CA1217768A - Process for the preparation of pyrimidinones and their acid addition salts - Google Patents
Process for the preparation of pyrimidinones and their acid addition saltsInfo
- Publication number
- CA1217768A CA1217768A CA000429507A CA429507A CA1217768A CA 1217768 A CA1217768 A CA 1217768A CA 000429507 A CA000429507 A CA 000429507A CA 429507 A CA429507 A CA 429507A CA 1217768 A CA1217768 A CA 1217768A
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- Canada
- Prior art keywords
- group
- hydroxy
- carbon atoms
- methoxy
- methyl
- Prior art date
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
Abstract
Abstract Process for preparation of pyridimidinones of the general formula
Description
In our Canadian Patent Application Serial No. 392,067 are described new pyrimidinones of the general formula B ~ \ ~ ~ O - D - N (I) and the acid addition salts thereof, especially their physiolog-ically compatible acid addition salts with inorganic and organic acids, as well as processes for their preparation. These compounds show valuable pharmacological properties, especially a hypotensive, antiarrhythmic and ~-receptor blocking activity.
In the above mentioned general formula I
A and B together with both carbon atoms to which they are attached, represent a pyridine or phenyl ring, which phenyl nucleus may be substituted by the residues Rl and R2, wherein Rl represents a hydrogen or halogen atom, an amino or nitro group, and alkyl or alkoxy group each with 1 to 3 carbon atoms and R2 represents a hydrogen atom or an alkoxy group with 1 to 3 carbon atoms D represents an alkylene group with 3 or 4 carbon atoms optionally substituted by a hydroxy group, R3 and Rs, which may be the same or different, each represent a hydrogen atom or an alkyl group with 1 to 3 carbon atoms.
,~ ?
; 7'~
R4 represents a hydrogen atom or an alkoxy group with 1 to 3 carbon atoms, and R6 represents a straight-chain or branched alkyl group with 1 to 6 carbon atoms or a straight-chain saturated alkylene group with 2 to 4 carbon atoms optionally sub~tituted by a hydroxy group, which is terminally substituted by a phenyl or phenoxy group, whereby each phenyl nucleus may be mono or disubstituted by alkyl and/or alkoxy groups with each 1 to 3 carbon atoms.
The above mentioned meanings of the definition of the residues A, B, D, R3, R4, R5 and R6 include for example for A and B together with the both carbon atoms to which they are attached, the pyridine, phenyl, chlorophenyl, bromophenyl, fluorophenyl, aminophenyl, nitrophenyl, methoxy-phenyl, ethoxyphenyl, propoxyphenyl, isopropoxyphenyl, dimethoxyphenyl, diethoxyphenyl, methoxy-ethoxyphenyl, methoxy-propoxyphenyl, ethoxy-isopropoxyphenyl, methoxychlorophenyl, ethoxy-bromophenyl or isopropoxy-fluorophenyl ring, for D the n-propylene, n-butylene, 2-hydroxy-n-propy-lene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group, for R3 and R5 each a hydrogen atom, the methyl, ethyl, propropyl or isopropyl group, for R4 a hydrogen atom, the methoxy, ethoxy, propoxy or isopropoxy group, l' ? ~ ~7 7t~
for R6 the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, neopentyl, tert.
pentyl, hexyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-hydroxy-3-phenylpropyl, 2-hydroxy 4-phenylbutyl, 3-hydroxy-4-phenyl-butyl,
In the above mentioned general formula I
A and B together with both carbon atoms to which they are attached, represent a pyridine or phenyl ring, which phenyl nucleus may be substituted by the residues Rl and R2, wherein Rl represents a hydrogen or halogen atom, an amino or nitro group, and alkyl or alkoxy group each with 1 to 3 carbon atoms and R2 represents a hydrogen atom or an alkoxy group with 1 to 3 carbon atoms D represents an alkylene group with 3 or 4 carbon atoms optionally substituted by a hydroxy group, R3 and Rs, which may be the same or different, each represent a hydrogen atom or an alkyl group with 1 to 3 carbon atoms.
,~ ?
; 7'~
R4 represents a hydrogen atom or an alkoxy group with 1 to 3 carbon atoms, and R6 represents a straight-chain or branched alkyl group with 1 to 6 carbon atoms or a straight-chain saturated alkylene group with 2 to 4 carbon atoms optionally sub~tituted by a hydroxy group, which is terminally substituted by a phenyl or phenoxy group, whereby each phenyl nucleus may be mono or disubstituted by alkyl and/or alkoxy groups with each 1 to 3 carbon atoms.
The above mentioned meanings of the definition of the residues A, B, D, R3, R4, R5 and R6 include for example for A and B together with the both carbon atoms to which they are attached, the pyridine, phenyl, chlorophenyl, bromophenyl, fluorophenyl, aminophenyl, nitrophenyl, methoxy-phenyl, ethoxyphenyl, propoxyphenyl, isopropoxyphenyl, dimethoxyphenyl, diethoxyphenyl, methoxy-ethoxyphenyl, methoxy-propoxyphenyl, ethoxy-isopropoxyphenyl, methoxychlorophenyl, ethoxy-bromophenyl or isopropoxy-fluorophenyl ring, for D the n-propylene, n-butylene, 2-hydroxy-n-propy-lene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group, for R3 and R5 each a hydrogen atom, the methyl, ethyl, propropyl or isopropyl group, for R4 a hydrogen atom, the methoxy, ethoxy, propoxy or isopropoxy group, l' ? ~ ~7 7t~
for R6 the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, neopentyl, tert.
