DE2140280A1 - 4 Amino 2 square brackets on 2 (5 Nitro 2 furyl) vinyl square brackets on quinazoline derivatives, manufacturing processes for them and medicines made from them - Google Patents

Description

DR. EYSENBACH

PATENT LAWYER PULLAC H / MO NCHEN 21A0280

Date: Aug 11, 1971 Sign: Sq-14 / H-51-P

description

to the
Patent application

4 ~ Ara.ino-2- _j / 2- (5-nitro-2-furyl) vinyl7quinaz; oline derivatives, manufacturing processes therefor and medicinal products made therefrom

Applicant:

Chemical! Factory of Heyden GmbH, Munich Case 63 327-H

Priority: August 12, 1970 U.S.A. No. 63,327

The invention relates to new 4-amino-2- / 2- (5-nitro-2-furyl) vinyl7-quinazoline derivatives, suitable processes for their production and the pharmaceuticals prepared from such active substances, which one have antimicrobial effects.

The new compounds have the general formula I.

(D

wherein R 'is hydrogen, halogen or nitro;

IL and E ₂ either separately each denote hydrogen, lower alkyl, hydroxyniüdrigalkyl or together, namely, together with the nitrogen atom they carry, a 5- to 7-membered,

209808/1916

'- —2—

nitrogen-containing, monocyclic heterocyclic radical with "bis to represent 18 atoms (excluding the hydrogen atoms). These Definitions apply to the entire description.

All four known halogens can serve as halogens, but chlorine and bromine are preferred. The designated as IT-lower alkyl Groups represent hydrocarbon radicals with up to 7 carbon atoms represent such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like, the first two radicals being are preferred. Those as lower alkoxy (mentioned below) and Groups designated as hydroxy-lower alkyl represent similar alkyl groups, but which contain an oxygen atom or a hydroxyl group contain, for example Hethoxy, Propoxy, Ithoxy, Isopropoxy, hydroxymethyl, hydroxyethyl and the like.

In the group containing the basic nitrogen atom of the general As already mentioned, formula I denotes R ^ and Rp, if appropriate in each case separately hydrogen, lower alkyl or hydroxy-lower alkyl, whereby this entire group is a basic one Radical like amino and lower alkylamino, e.g. !! ethylamino, Ethylamino, isopropylamino, also di (lower alkyl) amino, so e.g. dimethylamine, diethylamino, dipropylamino, furthermore (Hydroxy-lower alkyl) amino, e.g. hydroxyethylamino, also Di (hydroxy-lower alkyl) amino, e.g. di (hydroxyethyl) amino and the like forms.

On the other hand, however, the nitrogen atom with the by R ^ and Ro represent radicals a 5- »6- or 7-membered, monocyclic, Form heterocyclic ring system, which in the ring system also contains an oxygen atom, a sulfur atom or a additional nitrogen atom (more than two heteroatoms should not be contained in the ring system), e.g. Radicals such as piperidino, pyrrolidino, morpholino, thiamorpholino, Piperazino, hexamethyleneimino and homopiperazino. These heterocyclic ring systems can also be replaced by one or by two simple groups be substituted, namely by IT-lower alkyl, lower alkoxy, hydroxy-lower alkyl or alkanoyloxy-lower alkyl. Those as lower alkyl, lower alkoxy and hydroxy-lower alkyl designated groups have the same meaning as them

209808/1916 " ³ "

3 2H0280

is already defined; the alkanoyl radicals are acyl radicals from lower fatty acids such as acetyl, propionyl, butyryl and the same; but they can also contain acyl radicals from higher ones Be fatty acids with up to 12 carbon atoms.

Representative for the data represented by the radical -NE _-1 hetero-

i ι

cyclic groups are listed below? Piperidino and di (lower alkyl ^ piperidino, ζ "Β. 2,3-Mmetliylpiperidinoj 2-, 3- or 4- (LIiedrigalkoxy) piperidinOj e.g. 2-methoxypiperidino; 2-, 3- or 4- (I-lower alkyl) piperidino, e.g. 2- , 3- or 4-methylpiperidino and IT-kethylpiperidino; pyrrolidino and (lower alkyl) pyrrolidino, Z ₀ B ₀ 2-methylpyrrolidino; di (lower alkylpyrrolidino, e.g. 2,3-dimethylpyrrolidino; (lower alkoxy) pyrrolidino, e.g. 2-ethoxypyrrolidino; ET -Hiedrigalkylpyrrolidino, e.g. Η-Methyl- ™ pyrrolidino; morpholino and (IT-lower alkyl) morpholino, e.g. N-methylmorpholino or 2-methylmorpholino; di (lower alkyl) morpholino, e.g. 2,3-dimethylmorpholino; (lower alkoxy) mor ^ iholino, for example 2-Äthoxymorpholino§ (Ehiamorpholino and (Hiedrigalkyl) thiamorpholino, for example, IT-Methylthiamorpholino or 2-Methylthiamorpholino; di (lower alkyl) thiamorpholino, _o for example 2,3-or 2,3-Diäthylthiamorpholino Dimethylthiamorpholino; (lower alkoxy) thiamorpholino, including 2-methoxythiamorpholino; piperazino and (lower alkyl) -piperazino, e.g. ^ -methylpiperazine o or 2-methylpiperazino; (Hydroxy-lower alkyl) piperazino, for example 4- (2-hydroxyethyl) piperazino · di (lower alkyl) piperazino, for example 2,3-dimethylpiperazino; Alkanoyloxy (lower alkyl) piperazino, such as N _e - (2-Dodecano'y'loxyäthyl) - ä piperazino or homopiperazino Hexamathylenimino as well.

