HU190846B - Process for the production derivatives of pyrimidinones and of their acid addition salts - Google Patents

Abstract

The invention relates to a process for the preparation of pyrimidinones for use as medicaments. The aim of the invention is the provision of compounds with antihypertensive, antiarrhythmic and beta-receptor blocking action. According to the invention, pyrimidinones of general formula I are prepared in which, for example: A and B, together with the two intervening carbon atoms, represent an optionally substituted phenyl ring or a pyridine ring, D an alkylene-o. Hydroxyalkylene group, R deep 3 u. R deep 5 each a hydrogen atom o. An alkyl group, R deep 4 is a hydrogen atom o. An alkoxy group u. R 6 is an alkyl group, an alkylene or hydroxyalkylene group which is terminally substituted by an optionally substituted phenyl or phenoxy group, and salts thereof.

Description

The present invention relates to novel processes for the preparation of the novel compounds of the formula I and their acid addition salts.

Hungarian Patent Application Publication No. 187,384, which has not yet been published prior to the priority date of this application, discloses pyrimidinone derivatives of the formula I and their acid addition salts, in particular their physiologically tolerable acid addition salts with inorganic and organic acids and processes for their preparation. The compounds have valuable pharmacological properties, in particular antihypertensive, antiarrhythmic and β-receptor blocking effects. The present invention is directed to novel processes for the preparation of these compounds.

In the general formula (I)

A and B, taken together with the two carbon atoms between them, form a pyridine or benzene ring which may be substituted by R ₁ and / or R ₂ ,

R, halogen, nitro, C1-C3 alkyl or alkoxy;

R _{2 is C} 1-3 alkoxy,

D represents a C3 or C4 alkylene group optionally substituted by hydroxy,

R ₃ and R ₅ each independently represent hydrogen or C 1-3 alkyl,

R _{4 is} hydrogen or C 1-3 alkoxy; and

R _{6 is C} 1 -C ₆ straight or branched alkyl or C 2 -C 4 straight chain alkylene which may be optionally substituted with phenyl or phenoxy and the phenyl ring may be mono- or disubstituted with C 1 -C 3 alkyl and / or alkoxy groups .

A, B, D, R _3, R _4, R _s and R ₆ above example, reports may include:

A and B, together with the carbon atoms between them, are pyridine, benzene, chlorobenzene, bromobenzene, fluorobenzene, nitrobenzene, methoxybenzene, ethoxybenzene, propoxybenzene, isopropoxybenzene, dimethoxybenzene, diethoxybenzene, methoxyethoxybenzene, methoxypropoxybenzene, ethoxyisopropoxybenzene, methoxychlorobenzene, ethoxybromobenzene or isopropoxy-fluorobenzene,

D η-propylene, η-butylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene,

R ₃ and R _{s are} hydrogen, methyl, ethyl, propyl or isopropyl;

R _{4 is} hydrogen, methoxy, ethoxy, propoxy or isopropoxy;

Re is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, 2-phenylethyl, 3-phenyl- propyl, 4-phenylbutyl, 2- (methoxyphenyl) ethyl, 3- (methoxyphenyl) propyl, 4- (methoxyphenyl) butyl, 2- (ethoxyphenyl) - ethyl, 3- (isopropoxyphenyl) propyl, 2- (dimethoxyphenyl) ethyl, 3- (dimethoxyphenyl) propyl, 2- (methylphenyl) ethyl, 2- (isopropylphenyl) ethyl, 3- (methylphenyl) propyl, 4- (methylphenyl) butyl, 2- (dimethylphenyl) ethyl, 3- (dimethylphenyl) propyl, 2 phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 2- (methoxyphenoxy) ethyl, 3- (methoxyphenoxy) propyl, 4- (methoxyphenoxy) butyl, 2- (ethoxyphenoxy) ethyl, 3- (isopropoxyphenoxy) propyl, 2- (dimethoxyphenoxy) ethyl, 3- (dimethoxyphenoxy) propyl, 2- (methyl2 phenoxy) ethyl- , 2- (isopropylphenoxy) ethyl, 3- (methylphenoxy) propyl, 4- (methylphenoxy) butyl, 2- (dimethylphenoxy) ethyl, 3- (dimethylphenoxy) propyl -, 2- (methylmethoxyphenyl) ethyl, 3- (methylmethoxyphenyl) propyl, 4- (methylmethoxyphenyl) butyl, 2- (methyl 1-ethoxyphenyl) ethyl, 3- (ethyl ethoxyphenyl) propyl, 2- (methylmethoxyphenoxy) ethyl, 3- (methylmethoxyphenoxy) propyl, 4 (methyl- methoxyphenoxy) butyl, 2- (isopropylmethoxyphenoxy) ethyl.