pentyl, hexyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-hydroxy-3-phenylpropyl, 2-hydroxy 4-phenylbutyl, 3-hydroxy-4-phenyl-butyl,
2-(methoxyphenyl)-ethyl, 3-(methoxyphenyl)-propyl, 4-(methoxyphenyl)-butyl, 2-hydroxy-3-(methoxy-phenyl)-propyl, 2-(ethoxyphenyl)-ethyl, 3-(iso-propoxyphenyl)-propyl, 2-(dimethoxyphenyl)-ethyl, 3-(~imethoxyphenyl)-propyl, 2-hydroxy-
3-(dimethoxyphenyl)-propyl, 2-(methylphenyl)-ethyl, 2-(isopropylphenyl)-ethyl, ~-(methylphenyl)-propyl, 2-hydroxy-3-(methylphenyl)-propyl, 4-(methylphenyl)-butyl, 2-(dimethylphenyl)-ethyl, 3-(dimethylphenyl)-propyl~ 2-hydroxy-3-(dimethylphenyl)-propyl, 2-phenoxy-ethyl, 3-phenoxypropyl, 4-phenoxybutyl, 2-hydroxy-3-phenoxypropyl, 2-hydroxy-4-phenoxybutyl, 3-hydroxy-
4-phenoxy-butyl, 2-(methoxyphenoxy)-ethyl., 3-(methoxy-phenoxy)-propyl, 4-(methoxyphenoxy)-butyl, 2-(ethoxy-phenoxy)- ~hyl,3-(isopropoxyphenoxy)-propyl, 2-(di-methoxyphenoxy)-ethyl, 3-(dimethoxyphenoxy)-propyl, 2-hydroxy-3-(dimethoxyphenoxy)-propyl, 2-hydroxy-4-(dimethoxypheno~y)-butyl, 2-(methylphenoxy)-ethyl, 2-(isopropylphenoxy-ethyl, 3-(methylphenoxy)-propyl, 2-hydroxy-3-(methylphenoxy)-propyl~ 4-(methylphenoxy)-butyl, 2-(dimethylphenoxy)-ethyl, 3-(dimethylphenoxy)-propyl, 2-hydroxy-3-(dimethylphenoxy)-propyl, 2-(methyl_methoxyphenyl)-ethyl, 3-(methyl-methoxyphenyl)-propyl, 2-hydroxy-3-(methyl-methoxyphenyl)-propyl, 4-(methyl-methoxyphenyl)-butyl, 2-(methyl-ethoxyphenyl)-ethyl, 3-(ethyl-ethoxyphenyl)-propyl, 2-hydroxy-3-(methy~-propoxyphenyl)-propyl, 2-(methyl-methoxyphe-noxy)-ethyl, 3-(methyl-methoxyphenoxy)-propyl, 2-hydroxy-3-(methyl-methoxyphenoxy)-propyl, 4-(methyl-methoxy-phenoxy)-butyl, 2-(isopropyl-methoxyphenoxy)-ethyl,~
2-hydroxy-3-(methyl-isopropoxyphenoxy)-propyl- or 3-hydroxy-3-(isopropyl-isopropoxyphenoxy)-propyl group.
Preferred compounds of the general formula I are however these wherein A and B together with both carbon atoms to which they are attached, represent a pyridine ring or a phenyl ring, which may be substituted by the residues Rl and R2, whereby Rl represents a hydrogen or chlorine atom, a methyl, methoxy or a nitro group, and R2 represents a hydrogen atom or a methoxy group, D represents a n-propylene, n-butylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group, R3 and R5, which may be the same or different, represent each an alkyl group with 1 to 3 carbon atoms or a hydrogen atom, R4 represents a hydrogen atom or the methoxy group, and R6 represents an alkyl group with 1 to 4 carbon atoms, an ethyl group substituted in 2-position by a methoxyphenyl, dimethoxyphenyl, methyl-phenoxy or methoxyphenoxy group or a 2-hydxoxypropyl group substituted in 3-position by a methoxyphenoxy or methylphenoxy group, and the physiologically compatible acid addition salts thereof.
Especially preferred compounds of the general formula I
are however these, wherein A and B together with both carbon atoms to which they are attached, represent a phenyl, methoxyphenyl, dimethoxyphenyl or pyridine ring D represents the n-propylene or 2-hydr~xy-n-propylene group, R3 represents a hydrogen atom or the methyl group, '7~
- 4a -R4 represents a hydrogen atom or the methoxy group, R5 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, and R6 represents an alkyl group with 1 to 4 carbon atoms, an ethyl group substituted in 2-position by a methoxyphenyl, dimethoxyphenyl, methylphenoxy or methoxyphenoxy group or a 2-hyclroxypropyl group substituted in 3-position by a methoxyphenoxy or methylphenoA~y group) especially the compounds of the general formula Rl ~ N
R2 ~ N ~ ~ - O-cH2-cH-cH
~ R6 4 ,(Ia) wherein Rl represents a methoxy group in 6- or 8-position, R2 represents a hydrogen atom or a methoxy group in 7-position, and R5 and R6 together with the nitrogen atom to which they are attach-ed, represent an isopropylamino, tert.butylamino, N-methyl-2-(3,4-dimethoxy-phenyl)-ethylamino, 2-~2-methoxyphenyl)-ethylamino, 2-~2-methylphenoxy)-ethylamino or 2-(4-methoxyphenoxy)-ethylamino group, and the physiologically compatible acid addition salts thereof with inorganic or organic acids.
Now, it has been found that the new compounds can also be prepared by the following processes:
a) Reaction of a hydroxyphenyl compound of the general formula o A \ ~ N ~ R3 B / ~ N ~ 011 ,~11) o 7~
wherein R3, R4, A and B are as hereinbefore defined, with a compound of the general formula X - D' - N ~ 5 (III) wherein R5' represents a protectlve group for an amino group or has the meanings as hereinbefore defined for R5' R6' represents a str~ight-chain saturated alkylene group with 2 to 4 carbon atoms (substituted by a hydroxy group, whereby the hydroxy group is protected by a protective group for a hydroxy group) r which is substituted on the terminal carbon atom by a phenyl or phenoxy group, wherein each phenyl nucleus may be mono or disubstituted by alkyl or alkoxy groups each with 1 to 3 carbon atoms, whereby the substituents may be the same or different, or has the meanings as hereinbefore defined for R6 l D' represents an alkylene group with 3 or 4 carbon atoms substituted by a hydroxy group, whereby the hydroxy group is protected by a protective group for a hydroxy group~ or has the meanings as hereinbefore defined for D, and X represents a halogen atom, or X together with the ~- and ~-carbon atoms of D' forms an epoxy group, and if required, subsequently removing the optionally used protective groups by means of catalytic hydrogenation or by hydrolysis in tne presence of an acid or base - 6a ~
The reaction is optionally carried out in a solvent such as e.~. ethanol, isopropanol, tetrahydrofurane, toluene, dimethylformamide or dimethylsulfoxide, preferably in the presence of an acid binding agent, e.g. an alcoholate or a~ ali carbonate as potassium tert. butylate or potassium carbonate, and optionally in a closed vessel at temperatures between 50 to 200C, preferably at temperatures between 70 to 150C. The reaction can, if desired, also be carried out without a solvent.
