PL112638B1 - Process for preparing novel derivatives of 4-amino-2-piperi-dinequinazoline - Google Patents

Description

The subject of the invention is a method for preparing new derivatives of 4-amino-2-piperidinoquinazoline, and in particular derivatives substituted in the 4-position of the piperidine group with an alkoxy group. These compounds are useful as agents regulating the activity of the cardiovascular system, and especially in the treatment of hypertension. The new derivatives obtained by the method according to the invention are compounds of the general formula I, wherein R is a lower alkyl group and X is a group of the formula —O—alk—OR1, wherein alk is an ethylene group optionally substituted with one or two lower alkyl groups and R1 is a hydrogen atom, a lower alkyl group, a cycloalkyl group having 3-6 carbon atoms or a group of the formula II, wherein R2 and R3 independently of each other are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a group of the formula —CONR4R* or —SO2NR*Rs, wherein R4 and R5 independently of each other represent a hydrogen atom or a lower alkyl group, optionally in the form of their pharmaceutically acceptable acid addition salts. The term halogen atom denotes a fluorine, chlorine, bromine or iodine atom. The term "lower" in relation to an alkyl or alkoxy group means that such a group contains 1-6 carbon atoms, preferably 1-4 carbon atoms, and when such a group contains 3-6 carbon atoms, it may be a straight-chain or branched-chain group. Pharmaceutically acceptable acid addition salts are understood to mean salts formed with acids which form non-toxic addition salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or biphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate or p-tofluenesulfonate. Compounds of formula I containing one or more asymmetric centers may exist in the form of one or more pairs of enantiomers and such pairs or individual isomers may be separated by physical methods, e.g. by fractional crystallization of suitable salts. The invention covers the separated pairs as well as their mixtures, as racemic mixtures or as separated d- or l-optically active isomeric forms. R preferably denotes a methyl group. X preferably denotes groups of the formulae —OCH2CH2OR1, —OCHz—CH(CH3)—OR1 or —O—CHz—C(CH3)2——OR1. R1 preferably denotes a hydrogen atom, an alkyl group having 1-4 carbon atoms, a cyclopentyl group or a phenyl group optionally substituted with a lower alkyl group, a lower alkoxy group, a methyl ... 112 638 4 halogen, trifluoromethyl or carbamyl group. In one preferred group of compounds R1 is other than a cycloalkyl group of 3-6 carbon atoms and R2 and R3 are other than a trifluoromethyl group. Two preferred individual compounds are those in which R is a methyl group, alk is an ethylene group and R1 is an ethyl group, or R is a methyl group, alk is an ethylene group and R1 is a phenyl group. By the process of the invention, new 4-amino-2-piperidinoquinazoline derivatives are prepared by: 1) The compounds are prepared by reacting a quinazoline of general formula (I), wherein Q is an easily separable group such as chlorine, bromine, iodine, lower alkylthio, lower alkylsulfonyl, with a piperidine of general formula (IV), wherein in formula (III) Q preferably represents chlorine or bromine. The reactions are usually carried out in the presence of a base such as triethylamine or an excess of the reagent. of formula 4. In a typical procedure, the reactants are heated together, e.g., at 70-130°C, preferably at reflux, in an inert organic solvent, e.g., n-butanol, for up to about 48 hours. The product can be isolated and purified by conventional methods. For example, the product is usually obtained in crude form by evaporation in vacuo of the reaction mixture, and the crude product is purified by recrystallization from a suitable solvent or by conversion, e.g., to the hydrochloride, by reaction with hydrogen chloride, e.g., in ethanol, followed by recrystallization of the salt. In some cases, the reaction product will be a salt such as the hydrochloride. Also, in some cases, the crude product can be purified chromatographically, e.g., by treatment with a base and extraction with chloroform, evaporation of the chloroform and chloroform extracts. The residue is then chromatographed, for example, on neutral aluminium oxide, wherein the product is eluted with chloroform or a mixture of chloroform and methanol. The eluted product can be purified by conversion to the hydrochloride salt and subsequent recrystallization as above. The intermediate compounds of formula 3 are generally known compounds or can be prepared by methods analogous to known ones. The intermediate compounds of formula 4 are either known compounds or can be prepared by conventional methods, for example as shown in: a) Scheme 1 in the drawing, where N-acetyl-4-hydroxypiperidine of formula 5 in dimethylpharmamide is treated with DMF in the presence of sodium hydride with a compound of formulae R1 O-alk-Br, R1 O-Alk-Cl or R* O-alk-mesyl, in which R is other than hydrogen, followed by acidic or basic hydrolysis of the resulting compound of formula VI to remove the acetyl group. b) Piperidines in which "alk" denotes an ethylene group substituted with one or two lower alkyl groups may also be prepared from the corresponding N-acetyl-4-alkenoxypiperidines of formula V, for example as shown in Scheme 2. In the case of the reactions shown in Scheme 2, R1 may be hydrogen. c) 4-(2-hydroxyethoxy)piperidine of formula XII may be prepared in the previously described manner