EP0204731A1 - 4-SUBSTITUTED-PYRIMIDO AD6,1-a BD ISOQUINOLINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF - Google Patents
4-SUBSTITUTED-PYRIMIDO AD6,1-a BD ISOQUINOLINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOFInfo
- Publication number
- EP0204731A1 EP0204731A1 EP19850905657 EP85905657A EP0204731A1 EP 0204731 A1 EP0204731 A1 EP 0204731A1 EP 19850905657 EP19850905657 EP 19850905657 EP 85905657 A EP85905657 A EP 85905657A EP 0204731 A1 EP0204731 A1 EP 0204731A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenyl
- general formula
- alkyl
- alkoxy
- stands
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to new pyrimido/6,1-a/ isoquinolines, acid addition and quaternary ammonium salts thereof and process for the preparation thereof.
- R 1 and R 2 stand for alkoxy containing 1 to 2 carbon atoms
- R 3 stands for C 1-7 alkyl, C 3-7 cycloalkyl, phenyl optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, hydroxy or amino, or stands for naphtyl, phenyl- C 1-4 alkyl optionally substituted on the phenyl group by C 1-4 alkoxy, or a pyridyl group.
- compounds of the general f ormula II are reduc ed in an organic solvent or an aqueous-organic solvent medium or an aqueous medium by catalytic hydrogenation, or hydrogenation in situ or by chemical reducing agent.
- noble metal catalysts such as palladium or ac tivated nonnoble metal catalysts , such as Raney nickel
- solvents or diluting agents water organic solvents , pref erably methanol, ethanol, ethyl ac etate , dioxan or a water- organic solvent mixture may be employed.
- Acidification can preferably be conducted with aqueous inorganic acids /hydrochloric acid, sulfuric acid/ or organic acids /acetic acid, formic acid/.
- Compounds of the general formula I can preferably be formed after acidifying the ethanol solutions of the compounds of the general formula II with a mixture of water and hydrochloric acid at 20-25 °C under atmospheric pressure in the presence of palladium /active coal catalyst. After removing the catalyst by filtration and evaporating the solvent the hydrochloride salt of the compounds of the general formula I is obtained.
- the reduction of the compounds of the general formula II is conducted with hydrogen in situ, one may preferably proceed by developing hydrogen by reacting a suitable metal /zinc, tin, iron/ with an aqueous acid.
- a suitable metal /zinc, tin, iron/ As acids hydrochloric acid, sulfuric acid, acetic acid may be used, preferably in aqueous or aqueous-organic, particularly in aqueous ethanolic medium.
- chemical reducing agent acid type reactants such as ferrosulphate may be employed, preferably in aqueous mineral acid medium.
- T wave elevation/ particularly those compounds are efficient, wherein R 3 stands for phenyl, substituted phenyl, phenyl-alkyl, substituted phenyl-alkyl, pyridyl, and particularly active are those compounds wherein R 3 stands for phenyl, or pyridyl.
- the compounds significantly increase the contractility of the left heart chamber at a dose of 0.5-1.0 mg/kg i,v., they improve the minute/volume labour of the heart, decrease the coronary resistance, i.e. improve the blood perfusion.
- the compounds also show a significant antiarrythmic activity, and they also show a lasting hypotensive activity.
- the favourable effect of the compounds is also due to the direct heart effect.
- the compounds also exhibit a considerable activity in the human blood in inhibiting the platelet aggregation caused by ADP and arachidonic acid.
- compositions containing the active ingredient and non-toxic inert, pharmaceutically acceptable organic and inorganic carriers.
- the compositions may be formulated into solid form, such as tablets, film coated dragees, enterosolvent dragees, pills, capsules or into liquid form, such as suspensions, solutions or emulsions.
- carriers e.g. talc, starch, gelatine, water, polyalkylene glycols etc. may be used.
- compositions can optionally contain other excipients, such as wetting agents, emulsifiers or suspending agents, salts and buffers, promoting the change of osmotic pressure, disintegrating agents and/or other pharmaceutically active agents.