An acyl residue optionally used as protective group may be split off subsequently hydrolytically in the presence of an acid or a base, preferably in the presence of a base such as sodium hydroxide at temperatures up to t~e boiling tempera-ture of the used solvent, and a benzyl group used as protective group may be split off hydrogenolytically, preferably with hydrogen in the presence of palladium/coal or of platinum, at temperatures between 0 and 50C.
~ 7 b) Dehydr~ger,ation of a compound of the general formula R
~ ~ H ~ 5 B , ~ 0 ~ D - ~ _ ,(IY) wherein R3 to R6, A, B and D are as hereir.before defined.
- The dehydrogenation i5 carried out with a dehydroge~a-ting agent such as sulfur, selenium dioxide, per.-benzoic acid, copper-chromium oxide, sodium borohydride, with a quinone sucb as o-chloranil, 1,4-benzo-quinone or 2,3-dichloro-5,6-dicyano-1,4-benzo~ one or with a hydrogenation catalyst such as palladium, Raney-nickel, ~ickel-cobalt or platinium in the melt or in a suitable ~olvent or i~ a mixture thereof suoh as be~zene, toluene, ~itrob~en~, dimethysulfoxide or tetrachloro-ethane and at temperatures between 0 to 200C, depe~-d~ng ~rom the used dehydrating agent. The dehydro-genation with sulfur for ln~tance is preferably carried out in the melt at temperatures between 140 to 180C
a~d wit~ o-c~lora~il at temperatures between 20 a~d 50C.
`7~3 The new compounds obtained according to the invention may, if desired, be converted into their acid addition salts, especially into their physiologically compatible salts with inorganic and organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid~ tartaric acid, oxalic acid or maleic acid.
The compounds of general formulae II to IV used as starting materials may be obtained according to processes kno~n from the literature or are known in the literature respectively.
Thus for example a compound of the general formula II may be ob-tained by reaction (see for example J. chem. Soc. 1972, 709;
NL-A-72.04029 published September 29, 1972; Cassella Farbwerke Mainkur and Syn. Comm. 10, 241-243 (1980) of a corresponding oxazine of the general formula A ~ O
B ~ ~ N ~l~ ~ O - COCH3 (V) with a corresponding amine of the general formula R3 NH2 (VI) followed by splittung off the acetyl group.
~ j'7t~
_ 9 _ Starting materials of the general formula IV may be obtained, for instance, by reaction of a corresponding amide of the general formula ~J ~ (VII) B ~ CONH-R3 with a corresponding aldehyde of the general formula O - D - N (VIII) , ~ ~ R6 in the presence of a base (see US-A 3.265.697 issued August 9, 1966; E.S. Schipper).
As already mentioned above, the new compounds of the general formula I as well as their physiologically compatible acid addition salts with inorganic and organic acids show valuable pharmacological properties, especially a hypotensive, antiarrhythmic and ~-receptor blocking activity.
The following examples serve to illustrate the pre$ent invention:
7`~
_ 10 -Example 1 2-fZ;-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl7-0,52 g (1,8 mmol) of 2-(4-hydroxyphenyl)-3-methyl-6-methoxy-3,4-dihydro-quina~olin-4-one were refluxed in 50 ml ethanol with 2,2 ml of 2n sodium hydroxide solution (2 mmol + 10 %) and with 1,4 g (8 mmol) of l-chloro-3-tert.butylamino-2-propanol (prepared analogously to M. Dubes et al., J. Med. chem. 14, 328 (1971)) for 10 hours. After evaporating to dryness, the obtained residue was dissolved in water and the solution extracted with methylene chloride.
The combined organic extracts were washed with 2n sodium hydroxide solution and with water, dried o~er sodium sulfate and evaporated.
Yield: 210 mg (27,6 % of theory), Melting point: 154-156C (acetone) c23H29N34 Calc.: C 67,13 H 7,10 N 10,21 Found: 67,06 7,08 10,16 Example 2 2~ (2-Hydroxy-3-tert.butylaminopropoxy)-phenyl7-3-meth~l-6-metho~cy-3,4-dihydro-quinazolin-4-one 2,06 g (5 mmol) of 2-Ll;-(2-hydroxy-3-tert.butylamino-propoxy)-phenyl7-3-methyl-6-methoxy-1,2,3,4-tetra-hydro-quinazolin-4-one were reacted with 180 mg (5 mmol + 10 %) of sulfur at 170G. After 3 hours the reaction was finished and the obtained crude material was purified o~er a silica gel column (grain 76&~
size: 0,2-o,5 mm; eluating agent: methylene chloride:
methanol = 19:1, 9:1). The colourles oil resulting after evaporation was crystallized from acetone.
