DD140145A5 - PROCESS FOR PREPARING 4-AMINO-2-PIPERIDINO-CHINAZOLINE DERIVATIVES - Google Patents

Description

The invention "refers to therapeutically active agents which are novel derivatives of 4-amino-2-piperidino-quinazoline, in particular to those derivatives having a substituted alkoxy group in the 4-position of the piperidine group." Such compounds are useful as regulators of the cardiovascular system. The invention further relates to processes for their preparation and medicaments containing such derivatives.

The new compounds according to the invention are those of the general formula

RO

(I)

wherein R is lower alkyl and X is a group of the formula

-O-alk-OR ¹ ,

'wherein' alk 'is an ethylene group optionally substituted by 1 or 2 lower alkyl groups, and R is hydrogen, lower alkyl, C 1 -C 8 cycloalkyl or a group of the formula

ff

2 3

wherein R and R are each independently hydrogen, lower alkyl, lower alkoxy, halogen,. CF ^, -COEErR -SOpM R, where R and ^

OAER

piiXi. ^ pj-iiuj wuucj. ι ". each of which is independently hydrogen or lower alkyl, and their pharmaceutically acceptable acid addition salts.

Here, "halogen" means fluorine, chlorine, bromine or iodine. The term "lower" used in connection with an alkyl or alkoxy group indicates ₅ that such a group contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and when such group has 3 to 6 carbon atoms , can it be straight-chain or branched-chain? «

Pharmaceutically acceptable acid addition salts are those with acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochlorides hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, Gluconate, saccharate or p-toluenesulfonate.

The compounds of this invention having one or more asymmetric centers exist as one or more pairs of enantiomers, and such pairs of individual isomers can be separated by physical methods, e.g. durchfraktionierte crystallization of suitable salts. The invention includes the separated pairs as well as mixtures thereof, racemic mixtures or separate d- and 1-optically active isomeric forms.

R is preferably methyl. CH,

1 '1

X is preferably -OCH ₂ CH ₂ OR, -OCH ₂ -CH-OR or

-0-CH ₀ -C-OR ¹

² /

R is preferably hydrogen, C, -C, alkyl, cyclopentyl or phenyl, optionally substituted by alkyl, lower alkoxy, halogen, trifluoromethyl or carbamoyl.

1 In a preferred group of compounds, R has one

2 3

have meaning other than C ^ -Cg-cycloalkyl and R and R have

meanings other than trifluoromethyl.

The two preferred single compounds are those in which (a) R is CH ₅ , "alk" is -CH ₂ CH ₂ - and R ^{1 is} C ₂ H ₅ and (b) R is CH ₅ . "alk" is -CH ₂ CH ₂ - and R ^{1 is} phenyl.

The compounds according to the invention can be prepared according to several ways, including:

(1) The compounds can be prepared by reacting a quinazoline of the formula

- (H)

wherein Q is a readily leaving group such as chlorine, bromine, iodine, lower alkoxy, (lower alkyl) thio or (lower alkyl) sulfonyl, with a piperidine of the formula

- (III)

getting produced. Q is preferably chlorine or bromine »

The reaction is typically carried out in the presence of a base, such as triethylamine, or excess reagent of formula (III).

In a typical procedure, the Reaktionskompo be ~ components heated together, 'for example to a temperature of 70 to 130 ⁰ C, preferably under reflux in an inert organic solvent, for example n-butanol, for. up to about 48 h. The product can be isolated and cleaned according to conventional procedures.

For example, the product is typically obtained in crude form by concentration of the reaction mixture in vacuo, and it may be prepared either by recrystallization from a suitable solvent or by transferring e.g. into the hydrochloride by reaction with hydrogen chloride e.g. in ethanol with subsequent recrystallization of the salt cleaned v / earth. In some cases, of course, the reaction product is the hydrochloride. In some cases, the crude product can also be purified by chromatography »e.g., by basifying and extracting with chloroform, concentrating the chloroform extracts and adding the residue e.g. chromatographed on neutral alumina, to which the product is eluted with chloroform or with a mixture of chloroform and methanol. The eluted product may be purified by conversion to the hydrochloride followed by recrystallization as above.

The intermediates of formula (II) are generally known compounds or can be prepared by methods analogous to the prior art.

The intermediates of formula (III) are either known compounds or can be prepared by conventional methods, e.g. v / ie follows:

(i) NaH / DMF

(2) RJO-alk-Br,

R * O-alk-Cl or R O-alk-mesyl (R ¹ ± H)

O Hydroysis (acid or basic)

C = O

CH ₃

/ DMF = dimethylformamide /

9 133

(b) The piperidines in which "alk" is an ethylene group substituted by 1 or 2 lower alkyl groups can also be prepared via the corresponding 1-acetyl-4-alkeno: xypiperidines, ζ _β Β _β (R may be hydrogen in this route) ):

C = OCH.

(1) NaH / DMF

(2) CH ₂ = CH.CH ₂ Br

OCH .CH = CH

(I) HgOAc / R OH - (2JNaBH,

C = O

CH.

P. CH CHORUS

«C 1

Hydrolysis 4 / (acidic or basic)

O.CH_CHOR • 2i

(c) 4 ~ (2-Hydroxyethoxy) piperidine can be prepared on the Yfeg described earlier:

LiAlH ₄ / feLCl

CH ₂ Ph

OCH ₂ CH ₂ OH

H2 / PCL,

OCH ₀ CH ₀ OH ι 2. Z

(d) 4 '(2-Hydroxyalkoxy) piperidines may also be prepared by the following conventional routes:

ζ-B- (i)

OH

Prot.

R "OEt NaH / BrCHCH '

R "I

OCH.CH OH

DMF

NaBH.