as shown in Scheme 3. (d) 4-(2-hydroxyalkoxy)piperidine may also be prepared as shown in Schemes 4, 5 and 6, where in Formulae 13-19 Prot represents a suitable nitrogen protecting group, for example acetyl or benzyl, which may be removed in the last step by known methods, and "R" represents a hydrogen atom or a lower alkyl group. e) 4-(2-Alkoxyalkoxy)piperidines may be prepared by reacting an N-protected 4-(2-hydroxyalkoxy)piperidine obtained by one of the above methods with an alkyl halide or alkyl mesylate in the presence of a strong base, e.g. as shown in Scheme 7, wherein R" and R'" represent hydrogen or a lower alkyl group. (f) 4-(2-aryloxyalkoxy)piperidines of formula 26 may be prepared by reacting N-acetyl-4-(2-hydroxyalkoxy)piperidine of formula 23 obtained as above with an appropriately substituted phenol of formula 24 in the presence of triphenylphosphine and dimethyl azodicarboxylate (DEAD) as shown in Scheme 8. R" and R"' in this scheme are as defined above. Alternatively, 4-(2-aryloxyalkoxy)piperidines may be prepared from N-protected 4-(2-hydroxyalkoxy)piperidine obtained as above and fluorobenzene or substituted fluorobenzene in the presence of NaH and dimethylfluoroamide as shown in Scheme 9. R" and R"' are as defined above. 2. Pharmaceutically acceptable acid addition salts of the compound of formula I may be prepared in a conventional manner, e.g., by mixing the free base with the appropriate acid in a suitable solvent, e.g., isopropanol, filtering, and, if necessary, recrystallizing the salt so obtained to obtain the pure product. Often, the product of the above reaction cycle as shown in Schemes 1-9 will be in the form of acid addition salts. The invention also encompasses pharmaceutically acceptable bioprecursors of the compounds of formula I and their said salts. The term "pharmaceutically acceptable bioprecursors" requires some explanation. It is, of course, common practice in pharmaceutical chemistry to circumvent certain undesirable physical or chemical properties of drugs by converting the drug into a chemical derivative which does not exhibit the undesirable properties but which, when administered to an animal or human, is converted back into the parent drug. For example, if a drug is not well absorbed after oral administration to an animal or human, it is possible to convert the drug into a chemical derivative that is well absorbed and that is converted back to the parent drug in the plasma or tissue. Similarly, if the drug is not stable in solution, it may be possible to prepare a stable chemical derivative of the drug that can be administered in solution but that is converted back to the parent drug in the body. The pharmaceutical chemist is generally well acquainted with the possibility of circumventing the natural disadvantages inherent in given drugs by chemical modifications which are only temporary and, after administration to an animal or a patient, are subject to a return to the initial state. In the present description, the term pharmaceutically acceptable bioprecursor of a compound of formula 1 means a compound having a different structural formula than the compound of formula 1, but which, after administration to an animal or a human, is nevertheless converted in the body of the patient into the compound of formula 1. The antihypertensive activity of the compounds obtained by the method according to the invention is demonstrated by their ability to reduce consciously induced spontaneous blood pressure in rats and consciously induced renal blood pressure in dogs after administration. orally in doses up to 5 mg/kg. The compounds of the invention can be administered alone, but are generally administered mixed with a pharmaceutical carrier selected with regard to the intended route of administration and pharmaceutical practice. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, either alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example intramuscularly, intravenously, or subcutaneously. For parenteral administration, they are preferably used in the form of sterile aqueous solutions which may contain other solutes, for example salts or glucose in sufficient quantity to render the solution isotonic. A pharmaceutical composition may comprise a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier. The compounds of the invention may be administered to humans for the treatment of hypertension by either the oral or parenteral route. The oral dosage may be administered as a single dose or divided into three doses at a level of approximately 1-20 mg/day for an average adult patient (70 kg). Intravenous dosage levels would be expected to be 1/5 to 1/10 of the oral daily dose. Thus, for the average adult patient, individual oral doses in tablets or capsules will contain approximately 5-100 mg of active compound. Those skilled in the art will recognize that certain variations may be necessary depending on the weight and condition of the patient, and particularly the chosen route of administration. In the treatment of patients with hypertension, an antihypertensive effective dose of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof or the composition discussed above is administered to animals and humans. The following examples illustrate the invention: Example 1. 4-amino-6,7-dimethoxy-2-[4-(2-ethoxyethoxy)piperidino]piperidinoquinazoline hydrochloride. The preparation of this compound is illustrated in Scheme 10. 