Preferred compounds of the formula I are those in which E is hydrogen or halogen, in particular chlorine. Those compounds are outstanding in which E _x and E ^ are each for themselves lower alkyl (in particular methyl or ethyl) or hydroxy-lower alkyl (in particular hydroxyethyl) or in which E ^ is lower alkyl and E _{2 is} hydroxy-lower alkyl. Morpholino and 4-methylpiperazino are preferred heterocyclic radicals

The compounds of the formula I according to the invention are expediently prepared from a precursor of the formula II

209808/1916

2H0280

Cl

^ j— CH = CH-

(II)

NO,

by matching this precursor with a jkmin of the general formula III

1.

(III)

in a hydrocarbon solvent such as benzene or toluene or in a solvent such as ether, dioxane, tetrahydrofuran or the like "at a temperature in the region of room temperature "until et v / a 110 C (depending on the reactivity of the amine used) for implementation".

The precursors according to formula II are obtained by reacting a quinazoline of the general formula IV

(IV)

with 5-nitro-2-furaldehy & in the presence of an acid anhydride, especially acetic anhydride, "at a temperature of about .80 ⁰ C, which comprises bringing to. boiling for about 1 to 4 hours at reflux.

The intermediate of formula V thus obtained

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—5—

2H0280

V'ird with phosphorus oxychloride, phosphorus pentachloride, thionyl chloride or the like in a solvent such as dimethylaniline or a hydrocarbon solvent such as benzene, toluene, xylene and the like chlorinated at the reflux temperature of the solvent, whereby a compound of formula II is obtained.

The new compounds according to the general formula I are useful as antimicrobial agents and can be used to combat infections in mammals, such as mice, rats, dogs, guinea pigs, calves and the like, when attacked by microorganisms Avie Trichomonas vaginalis , Trichomonas fetus , Staphylococcus aureus , Salmonella schottmuelleri , Klebsiella pnemaoniae , Proteus vulgaris , Escherichia "coli or Trichophyton mentagrophytes . For example, a compound or a mixture of compounds according to formula I is administered orally or by filling into a body cavity of the infected animal, for example a mouse, in an amount from about 5 to 25 mg per kilogram per day, appropriately divided into 2 to 4 individual doses. This liquid presentations may be formulated conventionally, as tablets, · ä elixirs, or sterile solutions containing from about 10 mg capsules to 250 per dosage unit by, one the active substance or active substances with usual en excipients, carriers, binders, protective agents, flavorings as they are customary in pharmaceutical practice, mixed. Since the compounds according to the invention are not well absorbed in the gastrointestinal tract, they are particularly suitable as preoperative GI sterilants or for the treatment of infections of the GI tract as a result of infection with Salmonella , Shisella or enteropathogenic Escherichia coli , for example in Colibacillosis can also be applied topically, for example in dermatophytosis in guinea pigs, in the form of a lotion, ointment or cream in a concentration of about 0.01 to 3 percent by weight. 209808/1916

2U0280

The fabrics can also be used as surface disinfectants will. At a level of -0.01 Ms 1 weight percent each These substances dispersed in an inert solid powder or in a liquid such as water they can be used as Dusts or sprays can be used. They are also incorporated into a soap or other cleaning agent, for example, e.g. for the production of a solid or liquid detergent or a detergent preparation, for example for general cleaning or cleaning of dairy or dairy equipment or cleaning of food shops or equipment for such facilities.

The following examples explain the invention on the basis of preferred embodiments. Other representatives of the claimed Classes of the invention can be prepared in a similar manner by modifying the starting materials with appropriately suitable ones Substituents.

example 1

during (a) The mixture is stirred for 3 hours at 100 ⁰ O A mixture of 270 g 2-methyl-4 (3H) -quinazolinone, 2000 ml of acetic anhydride and 320 g of 5-nitro-2-furaldehyde. A brownish-yellow excretion forms here. After cooling, the mixture is filtered off with suction and the precipitate is washed first with glacial acetic acid and then with ether. The yield is 317 g of 2- / 2- (5-nitro-2-furyl) vinyl7-4- (3H) quinazolinone, the melting point of which is higher than 300.degree.