R "

OEt

OCH.CH '

OEt

Prot.

H + / H ₂ 0

OCH.CHO

Prot.

Prot.

(where Prot is a suitable N-protecting group, e.g., acetyl or benzyl, and can be removed by conventional methods in the final step, and R "is H or lower alkyl)

Ui).

(i) Nall / DMF

R "(ii) BrCHCO ₂ H

(iii) EtOH / H +

Prot.

Prot.

_R OCHCH ₂ OH

(Prot, and R "are as oben'definiert) ^Prot ·

CDER (iii)

(i) NaH, DMF, THF (ii)

OCH-CH 2

R "

 OH

(Prote and R "are defined above)

(e) 4 ~ (2 "alkoxyalkoxy) piperidines can be prepared by reacting an N-protected 4- (2-hydroxyalkoxy) piperidine obtained in one of the above ways with an alkyl halide or mesylate in the presence of a strong base .

e.g.

(i) NaH / DMF (ii) R ¹ I, R ¹ Br

Prot.

or R ^{1 is} OSO ₂ CH ₃ .

R "R ^m II

OCH-CH

Prot.

Deprotection

R "R"

I i

OCH-CH

(Prot and R "are as defined above, R" ^f = H or lower alkyl) and

9 13

(f) 4- (2-Aryloxyalkoxy) piperidines can be prepared by

(i) reacting an N-acetyl-4- (2-hydroxyalkoxy) piperidine as obtained above with an appropriately substituted phenol in the presence of triphenyl phosphine and diethyl azodicarboxylate

R "R ¹ " (t

OCH-CH-OH

C = O

CH.

P ^ P / D.E.A.D., THF

R "R ¹ " II

OCH-CH-O

Hydrolysis (acidic or R ¹¹ 'basic)

(R "and R" ¹ are as defined above)

(ii) 4- (2-Aryloxyalkoxypiperidines may alternatively be prepared from a 4- (2-hydroxyalkoxy) piperidine with N-protecting group as obtained above and fluorobenzene or a substituted fluorobenzene in the presence of NaH and DMF:

R "R" '

I i

CH-CH-OH

C = O

CH.

R "R ¹ "<I

OCH-CH

hydrolysis

(R "and B" 'are as defined above)

(2) The pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared by conventional procedures, e.g. by mixing the free base with the appropriate acid in a suitable solvent, ZeB. iso-propanol, filtering and, if necessary, recrystallizing the salt thus prepared to purity. Often, of course, the product of Y / eges (1) is in the form of an acid addition salt.

The invention also includes the pharmaceutically acceptable bioprecursors of the compounds of formula (I) and their acid addition salts.

The term "pharmaceutically acceptable bioprecursor" requires an explanation. It is of course in the pharmaceutical

Chemistry common practice to overcome some undesirable physical or chemical properties of a drug by converting it into a chemical derivative that does not have the undesirable property, but that is converted back to the animal drug after administration to an animal or human being. If e.g. For example, if a drug administered to an animal or a patient is not well absorbed orally, it may be converted to a chemical derivative that is readily absorbed and reconverted into the starting drug in serum or tissues. Even if an active ingredient is unstable in solution, a chemical derivative can be prepared which is stable and can be administered in solution, but which is converted back into the starting drug in the body. The pharmaceutical chemist is well aware of the possibility of overcoming inherent disadvantages of the nature of an active ingredient by chemical modifications which are reversible only temporarily and after administration to the animal or the patient.

In the present specification, the term "pharmaceutically acceptable bioprecursor" of a compound of formula (I) means a compound having a structural formula other than the compounds of formula (i), but which is administered to an animal or human in the patient's body is converted into a compound of formula (I).

The antihypertensive activity of the compounds of the present invention is demonstrated by their ability to lower the blood pressure of conscious, spontaneously hypertensive rats and conscious renal hypertensive dogs by oral administration at doses of up to 5 mg / kg.

The compounds of the invention may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard 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 in admixture with excipients, or in the form of elixirs or suspensions with flavoring and coloring agents. * They may be injected parenterally, eg. intramuscularly, intravenously or subcutaneously · For purely parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, ζ.B * enough salts or glucose to render the solution isotonic «

Thus, the invention also provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable diluent or carrier. The compounds of the present invention may be administered to humans for the treatment of hypertension, either orally or parenterally, orally at dosages, for example, in the range of 1 to 20 mg / day for an average adult patient (70 kg), in a single dose or in up to three divided doses. Intravenous doses are approximately 1/5 to 1/10 of the daily oral dose. "Thus, for an average adult patient, single or oral doses in tablet or capsule form are in the range of 5 to 100 mg of the active compound. Variations are necessarily dependent on the weight and condition of the subject being treated and the particular route of administration, as understood by one skilled in the art.

The invention further provides a method of treating an animal, including humans, with hypertension,

wherein the animal is administered an antihypertensive amount of a compound of formula (I) or its pharmaceutically acceptable acid addition salt or a drug as defined above.

EXAMPLES

The following examples illustrate the invention:

example 1

Preparation of 4-amino-6,7-dimethoxy-2- / 4- (2-ethoxyethoxy) -piperidinoy-quinazoline ° Hydrochloride

CH ₃ O

/ V

OCH-CH ₀ OC ₀ K

4-Amino-2-clilor-6,7-dimethoxyquinazoline (4.3 g) 4- (2-ethoxyethoxy) piperidine (3.2 g) and triethylamine (10 ml) in n-butanol (400 ml) were heated to reflux overnight under a nitrogen atmosphere. The mixture was then cooled, concentrated in vacuo, and the residue (basified with aqueous Na ₂ C (X) and extracted three times with chloroform The combined chloroform extracts were concentrated and the residue was neutralized with alumina (150 g, grade I) , eluted with 5 ml of V / water), eluting with chloroform gave a crude product (3.6 g) which was converted to the hydrochloride by treatment with hydrogen chloride in ethanol, and the hydrochloride was then recrystallized from ethanol / isopropanol to give Amino-6,7-dimethoxy-2- / 4- (2-ethoxyethoxy-piperidino) quinazoline hydrochloride (3.4 g), m.p. 219-220 ^r

C.