4.3 g of 4-amino-2-chloro-6,7-diinethoxyquinazoline, 3.2 g of 4-7-ethoxyethoxypiperidine and 10 ml of triethylamine in 400 ml of n-butanol were heated under reflux. Table 1 Example No. II III IV V VI • vii X —OCH2CH2O-n-C4H9 ^OCH2-C(CH3)2OH —OCH2-C (CH3)2OC2H5 —OCHzCHjOCHCCHsJa „ —OCH2CH(CH3)-OC6H5 Formula 34 Isolated form and melting point Hydrochloride 199—201° Free base 204—205° Hydrochloride monohydrate 244^-246° Aqueous base * 130—134° Hydrochloride 222—223° Hydrochloride 210—211° Elemental analysis */o (Theoretical values in parentheses) C 57.5 (57.2) 61.0 {60.6) 54.7 (55.0) 60.9 (61.5) 60.1 (60.7) 57.9 (58.3) H 7.6 (7.5) , 7.7 (7.5) 7.5 (7.7) 7.7 (7.7) 6.4 L6.6) 7.2 (7.4) .N 12.7 (12.7) 14.9 (14.9) 12.1 (12.2) 13.8 (14.4) ' 12.0 (11.8) 12.4 (12.4)112 638 8 overnight under nitrogen. The mixture was then cooled, evaporated in vacuo, and the residue was made basic with aqueous Na2CO3 solution and extracted three times with chloroform. The combined chloroform extracts were evaporated, and the residue was chromatographed on neutral alumina (150 g, Grade I, deactivated with 5 ml of water). Elution with chloroform gave 3.6 g of crude product, which was converted to the hydrochloride salt by treatment with ethanolic hydrogen chloride. The hydrochloride salt was then recrystallized from ethanol-isopropanol to give 3.4 g of 4-(2-hydroxybenzoate)-3-dimethylbenzoate hydrochloride. -amino-6,7-dimethoxy-2-i[4-/2-etoik6ye1x)oxy(piperidino]quinazolines with a melting point of 219-220°C. 10 15 Elemental analysis: calculated for Ci9H28N404. HCL C 55.3 H 7.1 N 13.6; found °/o: C 55.4 H 7.2 N 13.5. Examples II-VII. Quinazolines of formula 33 covered by the general formula 1, in which R is a methyl group and The product was isolated in the form indicated in Table 1. The only differences in relation to the procedure according to Example I were: in Example III, the product after chromatographic purification was recrystallized directly without conversion into the hydrochloride. In Examples V and VII, for purification of chromatography, Table 2 Number of Example IX X XI XII XIII XIV XV XVI XVII XVIII XIX XX XXI • XXII X —OCH2CH2OH formula 35 formula 36 formula 37 formula 38 formula 39 formula 35 formula 41 formula 40 ^OCHzCHAOCHa —OCH2CH2OC6H5 —OCH2CH(CH3)OH —OCH2CH(CH3)OaCH5 —OCH2C(CH3)aOCH3 Isolated form and melting point °C • Hydrochloride hemihydrate 252—253° hydrochloride hemihydrate 216—217° hydrochloride 226—227° hydrochloride hydrate 195—196° hydrochloride 203—204° hydrochloride hemihydrate 207—209° hydrochloride 259—261° hydrochloride hydrate 167—169° hydrochloride hemihydrate 272—273° hydrochloride 220—222° hydrochloride 232—233° hydrochloride hemihydrate 245—246° hydrochloride hemihydrate 217—218° hydrochloride 239—242° Elemental analysis •/• (Theoretical values in brackets) C 51.8 (51.8) 60.0 (59.6) 57.6 (57.7) 56.8 (56.6) 57.5 (57.6) 57.4 <57.7) 54.0 (54.5) 55.2 (55.2) 56.4 (56.2) 53.8 (54.2) 59.5 <59.9) 52.8 (53.0) 55.6 (55J) 56.0 (56.3) H 6.3 (6.7) 5.4 (6.7) 5.9 (5.9) 6.2 (6.5) 6.3 (6.4) 6.3 (6.4) 5.4 (5;3) 6«2 (6.2) 5.9 (6.1) 7.0 (6.8) 6.6 (6.3) 6.7 (6.7) 7.2 (7.4) 7.5 (7.3) N 14.1 (14.2) 11.8 (H.6) 12.0 (11.7) 11.1 (11.0) 10.7 (10.8) 11.0 (iii) 10.9 (10.6) 13.4 (13.4) 14.0 (13.7) 14.1 (14.0) 12.3 (12.2) | 13.7 (13.7) 12.5 (12.8) 12.8 (13.1) | 112 638 9 10 15 Example VIII. Hydrochloride 4amino-6,7-dimethoxy-2-[4-/2-methoxy-n-propoxy/piperidino]chiinazoline. 3.6 g of 4-amino-2-chloro-6,7-diinethoxyquinazoline, 3.0 g of 4-((/2Hme*oxy-n-propoxy)piperidine and 1.5 g of triethylamine in n-ibutanol were refluxed for 30 hours. The solvent was evaporated in vacuo, the residue was stirred with ethyl ether, the solid was collected and recrystallized twice from iso-propanol to obtain 2.8 g of 4-amino-6,7-dimethoxy-2^[4-(/l2-methoxy-n-propoxy/pi-) hydrochloride [peridino]quinazoline, melting point 239-2410C. Elemental analysis: calculated for C19Hg8N4O4. HClV0 C55.2 H7.1 N13.6; % found: C55.1 H7.2 N13.6. Examples IX-XXII. Quinazolines of the general formula I, in which R is a methyl group and X is as defined in Table 2, were prepared by the method given in Example 8, starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and an appropriately substituted piperidine. The product was isolated in the form shown in Table 2. The following examples illustrate the preparation of some of the starting materials used in the preceding examples: Example XXIII. Preparation 4n(2-methoxyethoxy)piperidine. A solution of 30.5 g of N-acetyl-4-hydroxypiperidine in 200 ml of dimethylformamide was added dropwise to a stirred suspension of sodium hydride (11.26 g, 50% dispersion in mineral oil) in 300 ml of dimethylformamide under a nitrogen atmosphere. The temperature of the reaction mixture was kept below 30°C by external cooling, and after the addition was complete, stirring was continued for a further 1 hour 15 minutes. A solution of 32.6 g of 1-bromo-2-methoxyethane in 100 ml of dimethylformamide was then added dropwise with external heating, and the resulting clear solution was stirred overnight at The reaction mixture was then evaporated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried over Na2SO4 and evaporated to give 16.1 g of crude residue. The above aqueous phase was saturated with sodium chloride and then extracted with chloroform, and the aqueous phase dried over Na2SO4 and evaporated to give 9.2 g of further residue. This residue was combined with the original residue and heated on a steam bath overnight with 243 ml of 2N hydrochloric acid. The reaction mixture was extracted with chloroform to remove residual mineral oil, the aqueous phase was concentrated, basified to pH 12 with sodium hydroxide, and then re-extracted. chloroform. The