(B) 141.5 g (0.5 mol) of the product obtained in process stage (a) are suspended in 2 liters of toluene. There are then 242 g (2 mol) of dimethylaniline and 107 g (0.7 mol) of phosphorus oxychloride added and brought to the boil with stirring under reflux. After 4 hours the starting material has dissolved. The solution is refluxed for a further hour, then cooled, filtered off with suction and with methanol and then washed with ether. The product, 2- / 2- (5-nitro-2-furyl) vinyl7-4 ~ chloroquinazoline, is recrystallized from o-xylene and then melts at 263 to 265 °.

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2U0280

(c) 14 g of morpholine are added to a suspension of 9 g of the product obtained in process step (b) in 200 ml of toluene, this mixture is heated to 70 to 80 ° C. for half an hour, then cooled and the solid is filtered off with suction which is washed with methanol. The product, 2- _/ / 2- (5-nitro-2-furyl) vinyl / ^ - iaorpholinoquinazoline, is recrystallized from toluene, melting point: 243 to 245 ° C.

Examples 2 - 6

By carrying out the process described in Example 1 while replacing the morpholine in process stage (c) with diethanolamine, (if-ethyl ethanolamine or (N-methyl ethanolamine is obtained in each case the substances given in the table below as Examples 2 to 4. If you follow the procedure according to Example 1 executes and in process step (a) instead of the one used there 2-methyl-4 (3H) -quinazolinone either 6-chloro-2-methyl-4 (3H) -quinazolinone or 6-nitro-2-methyl-4 (3H) -quinazolinone is used, the substances given in the table are obtained according to Examples 5 and 6.

Example R - * ^ 'melting point

^R 2

2 H. CH-CH-OH 176-178 °

H -N ^X ■ * ⁵ 136-139 °

CH ₃

H -N ^ 178-179 °

'CH ₂ -CH ₂ -OH

Cl -N O 242-245 °

-N O 264-266 °

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Examples 7 -

If the process according to Example 1 is carried out and instead of the morpholine in process stage (c) ammonia, methylamine, diethylamine _s n-butylamine, piperazine, pyrrolidine, _{4- methylpiperazine or 2 5} 3-dimethylmorpholine are used, compounds according to the Examples 7 to below

example

• R,

-Ν "

8 9

-NHCH.

KHCH ₂ CH ₂ CH ₂ CH ₃

N-CH.

CH ₃ CH-

203808 / 1916-

1402

Beismele 15-19

If the process according to Example 1 is carried out and instead of the 2-methyl-4 (3H) -quinazolone used in process step (a) 6-chloro-2-methyl-4 (5H) quinazolone is used and instead of morpholine in process stage (c) ammonia, isopropylamine, Thiamorpholine, 4- (2-hydroxyethyl) piperazine or hexamethyleneimine uses, compounds according to the following are obtained Tabel.

CH = CH ■

t — NO

Example

-N

■ · 2

15th

-NH,

16

-NH-CH '

CH.

CH.

18th

19th

209808/1918

Claims (1)

2H0280 Date: August 11, 1971 Symbol: Sq-14 / H-51-P Patent claims .before 1. 4-Amino-2- / 2- (5-nitro-2-furyl) vinyl7cliinazoline derivatives of the general formula I. (D where E signifies hydrogen, halogen or nitro "as well as E. and Ep either jexveils by themselves, separately hydrogen, low alkyl, hydroxy-lower alkyl or together, namely together with the nitrogen atom carrying them, a 5- "to 7-membered, nitrogen-containing, represent monocyclic, heterocyclic single system with up to 18 atoms, excluding the hydrogen atoms. 2. A compound according to claim 1, wherein R is hydrogen. 3. A compound of Claim 1 wherein R is halogen. 4. A compound according to claim 3 »in which the halogen is chlorine. 5 »Compound according to claim 1, 2, 3 or 4, in which R ^ medrigalkyl and E2 is hydroxy-lower alkyl. 6. A compound according to claim 5 »in which the 111 edrigalkyl group is methyl and the hydroxy-lower alkyl group is 2-hydroxyethyl. 7. Compound according to Claim 5, in which the lower alkyl group Ityl and the hydroxy-lower alkyl group is 2-hydroxyethyl. 8. A compound according to any one of claims 1 to 4, wherein R ^ and each R2 is hydroxy-lower alkyl. 209308/1316 9o compound according to claim 8 ₉ in which the hydroxy = lower alkyl group is in each case hydroxyethyl « A compound according to any one of claims 1 to 4 wherein the _S Radical -NR _x , morpholine) is.
ι I 11. Method of making a connection with the in An = Claim 1 given general formula I, thereby g e k e η η draws that 1 amine of the general formula III . ^E 2 wherein R “and R _{0 have} the same meanings as in formula I j with a compound; of formula II implements Cl (H) CH — CK "ν s \ s « v »* Yjorin R has the meaning given for formula I in claim 1. . 12 c Medicinal products containing one or more of these? Compounds according to claims 1 to 10 « 209808/191