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WO1983000866A1 - Substituted piperidinyl quinazolines - Google Patents

Substituted piperidinyl quinazolines Download PDF

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Publication number
WO1983000866A1
WO1983000866A1 PCT/FI1982/000034 FI8200034W WO8300866A1 WO 1983000866 A1 WO1983000866 A1 WO 1983000866A1 FI 8200034 W FI8200034 W FI 8200034W WO 8300866 A1 WO8300866 A1 WO 8300866A1
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formula
compound
compounds
hydroxy
reacted
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PCT/FI1982/000034
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French (fr)
Inventor
Oy Orion-Yhtymä
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Orion Oyj
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Orion Yhtyma Oy
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Priority to FI831585A priority Critical patent/FI831585A7/en
Publication of WO1983000866A1 publication Critical patent/WO1983000866A1/en
Priority to DK181083A priority patent/DK181083A/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention concerns 2-(4-substitutedpiperidino)- 4-amino-6,7-dimethoxyquinazolines. These new compounds have valuable pharmacological properties.
  • Patents FR 2 350 101 and PR 2 389621 refer to 2-(4-phenylpiperidino)-4-amino-6,7-dimethoxyquinazoline and corresponding compounds, in which the phenyl group is subs tituted with a fluoro or methoxy group.
  • Published patent application PI 80 0481 refers to 2-(4-alkylcarbonylpiperidino)- and 2-(4-cycloalkylcarbonyl- piperidino)-4-amino-6,7-dimethoxyquinazoline.
  • This invention deals with compounds of the formula
  • R is a cycloalkyl containing 3 to 7 carbon atoms, an alkenyl containing 2 to 6 carbon atoms, or a benzyl group.
  • This invention also deals with the methods for the preparation of the compounds with formula I, in which a) a compound with the formula
  • the invention also deals with the compounds of formula II, which are valuable intermediates for the prepara tion of the formula I compounds.
  • the formula I compounds can be used as pharmaceutical agents for the treatment of hypertension.
  • Pormula VI compounds can be pre pared from the corresponding ketones by reduction.
  • 4-(1-nydroxyethyl.)piperidi ⁇ e is l ⁇ fow ⁇ from J. Org. Chem.
  • the method;e -reduction is carried out with hydrogen under about 1 to 7 atm pressure and at about 20 to 100°C using common hydrogenation catalysts such as palladium, platinum or nickel.
  • common hydrogenation catalysts such as palladium, platinum or nickel.
  • Other reducing agents can also be used, e.g. sodium borohydride or aluminium isopropoxide.
  • Example 1 1.3 g of NaBH 4 in 15 ml of water is added at 0 °C toa-solution of 4.7 g (0.026 mol) of 4-cyclopentylcarbonyl- piperidine in 50 ml of methanol. This is stirred for 1 h at 0 °C and for 2 h at 20 °C. The methanol is evaporated off, water is added and the solution is extracted with chloroform and the extract evaporated to dryness. 3.4 g of 4-(1-hydroxy-1-cyclopentylmethyl)piperidine (VI) is obtained; mp. 123 - 5 °C, yield 72 %.
  • Method e 1.2 g of NaBH.in 10 ml of water is added in an ice bath to a solution of 4.35 g (0.01 mol) of 2-(4-cyclohexylcarbonylpiperidino)-4-amino-6,7-dimethoxy- quinazoline hydrochloride and 20 ml of 0.5 N NaOH solution in 80 ml of methanol. The solution is stirred for 1 h at 0 °C and for 18 h at 20 °C. Some of the methanol is removed under reduced pressure, the precipitate formed is filtered off, washed with water and dried. The product is dissolved in acetone and precipitated with gaseous HCl.
  • Method c A solution of 2.4 g (0.01 mol) of 2-chloro- 4-amlno-6,7-dimethoxyquinazoline and 2.0 g (0.01 mol) of 4-(1-hydroxy-1-cyclohexylmethyl)piperidine in 30 ml of iso amyl alcohol is refluxed for 18 h and cooled. The precipitated product is filtered, washed with ether and dried. De sired product is obtained.
  • Method d A solution of 2.5 g (0.01 mol) of S-methyl- N-cyano-N'-(3-,4 dimeth ⁇ xyphenyl)isothioufea and 3.0 g (0.01 mol) or 4-(1-hydroxy-1-cyclohexylmethyl)piperidine in 35 ml of diglycoldimethylether Is refluxed for 5 h and cooled.Water is added to the mixture, followed by extraction with chloroform. The solvent is evaporated off from the extract, and the residue is dissolved in acetone, into which HCl gas is led. Desired product is obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