organic extracts were washed with brine, dried over Na2SO4, and evaporated to give 8.3 g of 4-(2-methoxyethoxy)piperidine. An ethyl acetate sample of the product was converted to the oxalate salt by the addition of ethereal oxalic acid and subsequent crystallization from ethanol. The oxalate salt obtained had a melting point of 86-88°C. Elemental analysis: calculated for C8H17NO2. (CO2H)2% C48.2 H7.7 N5.6; found %: C48.1 H7.6 N5.6. By a similar procedure to that given in Example 23, the following piperidine derivatives were prepared starting from N-acetyl-4-hydroxypiperidine hydride and the corresponding bromide. The N-acetyl intermediate of Examples XXIV and XXVI was prepared using dilute sodium hydroxide instead of dilute hydrochloric acid. Example XXVII. Preparation of N-acetyl-4-aryloxypiperidine. A solution of 100 g of N-acetyl-4-hydroxypiperidine in 250 ml of dimethylformamide was added dropwise to sodium hydride (38 g, 50% dispersion in mineral oil). Table 3. Compounds of formula 4a prepared. Example No. XXIV XXV XXVI Y —OCH2CH2OC6H5 —OCH2CH2O—n-C4H9 —OCHaCHjOCaHs Isolated form and melting point °C oxalate 144°-145° oxalate hemihydrate 86-88° Oxalate 93-95° Elemental Analysis (Theoretical values in parentheses) C 58.5 (57.9) 52.4 (52.0) 50.5 (50.2) H 6.8 (6.8) 8.4 (8.7) 8.2 (8.0) N 4.3 (4.5) 4.8 (4.7) 5.2 1 <5.3)112 638 11 12 ral) under nitrogen. The mixture was stirred for 2 hours, then 93 g of allyl bromide was slowly added, maintaining the reaction temperature at 25°C by external cooling. The mixture was then stirred at room temperature overnight, diluted with 20 ml of isopropanol and 500 ml of ether, filtered and evaporated in vacuo. Distillation of the residue gave 108.8 g of N-acetyl-4-alkoxypiperidine, boiling at 128°C at 2 mm Hg, identified spectroscopically. Example XXVIII. Preparation of 4-(2-ethoxy-n-propoxy)piperidine. A solution of 6.4 g of N-acetyl-4-alkoxypiperidine in 10 ml of absolute ethanol was added dropwise to a stirred suspension of 11.5 g of mercuric acetate in 50 ml of ethanol at room temperature. After 20 minutes the mercuric acetate had dissolved and the mixture was stirred for a further 40 minutes, cooled with ice-cold water and then 20 ml of 5N sodium hydroxide. A yellow precipitate formed during the addition. A solution of 1.3 g of sodium borohydride in 20 ml of 5 N sodium hydroxide was then added, the mixture was stirred for 10 minutes, and ethyl acetate was added to pH 6. The mixture was filtered from the precipitated mercury, the ethanol was evaporated in vacuo, and the resulting aqueous phase was extracted with chloroform. The ether extracts were dried over Na2SO4, evaporated in vacuo, and the resulting crude solid residue (7.5 g) was dissolved in 50 ml of ethanol and heated under reflux overnight with 20 ml of 5 N sodium hydroxide and 20 ml of water. Most of the ethanol was then The aqueous layer was removed in vacuo, the aqueous layer was extracted with ether, the extracts were dried over Na2SO4 and evaporated to give 5 g of residue. Thin-layer chromatography showed incomplete hydrolysis of the acetyl group, so the residue was treated with 20 ml of 2 N hydrochloric acid and heated on a steam bath for 10 hours. The mixture was then washed with ether, the aqueous phase was analyzed with Na2CO3, extracted with ether, and the organic extract was dried over Na2SO4 and cyclohexylglycerin, giving 4.3 g of residue. Distillation of the residue gave 3.0 g of 4-(2-ethoxy-n-propoxy)piperidine, b.p. 112-116°C/10 mm Hg, from which the sesquioxalate was prepared by reacting an ethereal solution of piperidine with an ethereal solution of oxalic acid and subsequent recrystallization from ethyl acetate. The oxalate melted at 68-70°C. Elemental analysis: calculated for C10H1NOa 1.5(C02H)2 C 48.4 H 55 7.5 N 4.4; found: C 48.3 H 7.5 N 4.7. Example 29. Preparation of 4-(2-hydroxy- • -n-propoxy)piperidine 18 g of N-acetyl-4-allylyloxypiperidine in 30 ml of tetrahydrofuran were added dropwise to a stirred yellow suspension of 34 g of mercuric acetate in mixture of 120 ml of water and 120 ml of tetrahydrofuran. The suspension dissolved during the addition, and the resulting clear solution was stirred at room temperature for 20 minutes, then 70 ml of 5N sodium hydroxide were added while cooling with an ice-water mixture. The intermediate thus obtained was reduced by adding 2 g of sodium borohydride in 40 ml of 5N sodium hydroxide; the excess hydride was destroyed after 10 minutes with glacial acetic acid. The liquid phase was then decanted, saturated with sodium chloride, the organic phase was separated, and the remaining aqueous layer was extracted four times with chloroform. The combined organic phases were dried over Na2SO4 and evaporated in vacuo, yielding 23 g colorless oil. This oil was stirred with 5N sodium hydroxide at room temperature for 16 hours and then at 100°C for 2 hours. The solution was then extracted with chloroform four times, the combined extracts were dried over Na2SO4 and evaporated in vacuo, giving 16.1 g of crude crystalline product. This product was dissolved in methylene chloride, filtered, evaporated, and the residue was triturated with petroleum ether (b.p. 40/60°C), giving 11.0 g of 4-(2-hydroxy-n-propoxy)piperidine, melting at 55-57°C. The oxalate salt of this derivative was prepared as in Example 28 and recrystallized from isopropanol. It had a m.p. Melting point 104-105°C. Elemental analysis: calculated for C8H17NO2 • (CO2H2/o: C48.2 H7.7 N5.6; found %: C48.2 H7.7, N5.6. Example XXX. Preparation of -N-acetyl-4(2-methylallyloxy)piperidine. This compound was prepared similarly to Example XXVII, starting from N-acetyl-4-hydroxypiperidine and 2-methylallyl chloride. The product obtained was distilled and used directly in the next stage. It had a boiling point of 128°C at 1 mm. Example XXXI. Preparation of 4(2-methoxy-2-methyl-n-propoxy)piperidine. This compound was prepared The reaction was carried out similarly to Example XXVIII, starting from N-acetyl-4-12-methylalhloxypiperidine and a mercury acetate/methanol mixture. The compound's semi-oxalate had a melting point of 208-210°C. Elemental analysis: calculated for Ci0H2 and NO2. 