Analyjse ^

for over

O * HCl:

C 55.4; H 7.2 N 15.5 % C 55.5; H 7.1 N 13.6 %

Examples 2-7

The following quinazolines were prepared similar to Example 1 starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and their suitably substituted piperidine, and were isolated in the indicated Porm.

example X isolated form, -u. Schmp. <° c> Analysis% (Theoriziscli in brackets) C H 'N 2 -OCH ₂ CH ₂ O-Jl-C ₄ H Hydrochloride 199-201 ° 57.5 7.6 12.7 (57.2 7.5 12.7) 3 Γ ³ -OCH-C-OH CH ^CH 3 free base, 204-205 ° 61.0 7.7 14.9 (60.6 7.5 14.9) 4 -OCH ₀ -C-OC-H ,. 2 j 2 5 CH ₃ Hydrochloride monohydrate 244-246 ° 54.7 7.5 12.1 (55.0 7.7 12.2)

example * isolated form Analysis ί C H H brackets) N u. M.p. (° c) (Theoretically in 60.9 7.7 13.8 (61.5 7.7 14.4) C free money, 2 2 3 2 130-134 ° 60.1 6.4 12.0 ^CH 3 (60.7 6.6 11.8) 6 -OCH ₀ CH-OC-H ₁ . Hydrochloride, 57.9. 7.2 12.4 <£ ob 22X - 223 ° (58.3 7.4 12.4) 7 -OCH ₂ CH ₂ O- ^ J hydrochloride 210-21 ίο '

-π- 209 133

The following minor differences in the operation over Example 1 should be mentioned. In Example 3, the product from the chromatographic purification was directly recrystallized without conversion to a hydrochloride. In Examples 5 and 7, silica was used for the chromatographic purification. In Example 6, after concentrating the original reaction mixture (which was a hydrochloride), the residue was recrystallized from dimethylformamide and then chromatographed directly on silica.

Example 8

4-Amino-6,7-dimethoxy-2- / 4- (2-methoxy-n-propoxy) -piperidine -quat-quinazoline-hydroki or id '

4-Amino-2-chloro-6,7-dimethoxy-quinazoline (3.6 g), 4- (2-methoxy-n-propoxy) -piperidine (3.0 g) and triethylamine (1.5 g) in n-butanol were refluxed for 30 hours. The solvent was evaporated in vacuo, the residue stirred with diethyl ether, the solid collected and recrystallized twice from isopropanol to give 4-amino-6,7-dimethoxy-2-4- (2-methoxy-n-propoxy) -piperidino_7-quinazoline hydrochloride to give 241 ⁰ C, - (2.8 g), m.p. 239th.

Analysis:

gef *: - C 55,1; H 7.2; N 13.6 %

Calc. for C ₁ QH ₉₀ N ₇₁ O.-HCl: C 55.2; H 7.1; N 13.6 %.

Examples 9-22

The following quinazolines were prepared and purified similar to Example 8 starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and the appropriately substituted piperidine.

ΟΗ, Ο

example X -OCH ₂ CH ₂ OH. isolated form u. M.p. (° c) Analysis Θ% (Theoretical, in brackets) C H N -9 -OCH CH 0 -VV ~~ ^CH , \ / / Hydrochloride hemihydrate, 252-253 ° 51.8 6.3 14.1 (51.8 6.7 14.2) ΙΌ -OCH ₂ CH ₂ O --γ y- F Hydrochloride hemihydrate, 216-217 ° 60.0 6.4 11.8 (59.6 6.7 11.6) * 11 Hydrochloride 226-227 ° 57.6 5.9 12.0 (57.7 5.9 11.7)

CH ₃ O

example X isolated Porm u, m.p. (° c) Analysis% (Theoretic in brackets) C H N- 1-2 -OCH-CH ₀ O (f 7 OCH, \ - · / Hydrochloride hydrates, 195-196 56.8 6.2. 11.1 (56.6 6.5 11.0) 13 CH ₃ O--, -v -OCH ₂ CH ₂ O - (/ y Hydrochloride, 203-204 ° 57.5 6.3 10.7 (57.6 6.4 10.8) 14 -OCH ₂ CH ₂ O - (ζ. Y ^ OCH ₃ Hydrochloride hemihydrate, 207-209 57.4 6.3 11.0 (57.7 6.4 11.2)

example X if isolated form u. Schmp. ^FO c) Analyze Θ% (Theoretically in brackets) C H N- IS -OCH ₀ CH ₀ O - () - CF, HydrOchloride, 259-261 ° 54.0 5.4. 10.9 (54.5 5.3 10.6) 16 / -S. ° -OCH ₀ CH ₀ O - ( 7 CNH ₀ Hydrochloride hemihydrate, 272-273 ° 56.4 5.9 14.0 (56.2 6.1 13.7) 17 -OCH ₂ CH ₂ O - ^ ^> ₀ CNH ₂ Hydrochloride id. Hydrate, · 167-169 ° 55.2 6.2 13.4 (55.2 6.2 13.4)

CH ₃ O

example X S isolated JOrm u. Schmp. (O Analysis% (Theoretically in brackets) CHN ^'18 ι -OCH-CH ₉ OCH Hydrochloride 220 - 222 ° 53.8 7.0 14.1 (54.2 6.8 14.0)