Among the compounds of formula (I), those in which

A and B, taken together with the two carbon atoms between them, form a pyridine or benzene ring, and. it may be substituted by R and / or R ₂ - R, chloro, methyl, methoxy or nitro and R _{2 is} methoxy -

D is n-propylene, η-butylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene,

R ₃ and R each independently represent C 1 -C 3 alkyl or hydrogen,

R _{4 is} hydrogen or methoxy; and

R _{6 is C} 1 -C 4 alkyl, ethyl substituted with 2-methoxyphenyl, dimethoxyphenyl, methylphenoxy or methoxyphenoxy, and their physiologically acceptable acid addition salts.

Particularly preferred are compounds of formula I wherein

A and B are taken together with the two carbon atoms to form a benzene, methoxybenzene, dimethoxybenzene or pyridine ring,

D is n-propylene or 2-hydroxy-n-propylene,

R _{3 is} hydrogen or methyl,

R _{4 is} hydrogen or methoxy,

R _s is hydrogen or C 1-3 alkyl and

R 4 is C 1 -C 4 alkyl, ethyl substituted with 2-methoxyphenyl, dimethoxyphenyl, methylphenoxy or methoxyphenoxy.

Particularly preferred are the compounds of formula (Ia) in which

Rj is a 6- or 8-position methoxy group,

R _{2 is} hydrogen or 7-methoxy,

R _{4 is} hydrogen or methoxy,

R 1 and R ₆ together with the nitrogen atom between them are isopropylamino, tert-butylamino, N-methyl-2- (3,4-dimethoxyphenyl) ethylamino, 2- (2-methoxyphenyl) - ethylamino, 2- (2-methylphenoxy) ethylamino, or 2- (4-methoxyphenoxy) ethylamino, and their physiologically acceptable acid addition salts with inorganic or organic acids.

It has now been found that the novel compounds of this invention may be prepared by the following processes:

a) A hydroxyphenyl derivative of formula II, wherein R ₃ , R ₄ , A and B are as defined above, with a compound of formula III, wherein R _6, R ₆ and D are as defined above , and X represents a nucleophilic interchangeable group, such as halogen.

190,846

The reaction is optionally in a solvent such as ethanol, isopropanol, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, preferably in the presence of an acid acceptor such as an alcoholate or an alkali carbonate such as potassium tert-butylate or potassium carbonate, and is carried out in a vessel at 50 to 200 ° C, preferably at 70 to 150 ° C, but can be carried out without solvent.

b) (IV) compound of the formula - R _3, R _4, R _s, R, A, B and D are as defined above - dehydrogenated.

The dehydrogenation may be carried out with a dehydrogenating agent such as sulfur, selenium dioxide, selenium, perbenzoic acid, copper chromium oxide, sodium borohydride or a quinone such as o-chloranil,

1,4-benzoquinone or 2,3-dichloro-5,6-dicyano-L, 4-benzoquinone or a hydrogenation catalyst such as palladium, Raney nickel, nickel cobalt or platinum, in a melt or in a suitable solvent or solvent mixture such as benzene, toluene, nitrobenzene , dimethyl sulfoxide or tetrachloroethane, depending on the dehydrogenating agent used, between 0 and 200 ° C. For example, sulfur is preferably used in the melt at 140 to 180 ° C and o-chloranil is used at 20 to 50 ° C.

The novel compounds of the present invention can then, if desired, be converted into their acid addition salts, in particular their physiologically tolerable salts, with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, or oxalic acid.

The starting compounds of formula (II), (III) and (IV) may be prepared according to methods known in the art or known in the art, for example, to prepare a compound of formula (II), an appropriate oxazine of formula (V) ), and the acetyl group is cleaved (see, e.g., J. chem. Soc., 1972, 709; German Patent Publication No. 2 114 884; Syn. Comm. 10: 241-243 (1980)].

For example, the starting compound of formula (IV) is prepared by reacting a corresponding amide of formula (VII) with an appropriate aldehyde of formula (VIII) in the presence of a base (U.S. Patent No. 3,265,697).

As mentioned in the introduction, the novel compounds of formula I and their physiologically tolerated acid addition salts with inorganic and organic acids have valuable pharmacological properties, in particular their antihypertensive, antiarrhythmic and β-receptor blocking activity.

The following examples illustrate an embodiment of the process of the invention.

Example 1

2- [4- (2-Hydroxy-3-tert-butylaminoprop ()) phenyl] -3-methyl-6-methoxy-3,4-dihydroquinazolin-4-one

0.52 g (1.8 mmol) of 2- (4-hydroxy-phenyl) -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one in 50 ml of ethanol with 2.2 ml of 2N sodium hydroxide + 10%) and 1.4 g (8 mmol) of 1-chloro-3-tert-butylamino-2-propanol (prepared analogously to M. Dubes et al., J. Med. Chem. 14, 328 (1971)] is refluxed for 10 hours. After evaporation to dryness, the residue is taken up in water and extracted with methylene chloride. The combined organic extracts were washed with 2N sodium hydroxide and water, dried over sodium sulfate and evaporated.