1/2 (C02H)2 f/e: C 56.9 H 9.6 N 6.0; found •/•: G 56.7 H 9.5 N 5.9. Example XXXII. Preparation of 4-(2-hydroxy-2-methyl-n-propoxy)piperidine. This compound, melting point: 0-82°C, was prepared similarly to Example XXIX, starting from N-acetyl-4-(2-methylallyoxy)piperidine and mercury acetate in a mixture of water and tetrahydrofuran. Elemental analysis: calculated for C5Hi9N02 •/•: C 62.4 H 11.1 N 8.1; found •/•: C 62.2 H 11.1 N 8.3. Example XXXIII. Preparation of 4-(2-ethoxy-2-methyl-n-propoxy)piperidine This compound was prepared similarly to Example XXVIII, starting from N-acetyl-4-(2-methyla41yloxy4)iperidine and a mixture of mercury acetate-13 112 638 14/ethanol and the following basic hydrolysis to remove the N-acetyl group. The sample was converted into a semi-oxalate salt which was crystallized from a mixture ethyl acetate/methanol to give a product with a melting point of 184-185°C. 5 Elemental analysis: calculated for C1A3NO2 • 1/2 C2H204 Vo: C 58.5 H 9.8 N 5.7; Vo found: G 58.6 H 9.7, N 5.8. Example XXXIV: Preparation of 4-^2-isopropo-xyethoxy/piperidine This compound was prepared in a manner similar to Example XXIII from N-acetyl-4-hydroxypiperidine and 1-bromo-2-isopropoxyethane. The compound was characterized using spectroscopic techniques. 15 Example XXXV. Preparation of 4-v'2-methoxy-n-propoxy/ipiperidine This compound was prepared similarly to the example XXVIII starting from N-acetyl-4Hallyloxy-piperidine and mercury acetate in methanol. In order to improve the conversion of the starting material to the product, the addition of mercury acetate and methanol was repeated twice to obtain N-acetyl-4-(2-methoxy-n-propoxy)piperidine, which was hydrolyzed in a solution of sodium hydroxide and methanol to obtain 4-(e-methokisy-n-pro|poxy/piperidine. The sample was characterized in the form of an oxalate salt, which had a melting point of 89-91°C. Elemental analysis: calculated for C 50.2 H 8.1 30 N 5.3; found °/t: C 49.6 H 7.9 N 5.3. Example XXXVI: Preparation of 4-(2-phenoxy-nipropoxy)piperidine 12 g of N-acetyl-4-(2-hydroxy-n-propoxy)piperidine in 50 ml of dry dimethylformamide were added dropwise to a stirred suspension of sodium hydride (5.0 g of a 50% dispersion in mineral oil) in 50 ml of dimethylformamide at 60-70°C under nitrogen. The suspension was stirred for 3 hours, then 6.4 g of fluorbenzene in 50 ml of dimethylformamide was added dropwise and the suspension stirred at 100°C for 50 hours. The cooled solution was treated with 20 ml of isopropanol and then 200 ml of water, extracted three times with 200 ml portions. ml of petroleum ether and three times with 200 ml portions of chloroform. The combined chloroform extracts were dried over Na2SO4, and the solvent was evaporated in vacuo. To obtain a solution from the residue, 9.0 g of it was heated under reflux in 20 ml of 5N sodium hydroxide and 20 ml of methanol for 5 hours. The methanol was evaporated, the residue diluted with water, and then extracted three times with 50 ml portions of chloroform. The combined chloroform extracts were washed three times with 30 ml portions of 2N HCl, the combined aqueous extracts were basified to pH 12 with sodium hydroxide solution, and extracted three times with 50 ml portions of chloroform. The combined chloroform particles were dried over Na2SO4, the solvent was evaporated in vacuo, the residue was triturated with ether and filtered. The filtrate was concentrated and then distilled to obtain 0.5 g of 4H(2-phenophoxy-n-propoxydine with a boiling point of 118-122°C) 0.3 mm, characterized spectroscopically. Example XXXVII. 4-[2-/2,6-dimethoxyphenoxy/ethoxy] piperidine The reactions leading to the preparation of this compound are presented in scheme 11 in the drawing, in which Ac denotes a group with the formula CH3CO—. 23 g of methanesulfonyl chloride were added dropwise to a stirred solution of 20 g of 2-(2,6-dimethoxyphenoxy) ethanol (J. Med. Chem. 1969, 12, 326) in 50 ml of piperidine. The solution was left at room temperature for 60 hours, then the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, washed three times with 100 ml of water and three times with 100 ml of 5% sodium bicarbonate solution, dried, and the solvent was evaporated. The residue was triturated with n-hexane, the solid collected, giving 11.3 g of 2-(2,6-dimethoxyphenoxy)ethyl mesylate, characterized spectroscopically. 