DE2347376A1 - NEW BIS- (QUINAZOLINYL-PIPERIDYL) AND METHODS FOR THEIR PRODUCTION - Google Patents

Description

P 23 47 576.9

SANDOZ AG. Basel / Switzerland

Case 600-6512

New bis (ehinazolinyl piperidyl) alkylenes and processes for their manufacture

The invention relates to new compounds of the formula I,

H- (CH ₂ ) (CH) _1n

RR ₁

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wherein R and R are the same or different and are each hydrogen or alkyl having 1-4 carbon atoms mean,

the radicals Y are identical or different and each represents hydrogen, chlorine, bromine or alkyl with 1-4 Carbon atoms stand,

η stands for O, 1, 2, 3 or 4,
m means the number 0 or 1,

and the rings A and B are identical or different and

each for an unsubstituted or substituted ring of the formula II,

^Υ Γ

^Y 2

stand,

wherein either γ, γ and Y are the same or different

and each hydrogen, fluorine, chlorine, bromine, alkyl with 1-4 carbon atoms, Alkoxy or alkylthio with 1-3 carbon atoms each, nitro or trifluoromethyl mean,

where, however, at most two of the substituents Y ₁ , Y and Y are nitro, alkylthio or trifluoromethyl and where, if one of the substituents Y, Y or Y is tert. Butyl stands, then none of the other substituents tert. Means butyl on adjacent carbon atoms,

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or in which two of the substituents Y ₁ , Y,

and

together 6,7-methylenedioxy or 6,7-ethylenedioxy mean and the other stands for hydrogen.

According to the invention one arrives at the compounds of the formula I by adding a compound or compounds of the formula III,

III

where Y, Y ,, Y and Y have the above meaning, and Q is chlorine, bromine or a radical -WZ, in which W is oxygen or sulfur and Z represents alkyl with 1-4 carbon atoms, phenyl. Or benzyl,

with a compound of the formula IV,

IV

where R, R, η and m have the above meaning,

implements.

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The process is conveniently carried out at temperatures from 0 to 160 ⁰ C, preferably 20 and 100 ° C and in an inert organic solvent, for example an aromatic solvent such as benzene, an ether such as dioxane, or an alkanol having 1-6 carbon atoms , like isopropanol. It is expedient to work in the presence of an acid binder, such as sodium carbonate or triethylamine. If desired, the reaction can be carried out under an inert atmosphere, for example under nitrogen. Of course, if the rings -A and B and the radicals Y are the same in the desired end product, one can start from a single compound of the formula III. However, if they differ from one another, then a mixture of compounds of the formula III is used. In general, the compounds of the formulas III and IV are used in a molar ratio of at least 2: 1.

The compounds of the formula I obtained can be isolated and purified in a manner known per se. Your free If necessary, bases can be converted into acid addition salts and vice versa. Furthermore, you can also Making hydrates.

Certain compounds of the formula III are known. The unknown compounds from this can be prepared in a manner known per se from customary starting materials. Thus, one can obtain compounds of the formula III in which two of the substituents Y ^ Y ₂ ^{and Y} 3 ^represent 6,7-ethylenedioxy, by proceeding for example by the in Examples 3 and 4 given procedure.

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The compounds of the formula IV are known or can be prepared in a manner known per se [s. for example Varna et.al., J.Am.Chem.Soc. 70, 2330-3 (1948), English Patent 1,173,244, U.S. Patent 2,624,737 and 2,624,738 and Tolbert et.al., J. Heterocycl.Chem. 6_ (6): 963-4 (1969) (Eng.)].

The compounds of the formula I are pharmacologically active and can therefore be used as medicaments. they seem especially against obesity and anti-diabetic, so that they are used as a means against obesity and against diabetes permit. They are administered in a daily dose of between about 30 and 1000 mg, expediently in several partial amounts between 8.5 and 500 mg, two to four times a day, or in sustained-release form for use.

The compounds of formula I can also be used as agents against Angina can be used as well as for appropriate prophylactic use. They do this in a dose of 10 to 500 mg per renata for use. For prophylactic purposes, a suitable daily dose is between 10 and 500 mg, conveniently administered in portions between about 2.5 and 250 mg, two to four times a day, or in sustained release form.

The compounds of the formula I can be mixed with customary, “pharmaceutically acceptable diluents or carriers mix and can be administered, for example, in the form of tablets or hard-filled capsules.

