FI63935B - PROCEDURE FOR FRAMSTATION OF AV 4-AMINO-6,7-DIMETOXY-2- (4- (SUBSTITUTES WITH ALCOXY) PIPERIDINO) QUINAZOLINE ANVAENDBARA SAOSOM ANTIHYPERTENSIVE MEDEL - Google Patents

Description

RSF ^ 1 [B] (11) NOTICE OF ADVERTISEMENT

Ma l j 1 'utlAggningsskrift οό ^ όο C (45) :::? 1 ^ sy & rj 3 3 c 07 D 4-01 / 04 (51) Kv.ik./intci. // c 07 d 239/95 SUOM I —FI N LAN D (21) Pstunttlhsksmus - Pstsntsnseknlng 703 * 07 (22) HaktmltpUvl - An * eknlng »d» g lU .11.78 ^ (23) AlkupiWft— Giklghutadag lU. 11.78 (41) Became Stuck - Bllvlt offantlig 17 .05.79 P »tBntti- ja regististerallitus (44) NlhUvIktlpwen |. moonLHkmbun p * m. -

Patent- och registerstyreisen An tökin utltgd och uti.tkrtft * n publicund 31.05.83 (32) (33) (31) Pursuit of the right of use— Begird prtoritet ^ # γγ

England-England (GB) * + 7503/77 (71) Pfizer Corporation, Calle 151/2, Avenida S.anta Isabel, Colon,

Panama (PA) (72) Simon Fraser Campbell, Kingsdown, Deal, Kent, John Christopher Danilewicz, Ash, no. Canterbury, Kent, Colin William Greengrass,

Woodnesborough, Sandwich, Kent, England-England (GB) (7 * 0 Oy Kolster Ab (5 * +) Method for use as antihypertensive agents) i-amino-6,7-dimethoxy-2 - (* + - / substituted alkoxy / »Piperidino) for the preparation of quinazolines - Preparation of the quaternary form of U-amino-6,7-dimethoxy-2- (i + - / substituted alkoxy, piperidino) quinazoline in the form of an antihypertensive agent

The invention relates to an analogous process for the preparation of 4-amino-6,7-dimethoxy-2- (4- / substituted alkoxy7, piperidino) quinazolines of the formula I or anti-pharmaceutically acceptable acid addition salts thereof, used as antihypertensive agents, cH3YyvCl2 (i)

ch3oA ^ YN

Wherein H2 is a group of the formula -OCt ^ C ^ OR1, -OCH2CH (CH3) OR1 or -OCH2C (CH3) OR1, and R1 is hydrogen, C1-4alkyl, 63935 cyclopentyl or phenyl which is optionally para-substituted with methoxy or halogen. Such compounds are useful as regulators of the cardiovascular system, and especially in the treatment of hypertension.

SE Publication No. 342,454 describes antihypertensive compounds which closely resemble the compounds of the present application. However, these groups of compounds differ in that 4-alkoxypiperidinoquinazolines are disclosed in the SE in question, while the compounds of the present application are certain 4-alkoxypiperidinoquinazolines in which the alkoxy group is substituted with -OR1. It has now surprisingly been found that the compounds of the present application are considerably more active than the corresponding 4-methoxy and 4-ethoxy-piperidinoquinazolines of SE.

In this patent application, "halogen" means fluorine, chlorine, bromine or iodine.

Pharmaceutically acceptable acid addition salts are formed with acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions. Examples are the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.

Compounds of the invention containing one or more centers of asymmetry exist in one or more enantiomeric pairs. These and the individual isomers can be separated by physical methods, e.g. by crystallization of the appropriate salts of the fractions.

In particularly preferred compounds of the invention, X is -OCH 2 Cl 2 OR 2 and R 2 "is ^ 2 ^ 5 *" a phenyl *

Compounds of formula I are prepared by reacting a compound of formula II (ii> ch3o y nh2 3 63935 wherein Q is a readily leaving group / such as chlorine / bromine, iodine, lower alkoxy, lower alkylthio or lower alkylsulphonyl) with piperidine of formula III

X

(III)

B

wherein X is as defined above, after which the compound of formula I is optionally converted into a pharmaceutically acceptable acid addition salt by reacting it with a non-toxic acid.