4.3 g of N-acetyl-4-hydroxypiperidine in 50 ml of dimethylformamide was added dropwise to a stirred suspension of sodium hydride. (3.0 g of 50% dispersion in mineral oil) in 50 ml of dimethylformamide under nitrogen. After stirring for 3 hours at room temperature, 9.0 g of 2-(2,6-dimethoxyphenoxy)ethyl mesylate in 50 ml of dimethylformamide was added dropwise and stirring was continued for 20 hours at room temperature. The solvent was evaporated in vacuo, the residue was dissolved in water, extracted three times with 100 ml portions of chloroform, the organic layer was dried over Na2SO4 and the solvent was evaporated. After distillation, 6.0 g of N-acetyl-4-[2-(2,6-dimethoxyphenoxy)ethoxylpiperidine] was obtained, boiling at 200°C at 1 mm Hg. 6.0 g of this product in 40 ml of methanol and 20 ml of 5 N sodium hydroxide solution were heated under reflux for 20 hours. The methanol was evaporated under reduced pressure, the aqueous residue was extracted with petroleum ether three times, using 30 ml portions each, and with diethyl ether three times, using 30 ml portions each. The ether extracts were dried over Na2SO4 and the solvent was evaporated. The ether residue was treated with ethereal hydrogen chloride solution, and the precipitated solid was recrystallized from isopropanol, yielding 1.4 g of 4-[2-(2,6-dimethoxyphenoxy)ethoxylpiperidine hydrochloride, melting at 143-145°C. Elemental analysis: calculated for CicH23N04-HCl*/«: C 56.7 H 7.6 N 4.4; found •/•: C 56.4 H 7.6 N 4.3. Example XXXVIII.A. Preparation of N-acetyl-4-(2,2-diethoxy)piperidine. 57.2 g of N-acetyl-4-hydroxypiperidine in 250 ml of dry dimethylformamide were added dropwise to a stirred suspension of sodium hydride (23.2 g, 50% dispersion in mineral oil) in 200 ml of dry dimethylformamide under a nitrogen atmosphere with external cooling in the bath. ice-water. The suspension was allowed to warm up to room temperature and then stirred for 5 94.7 g of bromoacetaldehyde diethylacetal was slowly added to the stirred reaction mixture with cooling, and the mixture was stirred at room temperature for 18 hours. A further 23.2 g of sodium hydride was added in portions, and stirring was continued until effervescence ceased. A further 100 ml of dry dimethylformamide was added, and the mixture was cooled in an ice-water bath while a second portion of 94.7 g of bromoacetaldehyde diethylacetal was slowly added. The mixture was stirred at room temperature for 3 hours, then 150 ml of isopropanol was added to destroy excess sodium hydride. The suspension was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in water and extracted. chloroform. The chloroform extract was dried over Na2SO4, the solvent was evaporated in vacuo, the residue was distilled to obtain 61.5 g of N-acetyl-4-/2,2-diethoxyethoxy (piperidine with a boiling point of 142-145°C) 3 mm, characterized by njm.r.B. Preparation of ~N-acetyl-4-(2-hydroxyethoxy)piperidine. 12 g of N-acetyl"4-(2,2-diethoxyethoxy)pipeTidine in 50 ml of 0.5 N hydrochloric acid were stirred at room temperature overnight. The solution was saturated with sodium chloride and extracted several times with chloroform (total amount 500 ml). The chloroform extract was dried over Na2SO4 and the solvent was evaporated in vacuo, with the bath temperature below 30°C. The resulting intermediate, i.e., the aldehyde (9.8 g), was immediately reduced with sodium borohydride (0.75 g) in 75 ml of ethanol at pH 6. After stirring for 3 hours at room temperature, the reduction was complete. Water was then added to the stirred solution and the organic solvent was evaporated in vacuo. The residue was dissolved in 30 ml of water and extracted with chloroform ten times in 30 ml portions. The combined chloroform extracts were dried over Na2SO4 and the solvent was evaporated in vacuo. The residue was dissolved in 70 ml of water and washed with petroleum ether twice with 10 ml each. The aqueous phase was concentrated to obtain 6.9 g of N-acetyl-4-(2-hydroxyethyloxyethylene)piperidine, characterized spectroscopically. The distilled sample had a boiling point of 139-140°C/0.3 mm. Elemental analysis: calculated for C9Hi7N030/o: C 57.8 H 9.1 N 7.5; found °/o: C 57.5 H 9.1 N 7.6.C. 4-(2-Cyclopentyloxyethoxy)piperidine 5.0 g of N-acetyl-4-(2-hydroxyethoxy)piperidine in 25 ml of dimethylformamide was added dropwise to a stirred suspension of sodium hydride (1.28 g, 50% suspension in mineral oil) in 50 ml of dry dimethylformamide under nitrogen. When effervescence had ceased, 4.4 g of cyclopentyl mesylate (Tetrahedron 1972, 28, 2469) in 10 ml of dimethylformamide was slowly added and the mixture was stirred at room temperature for 40 hours. An additional 0.64 g of sodium hydride was added. sodium and then 2.2 g of cyclopentyl mesylate were added, and the mixture was stirred at 60°C for 7 hours and then at room temperature for 64 hours. Isopropanol was added, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was heated in 30 ml of 5 N sodium hydroxide solution at reflux for 3 hours. The ethanol was removed in vacuo, the residue diluted with water and extracted with chloroform. The chloroform extract was dried over Na2SO4, the solvent evaporated in vacuo, and the chloroform residue was treated with ethereal hydrogen chloride. The solvent was decanted and the residue triturated with ether to give 4-(2-cyclopentyloxyethoxy)piperidine hydrochloride as a gum. The product contained some 4-(2-hydroxyethoxy)piperidine as an impurity but was used directly. Example XXXIX Preparation of 4(2-p-fluorophenoxyethoxy)piperidine A solution of 5.0 g of N-azoethyl-4-(2-hydroxyethoxy)piperidine, 8.4 g of triphenylphosphine, 5.6 g of diethyl azodicarboxylate and 3.36 g of p-fluorophenol in 75 ml of freshly distilled tetrahydrofuran was stirred in an ice bath for 2 hours and then left at room temperature for 48 hours. The solvent was evaporated in vacuo, the residue was dissolved in chloroform and washed twice with 1N sodium hydroxide solution and twice with water, dried over Na2SO4 and the solvent was evaporated in vacuo. The residue was dissolved in a minimum volume of 35 of refluxing ether and then set aside to cool in a refrigerator. The