2-(4-(1-hydroxy-1-méthyle substitué)pipéridino)-4-amino-6,7-diméthoxyquinazolines de formule:$(10,)$dans laquelle R est un cycloalkyle contenant de 3 à 7 atomes de carbone, un alkényle contenant de 2 à 6 atomes de carbone, ou un groupe benzyle. Les composés sont préparés en faisant réagir du méthyl N-(2-cyano-4,5-diméthoxyphényle)(4-(1-hydroxy-1-méthyle substitué)pipéridino)thioformamidate avec du chlorure d'ammonium dans du formamide à environ 120oC. Les composés abaissent la pression artérielle.2- (4- (1-hydroxy-1-substituted methyl) piperidino) -4-amino-6,7-dimethoxyquinazolines of formula: $ (10,) $ in which R is a cycloalkyl containing from 3 to 7 carbon atoms , an alkenyl containing from 2 to 6 carbon atoms, or a benzyl group. The compounds are prepared by reacting methyl N- (2-cyano-4,5-dimethoxyphenyl) (4- (1-hydroxy-1-substituted methyl) piperidino) thioformamidate with ammonium chloride in formamide at about 120oC . The compounds lower blood pressure.

Description

SUBSTITUTED PIPERIDINYL QUINAZOLINES
The invention concerns 2-(4-substitutedpiperidino)- 4-amino-6,7-dimethoxyquinazolines. These new compounds have valuable pharmacological properties.
Patents FR 2 350 101 and PR 2 389621 refer to 2-(4-phenylpiperidino)-4-amino-6,7-dimethoxyquinazoline and corresponding compounds, in which the phenyl group is subs tituted with a fluoro or methoxy group.
Published patent application PI 80 0481 refers to 2-(4-alkylcarbonylpiperidino)- and 2-(4-cycloalkylcarbonyl- piperidino)-4-amino-6,7-dimethoxyquinazoline.
These compounds lower the blood pressure.
This invention deals with compounds of the formula
Figure imgf000003_0001
in which R is a cycloalkyl containing 3 to 7 carbon atoms, an alkenyl containing 2 to 6 carbon atoms, or a benzyl group. This invention also deals with the methods for the preparation of the compounds with formula I, in which a) a compound with the formula
II
Figure imgf000003_0002
is reacted with ammonia, ammonium halide, urea, or urea hydrohalide, or b) accompound with the formula III
Figure imgf000004_0005
in which Z is a cyano or amidino group, is reacted with a compound with the formula
IV
Figure imgf000004_0004
in which Z' is a cyano or amidino group, or c) a compound with the formula
Figure imgf000004_0003
in which X is a halogen such as chlorine, is reacted with a compound with the formula
VI
Figure imgf000004_0002
or, d) a compound with the formula
VII
Figure imgf000004_0001
is reacted with a compound with formula VI, or e) a carbonyl compound with the formula VIII
Figure imgf000005_0001
is reduced to the corresponding alcohol.
The invention also deals with the compounds of formula II, which are valuable intermediates for the prepara tion of the formula I compounds.
The formula I compounds: can be used as pharmaceutical agents for the treatment of hypertension.
The methods a, b, c and d are carried out as described in PI 80 0481. Pormula VI compounds can be pre pared from the corresponding ketones by reduction. 4-(1-nydroxyethyl.)piperidiήe is lάfowή from J. Org. Chem.
31 (1976.) 1732.
The method;e -reduction is carried out with hydrogen under about 1 to 7 atm pressure and at about 20 to 100°C using common hydrogenation catalysts such as palladium, platinum or nickel. Other reducing agents can also be used, e.g. sodium borohydride or aluminium isopropoxide.
The effect of the compounds, administered perorally, on spontaneus hypertension v/as studied in rats and compared with that of the compounds described in PI 800481. A dose of 0.5 umol/rat of the compound of example 3 produced a
30 mmHg decrease in blood pressure within 3 hours of the administration. This was more than with the compounds in
PI 800481. The toxicity of the new compounds? is also somewhat less than that of the known compounds^
The following examples illustrate the invention.