CH ₃ O

example X ' -OCH ₀ CH ₀ OC-H- isolated form u. M.p. (° c) Analysis e% (Theoretic in brackets) CHN 1'9 fs -OCH ₂ CHOH Hydrochloride 232-233 ° 59.5 6.6 12.3 (59.9 6.3 12.2) 20 CH I ³ -OCH ₀ CK-OC ₀ H Hydrochloride hemihydrate 245-246 ° 52.8 6.7 13.7 (53.0 6.7 13.7) 21 CH. I ³ -OCH-C.OCH- 2, 3 CH Hydrochloride hydrate · 217-218 ° 55.6 7.2 12.5 (55.1 7.4 12.8) • 22 Hydrochloride id 239-242 ° 56.0 7.5 12.8 (56.3 7.3 13.1)

-23- 209 1

The following examples illustrate the preparation of certain starting materials used in the previous examples:

Example A Preparation of 4- (2-methoxyethoxy) piperidine

A solution of N-acetyl-4-hydroxypiperidine (30.5 g) in dimethylformamide (200 ml) was added to a stirred suspension of sodium hydride (11.26 g, 50% dispersion in mineral oil) in dimethylformamide (500 ml) under a vacuum Nitrogen atmosphere dropped. The reaction temperature was maintained by external cooling below 30 ⁰ C and after "completion of the addition another 1.25 was stirred. A solution of 1-bromo-2-methoxyäthan (32.6 g) in dimethylformamide (100 ml) was then, with external cooling The resulting clear solution was stirred at room temperature overnight The reaction mixture was then concentrated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried over Na ₂ SO ₄ and concentrated to give a crude residue (16 The above aqueous phase was saturated with sodium chloride, further extracted with chloroform, and the organic phase was dried (over NapSO4) and concentrated to leave another residue (9.2 g) combined with the first residue and heated to a steam bath with hydrochloric acid (243 mL, 2N) overnight The reaction mixture was extracted with chloroform to give residual mineral oil e.g. u, the aqueous phase was concentrated, basified with sodium hydroxide (pH 12), then extracted again with chloroform.

The organic extracts were washed with brine, dried (over Na ₂ SO 4), and concentrated to give 4- (2-methoxyethanol).

oxy) piperidine (8.3 g). A sample of this product in ethyl acetate was converted by the addition of ethereal oxalic acid in the oxalate, to which was recrystallized from ethanol j The oxalate had mp of 86 -. 88 ⁰ C.

Analysis:

over for

C 48.1; H 7.6; N 5.6 % C 48.2; H 7,7; N 5.6%

The following piperidine derivatives were prepared by procedures similar to those of Example A, starting from N-aeetyl-4-hydroxypiperidine and the appropriate bromide. Hydrolysis of the N-acetylated intermediates in Examples B and D was performed using dilute sodium hydroxide instead of dilute hydrochloric acid.

"O ~

Step Example Y isolated form u. M.p. (° c) C Analysis e% (Theoretical brackets) H in N B -OCH ₂ CH ₂ OC ₆ H ₅ Oxalate 144 - 145 ° 58.5 (57.9 6.8 6.8 4.3 4.5) C -OCH ₂ CH ₂ O-Ii-C ₄ H ₉ Oxalate hemihydrate 86-88 ° 52.4 (52.0 8.4 8.7 4.8 4.7) D -OCH ₂ CH ₂ OC ₂ H ₅ Oxalate 93 - 95 ° 50.5 (50.2 8.2 8.0 5.2 5.3)

-25- 209 1

Example E Preparation of N-acetyl-4-allyloxypiperidine

A solution of N-acetyl-4-hydroxypiperidine (100 g) in dimethylformamide (250 ml) was added dropwise to sodium hydride (38 g, 50% mineral oil dispersion) under a nitrogen atmosphere. The mixture was stirred for 2 h, then allyl bromide (93 g) was added slowly, keeping the reaction temperature was maintained by external cooling at 25 ⁰ C. The mixture was then stirred at room temperature overnight, diluted with isopropanol (20 ml) and ether (500 ml), filtered and concentrated in vacuo. Distillation of the residue afforded N-acetyl-4-allyloxypiperidine (108.8 g), b.p. 128 ° C / 2 mm, spectroscopically identified.

Example F Preparation of 4- (2-ethoxy-n-propoxy) piperidine

A solution of N-acetyl-4-allyloxypiperidine (6.4 g) in absolute ethanol (10 ml) was added dropwise to a stirred suspension of mercury (II) acetate (11.5 g) in ethanol (50 ml) at room temperature. After 20 minutes, the mercury (II) acetate had dissolved and the mixture was stirred for an additional 40 minutes, cooled in ice-water, and then sodium hydroxide (20 ml, 5N) was added. During the addition, a yellow precipitate formed. A solution of sodium borohydride (1.3g) in sodium hydroxide (20ml, 5n) was then added, the mixture stirred for 10min and acetic acid added to bring the pH to S. The mixture was filtered from the precipitated mercury, the ethanol concentrated in vacuo and the resulting aqueous phase extracted with chloroform.