precipitated solid was collected, the filtrate was evaporated, and the residue was dissolved in ether and set aside to cool. The precipitated solid was removed again, the filtrate was evaporated, and the residue was extracted five times by heating it under reflux with 100 ml of petroleum ether (60-80°). The solvent was evaporated in vacuo, and the residue in 50 ml of ethanol and 50 ml of sodium hydroxide solution was heated under reflux for 5 hours, then neutralized with 2N hydrochloric acid, and the organic solvent was evaporated. The aqueous residue was acidified to pH 2 with 2N 5O hydrochloric acid and extracted twice with ether. The aqueous phase was basified to pH 12 with sodium hydroxide solution and then extracted three times with 100 ml portions of chloroform. The combined chloroform extracts were dried over Na2SO4 and the solvent evaporated in vacuo to give 1.3 g of 4-(2-p-fluorophenoxyethoxy)piperidine. A sample of this product in chloroform was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride. The melting point of the sample was 144-145°C. Elemental analysis, calculated for C1aHisFNO4HCWo: C56.6 H6.9 N5.1; found %: C56.1 H6.8 N 5.5. Examples XL-XLIII. By a method similar to that described in Example XXXIX, 17 112 638 was prepared. Table 4 18 Example No. XL XLI XLII XLIII Ri Formula 48 Formula 49 Formula 50 Formula 51 Isolated form and melting point °C hydrochloride 145—146° hydrochloride 197—198° oxalate 122—123° oxalate 151—153° Elemental analysis (Theoretical values in parentheses) C 61.4 (61.9) 58.3 (58.4) 50.4 (50.7) 56.2 (56.3) H 8.1 (8.2) 7.8 (77) 5.3 (5.3) 6.9 (6.8) N 5.1 (5.2) 4.6 (4.9) - 3.7 (3.7) • 4.2 (Z4.1), the following piperidine derivatives listed in Table 4 were prepared from N-acetyl-4-(2-hydroxyethoxy)piperidine and the appropriate phenol. The compounds obtained corresponded to the formula (47). Example 44. Preparation of 4-[2-(4-piperidyloxy)benzamide. 1.0 g of N-acetyl-4-(2-hydroxyethoxy)piperidine, 0.82 g of 4-hydroxybenzaimide, 1.12 g of diethyl azodicarboxylate and 1.68 g of triphenylphosphine in 30 ml of tetrahydrofuran were stirred at room temperature for 66 hours. precipitated solid and dried to obtain 0.72 g of 4-[2-(N-aoethyl-4-pdperidyloxy/ethoxy]benzamide at a temperature of 154-155°C. Elemental analysis: calculated for CieHj^O^/o: C 62.7 H 7.2 N 9*2; found */o: C 62.7 H 7.1 N 9.1. 4.3 g of 4-[2-(N-acetyl-4-ipiperidyloxy)ethoxy]ibenzamide in 60 ml of ethanol, 30 ml of water and 10 ml of 2N hydrochloric acid were refluxed for 24 hours. The solvent was evaporated in vacuo. The residue was dissolved in water and extracted three times with chloroform, the aqueous phase was adjusted to pH 12 with sodium carbonate solution and extracted three times with chloroform. The combined chloroform extracts were discarded, the aqueous phase was saturated with sodium chloride and extracted with chloroform, the chloroform layer was dried over Na*5O4 and the solvent was evaporated in vacuo to obtain 0.36 g of 4-[2-(4-piperidylloxy)ethoxy]benzamide. The aqueous phase was concentrated in vacuo and the solid residue was extracted with 200 ml of ethyl acetate under reflux. The solid residue was removed by filtration and the filtrate was evaporated in vacuo to give 0.30 g of 4- [2-(4-Piperidyloxy)ethophenyl]benzamide identical to that obtained above. A sample of this product in chloroform/methanol solution was converted into the hydrochloride by treatment with ethereal hydrogen chloride and then recrystallized from ethyl acetate/isopropanol solution. The product had a melting point of 244-246°C and was characterized spectroscopically. Example XLV. Preparation of 3-[2-(4-piperidinyloxy)ethoxy]benzamide 20 25 30 36 40 50 55 65 5.0 g N-acetyl-4-(2-hydroxyethoxy)piperidine, 4.4 g 3-hydroxybenzamide, 5.6 g ethyl azodicaroxylate and 8.4 g triphenylphosphine in 100 ml dry tetrahydrofuran were stirred at 0°C for 2 hours and then at room temperature for 64 hours. The solvent was evaporated in vacuo, then the residue was treated with 3 fractions of 100 ml portions of ether under reflux, and then the mother liquor was decanted. The remaining oil was dissolved in chloroform and washed with 40 ml of dilute sodium hydroxide solution and 40 ml of water. The chloroform layer was dried over MgSO4 and then the solvent was evaporated in vacuo. The remaining oil was treated with 50 ml of ether and set aside in the refrigerator. The resulting solid was collected, suspended in 30 ml of ether, filtered, and the solid was washed with 30 ml of ether, yielding 3.7 g. 4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide containing triphenylphosphine oxide, approximately 25% by mass. The product was heated in 48 ml of ethanol, 24 ml of water and 8 ml of 2N hydrochloric acid under reflux for 24 hours, then the ethanol was evaporated in vacuo. The aqueous residue was extracted twice with 100 ml portions of ether, then with 100 ml of chloroform, after which the aqueous phase was adjusted to pH 12 with sodium hydroxide solution and extracted twice with 100 ml portions of chloroform. The organic layer was dried over MgSO4 and the solvent evaporated in vacuo. to give 0.55 g of 3-[2-(4-piperidyloxy)ethoxy]benzamide. The aqueous phase was saturated with sodium chloride and extracted three times with 100 ml portions of chloroform. The combined chloroform extracts were dried over MgSO4 and the solvent evaporated in vacuo to give a second crop of 3-[2-(4-piperidyloxy)ethoxy]benzamide, 0.26 g, identical to that obtained above. This sample was characterized as the hydrochloride salt by treatment