Yield: 462 mg (23 % of theory), Melting point: 158-160C
' C23H29N34 Calc.: C 67,13 H 7,10 N 10,21 Found: 67,10 7,08 10,09 The following compounds have been prepared analogously:
2- ~-(3-Diethylamino-propoxy)-phenyl7-3-methyl-3,4-dihydroquinazolin-4-one-hydrojodide Melting point: 218-222C
2- ~-(3 tert.Butylamino-propoxy)-phenyl7-8-methoxy-3,4-dihydroquina~ ~n-4-one Melting point of the dihydrochloride: 133-135C
2- ~ -t3-tert.Butylamino-propoxy)-pheny ~-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4~one Melting point of the hydrochloride: 283-286C
2- ~ -(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl7-3-methyl-6-nitro-3,4-dihydro-quinazolin-4-one Melting point: 267-270C (acetone/ether) 2- ~ - ~ -(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-butox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quina-zolin-4-one Melting point o~ the hydrochloride: 105-107C
2- ~ - ~ -Hydroxy-3-(2-(3,4-dimethoxyphenyl)-N-methyl-ethylamino)-propoxy7-phenyl~-3- methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point of the dihydrochloride: 152-155C
t~ 7~
_ 12 -2-fZ;-~-(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-propox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quina-zolin-4-one Melting point: 134-136C
2-LZ;-(2-Hydroxy-3-tert,butylamino-propoxy)-phenyl7-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 189-191C
2-LZ;-L~-Hydroxy-3-(2-(2-methoxyphenyl)-ethylamino)-propox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quina-zolin-4-one Melting point of the dihydrochloride: 156-158C
2-LZ;-(2-Hydroxy-3-diethylamino-propoxy)-phenyl7-3-methyl-6-methoxy-3,4-dihydro-qUinazolin-4-one Melting point: 123-125C (acetone/ether) 2-~;-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-3-methyl-6-methoxy-3,4-dihydro-~uinazolin-4-one Melting point: 130-132C
2-LZ;-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 198-201C
2-~ Hydroxy-3-(2-(2-methoxyphenyl)-ethylamino)-propoxy7-phenyl7-3-methyl-8-methoxy-3,4-dihydro-quina-zolin-4-one Melting point of the dihydrochloride: 120-123C
2-LZ;-(2-Hydroxy-3-diethylamino-propoxy)-phenyl7-3-methyl-8-methoxy-3,4-dihydro- quinazolin-4-one Melting point of the dihydrochloride: 127-130C
lZ~ ~ 7~
2- ~ - ~ -Hydroxy-3-(2-(2-methylphenoxy)-ethylamino)-propox~7-phenyl7-3-methyl-8-methoxy-3,4-dihydro-quinazolin-4-one Meltlng point of the hydrochloride: 122-125 C
2- ~ - ~ -(2-Hydroxy-3-(~ methylphenoxy)-propylamino)-propoxy7-phenyl7-3-methyl-8-methoxy-~,4-dihydro-qulna-zolin-4-one Melting point: 138-140C
2-~ - ~ -Hydroxy-3-(2-(2-methoxyphenyl)-ethylamino)-propoxy7-phenyl7-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one Melting point of the trihydrochloride: 188-192C
2-~ - ~ -Hydroxy-3-(2-(2-methylphenoxy)-ethylamino)-propoxy7-phenyl7-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one Melting point: 195-198C
2- ~ - ~ -(2-Hydroxy-3-(3-methylphenoxy)-propylamino)-propox~7-phenyl7-3-methyl-6,7-dimetho~y-3,4-dihydro-quinazolin-4-one Melting point of the hydrochloride: 222C
2-~ -Methoxy-4-(2-hydroxy-3-tert.butylaminopropoxy)-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 102-105C (acetone/ether) 2- ~ -(2-Hydroxy-3-tert.butylaminopropo~y)-phenyl7-3~6-dimethyl-3,4-dihydro-quinazolin-4-one Melting point: 146-150C (acetone/ether) 2- ~ -(2-Hydroxy-~-isopropylaminopropo~y)-phenyl7-3,6-dimethyl-3,4-dihydro-quinazolin-4-one Melting point: 150-153C (acetone/ether) ~ Z ~
_ 14 -2- ~ -(2-Hydroxy-~-tert.butylaminopropoxy)-pheny ~ -3-methyl-6-chloro-3,4-dihydro-quinazolin~4 one Melting point: 166-168C (acetone/ether) 2- ~-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-3-methyl-3,4-dihydro-pyrido~ ,3-e7pyrimidine-4-one Melting point of the dihydrochloride: 142-145C
2- ~ -(2-Hydroxy-3-tert.butylamino-propoxy)-pheny ~ -3-methyl-3,4-dihydro-pyrido ~ ,3-e7pyrimidine-4-one Melting point of the dihydrochloride: 168-171C
2- ~ - ~ -Hydroxy-3-~2-(4-methoxy-phenoxy~-ethylamino)-propox~7-phenyl7-3-methyl-3,4-dihydro-pyrido ~ ,3-pyrimidine-4-one Melting point: 132-135C
2- ~ -(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-3-methyl-3,4-dihydro-pyrido ~ ,4-~7pyrimidine-4-one Melting point of the dihydrochloride: 122-125C
2- ~-(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl7-3-methyl-3,4-dihydro-pyrido ~ ,4-e7pyrimidine-4-one Melting point of the dihydrochloride: 171-173C
2- ~ - ~ -(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-propox~7-phenyl7-8-methoxy-3,4-dihydro-quinazolin-4-one Melting point of the dihydrochloride: 190-193~C
2- ~ -(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl7-3-isopropyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 145-147C
2- ~ - ~ -Hydroxy-3-(2-(3 9 4-dimethoxyphenyl)-N-propyl-ethylamino)-propox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting range: 112-117C.
2-hydroxy-3-(methyl-isopropoxyphenoxy)-propyl- or 3-hydroxy-3-(isopropyl-isopropoxyphenoxy)-propyl group.
Preferred compounds of the general formula I are however these wherein A and B together with both carbon atoms to which they are attached, represent a pyridine ring or a phenyl ring, which may be substituted by the residues Rl and R2, whereby Rl represents a hydrogen or chlorine atom, a methyl, methoxy or a nitro group, and R2 represents a hydrogen atom or a methoxy group, D represents a n-propylene, n-butylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group, R3 and R5, which may be the same or different, represent each an alkyl group with 1 to 3 carbon atoms or a hydrogen atom, R4 represents a hydrogen atom or the methoxy group, and R6 represents an alkyl group with 1 to 4 carbon atoms, an ethyl group substituted in 2-position by a methoxyphenyl, dimethoxyphenyl, methyl-phenoxy or methoxyphenoxy group or a 2-hydxoxypropyl group substituted in 3-position by a methoxyphenoxy or methylphenoxy group, and the physiologically compatible acid addition salts thereof.
