aromatic protons to benzylic protons is determinable at 11.56 (theoretical 11.5) in good agreement with the theoretical structure of the tetranicotinate.
WHAT WE CLAIM IS:
1. The tetra-nicotinic ester of papaveroline, i.e. a compound of the formula:
2. A process for the preparation of the tetra-nicotinic ester of papaveroline which comprises reacting nicotyl chloride hydrochloride with papaveroline.
3. A process as claimed in claim 2, wherein the reaction is conducted at a temperature of from 20 to 30″C.
4. A process as claimed in claim 2 or 3, wherein the product is isolated from the reaction mixture by diluting said mixture with water and ice and subsequently neutralizing the resulting mixture with sodium bicarbonate.
5. A process as claimed in claim 2, 3 or 4 wherein the papaveroline reactant is fed to the reaction vessel as a solution in pyridine.
6. A process as claimed in any one of claims 2-5, wherein the raw product is purified by crystallization from dioxane.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (8)
**WARNING** start of CLMS field may overlap end of DESC **. Empirical formula: C40H250sN5 M.W.: 705.708 Papaveroline base: 39.57% Nicotinic acid: 60.33% U.V. Spectrum The compound presents, in dioxane, two significative maxima: at 231 mF ( = 57000 + 1%) characteristic of the nicotinic nucleus, at 258 mF ( E =28000 + 1%). practically referrable to the papaverolinic nucleus (papaveroline base max. ass. 250 m,u in 1 N HC1). The drop in the maximum is probably due to the different solvents employed. The presence of maximum absorptions in the U.V. permits determination of the concentration of the compound by spectrophotometric methods. The l.R. spectrum of the ester in suspension in Nujol (Registered Trade Mark) presents zones of absorption at 1740 cm-lm characteristic of the ester group C=O; at 1590 cm-l, characteristic of the groups C=C and C=N; and at 1225-1070 cm- , characteristic of the 1,2,3,4 substituted nucleus. The NMR spectrum (in chloroform) is very complex: in fact, since the ester, unlike papaveroline, is insoluble in dimethylsulfoxide it is difficult to make an exact evaluation of the NMR data. However, the ratio of aromatic protons to benzylic protons is determinable at 11.56 (theoretical 11.5) in good agreement with the theoretical structure of the tetranicotinate. WHAT WE CLAIM IS:
1. The tetra-nicotinic ester of papaveroline, i.e. a compound of the formula:
2. A process for the preparation of the tetra-nicotinic ester of papaveroline which comprises reacting nicotyl chloride hydrochloride with papaveroline.
3. A process as claimed in claim 2, wherein the reaction is conducted at a temperature of from 20 to 30″C.
4. A process as claimed in claim 2 or 3, wherein the product is isolated from the reaction mixture by diluting said mixture with water and ice and subsequently neutralizing the resulting mixture with sodium bicarbonate.
5. A process as claimed in claim 2, 3 or 4 wherein the papaveroline reactant is fed to the reaction vessel as a solution in pyridine.
6. A process as claimed in any one of claims 2-5, wherein the raw product is purified by crystallization from dioxane.
7. A process as claimed in Claim 2 substantially as hereinbefore described in the
foregoing Example.
8. The compound claimed in Claim 1 when prepared by a process as claimed in any one of Claims 2 to 7.
GB21857/78A
1977-05-30
1978-05-24
Tetranicotinic ester of papaveroline and process for the production thereof
Expired
GB1593598A
(en)
Applications Claiming Priority (1)
Application Number
Priority Date
Filing Date
Title
IT24141/77A
IT1143667B
(en)
1977-05-30
1977-05-30
PARAVEROLINIC DERIVATIVE WITH A DURABLE ACTION AND PROCEDURE TO OBTAIN IT
Publications (1)
Publication Number
Publication Date
GB1593598A
true
GB1593598A
(en)
1981-07-22
Family
ID=11212187
Family Applications (1)
Application Number
Title
Priority Date
Filing Date
GB21857/78A
Expired
GB1593598A
(en)
1977-05-30
1978-05-24
Tetranicotinic ester of papaveroline and process for the production thereof
Country Status (13)
Country
Link
JP
(1)
JPS53149982A
(en)
BE
(1)
BE867515A
(en)
BR
(1)
BR7803416A
(en)
CA
(1)
CA1084504A
(en)
CH
(1)
CH633446A5
(en)
DE
(1)