with ethanolic ethereal hydrogen chloride. Melting point 144-146°C. Elemental analysis, calculated for C12O3H2Cl4: C55.9, H7.1, N9.3; t found: C 56.0 H 7.2 N 9.2.1* Patent Claims 1. A method for preparing new 4-amino-2-piperidinoquinazoline derivatives of the general formula 1, wherein R is a lower alkyl group and X is a group of the formula -O-alk-OR1, wherein alk is an ethylene group optionally substituted with one or two lower alkyl groups and R1 is a hydrogen atom, a lower alkyl group or a group of the formula 2, wherein each of the substituents R* and R3 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a group of the formula -CONR4R5 - or -SO2NR4R*, wherein each of the substituents R4 and R5 is a hydrogen atom or a lower alkyl group, characterized in that the compound of the general formula 2. A process according to claim 1, characterized in that the compound of formula 3, wherein R is a methyl group, is reacted with a compound of formula 4, wherein X is a group of the formula —OCH₂CHaOR₁, —OCH₂CHCC₂OR₁ or —OCH₂C(CH₃)₂OR₁, wherein R₁ is a group of the formula —OCH₂CHaOR₁, —OCH₂CHCC₂OR₁, or —OCH₂C(CH₃)₂OR₁, wherein R₁ is a hydrogen atom, an alkyl group of 1-4 atoms, or an alkyl group of 1-4 atoms. carbon or a group of formula 2, wherein R2 and R3 are hydrogen, lower alkyl, lower alkoxy, halogen or cannabinoyl and Q is as defined above. 3. A method according to claim 1, characterized in that the compound of formula 3, in which R is a methyl group, is reacted with a compound of formula 4, in which X is a group of the formula -O-alk-OR1, in which aflk is an ethylene group and R1 is an ethyl or phenyl group and Q has the above-mentioned meaning. 4. A process for the preparation of new 4-amino-2-piperidinoquinazoline derivatives of the general formula I, wherein R is a lower alkyl group and X is a group of the formula -O-alk-OR1, wherein alk is an ethylene group optionally substituted with one or two lower alkyl groups and R1 is a cycloalkyl group having 3-6 carbon atoms, characterized in that a compound of the general formula III, wherein R has the above-mentioned meaning and Q is an easily cleavable group such as a chlorine, bromine, iodine atom, a lower alkoxy group, a lower alkylthio group or a lower alkylsulfonyl group, is reacted with a piperidine of the formula IV, wherein X has the above-mentioned meaning and optionally obtained - the product is converted into a fair-meceutically acceptable addition salt with a non-toxic acid. 5. A method for preparing new 4-amino-2-piperidinoquinazoline derivatives of the general formula 20, wherein R is a lower alkyl group and X is a group of the formula 1O-alk-OR1, wherein wherein the substituent alk denotes an ethylene group optionally substituted by one or two lower alkyl groups and R1 denotes a group of formula 2, wherein each of the substituents R* and R3 denotes a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group or a group of formula —CONR4Rs or —SO2NRW, wherein each of the substituents R4 and R* denotes a hydrogen atom or a lower alkyl group, provided that at least one of the substituents R2 and R3 included in the group of formula 2 denotes a trifluoromethyl group, characterized in that the compound of general formula 3, wherein R has the above meaning and Q denotes an easily separable group such as a chlorine, bromine, iodine, a lower alkyl group alkoxy, lower alkylthio or lower alkylsulfonyl group is reacted with piperidine of formula 4, wherein X has the meaning given above, and optionally the resulting product is converted into a pharmaceutically acceptable addition salt with a non-toxic acid. Formula 1 -X Formula 2 X 4^ H H Formula 4 Rz HN Y Formula 4a i,)NaH/DMF -L hlJdrdCza X , i2)Rxo-o« -Br, LJ^r CiJ C=O Or R*O-a(k -mesyl C=O CH3 CH3 Formula 6 Scheme 1 H Formula-1 OH V n'NaH/DMF. (2) CH,=CH.(HBr C=O CH3 Scheme 0CH2CH=CH2 O.CH2CHOR1 iHgOAc/RttH r^ CH3 (2)NaBH C=0 CH3 Formula ; c-o CH3 And hydrolysis y red Or nucleating Formula 8 O.CH,CHOR1 c, CH, H /i'av 9112 638 OuAlHVAO,r\unaPd OCMfHEPH 21 t ' xi\r CH^Ph CHaPh H Formula W Formula 11 Formula 12 Scheme 3 OH RB OEt R" /OEt S NaH/BrCHCK. OCHO< V — SA OEt ! DMF I T vH+/H2O 0CHCH£H R" NaBKi 0CH.CH0 Prot. Formula 16 Scheme 4 Prot. Formula 15112 638 OH W NqH/DMF | i^BrCHCOzH w. m) EtOH/H + mór 13 R" and 0CH.C02C2H5 W Prot illustrative formula 17 Li BH4/THF R" OCHCHzOH Scheme b Prot Formula 16 OH Prot (DNoH.DMRTHF Formula 18 Formula 13 Scheme 6 XH2pH: Prot. lA/zcr 19 .R" OH R" R" OCH-CH.UL ^NaH/DMF Prot (2)R1I(R1Br m R10SO2CH3 mór 20 Scheme 7 R" R'" OCH-CH Ndr1 Prot Formula 21 removal of protecting group R" R" 0CH-CH^0R1 Formula 22 H112 638 « r« R" ? OCH-CH-OH OH C=0 CH3 Formula 23 Formula 24 Ph,P/DEAD THF Scheme 8 PCH-CH-O—O' K c=o I CH3 Formula 25 acid hydrolysis Or base R- R- OCH-CH ~o£ H /y?#- OCHCH-OH \ NT NaH/DMF GO CH3 Formula 23 ""* 2? temperature JOO°C Scheme 9 R" R'" 0CH-CHx *0O T c=o CH '3 /Izcy ¦ hydrolysis R" ,R" OCH-CH so-/\ rt /tor CHP^^/N^/Cl CHp NH3 H CH£ -ii itcór 30 CH3O CH3O mor 31 Scheme 10 NH, /fcV &? N NH, X 0CH2CH,0 /-fay 3/ Wzd/- 33 XH2CH20^^V-C|_j mor 35 0CH2CH20 —-f\- F Formula 36 -ocH2cR,o^yOCH 3 PYzor 37 CHjO OCH,(HO f ^ 2.^*^2 CHJO' W/0/- 38 -owp^-CS \—/ x v /y/0/" ?o ¦och^chohO^Lh h/zor 40 -OCHzCI-tO r\ o . mór 41 CNH;112 638 OCH: OHPtOH CH3S0,Cl CH5 L— Formula 4Z CH3O OCH2Cl-yO CHjD Formula 46 hydrolysis H OCH3 x^0CH2CH20S02CH3 Formula 45 Scheme // Ht^^OCI^CHrOR1 Formula 47 "0"CH3 Formula 48 r\ OCH, Formula 49 'YX -CF, /V*V 50 r\ OCH, /Ya^ 5/ National Printing House Z-6, ordered 24/82 Price PLN 45 PL PL PL PL PL PL PL PL PL PL

Claims (1)

1.