Especially preferred compounds of the general formula I
are however these, wherein A and B together with both carbon atoms to which they are attached, represent a phenyl, methoxyphenyl, dimethoxyphenyl or pyridine ring D represents the n-propylene or 2-hydr~xy-n-propylene group, R3 represents a hydrogen atom or the methyl group, '7~
- 4a -R4 represents a hydrogen atom or the methoxy group, R5 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, and R6 represents an alkyl group with 1 to 4 carbon atoms, an ethyl group substituted in 2-position by a methoxyphenyl, dimethoxyphenyl, methylphenoxy or methoxyphenoxy group or a 2-hyclroxypropyl group substituted in 3-position by a methoxyphenoxy or methylphenoA~y group) especially the compounds of the general formula Rl ~ N
R2 ~ N ~ ~ - O-cH2-cH-cH
~ R6 4 ,(Ia) wherein Rl represents a methoxy group in 6- or 8-position, R2 represents a hydrogen atom or a methoxy group in 7-position, and R5 and R6 together with the nitrogen atom to which they are attach-ed, represent an isopropylamino, tert.butylamino, N-methyl-2-(3,4-dimethoxy-phenyl)-ethylamino, 2-~2-methoxyphenyl)-ethylamino, 2-~2-methylphenoxy)-ethylamino or 2-(4-methoxyphenoxy)-ethylamino group, and the physiologically compatible acid addition salts thereof with inorganic or organic acids.
Now, it has been found that the new compounds can also be prepared by the following processes:
a) Reaction of a hydroxyphenyl compound of the general formula o A \ ~ N ~ R3 B / ~ N ~ 011 ,~11) o 7~
wherein R3, R4, A and B are as hereinbefore defined, with a compound of the general formula X - D' - N ~ 5 (III) wherein R5' represents a protectlve group for an amino group or has the meanings as hereinbefore defined for R5' R6' represents a str~ight-chain saturated alkylene group with 2 to 4 carbon atoms (substituted by a hydroxy group, whereby the hydroxy group is protected by a protective group for a hydroxy group) r which is substituted on the terminal carbon atom by a phenyl or phenoxy group, wherein each phenyl nucleus may be mono or disubstituted by alkyl or alkoxy groups each with 1 to 3 carbon atoms, whereby the substituents may be the same or different, or has the meanings as hereinbefore defined for R6 l D' represents an alkylene group with 3 or 4 carbon atoms substituted by a hydroxy group, whereby the hydroxy group is protected by a protective group for a hydroxy group~ or has the meanings as hereinbefore defined for D, and X represents a halogen atom, or X together with the ~- and ~-carbon atoms of D' forms an epoxy group, and if required, subsequently removing the optionally used protective groups by means of catalytic hydrogenation or by hydrolysis in tne presence of an acid or base - 6a ~
The reaction is optionally carried out in a solvent such as e.~. ethanol, isopropanol, tetrahydrofurane, toluene, dimethylformamide or dimethylsulfoxide, preferably in the presence of an acid binding agent, e.g. an alcoholate or a~ ali carbonate as potassium tert. butylate or potassium carbonate, and optionally in a closed vessel at temperatures between 50 to 200C, preferably at temperatures between 70 to 150C. The reaction can, if desired, also be carried out without a solvent.
An acyl residue optionally used as protective group may be split off subsequently hydrolytically in the presence of an acid or a base, preferably in the presence of a base such as sodium hydroxide at temperatures up to t~e boiling tempera-ture of the used solvent, and a benzyl group used as protective group may be split off hydrogenolytically, preferably with hydrogen in the presence of palladium/coal or of platinum, at temperatures between 0 and 50C.
~ 7 b) Dehydr~ger,ation of a compound of the general formula R
~ ~ H ~ 5 B , ~ 0 ~ D - ~ _ ,(IY) wherein R3 to R6, A, B and D are as hereir.before defined.
- The dehydrogenation i5 carried out with a dehydroge~a-ting agent such as sulfur, selenium dioxide, per.-benzoic acid, copper-chromium oxide, sodium borohydride, with a quinone sucb as o-chloranil, 1,4-benzo-quinone or 2,3-dichloro-5,6-dicyano-1,4-benzo~ one or with a hydrogenation catalyst such as palladium, Raney-nickel, ~ickel-cobalt or platinium in the melt or in a suitable ~olvent or i~ a mixture thereof suoh as be~zene, toluene, ~itrob~en~, dimethysulfoxide or tetrachloro-ethane and at temperatures between 0 to 200C, depe~-d~ng ~rom the used dehydrating agent. The dehydro-genation with sulfur for ln~tance is preferably carried out in the melt at temperatures between 140 to 180C
a~d wit~ o-c~lora~il at temperatures between 20 a~d 50C.
`7~3 The new compounds obtained according to the invention may, if desired, be converted into their acid addition salts, especially into their physiologically compatible salts with inorganic and organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid~ tartaric acid, oxalic acid or maleic acid.
The compounds of general formulae II to IV used as starting materials may be obtained according to processes kno~n from the literature or are known in the literature respectively.
Thus for example a compound of the general formula II may be ob-tained by reaction (see for example J. chem. Soc. 1972, 709;
NL-A-72.04029 published September 29, 1972; Cassella Farbwerke Mainkur and Syn. Comm. 10, 241-243 (1980) of a corresponding oxazine of the general formula A ~ O
B ~ ~ N ~l~ ~ O - COCH3 (V) with a corresponding amine of the general formula R3 NH2 (VI) followed by splittung off the acetyl group.
~ j'7t~
_ 9 _ Starting materials of the general formula IV may be obtained, for instance, by reaction of a corresponding amide of the general formula ~J ~ (VII) B ~ CONH-R3 with a corresponding aldehyde of the general formula O - D - N (VIII) , ~ ~ R6 in the presence of a base (see US-A 3.265.697 issued August 9, 1966; E.S. Schipper).
As already mentioned above, the new compounds of the general formula I as well as their physiologically compatible acid addition salts with inorganic and organic acids show valuable pharmacological properties, especially a hypotensive, antiarrhythmic and ~-receptor blocking activity.
The following examples serve to illustrate the pre$ent invention:
7`~
_ 10 -Example 1 2-fZ;-(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl7-0,52 g (1,8 mmol) of 2-(4-hydroxyphenyl)-3-methyl-6-methoxy-3,4-dihydro-quina~olin-4-one were refluxed in 50 ml ethanol with 2,2 ml of 2n sodium hydroxide solution (2 mmol + 10 %) and with 1,4 g (8 mmol) of l-chloro-3-tert.butylamino-2-propanol (prepared analogously to M. Dubes et al., J. Med. chem. 14, 328 (1971)) for 10 hours. After evaporating to dryness, the obtained residue was dissolved in water and the solution extracted with methylene chloride.
The combined organic extracts were washed with 2n sodium hydroxide solution and with water, dried o~er sodium sulfate and evaporated.