Yield: 210 mg (27.6%).

154-156 ° C (from acetone).

Example 2

2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) phenyl] -3-methyl-6-methoxy-3,4-dihydroquinazolin-4-one

2.06 g (5 mmol) of 2- [4- (2-hydroxy-3-tert-butylaminopropoxy) phenyl] -3-methyl-6-methoxy-1,2,3,4-tetrahydroquinazoline-4- ont 180 mg (5 mmol + 10%) sulfur at 170 ° C. After 3 hours, the reaction was complete and the crude product was purified on a silica gel column (particle size: 0.2-0.5 mm; eluent: 19: 1 then 9: 1 v / v methylene chloride: methanol). After evaporation, a colorless oil is obtained, which is crystallized from acetone.

Yield: 462 mg (23%),

158-160 ° C.

The following compounds were prepared analogously:

2- [4- (3-diethylamino-propoxy) -phenyl] -3-methyl-3,4-dihydro-quinazolin-4-one hydroiodide; mp 218-222 ° C;

2- [4- (3-tert-Butylamino-propoxy) -phenyl] -8-methoxy-3,4-dihydro-quinazolin-4-one, dihydrochloride m.p. 133-135 ° C;

2- [4- (3-tert-Butylamino-propoxy) -phenyl] -3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one, m.p. 283-286 ° C;

2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) phenyl] 3-methyl-6-nitro-3,4-dihydroquinazolin-4-one, m.p. 267-270 ° C. (from acetone-ether mixture);

2- {4- [4- (2-hydroxy-3- (4-methoxyphenoxy) propylamino) butoxy] phenyl) -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4- on, m.p. 105-107 ° C for the hydrochloride;

2- {4- [2-hydroxy-3- (2- / 3,4-dimethoxy-phenyl / -N-methyl-amino) propoxy] phenyl} -3-methyl-6-methoxy-of 3,4 quinazolin-4-one, m.p. 152-155 ° C, dihydrochloride;

2- {4- [3- (2-hydroxy-3- (4-methoxyphenoxy) propylamino) propoxy] phenyl} -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4- m.p. 134-136 ° C; 2- [4- (2-hydroxy-3-tert-butylaminopropoxy) phenyl] 6-methoxy-3,4-dihydroquinazolin-4-one, m.p. 189-191 ° C;

2- {4- [2-hydroxy-3- (2- (2-methoxyphenyl) ethylamino) -propoxy] -phenyl} -3-methyl-6-methoxy-3,4-dihydro-31-kina

190,846 zolin-4-one, dihydrochloride m.p. 156-158 ° C;

2- [4- (2-Hydroxy-3-diethylaminopropoxy) phenyl] -3-methyl-6-methoxy-3,4-dihydroquinazolin-4-one, m.p. 123-125 ° C (acetone). ether mixture);

2- [4- (2-hydroxy-3-isopropylaminopropoxy) phenyl] 3-methyl-6-methoxy-3,4-dihydroquinazolin-4-one, m.p. 130-132 ° C;

2- [4- (2-hydroxy-3-isopropylaminopropoxy) phenyl] 6-methoxy-3,4-dihydroquinazolin-4-one, m.p. 198-201 C;

2- {4- [2-hydroxy-3- (2- / 2-methoxy-phenyl / ethylamino) -propoxy] -phenyl} -3-methyl-8-methoxy-3,4-dihydroquinazolin-4 on, melting point of dihydrochloride; 120123 'C;

2- [4- (2-Hydroxy-3-diethylaminopropoxy) phenyl] -3-methyl-8-methoxy-3,4-dihydroquinazolin-4-one, m.p. 127-130 ° C;

2- {4- [2-hydroxy-3- (2- / 2-methyl-phenoxy / -ethyl-amino) propoxy] phenyl} -3-methyl-8-methoxy-3,4-dihydroquinazolin-4 on, m.p. 122125 ° C;

2- {4- [3- (2-hydroxy-3- / 3-methylphenoxy / propylamino) propoxy] phenyl} -3-methyl-8-methoxy-3,4-dihydro-quinazolin-4- m.p. 138-140 ° C; 2- {4- [2-hydroxy-3- (2- / 2-methoxy-phenyl / ethylamino) -propoxy] -phenyl} -3-methyl-6,7-dimethoxy-3,4-dihydroquinazolin-4 -on, m.p. 188-192 ° C for trihydrochloride;

2- {4- [2-hydroxy-3- (2- / 2-methyl-phenoxy / -ethyl-amino) propoxy] phenyl} -3-methyl-6,7-dimethoxy-3,4-dihydroquinazolin-4 195-198 ° C;