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The compounds of the formula I can in the form of their free • Bases or in the form of their acid addition salts with pharmaceutical harmless acids are used, the salts being as effective in terms of magnitude as the free bases. Acids suitable for salt formation are, for example, methanesulfonic acid, nitric acid, - maleic acid, Fumaric acid or hydrochloric acid. The compounds of the formula I can also be used in the form of their hydrates.

Of the compounds of the formula I, the symmetrical forms are preferred. 1,3-bis is particularly preferred (4- [1- (7-nitroquinazolinyl-4) piperidyl] | propane.

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Example 1 : 1,3-bis / 4- [1- (6 _f 7-dimethylquinazollnyl-4) piperidyl]} propane

A mixture of 5.0 g of 4-chloro-6,7-diinethylquinazoline, 2.73 1,3-bis (piperidyl-4) propane g, 25 ml isopropanol and 3.0 g Sodium carbonate is refluxed for 3 hours, after which it is filtered and the filtrate in vacuo to a small Volume evaporates. Treatment with anhydrous diethyl ether gives solids of the free base of the Title compound, which you then in a with hydrogen chloride Dissolves saturated mixture of chloroform and ethanol and then adds diethyl ether to this and so to the 1,3-bis {4- [1- (6,7-dimethylquinazolinyl-4) piperidyl]} propane dihydrochloride which melts at over 270 ° C.

The dimethanesulfonate salt of the title compound prepared in a similar manner melts at 170 ⁰ C.

The tetrahydrochloride salt of the title compound melts at 165 ° C. with decomposition.

Example 2 : 1,3-bis {4- [1- (6 ^ -dimethoxyquinazolinyl ^) piperidyl]} propane

A mixture of 5.0 g of 4-chloro-6,7-dimethoxyquinazoline, 2.31 g of 1,3-bis (piperidyl-4) propane, 50.0 ml of isopropanol and 2.5g sodium carbonate is refluxed for 2 hours, whereupon it is filtered off and the filtrate is evaporated to an oil in vacuo. The OeI obtained is with 100 ml treated with anhydrous diethyl ether, and the resulting

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Solids are filtered, washed with diethyl ether and from ethanol / water (95: 5) to give to give the free base of the title compound, melting at 140 ° C and then at 149-151 ⁰ C.

The free base of the title compound is in a mixture of ι 30 ml of chloroform and 30 ml of ethanol dissolved, and the thereby The solution obtained is mixed with ethanol saturated with hydrogen chloride until the solution is strongly acidic. the crystals obtained in this way are filtered off and washed twice with ethanol, whereby the title compound is in The form of the dihydrochloric acid addition salt is obtained, which melts at 240 ° C. with decomposition.

Example 3 ; 1,3-bis {4- [1- (6,7-ethylenedioxychinazolinyl-4) piperidyl]} propane

a) 3 ^ 4-AethYlenediox ^ benzoic acid methyl ester

A solution of 4.20 g of methyl 3,4-dihydrobenzoate in 10 ml of methanol is brought together with 7.0 g of sodium ethoxide, whereupon 15.0 g of 1,2-dibromoethane are added. That The resulting mixture is refluxed under nitrogen for 24 hours, then cooled, filtered, in vacuo evaporated and the oil obtained dissolves in 50 ml of chloroform. The solution is filtered again and chromatographed over 100 ml of silica gel, eluting with chloroform and so on reaches the 3,4-ethylenedioxybenzoic acid methyl ester, the melts at 43-45 ° C.

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5.0 ml of 70% nitric acid are added dropwise at 50 to 60 ° C. to a solution of 5.0 g of methyl 3,4-ethylene dioxybenzoate in 5.0 ml of glacial acetic acid. After the addition has ended, the reaction mixture is ^{kept at 55 °} C. for 1 hour, whereupon it is cooled and 50 ml of ice / water are added. The precipitate obtained is filtered off / washed with water and dried, whereby the 6-nitro-3,4-ethylenedioxybenzoic acid methyl ester, which melts at 115-118 ° C., is obtained.

A mixture of 6.0 g of 6-nitro-3,4- "ethylenedioxybenzoic acid methyl ester, 150 mg of 5% palladium on carbon and 20 ml of glacial acetic acid are added under an initial pressure of 2.10 to 2.80

2
kg / cm nitrided without external heating. After 4 hours, the reaction mixture is filtered, diluted with 80 ml of ice / water, stirred for half an hour and the precipitate formed is filtered off, whereupon it is washed with water and dried, and so the 6-amino-3,4-ethylenedioxybenzoic acid methyl ester is obtained melts at 73-77 ⁰ C.