Example 1 1.3 g of NaBH4 in 15 ml of water is added at 0 °C toa-solution of 4.7 g (0.026 mol) of 4-cyclopentylcarbonyl- piperidine in 50 ml of methanol. This is stirred for 1 h at 0 °C and for 2 h at 20 °C. The methanol is evaporated off, water is added and the solution is extracted with chloroform and the extract evaporated to dryness. 3.4 g of 4-(1-hydroxy-1-cyclopentylmethyl)piperidine (VI) is obtained; mp. 123 - 5 °C, yield 72 %. 2.9 g (0.016 mol) of 4-(1-Hydroxy-1-cyclopentyl- methyl)piperidine in 25 ml of ethyl acetate is added in small portions at 0 - 5 °C to a solution of 3.5 g (0.016 mol) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile in 25 ml of ethyl acetate. The solution is stirred at 0 °C for 18 h. The precipitate obtained is filtered, washed with cold ethyl acetate and dried. 4.1 g of 2-(4-(1-hydroxy-1-cyclo- pentylmethyl)piperidino)thioformamido-4,5-dimethoxybenzo- nitrile is obtained; mp. 196 - 200 °C, yield 64 %.
A solution of 4.04 g (0.01 mol) of 2-( -(1-hydroxy- 1-cyclopentylmethyl)piperidino)thioformamido-4,5-dimethoxy- benzonitrile, 4.0 g of methyl iodide and 0.6 g of calcium oxide in 3.0 ml of ethyl acetate is slowly warmed to 60°C and kept at that temperature for 18 h. The cooled mixture is filtered, the filtrate washed with dilute NaOH solution a-ttd water and evaporated to dryness. 3.6 g of methyl U-(2-cyano-4,5-dimethoxyphenyl)-(4-(1-hydroxy-1-cyclo- pentylmethyl)piperidino)thioformamidate (II) is obtained; mp. 41 - 45 °C, yield 86 %.
A solution of 4.17 g (0.01 mol) of methyl N-(2-cyano- 4,5-dimethoxyphenyl)-(4-(1-hydroxy-1-cyclopentylmethyl)- piperidinothioformamidate and 15 g of ammonium chloride in 45 ml of formamide is heated and stirred under nitrogen flow for 24 h at 120 °C. The mixture is cooled and water is added, followed by extraction with chloroform. The extract is washed several times with water and the solvent Is removed under reduced pressure. The residue is dissolved in acetone and dry HCl gas Is led Into the solution. 2.8 g of 2-(4--(1-hydroxy-1-cyclopentylmethyl)- piperidino)-4-amino-6,7-dimethoxyquinazoline hydrochloride is obtained; mp. 269 - 73 °C, yield 66 %. Example 2
Method e: 1.2 g of NaBH.in 10 ml of water is added in an ice bath to a solution of 4.35 g (0.01 mol) of 2-(4-cyclohexylcarbonylpiperidino)-4-amino-6,7-dimethoxy- quinazoline hydrochloride and 20 ml of 0.5 N NaOH solution in 80 ml of methanol. The solution is stirred for 1 h at 0 °C and for 18 h at 20 °C. Some of the methanol is removed under reduced pressure, the precipitate formed is filtered off, washed with water and dried. The product is dissolved in acetone and precipitated with gaseous HCl. 2-(4-hydroxy- 1-cyclohexylmethyl)piperidino)-4-amino-6,7-dimehoxyquinazo- line hydrochloride is obtained; mp. 196 - 200 C. Method b: 0.75 g (0.03 mol) of sodium hydride is added to a solution of 1.78 g (0.01 mol) of 2 -amino-4,5-di- methoxybenzonitrile and 2.38 g g (0.01 mol) of 1-cyano- 4-(1-hydroxy-1-cyclohexylmethyl)piperidine in 25 ml of dry dimethylformamide. The solution is heated under a nitrogen atmosphere for 5 h at 80 °C, cooled, and water is added and extracted with chloroform. The solvent is removed under reduced pressure. The residue is dissolved in acetone into which dry HCl gas is led. Desired product is obtained. Method c: A solution of 2.4 g (0.01 mol) of 2-chloro- 4-amlno-6,7-dimethoxyquinazoline and 2.0 g (0.01 mol) of 4-(1-hydroxy-1-cyclohexylmethyl)piperidine in 30 ml of iso amyl alcohol is refluxed for 18 h and cooled. The precipitated product is filtered, washed with ether and dried. De sired product is obtained.
Method d: A solution of 2.5 g (0.01 mol) of S-methyl- N-cyano-N'-(3-,4 dimethόxyphenyl)isothioufea and 3.0 g (0.01 mol) or 4-(1-hydroxy-1-cyclohexylmethyl)piperidine in 35 ml of diglycoldimethylether Is refluxed for 5 h and cooled.Water is added to the mixture, followed by extraction with chloroform. The solvent is evaporated off from the extract, and the residue is dissolved in acetone, into which HCl gas is led. Desired product is obtained.