- excipients such as wetting agents, emulsifiers or suspending agents, salts and buffers, promoting the change of osmotic pressure, disintegrating agents and/or other pharmaceutically active agents.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Nouvelles 4-substitué-pyrimido AD6,1-a BD isoquinolines de formule générale (I), où R1 et R2 représentent alkoxy contenant de 1 à 2 atomes de carbone, R3 représente un alkyle composant de 1 à 7 C, un cycloalkyle comportant de 3 à 7 C, phényle, éventuellement substitué par un alkyle comportant de 1 à 4 C, un alkoxy comportant de 1 à 4 C, hydroxy ou amino, ou représente naphtyle, phényl-alkyle comportant de 1 à 4 C et éventuellement substitué dans le groupe phényle par un alkoxy comportant de 1 à 4 C, ou un groupe pyridyle. Sont décrits ces dérivés, leurs sels et un procédé de préparation.New 4-substituted-pyrimido AD6,1-a BD isoquinolines of general formula (I), where R1 and R2 represent alkoxy containing from 1 to 2 carbon atoms, R3 represents an alkyl component from 1 to 7 C, a cycloalkyl comprising 3 to 7 C, phenyl, optionally substituted by an alkyl comprising from 1 to 4 C, an alkoxy comprising from 1 to 4 C, hydroxy or amino, or represents naphthyl, phenyl-alkyl comprising from 1 to 4 C and optionally substituted in the phenyl group by an alkoxy having from 1 to 4 C, or a pyridyl group. These derivatives, their salts and a process for their preparation are described.
Description
4-SUBSTITUTED-PYRIMIDO[6,1-a]ISOQUINOLINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
Technical field
The present invention relates to new pyrimido/6,1-a/ isoquinolines, acid addition and quaternary ammonium salts thereof and process for the preparation thereof.
The new compounds can be characterized by the general formula
/I/
- wherein R 1 and R2 stand for alkoxy containing 1 to 2 carbon atoms, R 3 stands for C1-7 alkyl, C3-7 cycloalkyl, phenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, hydroxy or amino, or stands for naphtyl, phenyl- C1-4 alkyl optionally substituted on the phenyl group by C1-4 alkoxy, or a pyridyl group.
Background art
It has been known that from 1-cyanomethyl-3, 4-dihydro-isoquinolines 3-N-substituted or unsubstituted 1- cyano-pyrimido/6,1-a/isoquinoline derivatives may be prepared by reacting same with formaldehyde or an amine
/Harsanyi K, Kiss P, Korbonits D.: J.Met,Chem. 10., 4-35 /1973//. These pyrimido/6,1-a/isoquinoline derivatives show favourable effect on the heart and the circulation /Kiss P, Palosi E, Szegi J, Szentmiklόsi J.: 7th Int. Symp. on Medicinal Chemistry Torremolinos /Spain 1980. Abstract Poster 71./
Hoechst prepared pyrimido/6,1-a/isoquinoline-4-one derivatives from 1-cyanomethyl-3, 4-dihydro-isoquinoline derivatives /BE-PS 862 785, GB PS 1 597 717, DE-PS 2720085/ and they also reported on the favourable activity of the compounds on the heart circulation./Lab; B; D'Sa A Domauer H; De Souza HJ 33th Int.Pharm.Congress, Jaipur, 1981/.
Both synthesis methods show the disadvantage that the substituents on the C 4 atom of the molecule are constant. C 4 atom forms a CH2- group in method 1. and a CO group in method 2.
Disclosure of the invention
We wished to elaborate a new synthesis method in which the substituent of the C 4 atom of the pyrimido/6,1-a/ isoquinoline ring system can be changed.
We have found that the compounds of the present invention can be prepared by a simple method in high purity and with an excellent yield by reducing a compound of the general formula
/II/
or a salt thereof
- wherein R 1 and R 2 are as given above and R3 is as defined above or benzyloxy- or nitro-subs tituted phenyl and dehydrating the obtained compound of the general formula
/III/
wherein R 1, R2 and R3 are as given above - af ter isolation or without isolation and converting the obtained compound of th e general formula I to acid addition or quaternary ammonium salt thereof or setting it free from the salt thereof .
Compounds of the general formula II can be prepared by the method disclo sed in HU-PS 167 240.
According to a pref erred embodiment of the proc ess of the invention compounds of the general f ormula II are reduc ed in an organic solvent or an aqueous-organic solvent medium or an aqueous medium by catalytic hydrogenation, or hydrogenation in situ or by chemical reducing agent.