12 *}

A mixture of 2.0 g of 6-amino-3,4-äthylendioxybenzoesäuremethylester and 6 ml of 99% formamide is I ₇ 5 hours heated to reflux, followed by cooling, 5 ml of water and washed the precipitate obtained from

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filtered. It is washed with water and dried, and the 6,7-ethylenedioxy-quinazolin-4 (3H) -one, which ^{melts at 275 °} C., is obtained in this way.

A mixture of 25.3 g of 6,7-ethylenedioxychinazolin-4 (3H) -one and 50 ml of phosphorus oxychloride is refluxed for 10 minutes, cooled and stirred with 1 liter of ice offset. After adding concentrated ammonia, the mixture obtained is extracted with chloroform and chromatographed the chloroform solution then through 300 ml of silica gel, v / obei man eluted with chloroform. After evaporation of the elution one arrives at 4-chloro ~ 6,7-ethylenedioxy-chinazoline, which melts at 169-174 ° C.

grogan

Analogously to Example 1 or 2 and using suitable starting materials in appropriate amounts, the Title compound, its dihydrate dihydrochloride at 238-24O ° C melts.

Example 4 : 1,3-bis {~ 4- [1- (2-methyl-6,7-ethylenedioxychinazolinyl-4) piperidylj \ propane

l ⁴ '5-Ethylenedioxy-

One by mixing 15.2 g Ν, Ν-dimethylacetamide and 40 ml

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Phosphorus oxychloride produced mixture is batchwise with 35.0 g of 6-amino-3,4-ethylenedioxybenzoic acid methyl ester added, the temperature being kept at 40-45 ° C. That The reaction mixture is kept at 40 to 60 ° C. for 4 hours, after which it is added to ice with concentrated ammonia treated, extracted with chloroform and the chloroform solution evaporated and so an oil of 2- (ct-Dimethylaminoäthylidenamino) -4,5-ethylenedioxybenzoic acid methyl ester receives.

A mixture of 12 g of 2- (ct-Dimethylaminoäthylidenamino) 4,5-ethylenedioxybenzoic acid methyl ester, 12 g of ammonium chloride and 100 ml of liquid ammonia is in a. Bomb tube heated ^{to 110 °} C. for 10 hours. The ammonia is evaporated and the solids obtained are washed several times with water, whereupon they are dried to obtain 2-methyl-4-chloro-6,7-äthylenedioxychinazolin-4 (3H) -one, which melts at 275.degree .

Analogously to Example 3e) and using suitable starting materials 2-methyl-4-chloro-6,7-äthylendioxychinazolin is obtained in corresponding amounts, from mp. 168.5-169.5 ° C.

d) Analogously to Example 1 or 2 and using suitable starting materials in appropriate amounts, one arrives at

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to the title compound, its dihydrochloride at 270 ° C melts with decomposition.

Example 5 : 1,3-Bis JA- [1- (6,7,8-trimethoxyquinazolinyl-4) piperidyl]} propane

A mixture of 3.42 g of 4-benzylthio-6,7,8-trimethoxyquina- zoline, 1.05 g 1,3-bis (piperidyl-4) propane

. and 15 ml of isopropanol is refluxed for 18 hours. The reaction mixture is cooled and the crystalline product is filtered off, whereby the title compound is obtained, the dihydrochloride of which ^{melts at 110 °} C. with decomposition.

Example 6 ; 1,3-bis- {4- [1- (6,7,8-trimethoxyquinazolinyl - * - 4) piperidyl] j propane

Analogously to Example 5 and using 2.4 g of 4-methoxy-6,7,8-trimethoxyquinazoline instead of 4-benzylthio-6,7,8-trimethoxyquinazoline and heating for 16 hours instead of 18 hours gives the title compound, whose Dihydrochloride melts at 110 ° C with decomposition.