DE2822186A1
(en)
ES
(1)
ES470343A1
(en)
FR
(1)
FR2392987A1
(en)
GB
(1)
GB1593598A
(en)
GR
(1)
GR63731B
(en)
IT
(1)
IT1143667B
(en)
MX
(1)
MX5515E
(en)
PT
(1)
PT68115A
(en)
Families Citing this family (1)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
IN154316B
(en)
*
1979-07-19
1984-10-13
Andre Buzas
Family Cites Families (2)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
DE1175246B
(en)
*
1959-12-14
1964-08-06
Orsymonde Fa
Process for the preparation of dimethylpapa-verolin-bis-nicotinic acid ester and its acidic dimaleate
FR794M
(en)
*
1960-12-02
1961-09-11
1977
1977-05-30
IT
IT24141/77A
patent/IT1143667B/en
active
1978
1978-05-20
DE
DE19782822186
patent/DE2822186A1/en
not_active
Withdrawn
1978-05-24
GB
GB21857/78A
patent/GB1593598A/en
not_active
Expired
1978-05-26
BE
BE188060A
patent/BE867515A/en
not_active
IP Right Cessation
1978-05-29
MX
MX787104U
patent/MX5515E/en
unknown
1978-05-29
GR
GR56361A
patent/GR63731B/en
unknown
1978-05-29
BR
BR7803416A
patent/BR7803416A/en
unknown
1978-05-30
JP
JP6483078A
patent/JPS53149982A/en
active
Granted
1978-05-30
PT
PT68115A
patent/PT68115A/en
unknown
1978-05-30
FR
FR7816137A
patent/FR2392987A1/en
active
Granted
1978-05-30
CA
CA304,384A
patent/CA1084504A/en
not_active
Expired
1978-05-30
CH
CH587778A
patent/CH633446A5/en
not_active
IP Right Cessation
1978-05-30
ES
ES470343A
patent/ES470343A1/en
not_active
Expired
Also Published As
Publication number
Publication date
PT68115A
(en)
1978-06-01
ES470343A1
(en)
1979-01-01
FR2392987A1
(en)
1978-12-29
BR7803416A
(en)
1979-01-02
JPS53149982A
(en)
1978-12-27
IT1143667B
(en)
1986-10-22
BE867515A
(en)
1978-09-18
CA1084504A
(en)
1980-08-26
FR2392987B1
(en)
1982-04-23
GR63731B
(en)
1979-12-04
CH633446A5
(en)
1982-12-15
DE2822186A1
(en)
1978-12-14
MX5515E
(en)
1983-09-14
JPS572715B2
(en)
1982-01-18
Similar Documents
Publication
Publication Date
Title
Cain et al.
1975
Potential antitumor agents. 16. 4’-(Acridin-9-ylamino) methanesulfonanilides
CN110092745B
(en)
2022-12-30
Compound containing aromatic ring and application thereof
CN110092740B
(en)
2022-10-14
Fused ring compound and application thereof
KR20210136995A
(en)
2021-11-17
Bruton's Tyrosine Kinase Inhibitors
CN112920131A
(en)
2021-06-08
1,2, 4-triazole derivatives and preparation method and application thereof
SU683617A3
(en)
1979-08-30
Method of the preparation of 1-nitro-9-dialkylamineisoalkylamineacrydines or their salts
DE2809720C2
(en)
1992-01-16
US3316266A
(en)
1967-04-25
3-aminopyrazinoic acid derivatives and process for their preparation
US2924599A
(en)
1960-02-09
Derivatives of 1:3:5-triazanaphthalene
CN110240598B
(en)
2023-07-25
Process for preparing carboxamide derivatives and intermediate compounds thereof
GB1593598A
(en)
1981-07-22
Tetranicotinic ester of papaveroline and process for the production thereof
Parker et al.
1947
Substituted 2-Picolines Derived from 6-Amino-2-picoline1
US3585214A
(en)
1971-06-15
Hydroxyl derivatives of coumarine and processes for the preparation thereof
Robison et al.
1958
The Rearrangement of Isoquinoline-N-Oxides. II. Observations with N-Hydroxyisocarbostyrils and Other Substituted Derivatives1
US3872108A
(en)
1975-03-18
Novel chromone derivatives and the production thereof
CN112679430B
(en)
2023-05-05
Method for preparing isoquinolinones compound
WO2002085858A1
(en)
2002-10-31
Process for producing purified piperidine derivative
JPS5811874B2
(en)
1983-03-04
Pyrido (3,4-D) Pyridazine Luino Seizouhou
US3268511A
(en)
1966-08-23
5, 5-diloweralkyl-4-omicron-lower alkyl-2, 3-cyclocarbonato-l-pyranosyl halides
SU1711674A3
(en)
1992-02-07
Method for the synthesis of azonium spironortropanol ester
KR920010047B1
(en)
1992-11-13
Process for preparing 2-amino-5-oxo-5h-|1¨ benzopyrano |2,3-b¨ pyridine-3-carboxylic acid derivatives
FI65996C
(en)
1984-08-10
FORM OF THERAPEUTIC PREPARATION OF NUTRITIONAL N-2-FURYLMETHYL) -5-SULFAMOYL-ORTANYL SYROR OR DERAS SALTER
US4017490A
(en)
1977-04-12
Pyrido (3,4-d)pyridazines
US2489881A
(en)
1949-11-29
Oxazoiiones and rbrocess for
JPS6183179A
(en)
1986-04-26
Novel flavone derivative
Legal Events
Date
Code
Title
Description
1981-12-16
PS
Patent sealed
1991-01-23
PCNP
Patent ceased through non-payment of renewal fee