Claims

1. Compounds with the formula
Figure imgf000008_0004
in which R is a cycloalkyl containing 3 to 7 carbon atoms, an alkenyl containing 2 to 6 carbon atoms, or benzyl.
2. Compounds according to claim 1 in which R is a cycloalkyl containing 3 to 7 carbons.
3. Compounds according to claim 2 in which R is a cycloalkyl containing 5 or 6 carbons.
4. Compounds according to claim 3 in which R is a cyclohexyl.
5. A method for the preparation of the compounds with formula I, in which a) a compound with the formuia
Figure imgf000008_0003
is reacted with ammonia, ammonium halide , urea, or urea hydrohalide , or b) a compound with the formula
III
Figure imgf000008_0002
In which Z is a cyano or amidino group, is reacted with a compound with the formula
Figure imgf000008_0001
in which Z' is a cyano or amidino group, or c) a compound with the formula
V
Figure imgf000009_0004
in which X is a halogen such as chlorine, is reacted with a compound with the formula
VI
Figure imgf000009_0003
or, d) a compound with the formula
VII
Figure imgf000009_0002
is reacted with a compound with formula VI, or e) a carbonyl compound with the formula
VIII
Figure imgf000009_0001
Is reduced to the corresponding alcohol. 6) Compounds with formula II.
PCT/FI1982/000034 1981-09-09 1982-09-03 Substituted piperidinyl quinazolines Ceased WO1983000866A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
FI831585A FI831585A7 (en) 1981-09-09 1982-09-03 Process and intermediate for the preparation of substituted piperidinyl quinazolines.
DK181083A DK181083A (en) 1981-09-09 1983-04-25 SUBSTITUTED PIPERIDINYLQUINAZOLINES

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI812796 1981-09-09
FI812796810909 1981-09-09

Publications (1)

Publication Number Publication Date
WO1983000866A1 true WO1983000866A1 (en) 1983-03-17

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EP (1) EP0087456A1 (en)
JP (1) JPS58501513A (en)
AU (1) AU8906682A (en)
DK (1) DK181083A (en)
ES (1) ES8405389A1 (en)
FI (1) FI831585A7 (en)
IT (1) IT1156319B (en)
NO (1) NO831622L (en)
PT (1) PT75525B (en)
WO (1) WO1983000866A1 (en)
ZA (1) ZA826596B (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3517005A (en) * 1967-10-26 1970-06-23 Pfizer & Co C Certain 2- and 4-substituted quinazolines
DE2720545A1 (en) * 1976-05-07 1977-11-10 Synthelabo NEW CHINAZOLINE DERIVATIVES, THEIR MANUFACTURING AND PHARMACEUTICAL AGENTS
FR2389621A2 (en) * 1977-05-05 1978-12-01 Synthelabo Antihypertensive 4-amino 2-piperidino-quinazoline(s) - prepd. from a 2-halo-quinazoline and a piperidine
DE3003323A1 (en) * 1979-01-31 1980-08-14 Pfizer 4-AMINO-2-PIPERIDINOQUINAZOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING SUCH DERIVATIVES
EP0028473A1 (en) * 1979-11-01 1981-05-13 Pfizer Inc. Chloro- and alkoxy-substituted-2,4-diaminoquinazolines and pharmaceutical compositions containing them
EP0034471A1 (en) * 1980-02-19 1981-08-26 Orion-Yhtymä Oy Piperidinoquinazolines and a process for the preparation thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3517005A (en) * 1967-10-26 1970-06-23 Pfizer & Co C Certain 2- and 4-substituted quinazolines
DE2720545A1 (en) * 1976-05-07 1977-11-10 Synthelabo NEW CHINAZOLINE DERIVATIVES, THEIR MANUFACTURING AND PHARMACEUTICAL AGENTS
FR2389621A2 (en) * 1977-05-05 1978-12-01 Synthelabo Antihypertensive 4-amino 2-piperidino-quinazoline(s) - prepd. from a 2-halo-quinazoline and a piperidine
DE3003323A1 (en) * 1979-01-31 1980-08-14 Pfizer 4-AMINO-2-PIPERIDINOQUINAZOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING SUCH DERIVATIVES
EP0028473A1 (en) * 1979-11-01 1981-05-13 Pfizer Inc. Chloro- and alkoxy-substituted-2,4-diaminoquinazolines and pharmaceutical compositions containing them
EP0034471A1 (en) * 1980-02-19 1981-08-26 Orion-Yhtymä Oy Piperidinoquinazolines and a process for the preparation thereof

Also Published As

Publication number Publication date
ES515338A0 (en) 1983-11-01
NO831622L (en) 1983-05-06
EP0087456A1 (en) 1983-09-07
FI831585L (en) 1983-05-09
ZA826596B (en) 1983-11-30
DK181083D0 (en) 1983-04-25
PT75525A (en) 1982-10-01
IT8223168A0 (en) 1982-09-08
ES8405389A1 (en) 1983-11-01
DK181083A (en) 1983-04-25
IT1156319B (en) 1987-02-04
PT75525B (en) 1984-12-12
FI831585A0 (en) 1983-05-09
IT8223168A1 (en) 1984-03-08
FI831585A7 (en) 1983-05-09
AU8906682A (en) 1983-03-28
JPS58501513A (en) 1983-09-08

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