Yield: 210 mg (27,6 % of theory), Melting point: 154-156C (acetone) c23H29N34 Calc.: C 67,13 H 7,10 N 10,21 Found: 67,06 7,08 10,16 Example 2 2~ (2-Hydroxy-3-tert.butylaminopropoxy)-phenyl7-3-meth~l-6-metho~cy-3,4-dihydro-quinazolin-4-one 2,06 g (5 mmol) of 2-Ll;-(2-hydroxy-3-tert.butylamino-propoxy)-phenyl7-3-methyl-6-methoxy-1,2,3,4-tetra-hydro-quinazolin-4-one were reacted with 180 mg (5 mmol + 10 %) of sulfur at 170G. After 3 hours the reaction was finished and the obtained crude material was purified o~er a silica gel column (grain 76&~
size: 0,2-o,5 mm; eluating agent: methylene chloride:
methanol = 19:1, 9:1). The colourles oil resulting after evaporation was crystallized from acetone.
Yield: 462 mg (23 % of theory), Melting point: 158-160C
' C23H29N34 Calc.: C 67,13 H 7,10 N 10,21 Found: 67,10 7,08 10,09 The following compounds have been prepared analogously:
2- ~-(3-Diethylamino-propoxy)-phenyl7-3-methyl-3,4-dihydroquinazolin-4-one-hydrojodide Melting point: 218-222C
2- ~-(3 tert.Butylamino-propoxy)-phenyl7-8-methoxy-3,4-dihydroquina~ ~n-4-one Melting point of the dihydrochloride: 133-135C
2- ~ -t3-tert.Butylamino-propoxy)-pheny ~-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4~one Melting point of the hydrochloride: 283-286C
2- ~ -(2-Hydroxy-3-tert.butylaminopropoxy)-phenyl7-3-methyl-6-nitro-3,4-dihydro-quinazolin-4-one Melting point: 267-270C (acetone/ether) 2- ~ - ~ -(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-butox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quina-zolin-4-one Melting point o~ the hydrochloride: 105-107C
2- ~ - ~ -Hydroxy-3-(2-(3,4-dimethoxyphenyl)-N-methyl-ethylamino)-propoxy7-phenyl~-3- methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point of the dihydrochloride: 152-155C
t~ 7~
_ 12 -2-fZ;-~-(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-propox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quina-zolin-4-one Melting point: 134-136C
2-LZ;-(2-Hydroxy-3-tert,butylamino-propoxy)-phenyl7-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 189-191C
2-LZ;-L~-Hydroxy-3-(2-(2-methoxyphenyl)-ethylamino)-propox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quina-zolin-4-one Melting point of the dihydrochloride: 156-158C
2-LZ;-(2-Hydroxy-3-diethylamino-propoxy)-phenyl7-3-methyl-6-methoxy-3,4-dihydro-qUinazolin-4-one Melting point: 123-125C (acetone/ether) 2-~;-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-3-methyl-6-methoxy-3,4-dihydro-~uinazolin-4-one Melting point: 130-132C
2-LZ;-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 198-201C
2-~ Hydroxy-3-(2-(2-methoxyphenyl)-ethylamino)-propoxy7-phenyl7-3-methyl-8-methoxy-3,4-dihydro-quina-zolin-4-one Melting point of the dihydrochloride: 120-123C
2-LZ;-(2-Hydroxy-3-diethylamino-propoxy)-phenyl7-3-methyl-8-methoxy-3,4-dihydro- quinazolin-4-one Melting point of the dihydrochloride: 127-130C
lZ~ ~ 7~
2- ~ - ~ -Hydroxy-3-(2-(2-methylphenoxy)-ethylamino)-propox~7-phenyl7-3-methyl-8-methoxy-3,4-dihydro-quinazolin-4-one Meltlng point of the hydrochloride: 122-125 C
2- ~ - ~ -(2-Hydroxy-3-(~ methylphenoxy)-propylamino)-propoxy7-phenyl7-3-methyl-8-methoxy-~,4-dihydro-qulna-zolin-4-one Melting point: 138-140C
2-~ - ~ -Hydroxy-3-(2-(2-methoxyphenyl)-ethylamino)-propoxy7-phenyl7-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one Melting point of the trihydrochloride: 188-192C
2-~ - ~ -Hydroxy-3-(2-(2-methylphenoxy)-ethylamino)-propoxy7-phenyl7-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one Melting point: 195-198C
2- ~ - ~ -(2-Hydroxy-3-(3-methylphenoxy)-propylamino)-propox~7-phenyl7-3-methyl-6,7-dimetho~y-3,4-dihydro-quinazolin-4-one Melting point of the hydrochloride: 222C
2-~ -Methoxy-4-(2-hydroxy-3-tert.butylaminopropoxy)-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 102-105C (acetone/ether) 2- ~ -(2-Hydroxy-3-tert.butylaminopropo~y)-phenyl7-3~6-dimethyl-3,4-dihydro-quinazolin-4-one Melting point: 146-150C (acetone/ether) 2- ~ -(2-Hydroxy-~-isopropylaminopropo~y)-phenyl7-3,6-dimethyl-3,4-dihydro-quinazolin-4-one Melting point: 150-153C (acetone/ether) ~ Z ~
_ 14 -2- ~ -(2-Hydroxy-~-tert.butylaminopropoxy)-pheny ~ -3-methyl-6-chloro-3,4-dihydro-quinazolin~4 one Melting point: 166-168C (acetone/ether) 2- ~-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-3-methyl-3,4-dihydro-pyrido~ ,3-e7pyrimidine-4-one Melting point of the dihydrochloride: 142-145C
2- ~ -(2-Hydroxy-3-tert.butylamino-propoxy)-pheny ~ -3-methyl-3,4-dihydro-pyrido ~ ,3-e7pyrimidine-4-one Melting point of the dihydrochloride: 168-171C
2- ~ - ~ -Hydroxy-3-~2-(4-methoxy-phenoxy~-ethylamino)-propox~7-phenyl7-3-methyl-3,4-dihydro-pyrido ~ ,3-pyrimidine-4-one Melting point: 132-135C
2- ~ -(2-Hydroxy-3-isopropylamino-propoxy)-phenyl7-3-methyl-3,4-dihydro-pyrido ~ ,4-~7pyrimidine-4-one Melting point of the dihydrochloride: 122-125C
2- ~-(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl7-3-methyl-3,4-dihydro-pyrido ~ ,4-e7pyrimidine-4-one Melting point of the dihydrochloride: 171-173C
2- ~ - ~ -(2-Hydroxy-3-(4-methoxyphenoxy)-propylamino)-propox~7-phenyl7-8-methoxy-3,4-dihydro-quinazolin-4-one Melting point of the dihydrochloride: 190-193~C
2- ~ -(2-Hydroxy-3-tert.butylamino-propoxy)-phenyl7-3-isopropyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting point: 145-147C
2- ~ - ~ -Hydroxy-3-(2-(3 9 4-dimethoxyphenyl)-N-propyl-ethylamino)-propox~7-phenyl7-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one Melting range: 112-117C.