Example 7 : 1,3-bis / 4- [1- (2-chloro-6,7-dimethoxyquinazolinyl - 4) piperidyl]} propane

A flask equipped with a stirrer and a reflux condenser and flushed with nitrogen is filled with a mixture of 2.0 g of 2,4-dichloro-6,7-dimethoxyquinazoline, 1.92 g of 1,3-bis (piperidyl-4) propane, 2.01 g of sodium carbonate and 25 ml Dioxane is added and the mixture is refluxed for 4 hours under nitrogen;

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heated,

The solids are filtered off and washed Heih'yl'encHTöria / chloroform. The filtrate is evaporated to a / - which is treated with ether. The residue is crystallized from ethanol / methylene chloride to thus give the title compound which melts at 210-212 ^0C.

Example 8:

Analogously to the preceding examples and using appropriate starting materials in suitable amounts the following connections are obtained:

A) 1,3-bis {4- [1- _{(6/7-dimethoxy-2-methylchinazolinyl-4)} piperidyl]} propane, mp. 148-149 ⁰ C.

B) 1,3-bis (4- [1- (6-methoxyquinazoliny 1-4) piperidyl]] propane dihydrochloride, m.p. 249 ° C (decomposition), ·

C) 1,3-bis {4- [1- (6-chloroquinazolinyT-4) piperidyl]} propane, m.p. 162-163 ° C, m.p. of the dihydrochloride 246 ° C (decomposition),

D) 1,3-bis {4- [1- (quinazolinyl-4) piperidyl]} propane,

M.p. 128-129 ° C, m.p. of the dihydrochloride at over 270 ° C,

E) 1,3-bis {4- [1- (5-methoxyquinazolinyl-4) piperidyl]} propane, m.p. 223-225 ° C,

P) 1,3-bis {4- [1- (7-nitroquinazolinyl-4) piperidyl]}.

propane, m.p. of the dimethanesulfonate 90-95 ° C (decomposition),

G) 'bis {4- [1- (6,7-dimethylquinazoliny 1-4) piperidyl]} methane, m.p. of dimethanesulphonate 285-286 ° C,

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H) bis {4- [1- (7-nitroquinazolinyl-4) piperidyl] j methane, M.p. 212-213.5 ° C,

I) bis (4- [l- (6,7,8-trimethoxychinazolinyl-4) piperidyl3j methane. M.p. of dihydrate Dimethansulphonäts 206-207 ⁰ C,

K) Bis {4- [1- (6,7-dimethoxychinazolinyl-4) piperidyl]} methane, mp. 283-284 ⁰ C of Dimethansulfonäts,

L) bis - [4- [1- (6-methoxyquinazolinyl-4) piperidyl] jr methane, m.p. of dimethanesulfonate 269-271 ^Q C,

M) Bis {4- [1- (6-chlorchinazolinyl-4) piperidyl] jf methane, mp. Of the dihydrochloride 266-269 ⁰ C (decomposition),

N) bis {4- [1- (7-chloroquinazolinyl-4) piperidyl] j methane, Mp of the dimethanesulfonate 284-286 ° C,

0) 1,2-bis {4- [1- (7-nitroquinazolinyl-4) piperidyl]) ethane, M.p. 218-220 ° C,

P) 1,2-bis [4- [1- (6,7-dimethylquinazolinyl-4) piperidyl] jf ethane, m.p. of dimethanesulfonate 247 ° C (decomposition),

Q) 1,3-Bis {4- [1- (7-chloroquinazolinyl-4) piperidyl} ^ propane, m.p. of the hydrate dihydrochloride 110 ° C (decomposition),

R) 1,3-bis {4- [1- (6,7-dichloroquinazolinyl-4) piperidyl]} propane, m.p. 2O4-2O5 ° C,

S) 1,2-bis (4- [1- (7-trifluoromethylquinazolinyl-4) piperidyl]} ethane, m.p. of Dimethanesulfonäts 245-247 ° C,

T) 1,3-bis {4- [1- (7-trifluoromethylquinazolinyl-4) piperidyl] ^ propane, m.p. of the dimethanesulfonate 181-185 ° C,

ü) 1,3-bis {4- [1- (6-nitrpquinazolinyl-4) piperidyl] ^ propane, M.p. of the dihydrochloride 262-265 ° C (decomposition),

V) 1-, 3-bis {4- [1- (2-methyl-6,7,8-trimethoxyquinazolinyl-4) piperidyl]} propane, m.p. 147 ° C,

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W) 1,3-bis {4- [1- (6 _f 7-methylenedioxychinazolinyl-4) -piperidyl]} propane, melting point of the dimethanesulfonate 272 ° C. (decomposition),