2- {4- [3- (2-Hydroxy-3- (3-methyl-phenoxy) -propylamino) -propoxy] -phenyl} -3-methyl-6,7-dimethoxy-3,4-dihydro-quinazoline-4 on hydrochloride, m.p. 222 ° C;

2- [3-methoxy-4- (2-hydroxy-3-tert-butylaminopropoxy) -phenyl] -3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one, m.p. 102- 105 ° C (from acetone-ether);

2- [4- (2-Hydroxy-3-tert-butylamino-propoxy) -phenyl] -3,6-dimethyl-3,4-dihydro-quinazolin-4-one, m.p. 146-150 ° C (from acetone-ether); 2- [4- (2-Hydroxy-3-isopropylaminopropoxy) phenyl] 3,6-dimethyl-3,4-dihydroquinazolin-4-one, m.p. 150-153 ° C (acetone ether) ether);

2- [4- (2-hydroxy-3-tert-butylaminopropoxy) phenyl] 3-methyl-6-chloro-3,4-dihydroquinazolin-4-one, m.p. 166-168 ° C. (from acetone-ether mixture);

2- [4- (2-Hydroxy-3-isopropylaminopropoxy) phenyl] -3-methyl-3,4-dihydropyrido [2,3-e] pyrimidin-4-one, m.p. 142-145 'C;

2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) phenyl] 3-methyl-3,4-dihydropyrido [2,3-e] pyrimidin-4-one, m.p. 168-171 ° C; 2- {4- [2-hydroxy-3- (2- / 4-methoxyphenoxy / ethylamino) -propoxy] -phenyl} -3-methyl-3,4-dihydro-pyrido [2,3-e] pyrimidine -4-on, melting point; 132-135'C;

2- [4- (2-Hydroxy-3-isopropylaminopropoxy) phenyl] 3-methyl-3,4-dihydropyrido [3,4-e] pyrimidin-4-one, m.p. 122-125 ° C;

2- [4- (2-Hydroxy-3-tert-butylaminopropoxy) phenyl] 3-methyl-3,4-dihydropyrido [3,4-e] pyrimidin-4-one, m.p. 171-173 ° C;

2- {4- [3- (2-Hydroxy-3- (4-methoxy-phenoxy) -propylamino) -propoxy] -phenyl} -8-methoxy-3,4-dihydro-quinazolin-4-one, dihydrochloride mp 190 ₅₁₉₃ ° C;

2- [4- (2-hydroxy-3-tert-butylaminopropoxy) phenyl] 3-isopropyl-6-methoxy-3,4-dihydroquinazolin-4-one, m.p. 145-147 ° C. ; 2- {4- [2-Hydroxy-3- (2- (3,4-dimethoxyphenyl) -N-propyl-ethylamino) -propoxy] -phenyl} -3-methyl-6-methoxy-3,4 ^u dihydroquinazolin-4-one, melting range:

112-117 'C.

Claims (5)

Claims 15 A process for the preparation of pyrimidinone derivatives of the formula I in this formula A and B form a pyridine or benzene ring with the carbon atoms which may be substituted by R ₁ and / or ²⁰ R ₂ , R 1 is halogen or nitro or C 1-3 alkyl or alkoxy, R ₂ is C 1-3 alkoxy, D is a C3 or C4 alkylene group optionally substituted with hydroxy; R ₃ and R _s are independently hydrogen or C1-3 alkyl; R _{4 is} hydrogen or C 1-3 alkoxy, R _{6 is C} 1-6 straight or branched alkyl or C 2-4 straight alkylene which is ultimately substituted with phenyl or phenoxy and the phenyl ring is mono- or disubstituted with C 1-3 alkyl and / or alkoxy. and their acid addition salts, characterized in that a) a hydroxyphenyl derivative of formula II, wherein R ₃ , R ₄ , A and B are as defined above, with a compound of formula III, wherein R _s , R _e and D is, preferably are as defined above, X is a nucleophilic displaceable group halogen - are reacted, or 45 b) reacting a compound (IV) - in which R _3, R _4, R _s, R _b, a, b and D the already and dehydrogenating and, if desired, converting the compound of formula (I) into a physiologically acceptable acid addition salt thereof with an organic or inorganic acid. Process (a) or (b) according to claim 1, characterized in that the reaction is carried out in a solvent. 55 Process a) according to claim 1 or 2, characterized in that the reaction is carried out in the presence of an acid scavenger. Process (a) according to claim 1 or 2 or process according to claim 3, characterized in that the reaction is carried out between 50 and 200 'C, preferably between 70 and 150' C. Process b) according to claim 1 or 2, characterized in that the dehydrogenation is carried out between 0 and 200 ° C.