The organic extracts were dried (over Na 2 SO 4), im

9 133

133

Concentrated and the resulting crude residue (7.5 g) was taken up in ethanol (50 ml) and refluxed overnight with sodium hydroxide (20 ml, 5N) and water (20 ml). Most of the ethanol was then removed in vacuo, the aqueous layer extracted with ether, the extracts dried (over Na ₂ SO ₄ ) and concentrated to leave a residue (5 g). Thin-layer chromatography indicated incomplete hydrolysis of the acetyl function so that the residue was treated with hydrochloric acid (20 ml, 2N) and heated on a steam bath for 10 hours. The mixture was then washed with ether, the aqueous phase (basified with Na ₂ CO.,), Extracted with ether, and the organic extract (over Na ₂ SO.) Dried and concentrated to give a residue (4.3 g ) leave behind. Distillation of the residue afforded 4 ~ (2-ethoxy-n-propoxy) piperidine (3.0 g), b.p. 112-116 ° C / 10 mm, of which the sesquioxalate was prepared by reacting an ethereal solution of piperidine with ethereal oxalic acid. then was recrystallized from ethyl acetate, the oxalate had a mp of 68 - 70 ⁰ C.

Analysis;

found: C 48.3; H 7.5; N 4.7 %

calc. for C ₁₀ H ₂₁ NO ₂ .1.5 (CO ₂ H) ₂ : C 48.4; H 7.5; N 4.4 %

Example G Preparation of 4- (2- hydroxy-n-propoxy) piperidine

N-acetyl-4-allyloxypiperidine (18 g) in tetrahydrofuran (30 ml) was added dropwise to a stirred yellow suspension of mercury (II) acetate (34 g) in a mixture of water (120 ml) and tetrahydrofuran (120 ml). The suspension dissolved during the addition, and the resulting clear solution was dissolved at room temperature for 20 minutes, then became

Sodium hydroxide (70 ml, 5 η) was added while cooling with ice / water. The intermediate thus obtained was then reduced by addition of sodium borohydride (2 g) in sodium hydroxide (40 ml, 5N), whereupon the excess hydride was destroyed with glacial acetic acid after 10 minutes. The liquid phase was then decanted, saturated with sodium chloride, the organic phase separated and the remaining aqueous layer extracted four times with chloroform. The combined organic phases were dried (over Na ₂ SO ₄ ) and concentrated in vacuo to leave a colorless oil (23 g).

This oil was stirred with 5 η sodium hydroxide at room temperature for 16 h, then 2 h at 100 ⁰ C. The solution was then extracted with chloroform (four times), the combined extracts dried over Na 2 SO 4, and concentrated in vacuo to leave a crude, crystalline product (16.1 g). This was collected, filtered, concentrated in methylene chloride, and the residue was triturated with petroleum ether (bp. 40/60 ⁰ C) to give 4- (2-hydroxy-n-propoxy) piperidine (11.0 g), mp. 55 - 57 ⁰ C to deliver. The oxalate was prepared as in Example P and recrystallized from isopropanol, m.p. 104-105 ° C

Analysis;

found: C 48.2; H 7,7; N 5.6 %

calcd. for C ₈ H ₁₇ NO ₂ - (CO ₂ H) ₂ : C, 48.2; H 7,7; N 5.6 %

Example H Preparation of N-acetyl-4- (2-methylallyloxy) piperidine

This compound was prepared similarly to Example E, starting from N-acetyl-4-hydroxypiperidine and 2-Kethylallyl-

- 28 - fe> ^ y ^s --- - * *

Chloride, and was distilled and used directly in the next step. It had a bp of 128 ° C / 1 mm.

Example I Her position 4 ". (2 'methoxy-2 ~ methyl-n-propoxy) piperidin

This compound was prepared similarly to Example P, starting from N "acetyl" 4 - (2-ethylallyloxy) piperidine and mercury (II) acetate / methanol. The compound was characterized as hemioxalate, Schmp.208 - 21O ⁰ C.

Analysis;

Found: C 56.7; H 9.5; N 5.9 %

Toer. for C ₁₀ H ₂₁ NO ₂ '1/2 (CO ₂ H) ₂ : C 56.9; H 9.6; N 6.0 %

Example. J. Preparation of 4- (2-hydroxy-2H-methyl-n-propoxy) piperidine

This compound, mp 80-82 °, was prepared similarly to Example G, starting from N-acetyl-4-bis (2-methylallyloxy) -piperidine and mercury (II) acetate in a mixture of water and tetrahydrofuran.

Analysis;

found: · C 62.2; H 11.1; U .8.3 %

Calcd. for C ₉ H ₁₉ NO ₂ : C, 62.4; H 11.1; N 8.1 %

Example K.

Preparation of 4 "(2-ethoxy-2-methyl-n-propoxy) piperidine This compound was prepared similarly to Example P except

- 29 - 209 1 33

starting from N-acetyl-4- (2-methylallyloxy) piperidine and mercury (II) ace / ethanol, followed by basic hydrolysis to remove the N-acetyl group, a sample was converted to the hemioxalate prepared from ethyl acetate. Methanol was recrystallized, mp 184 - 185 ⁰ C.

Analysis;

gef. C 58.6; H 9,7; N 5.8 %

Calc. for C ^ H ₂₃ NO ₂ * 1 / 2C ₂ H ₂ O ₄ : C 58.5; H 9,8; N 5.7 %

Example L Preparation of 4- (2-isopropoxyethoxy) piperidine

This compound was prepared similar to Example A from N-acetyl-4-hydroxypiperidine and i-bromo-2-isopropoxyethane. The compound was characterized spectroscopically.