X) η 1,3-bis {4-fl- (6-methylchinazoliny 1-4) piperidyl]] propane, mp. 130.5 C ^0,

Y) of 1,3-bis {4-ti- (7,8-dimethylchinazolinyl-4) piperidyl]} propane. M.p. of the dihydrochloride 280-285 ⁰ C (decomposition),

Z) 1,3-bis {4- [I- (7-methylquinazolinyl-4) piperidyl]] propane, m.p. of the dimethanesulfonate 2-15-220 ° C (decomposition),

AA) 1,3-bis {4-ti- (6,8-dichloroquinazolinyl-4) piperidyl]] propane, m.p. of the dihydrochloride 230-24O ⁰ C,

AB) 1,3-bis {4- [I- (7-methoxyquinazolinyl-4) piperidyl]} propane, m.p. of the dimethanesulfonate 165 ° C,

AC) of 1,2-bis {4- [1- (6-methoxychinazolinyl-4) piperidyl]} ethane. M.p. of the dihydrochloride 272 ⁰ C,

■ r

AD) 1,2-bis {4- [1- (7-methylquinazolinyl-4) piperidyl]} ethane, Mp of the dimethanesulfonate 238-243 ° C,

AE) 1,2-bis (4- [1- (7-chloroquinazolinyl-4) piperidyl]} ethane, M.p. 213 ° C,

AF) 1,2-bis {4- [1- (7-methoxyquinazolinyl-4) piperidyl]} ethane, Mp of the dimethanesulfonate 272-273 ° C,

AG) 1,2-bis {4-fl- (6-chloroquinazolinyl-4) piperidyl]} ethane, • m.p. 229 ° C,

AH) 1,2-bis {4-fl- (6,7-dimethoxyquinazoliny1-4) piperidylήethane, m.p. 247 ⁰ C (decomposition),

AI) of 1,2-bis {4- [I- (7,8-dimethylchinazolinyl-4) piperidyl] \ ethane, mp. 232-234 ⁰ C of Dimethansulfonats,

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AJ) 1,2-bis 4- [1- (6-nitroquinazolinyl ~ 4) piperidyl] ethane, m.p. 226-228 ° C _f

AK) 1,3-bis 4- [6-raethylthioquinazolinyl-4) piperidyl] propane.

AL) 1- {4- / T- (7-chloroquinazolinyl-4) piperidyl7i-2-

{Ethan.

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Claims (3)

Claims: / piperidyl) -alkylene - (chii 1. Process for the production of new bis (quinazol-ynyl / of formula I, H (CH ₀ ) 2 'η wherein R and R are the same or different and each Denote hydrogen or alkyl with 1-4 carbon atoms, the radicals Y are identical or different and are each for Are hydrogen, chlorine, bromine or alkyl with 1-4 carbon atoms, η is 0, 1, 2, 3 or 4, m is the number 0 or 1, and the rings A and B are identical or different and each for an unsubstituted or substituted ring of the formula II, 409814/1232 600-6512 II wherein either stand, Y, Y and Y are the same or different J- ^ a O and each time hydrogen, fluorine, chlorine, Bromine, alkyl with 1-4 carbon atoms, alkoxy or alkylthio with 1-3 carbon atoms each, Mean nitro or trifluoromethyl, but where at most two of the substituents Y ₁ , Y ₂ and Y are nitro-, alkylthio or trifluoromethyl and where, if one the substituents · Y, Y Jl or Y for tert. «5 Butyl stands, then none of the other substituents tert. Butyl on neighboring Carbon atoms means or in which two of the substituents Υ _χ , and Y together 6,7-methylenedioxy or 6,7-ethylenedioxy mean and the other stands for hydrogen. characterized in that a compound or compounds of the formula III, III 409814/1232 - 19 - 600-6512 where Y, Y,, Y and Y have the above meaning, and Q is chlorine, bromine or a radical -WZ, in which W is oxygen or sulfur and Z represents alkyl with 1-4 carbon atoms, phenyl or benzyl, with a compound of the formula IV, ^(c v "- where R, R, η and m have the above meaning, implements. 409814/1 232 • 20 - 600-6512 Germany 2. New compounds of the formula I mentioned in claim 1. 3. Pharmaceutical preparation, characterized by a content of one or more compounds of the claim 1 mentioned formula I as active ingredient. 4098 U / 1 232