When performing catalytic hydrogenation as a catalyst noble metal catalysts , such as palladium or ac tivated nonnoble metal catalysts , such as Raney nickel can be used. As solvents or diluting agents water , organic solvents , pref erably methanol, ethanol, ethyl ac etate , dioxan or a water- organic solvent mixture may be employed.
Compounds of the general formula II can be used in the form of a base or salt. If the salt of the compounds of the general formula II is used as starting material, the
dehydration of the compound of the formula III takes place spontaneously.
One may also proceed by acidifying the solution of the compounds of the general formula II in the form of a base, i.e. the reductive condensation is carried out in an acidic medium. Acidification can preferably be conducted with aqueous inorganic acids /hydrochloric acid, sulfuric acid/ or organic acids /acetic acid, formic acid/.
Compounds of the general formula I can preferably be formed after acidifying the ethanol solutions of the compounds of the general formula II with a mixture of water and hydrochloric acid at 20-25 °C under atmospheric pressure in the presence of palladium /active coal catalyst. After removing the catalyst by filtration and evaporating the solvent the hydrochloride salt of the compounds of the general formula I is obtained.
If the reduction of the compounds of the general formula II is conducted with hydrogen in situ, one may preferably proceed by developing hydrogen by reacting a suitable metal /zinc, tin, iron/ with an aqueous acid. As acids hydrochloric acid, sulfuric acid, acetic acid may be used, preferably in aqueous or aqueous-organic, particularly in aqueous ethanolic medium.
As chemical reducing agent acid type reactants, such as ferrosulphate may be employed, preferably in aqueous mineral acid medium.
Compounds of the general formula I show on the basis of tests performed on test animals significant pharmacodynamic effects. According to rabbit tests the compounds show a significant antianginal activity in preventing coronary insufficiency caused by vasopressin /EKG
T wave elevation/, particularly those compounds are efficient, wherein R 3 stands for phenyl, substituted phenyl, phenyl-alkyl, substituted phenyl-alkyl, pyridyl, and particularly active are those compounds wherein R 3 stands for phenyl, or pyridyl.
According to tests performed on dogs the compounds significantly increase the contractility of the left heart chamber at a dose of 0.5-1.0 mg/kg i,v., they improve the minute/volume labour of the heart, decrease the coronary resistance, i.e. improve the blood perfusion. According to cat-tests the compounds also show a significant antiarrythmic activity, and they also show a lasting hypotensive activity. According to experiments carried out on isolated rabbit-heart the favourable effect of the compounds is also due to the direct heart effect.
The compounds also exhibit a considerable activity in the human blood in inhibiting the platelet aggregation caused by ADP and arachidonic acid.
On the basis of said effects the compounds of the general formula I can favourable be used in human therapy for curing diseases of heart circulation.
The compounds of the general formula I and salts thereof can be used in therapy in the form of pharmaceutical compositions containing the active ingredient and non-toxic inert, pharmaceutically acceptable organic and inorganic carriers. The compositions may be formulated into solid form, such as tablets, film coated dragees, enterosolvent dragees, pills, capsules or into liquid form, such as suspensions, solutions or emulsions. As carriers e.g. talc, starch, gelatine, water, polyalkylene glycols etc. may be used.
The compositions can optionally contain other excipients, such as wetting agents, emulsifiers or suspending agents, salts and buffers, promoting the change of osmotic pressure, disintegrating agents and/or other pharmaceutically active agents.
Further details of the invention can be found in the following Examples which serve merely for illustration and not for limitation.