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a pyrimidinone of the general formula (I) or a physiologically compatible salt thereof, wherein A and B together with both carbon atoms to which they are attached, represent a pyridine ring or a phenyl ring, which phenyl ring may be substituted by the residues R1 and R2 wherein R1 represents a hydrogen or halogen atom, an amino or nitro group, an alkyl or alkoxy group each with 1 to 3 carbon atoms, and R2 represents a hydrogen atom or an alkoxy group with 1 to 3 carbon atoms, D represents an alkylene group with 3 or 4 carbon atoms optionally substituted by a hydroxy group, R3 and R5, which may be the same or different, each represent a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R4 represents a hydrogen atom or an alkoxy group with 1 to 3 carbon atoms, and R6 represents a straight chain or branched alkyl group with 1 to 6 carbon atoms or a straight-chain saturated alkylene group with 2 to 4 carbon atoms optionally substituted by a hydroxy group, which is substituted on the terminal carbon atom by a phenyl or phenoxy group, wherein each phenyl nucleus may be mono or disubstituted by alkyl and/or alkoxy groups each with 1 to 3 carbon atoms, which process comprises a) reacting a hydroxyphenyl compound of the general formula (II) wherein R3, R4, A and B are as hereinbefore defined, with a compound of the general formula (III) wherein R5' represents a protective group for an amino group or has the meanings as hereinbefore defined for R5 R6' represents a straight-chain saturated alkylene group with 2 to 4 carbon atoms (substituted by a hydroxy group, whereby the hydroxy group is protected by a protective group for a hydroxy group), which is substituted on the terminal carbon atom by a phenyl or phenoxy group, wherein each phenyl nucleus may be mono or disubstituted by alkyl or alkoxy groups each with 1 to 3 carbon atoms, whereby the substituents may be the same or different, or has the meanings as hereinbefore defined for R6 D' represents an alkylene group with 3 or 4 carbon atoms substituted by a hydroxy group, whereby the hydroxy group is protected by a protective group for a hydroxy group, or has the meanings as hereinbefore defined for D, and X represents a halogen atom or X together with the .alpha.- and .beta.-carbon atoms of D' forms an epoxy group, and if required, subsequently removing the optionally used protective groups by means of catalytic hydrogenation or by hydrolysis in the presence of an acid or base ?
b) dehydrogenating a compound of the general formula (IV) wherein R3 to R6, A, B and D are as hereinbefore defined and, if required, converting the obtained compound of the general formula I into an acid addition salt thereof.
b) dehydrogenating a compound of the general formula (IV) wherein R3 to R6, A, B and D are as hereinbefore defined and, if required, converting the obtained compound of the general formula I into an acid addition salt thereof.
2. A process as claimed in claim 1, wherein the reaction is carried out in a solvent.
3. A process as claimed in claim 1a, wherein the reaction is carried out in the presence of an acid binding agent.
4. A process as claimed in claim 1a, 2 or 3, wherein the reaction is carried out at a temperature between 50 and 200°C.
5. A process as claimed in claim 1a, 2 or 3, wherein the reaction is carried out at a temperature between 70 and 150°C.
6. A process as claimed in claim 1b or 2, wherein the dehydrogenation is carried out at a temperature between 0 and 200°C.
7. A process as claimed in claim 1, 2 or 3 wherein A and B together with both carbon atoms to which they are attached, represent a pyridine ring or a phenyl ring, which may be sub-stituted by the residues R1 and R2, whereby R1 represents a hydrogen or chlorine atom, a methyl, methoxy or a nitro group, and R2 represents a hydrogen atom or a methoxy group, D represents a n-propylene, n-butylene, 2-hydroxy-n -propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group, R3 and R5, which may be the same or different, represent each an alkyl group with 1 to 3 carbon atoms or a hydrogen atom, R4 represents a hydrogen atom or the methoxy group, and R6 represents an alkyl group with 1 to 4 carbon atoms, an ethyl group substituted in 2-position by a methoxyphenyl, dimethoxyphenyl, methyl-phenoxy or methoxyphenoxy group or a 2-hydroxypropyl group substituted in 3-position by a methoxyphenoxy or methylphenoxy group.
8. A process as claimed in claim 1, 2 or 3 wherein A and B together with both carbon atoms to which they are attached, represent a phenyl, methoxy-phenyl, dimethoxyphenyl or pyridine ring, D represents the n-propylene or 2-hydroxy-n-propylene group, R3 represents a hydrogen atom or the methyl group, R4 represents a hydrogen atom or the methoxy group, R5 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, and R6 represents an alkyl group with 1 to 4 carbon atoms, an ethyl group substituted in 2-position by a methoxyphenyl, dimethoxyphenyl, methylphenoxy or methoxyphenoxy group or a 2-hydroxypropyl group substituted in 3-position by a methoxyphenoxy or methylphenoxy group.
9 A process as claimed in claim 1, 2 or 3 wherein A and B together with both carbon atoms to which they are attached represent a phenyl ring substituted by R1 and R2, wherein R1 represents a methoxy group in the 6- or 8-position, R2 represents a hydrogen atom or a methoxy group in the 7-position, R3 re-presents a methyl group, D represents a 2-hydroxy-n-propylene group and R5 and R6 together with the nitrogen atom to which they are attached, represent an isopropylamino, tert.butylamino, N-methyl-2-(3,4-dimethoxyphenyl)-ethylamino, 2-(methoxyphenyl)-ethylamino, 2-(2-methylphenoxy)-ethylamino or 2-(4-methoxy-phenoxy)-ethylamino group.