Example M Preparation of 4- (2-Hethoxy-n-propoxy) piperidine

This compound was prepared similar to Example F, starting from H-acetyl ^ -allyloxypiperidine and mercuric (II) acetate in methanol. To improve the conversion of the starting material into the product, the mercury (II) acetate / methanol treatment was repeated twice to provide N-acetyl-4- (2-methoxy-n-propoxy) piperidine, which hydrolyzed in sodium hydroxide and methanol solution was to afford 4- (2-methoxy-n-propoxy) piperidine. A sample was characterized as the oxalate, mp. 89 - 91 ⁰ C.

fi

Analysis;

Found: 'C. 49.6; H 7.9; N 5.3 %

Calc. for C ₉ II ₁₉ NO ₂ ⁰ C ₂ H ₂ O ₄ : C 50.2; H 8,1; N 5.3 %

' ^J. 2 example__N

He rs telJ-Uiig ^ jvon ^ 4.-, (2 -Phenoxy ° n ~ pr oxy) piperidine

N-acetyl-4- (2-hydroxy-n-propoxy) piperidine (12g) in dry DMF (50ml) was added to a stirred suspension of sodium hydride (5.0g, 50% dispersion in mineral oil) in DMF (50 ml) at 60 - 70 ⁰ C under a nitrogen atmosphere added dropwise. The suspension was stirred for 3 h, then fluorobenzene (6.4 g) in DMF (50 ml) was added dropwise and the suspension stirred at 100 ^° C. for 50 h. The cooled solution was washed with isopropanol (20 ml), then water (200 ml ), extracted with petroleum ether (3 × 200 ml) and chloroform (3 × 200 ml). The combined chloroform extracts were dried (over Na ₂ SO ₄ ) and the solvent was removed in vacuo. The residue (9.0 g) in sodium hydroxide (20 ml, 5N) and methanol (20 ml) was heated at reflux for 5 hours to bring it into solution. The methanol was evaporated, the residue diluted with water, then extracted with chloroform (3 x 50 ml). The combined chloroform extracts were washed with 2N HCl (3 x 30 ml), the combined aqueous extracts basified to pH 12 with sodium hydroxide solution and extracted with chloroform (3 x 50 ml). The combined chloroform layers were dried (over Na ₂ SO ₄ ), the solvent was evaporated in vacuo, then the residue was triturated with ether and filtered. The filtrate was concentrated, then distilled to give 4- (2-phenoxy-n-propoxy) piperidine (0.5 g), b.p. 118-122 ° C / O, 3 mm, which was characterized spectroscopically.

Example 0

4- (2- / 2 _f 6-dimethoxyphenoxy) ethoxy) piperidine

OCH,

OCH.

Ac-N V ~ OH

hydrolysis

2 ^C V °

/ Ac =

Methanesulfonyl chloride (23 g) was added to a stirred solution of 2- / 2,6-dimethoxyphenoxy-7-ethanol (20 g) (J. Med. Chem

1969, 1_2, 326) in pyridine (50 ml). The solution was left for 60 Ii "at room temperature, then the solvent was evaporated under reduced pressure. The residue was taken up in chloroform, washed with water (3 χ 100 ml) and sodium bicarbonate (5% _f 3 x 100 ml), dried and Solvent evaporated The residue was triturated with η-hexane and the solid collected to give 2- / 2,6-dimethoxyphenoxy-7-ethyl mesylate (11.3 g), which was characterized spectroscopically.

- 32 - & W W 1 J

N ~ acetyl-4-hydroxy-piperidine (4.3 g) in DMP (50 ml) was added dropwise to a stirred suspension of sodium hydride (3.0 g, 50% dispersion in mineral oil) in DMP (50 ml) under a nitrogen atmosphere. After stirring at room temperature for 3 hours, 2- (2-o-dimethoxyphenoxy) -xyl mesylate (9.0 g) in DMF (50 ml) was added dropwise and stirred at room temperature for a further 20 hours. The solvent was removed under reduced pressure, the residue was taken up in water, extracted with chloroform (3 × 100 ml), the organic layer was dried over Na ₂ SO ₄ , and the solvent was evaporated. Distillation afforded N-acetyl-4- (2- / 2,6-dimethoxyphenoxy-7-ethoxy) piperidine (6.0 g), bp 200 ° C / 1 mm.

This product (6.0g) in methanol (40ml) and sodium hydroxide solution (20ml, 5n) was heated to reflux for 20 hours. Methanol was evaporated under reduced pressure, the aqueous residue extracted with petroleum ether (3 x 30 ml) and ether (3 x 30 ml). The ether extract was dried (over Na ₂ SO ₄ ) and the solvent was evaporated. The residue in ether was treated with ethereal hydrogen chloride and the precipitated solid was recrystallized from isopropanol to give 4- (2- / 2,6-dimethoxyphenoxy-ethoxy) -piperidine-hydrochloride (1.4 g), cut. 143 - 145 ° C, to give.

Analysis;

Found: 'C 56.46; H 7.6; N4.3 %.

calc. for C ₁ PH _9x NO. HCl: C 56.7; H 7.6; H4 _f 4 V =

Example P (A) Preparation of N-acetyl-4- (2,2-diethoxyethoxy) piperidine

N-acetyl-4-hydroxy-piperidine (57.2g) in dry IMF (250ml) was added to a stirred suspension of sodium hydride (23.2g, 50% dispersion in mineral oil) in dry

Dropped DMP (200 ιοί) under a nitrogen atmosphere and external cooling in an ice / water bath. The suspension was allowed to warm to room temperature and was then stirred for 5 h. Bromoacetaldehyde diethyl acetal (94.7 g) was added slowly to the stirred reaction mixture with cooling, then the mixture was stirred at room temperature for 18 h. Additional sodium hydride (23.2 g) was added portionwise and stirring was continued until the effervescence ceased. Another 100 ml of dry DME ^{1 was} added to the mixture cooled in an ice / water bath while a second amount of bromoacetaldehyde-diethylacetal (94.7 g) was added slowly. The mixture was stirred for 3 h at room temperature, then isopropanol (150 ml) was added to destroy excess sodium hydride. The suspension was filtered, the filtrate concentrated under reduced pressure, then the residue taken up in water and extracted with chloroform. The chloroform extract was dried (over Na ₂ SO.), The solvent was concentrated in vacuo and the residue distilled to give N-acetyl-4- (2,2-diäthoxyäthoxy) piperidine (61.5 g), bp 142 -. 145 ⁰ C / 3 mm, characterized by NMR.