Examples
The preparation of the starting material
1-24./ 0.075 mole of α -N-[2-/3,4-dialkoxy-phenyl/-ethyl/]]- carbamoyl-acetamidoxime /HU-PS 167240/ are dissolved in 300 ml of anhydrous ethanol and to the solution 0.15 mole of ethyl carboxylate of the general formula R 3CO2C2H5 and
0.075 mole of sodium ethylate prepared of 1.73 g metal sodium and 75 ml of anhydrous ethanol are added. The mixture is heated under reflux for 6 hours. After cooling alcohol is distilled off and the residue is triturated with water and distilled off by suction, washed with water and dried, and crystallized from ethanol, Melting points of the thus obtained 3-[N-2-/3,4-dialkoxy- phenyl/-ethyl-/1/-carbamoyl]-methyl-5-substituted-1,2,4- oxadiazoles are enlisted in Table 1. /Compounds of the general formula
/IY/
25-48,/ 0,06 mole of the oxadiazole derivatives prepared according to a/ are dissolved hot in 200 ml chloroform and under boiling 0,36 mole of phosphoroxy chloride are slowly added dropwise, whereafter the mixture is boiled for further 3 hours under reflux. The solvent and the excess phosphoroxychloride are distilled off at reduced
pressure. The residue is dissolved in chloroform, alkalized cautiously with a 25 % ammonium hydroxide solution, the solution is washed with water and dried above magnesiumsulphate. The solvent is distilled off and the residue is crystallized from acetonitrile.
The melting points of the obtained compounds of the formula II and of the hydrochlorides thereof formed in ethyl acetate are summarized in Table 2,
Exam-pie 49
A mixture of 3.49 g /0.01 mole/ of 3-[/3,4-dihydro-6,7- dimethoxy-isoquinolin-l-yl/-methyl]-5-phenyl-1,2,4-oxadiazole and 350 ml of ethanol, 10 ml of a 10 % aqueous hydrochloric acid solution and 0.5 g 8 % active coal-palladium are hydrated at 20 ºC under atmospheric pressure under stirring. Hydration ceases after the consumption of 1 mole equivalent hydrogen gas. The mixture is filtered, washed with ethanol and thus the catalyst is removed and the solvent is distilled off at reduced pressure. The residual crystals /obtained in 100 % yield/ are recrystallized from water and 3,28 g of 9.10-dimethoxy-4-phenyl-6,7-dihydro-2H-2- imino-pyrimido [6, 1-a]isoquinoline-hydrochloride monohydrate are obtained, melting point: 231-232 ºC.
Examples 50-73
Process for the preparation of the compounds of the general formula I,
0,01 mole of 3-[/3,4-dihydro-6,7-dialkoxy-isoquinoline-1- y1/-methyl]-5-substituted-1,2,4-oxadiazole of the general formula II is hydrated with a mixture of ethanol at an amount of 100 times the weight of said compound, 10 ml 10 % aqueous hydrochloric acid, 0.5 g 8 % active coal-palladium at room temperature under atmospheric pressure. The mixture is then filtered and the residue is crystallized from
water, aqueous ethanol or ethanol and thus hydrochlorides of the compounds of the general formula I are obtained. Melting points of the obtained compounds are included in Table 3.
Example 74
7.86 g /0.02 mole/ 3-[/3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl/-methyl]-5-/4-methyl-phenyl/-1,2,4-oxadiazole are hydrated in 300 ml of dioxan with 2 g Raney-nickelcatalyst at 25 ºC under overpressure. The catalyst is removed by filtration, evaporated, treated with activated charcoal and the residue is heated to boiling with 200 ml of 2 % hydrochloric acid. Upon cooling 7.1 g of 9,10-dimethoxy- 4-/4-methyl-phenyl/-6,7-dihydro-2H-2-imino-pyrimido[6,1-a] isoquinolin-hydrochloride-monohydrate are obtained. M.p.: 258 °C /under decomposition/
Example 75
On 4.2 g iron dust 0.8 g 5 N hydrochloric acid is added dropwise and the mixture is stirred until the intensive bubbling ceases whereupon the mixture is boiled with 10 ml water for half an hour. After adding 15 ml water under stirring at 65 °C 5.74 g /0.02 mole/ of 3-[73,4-dihydro- 6,7-dimethoxy-isoquinolin-1-yl/-methyl]-5-methyl-1,2,4- oxadiazole and 40 ml of ethanol are added to the mixture. The mixture is boiled under stirring for 15 minutes, filtered by suction and the precipitate is washed with 20 ml ethanol. 5.77 g of crystallized 9,10-dimethoxy-4- methyl-6,7-dihydro-2H-2-imiho-pyrimido [6,1-a] isoquinoline hydrochloride are obtained. M.p.: 274-275 °C. After crystallization from 96 % ethanol the product melts at 277-278 °C.