10. A process as claimed in claim 1 wherein A and B
together with both carbon atoms to which they are attached represent a phenyl ring substituted by a methoxy group in the 6-position, R3 represents a methyl group, R4 represents a hydrogen atom, D represents a 2-hydroxy-n-propylene group, R5 represents a hydrogen atom and R6 represents a tert.-butyl group.
together with both carbon atoms to which they are attached represent a phenyl ring substituted by a methoxy group in the 6-position, R3 represents a methyl group, R4 represents a hydrogen atom, D represents a 2-hydroxy-n-propylene group, R5 represents a hydrogen atom and R6 represents a tert.-butyl group.
11. A process for preparing 2-[4-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one which comprises reacting 2-(4-hydroxyphenyl)-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one with 1-chloro-3-tert.-butylamino-2-propanol.
12. A process for preparing 2-[4-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one which comprises dehydrogenating 2-[4-(2-hydroxy-3-tert.-butylaminopropoxy)-phenyl]-3-methyl-6-methoxy-1,2,3,4-tetrahydro-quinazoline-4-one by reaction with sulfur.
13. A process as claimed in claim 1 ,2 or 3 wherein the acid addition salt is obtained by means of a physiologically compatible inorganic or organic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3220898.7 | 1982-06-03 | ||
| DE19823220898 DE3220898A1 (en) | 1982-06-03 | 1982-06-03 | Process for the preparation of pyrimidinones and their acid addition salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1217768A true CA1217768A (en) | 1987-02-10 |
Family
ID=6165198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000429507A Expired CA1217768A (en) | 1982-06-03 | 1983-06-02 | Process for the preparation of pyrimidinones and their acid addition salts |
Country Status (10)
| Country | Link |
|---|---|
| KR (1) | KR840005107A (en) |
| CA (1) | CA1217768A (en) |
| DD (1) | DD210904A5 (en) |
| DE (1) | DE3220898A1 (en) |
| DK (1) | DK250883A (en) |
| ES (2) | ES8403115A1 (en) |
| FI (1) | FI831914L (en) |
| HU (1) | HU190846B (en) |
| NO (1) | NO831994L (en) |
| PT (1) | PT76806B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009111943A1 (en) * | 2008-03-13 | 2009-09-17 | 中国科学院广州生物医药与健康研究院 | The compounds as the estrogen related receptors modulators and the uses thereof |
| CN1960977B (en) * | 2004-05-31 | 2010-07-21 | 万有制药株式会社 | Quinazoline derivative |
| US8853221B2 (en) | 2008-07-18 | 2014-10-07 | Guangzhou Institute Of Biomedicine & Health, Chinese Academy Of Sciences | Compounds of estrogen-related receptor modulators and the uses thereof |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9404485D0 (en) * | 1994-03-09 | 1994-04-20 | Cancer Res Campaign Tech | Benzamide analogues |
| CA2444704C (en) * | 2001-04-23 | 2012-07-10 | University Of Virginia Patent Foundation | Synthesis and evaluation of phthalimide mimics as anti-angiogenic agents |
| CA2502302A1 (en) * | 2002-11-04 | 2004-05-21 | Nps Pharmaceuticals, Inc. | Quinazolinone compounds as calcilytics |
-
1982
- 1982-06-03 DE DE19823220898 patent/DE3220898A1/en not_active Withdrawn
-
1983
- 1983-05-30 FI FI831914A patent/FI831914L/en not_active Application Discontinuation
- 1983-06-01 PT PT76806A patent/PT76806B/en unknown
- 1983-06-01 ES ES522898A patent/ES8403115A1/en not_active Expired
- 1983-06-01 DD DD83251638A patent/DD210904A5/en unknown
- 1983-06-01 KR KR1019830002442A patent/KR840005107A/en not_active Application Discontinuation
- 1983-06-02 CA CA000429507A patent/CA1217768A/en not_active Expired
- 1983-06-02 DK DK250883A patent/DK250883A/en not_active Application Discontinuation
- 1983-06-02 HU HU831976A patent/HU190846B/en unknown
- 1983-06-02 NO NO831994A patent/NO831994L/en unknown
- 1983-12-09 ES ES527906A patent/ES8406450A1/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1960977B (en) * | 2004-05-31 | 2010-07-21 | 万有制药株式会社 | Quinazoline derivative |
| AU2005247808B2 (en) * | 2004-05-31 | 2011-02-10 | Msd K.K. | Quinazoline derivative |
| WO2009111943A1 (en) * | 2008-03-13 | 2009-09-17 | 中国科学院广州生物医药与健康研究院 | The compounds as the estrogen related receptors modulators and the uses thereof |
| AU2009225171B2 (en) * | 2008-03-13 | 2014-05-01 | Guangzhou Institute Of Biomedicine And Health, Chinese Academy Of Sciences | The compounds as the estrogen related receptors modulators and the uses thereof |
| AU2009225171C1 (en) * | 2008-03-13 | 2014-11-27 | Guangzhou Institute Of Biomedicine And Health, Chinese Academy Of Sciences | The compounds as the estrogen related receptors modulators and the uses thereof |
| US8853221B2 (en) | 2008-07-18 | 2014-10-07 | Guangzhou Institute Of Biomedicine & Health, Chinese Academy Of Sciences | Compounds of estrogen-related receptor modulators and the uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| NO831994L (en) | 1983-12-05 |
| PT76806A (en) | 1983-07-01 |
| DK250883A (en) | 1983-12-04 |
| ES522898A0 (en) | 1984-03-01 |
| FI831914L (en) | 1983-12-04 |
| ES527906A0 (en) | 1984-08-01 |
| PT76806B (en) | 1986-04-09 |
| FI831914A0 (en) | 1983-05-30 |
| KR840005107A (en) | 1984-11-03 |
| DK250883D0 (en) | 1983-06-02 |
| ES8406450A1 (en) | 1984-08-01 |
| ES8403115A1 (en) | 1984-03-01 |
| DE3220898A1 (en) | 1983-12-08 |
| DD210904A5 (en) | 1984-06-27 |
| HU190846B (en) | 1986-11-28 |
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