(B) Preparation of N-acetyl-4- (2-hydroxy.-ethoxy) piperidine

N-acetyl-4- (2,2-diethoxyethoxy) piperidine (12 g) in 0.5 N hydrochloric acid (50 mL) was stirred at room temperature overnight. The solution was saturated with sodium chloride and extracted several times with chloroform (total 500 ml). The chloroform extract was dried (over Na ₂ SO ₄ ) and the solvent was removed in vacuo and at a bath temperature below 30 ^° C. The resulting aldehyde intermediate (9.8 g) was immediately reduced with sodium borohydride (0.75 g) in ethanol (75 ml) at pH 6. After stirring for 3 hours at room temperature, the reduction was complete. Then water was added to the stirred solution, and the organic

see solvent was removed in vacuo. The residue was taken up in water (30ml), extracted with chloroform (10 x 30ml), the combined chloroform extracts (over NapSO) dried and the solvent concentrated in vacuo. The residue was taken up in water (70ml) and petroleum ether (2x10 ml). The aqueous phase was concentrated to afford N-acetyl-4- (2-hydroxyethoxy) piperidine (6.9 g), characterized spectroscopically. A sample was distilled and had a bp of 139 - 14O ⁰ C / 0.3 mm. '

Analysis;

Found: C 57.5; H-9.1; N 7.6 %

Calcd. for C ₉ H ₁₇ NO ₅ : C 57.8; H 9.1 _; N 7.5 %

(C) 4- (2-Cyclopentyloxyethoxy) piperidine

N ~ acetyl = 4- (2-hydroxyethoxy) piperidine (5.0 g) in DKF (25 mL) was added to a stirred suspension of sodium hydride (1.28 g, 50% mineral oil dispersion) in dry DME ¹ (50 mL). dropped under nitrogen atmosphere. When effervescence had ceased, cyclopentyl mesylate (4.4 g) (Tetrahedron 1972, 28, 2469) in DME ¹ (10 mL) was added slowly and the mixture was stirred at room temperature for 40 h. Additional amounts of sodium hydride (0.64 g) and then cyclopentyl mesylate (2.2 g) were added and the mixture was stirred at 60 ^° C. for 7 h, then at room temperature for 64 h. Isopropanol was added, the mixture filtered, and the filtrate concentrated in vacuo. The residue in ethanol (30 ml) and 5 η sodium hydroxide solution (30 ml) was heated under reflux for 3 h. The ethanol was removed in vacuo, the residue diluted with water and extracted with chloroform. The chloroform extract was dried (over Na ₂ SO-), solvent removed in vacuo, then the residue treated in chloroform with ethereal hydrogen chloride. The solvent

209 133

was decanted and the residue was triturated with ether to give 4- (2-cyclopentyloxyethoxy) piperidine hydrochloride as a resin. The product contained some impurity on 4- (2-hydroxyethoxy) piperidine but was used directly.

Example Q Preparation of 4- (2-p-fluorophenoxyethoxy) piperidine

A solution of N-acetyl-4- (2-hydroxyethoxy) piperidine (5.0 g), triphenylphosphine (8.4 g), diethyl azodicarboxylate (5.6 g) and p-pluorophenol (3.36 g) in freshly distilled Tetrahydrofuran (75 mL) was stirred in an ice-bath for 2 h and then left at room temperature for 48 h. The solvent was removed in vacuo, the residue taken up in chloroform and washed twice with 1N sodium hydroxide solution and twice with water, dried (over Na ₂ SO ₄ ) and the solvent removed in vacuo. The residue was taken up in the minimum volume of ether at reflux, then cooled in a refrigerator. The precipitated solid was collected, the filtrate concentrated and the residue taken up in ether and set aside for cooling. The precipitated solid was removed again, the filtrate was concentrated and the residue was extracted with petroleum ether (60-80 °, 5 × 100 ml) under reflux. The solvent was removed in vacuo and the residue was refluxed in ethanol (50 ml) and sodium hydroxide solution (50 ml) for 5 h, then neutralized with 2N hydrochloric acid and the organic solvent was evaporated. The aqueous residue was acidified to pH 2 with 2N hydrochloric acid and extracted twice with ether. The aqueous phase was basified with 2N sodium hydroxide solution and then extracted with chloroform (3x100 ml). The combined chloroform extracts were dried (over Na ₂ SO 4) and the solvent removed in vacuo to afford 4- (2-p-fluorophenoxyethoxy) piperidine (1.3 g).

A sample of this product in chloroform was added to the Hydrochloric! By treatment with ethereal hydrogen chloride. transferred and had a Schmp, from 144 - 145 ° C.

Analysis; Found .:

for C.

_1δ ΕΝΟ ₂ · HCl:

C 56.1 j H 6.8; N 5.5 % C 56.6; H 6.9; N 5.1 %

Examples R to U

The following piperidine derivatives were prepared by a procedure similar to Example Q, starting from N-acetyl-4- (2-hydroxyethoxy) piperidine and the appropriate phenol.

Example V Preparation of 4- ^ ~ (4- piperidinyloxy) ethoxy-7benzamide

N-acetyl-4- (2-hydroxyethoxy) piperidine (1.0 g), 4-hydroxybenzaldehyde (0.82 g), diethyl azodicarboxylate (1.12 g) and triphenylphosphine (1.68 g) in tetrahydrofuran (30 ml) were stirred at room temperature for 66 h »The precipitated solid was collected and dried to give. 4- / 2- (N-acetyl-4-piperidyloxy) äthoxy7benzamid (0.72 g), mp 154 -. 155 ⁰ C to provide.