Table 1
Compounds of the general formula IV
Continuation of Table 1
Table 2
Compounds of the general formula II
Continuation of Table 2
Table 5 Hydrochloride salts of the compounds of the gen. formula I
= dihydrochloride
Continuation of Table 3
Claims
1. Process for the preparation of pyrimido[6,1-a]isoquinolines of the general formula
/I/
acid addition and quaternary ammonium salts thereof
- wherein R 1 and R 2 stand for alkoxy containing 1 to 2 carbon atoms, R 3 stands for C1-7 alkyl, C3-7 cycloalkyl, phenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, hydroxy or amino, or stands for naphtyl, phenyl- C1-4 alkyl optionally substituted on the phenyl group by C1-4 alkoxy, or a pyridyl group which comprises reducing a compound of the general formula
/II/ - wherein R 1 and R2 are as given above and R 3 is as given above or stands for benzyloxy - or nitrosubstituted phenyl - and dehydrating the obtained compound of the general formula /in/
- wherein R 1, R 2 and R 3 are as given above - after isolation or without isolation and converting the obtained compound of the general formula I into its acid addition or quaternary ammonium salt or setting it free from its salt,
2, Process as claimed in Claim 1 comprising conducting τhe reduction by catalytic hydration., with in situ hydrogen or chemical reducing agent.
3, Process as claimed in Claim 2 comprising using as a catalyst noble metal catalyst, preferably palladium, or activated non-noble metal catalyst, preferably Raney- nickel,
4. Process as claimed in Claim 2 comprising using as chemical reducing agent an acidic agent, preferably ferrosulphate.
5, Process as claimed in any of Claims 1 to 4 which comprises conducting reductive condensation in an organic solvent, aqueous organic solvent or aqueous medium.
6. Compounds of the general formula /I/
wherein R 1and R 2 stand for alkoxy containing 1 to 2 carbon atoms. stands for C1-7 alkyl, C3_7 cycloalkyl, phenyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, hydroxy or amino, or stands for naphtyl, phenyl- C1-4 alkyl optionally substituted on the phenyl group by C1-4 alkoxy, or a pyridyl group. and acid addition and quaternary salts thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU421084A HU193712B (en) | 1984-11-13 | 1984-11-13 | Process for preparing 4-substituted-pyrimido /6,1-a/ isoquinoline-derivatives |
| HU421084 | 1985-10-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0204731A1 true EP0204731A1 (en) | 1986-12-17 |
Family
ID=10967333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19850905657 Withdrawn EP0204731A1 (en) | 1984-11-13 | 1985-11-13 | 4-SUBSTITUTED-PYRIMIDO AD6,1-a BD ISOQUINOLINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0204731A1 (en) |
| HU (1) | HU193712B (en) |
| WO (1) | WO1986002928A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003102488A1 (en) | 2002-06-03 | 2003-12-11 | Philippe Courty | Double-barrelled body for a personal firearm |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013078413A1 (en) * | 2011-11-22 | 2013-05-30 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Modulators of lipid storage |
-
1984
- 1984-11-13 HU HU421084A patent/HU193712B/en not_active IP Right Cessation
-
1985
- 1985-11-13 WO PCT/HU1985/000066 patent/WO1986002928A1/en not_active Application Discontinuation
- 1985-11-13 EP EP19850905657 patent/EP0204731A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8602928A1 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003102488A1 (en) | 2002-06-03 | 2003-12-11 | Philippe Courty | Double-barrelled body for a personal firearm |
Also Published As
| Publication number | Publication date |
|---|---|
| HUT38933A (en) | 1986-07-28 |
| HU193712B (en) | 1987-11-30 |
| WO1986002928A1 (en) | 1986-05-22 |
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Inventor name: TARDOS, LASZLO Inventor name: SIMON, KALMAN Inventor name: VIRAG, SANDOR Inventor name: KOERMOECZY, PETER Inventor name: STADLER, ISTVAN Inventor name: KISS, PAL Inventor name: PALOSI, ENDRE Inventor name: HEJA, GERGELY Inventor name: KORBONITS, DEZSOE Inventor name: KOLONITS, PAL Inventor name: MARMAROSI, KATALIN Inventor name: GOENCZI, CSABA Inventor name: BATA, IMRE |