Analysis;

gef .: for

C 62.7; H 7.1; N 9.1 % C 62.7; H 7.2; N 9.2 %

HN V-OCH ₂ CH ₂ -OR ¹

example

isolated form u. Mp. (° c)

Analysis e% (Theoretically in brackets)

C HN

Hydrochloride '145 - 146 °

61.4 (61.9

8.1 8.2

5.1 5.2)

OCH,

Hydrochloride 197-198 °

58.3 (58.4

7.8 7.7

4.6 4.9)

Oxalate 122 - 123 °

50.4 (50.7

5.3 5.3

3.7 3.7)

OCH,

Qxalat, 151 - 153 ^C

56.2 (56.3

6.9 6.8

4.2 4.1)

4- / 2- (N-Aeetyl-4-piperidyloxy) ethoxybenzene Hud (4.3 g) in ethanol (60 ml), water (30 ml) and 2N hydrochloric acid (10 ml) were refluxed for 24 hours, then . The solvent was removed in vacuo. The residue was taken up 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 dried with extra-chloroform, the chloroform layer (over ITa ₂ SO.) And the solvent was concentrated in vacuo to give 4- (2- (4-piperidyloxy) ethoxybenzamide ( 0.36 g). The aqueous phase was concentrated in vacuo and the residual solid was extracted with ethyl acetate (200 ml) under reflux. The gum was filtered off and the filtrate concentrated in vacuo to give additional 4- / 2- (4-piperidyloxy) ethoxybenzamide (0.30 g) identical to that obtained above. A ..Probe of this product in chloroform / methanol was converted by treatment with ethereal hydrogen chloride in the hydrochloride, then recrystallized from ethyl acetate / isopropanol, mp. 244 - 246 ⁰ C, spectroscopically characterized.

Example W Preparation of 5-Z2- (47-piperidyloxy ) ethoxybenzamide

L-acetyl-4- (2-hydroxyethoxy) piperidine (5.0 g), 3-hydroxybenzamide (4.4 g), diethyl azodicarboxylate (5.6 g) and triphenylphosphine (8.4 g) in dry tetrahydrofuran (100 ml ) were stirred at ⁰ ° C. for ² h, then at room temperature for 64 h. The solvent was removed under reduced pressure, then the residue was treated with ether (3 × 100 ml) under reflux and the mother liquors were decanted off. The residual oil was taken up in chloroform and washed with dilute sodium hydroxide solution (40 ml and water (40 ml).

-39- 209 133

The mixture was dried over MgSO 4, then the solvent was removed in vacuo. The residual oil was treated with ether (50 ml) and placed in a refrigerator. The resulting solid was collected, slurried with ether (30 mL), filtered and washed with ether (30 mL) to give 4-Z 2 - (N-acetyl-4-piperidyloxy) ethoxy-7-benzamide (3.7 g) with some triphenylphosphine oxide (approx 25 % according to NMR).

The product was refluxed in ethanol (48 ml), Yfasser (24 ml) and 2N hydrochloric acid (8 ml) for 24 h, then the ethanol was removed in vacuo. The aqueous residue was extracted with ether (2 × 100 ml) then chloroform (100 ml), the aqueous phase was adjusted to pH 12 with sodium hydroxide solution and extracted with chloroform (2 × 100 ml). The organic layer was dried (over MgSO 4) and the solvent removed in vacuo to give 3-Z 2 - (4-piperidyloxy) ethoxy-7benzair, id (0.55 g). The aqueous phase was saturated with sodium chloride and extracted with chloroform (3 × 100 ml). The combined chloroform extracts were dried (over MgSO 4) and the solvent removed in vacuo to give a second crop of 3- / 2- (4-piperidyloxy) ethoxy-7-benzamide (0.26 g) identical to that previously obtained was. This sample was characterized by treating an ethanolic solution with ethereal hydrogen chloride as the hydrochloride, mp. 144 - 146 ⁰ C.

Analysis:

Found: C 56.0; H 7.2; N 9.2 %

Calc. for C ₁ .H _9n NpO, -HCl: C 55.9; H 7.1; N 9.3 %.

Claims (3)

- «fO - Invention claim: 1, Process for the preparation of compounds of the general formula NH ₁ wherein R is lower alkyl and X is a group of the formula -O-alk-OR ¹ , wherein "alk" is an optionally represented by 1 or 2 lower Alkyl groups substituted ethylene group, and E is hydrogen, lower alkyl, C "-C, -cycloalkyl or a Group of formula 2 3
wherein R and R are each independently hydrogen, Lower alkyl, lower alkoxy, halogen, CF_, -CONR R or 4 5 h 5 ^ -SO ₂ NR R, where R and R are each independently 9 1 Is hydrogen or lower alkyl, characterized in that a compound of general formula ro (51 Wherein R is as defined above and Q is a readily leaving group such as chlorine, bromine, iodine, lower alkoxy, lower alkylthio or alkylsulfonyl, with a piperidine of the formula wherein X is as defined above, then, if desired, the resulting compound of formula (I) is converted to a pharmaceutically acceptable acid addition salt. 2. The method according to item 1, characterized in that R Methy ψ ^ X is -OCH ₂ CH ₂ OR ¹ Z-OCH ₂ -CHOR ^{'is 1} or - CH. ι J -OCH ₉ -C-OR
* - t R is hydrogen, C 1 -C 4 -alkyl, cyclopentyl or a group of the general formula R ³ is in which 2 3 R and R each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl or carborayl. 3. The method according to item 1, characterized in that R is methyl, "alk" - CHgCHg - and R is ethyl or phenyl.