In the compounds of formula II, Q is preferably chlorine or bromine.

Typically, the reaction is performed in the presence of an excess of a base such as triethylamine or a reagent of formula III.

In a typical process, the reactants are heated together, e.g., at a temperature of 70 ° to 130 ° C, preferably at reflux in an inert organic solvent such as n-butanol for up to about 48 hours. The product can be isolated and purified by conventional methods.

Typically, the product is obtained in crude form, e.g. by evaporation of the reaction mixture in vacuo, and the crude product can be purified either by recrystallization from a suitable solvent or by conversion to e.g. the hydrochloride salt by reaction with hydrochloric acid in e.g. ethanol and then recrystallization. In some cases, the reaction product is obtained as the hydrochloride salt. In some cases, the crude product can also be purified chromatographically, e.g. by basification and extraction with chloroform, evaporation of the chloroform extracts and chromatography of the residue, e.g. with neutral alumina, eluting with chloroform or a mixture of chloroform and methanol. The eluted product can be purified as above by converting it to the hydrochloride salt and then recrystallizing.

The intermediates of formula II are generally known compounds or can be prepared by methods previously known in the art.

63935

The intermediates of formula III are either known compounds or can be prepared by conventional methods, e.g. as follows:

OH XX

1 (1) NaH / DMF 1. hydrolysis JL

(2) R 1 -O-alk-Br, (acidic or \ N RTO-alk-Cl basic

• or RO-alk- i H

C = O mesyl c = O * (R is not hydrogen) · CH 3 CH 3 / DMF = dimethylformamide / b) Piperidines in which X is -OCH, CH (CH 2) OR 1 or 1 O -OCH 2 C (CH 2) 2 OR are can also be prepared with the corresponding 1-acetyl-4-alkeneoxypiperidines, e.g. as follows (in which case R1 can be hydrogen):

Oi OCH, .CH = CH, O.CH-CHOR1 I 1 2 2. 1 μL pii (1) NaH / DMF ^ (1) HgQAc / R CK ^ 3 -> -> (2) CH, = CH.CH, Br (2) NaBH.

2 2 4

I I I

c = ° c = o c = o

I I I

CH, CH, CH, hydrolysis 6 -3 L (acidic or φ basic) O.CH ^ CHOR1 Λί ™ 3

B

I! 5 63935 c) 4- (2-hydroxyethoxy) -piperidine can be prepared in a known manner: J-i OCH2CH2OH och2ch2oh o o yk

LiAlH ^ / AlCl ^ ^ ^ H2 with Pd ^ ^ ^ ^ \ N '

^ s | B

^ N ^ CEAPh I 2 CH2Ph d) 4- (2-hydroxyalkoxy) -piperidines can also be prepared in the following conventional ways:

Eg I

f OEt f. 0Et ^ NaH / BrCHCH OCH.CH ^ 'N'v OEt 0Et i -> |

I I

Prot.

h + / h2o r r OCH.CH2OH och.cho ^ NaBH4

i I

Prot. Prot.

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

63935 6

Eg II

R "OH OCH.CC ^ C ^

(i) NaH / DMF

R "-> k. N (ϋ) Br0CO 2 H \ N ^ I (iii) EtOH / H + | I. Prot.

Prot.

I Li £ H4 / THF R "

OCHCH ~ OH

O

(Prot. And R "have the same meaning as'

Prot.

above)

or e.g. III

R "

OH OCH2CH

JL JL ^ OH

f (i) NaH, DMF, THF f ->

k S (ii) <° 1 k J

^ N ^ R "^ N ^

I I

Prot. Prot.

(Prot. And R "have the same meaning as above).

e) 4- (2-Alkoxyalkoxy) -piperidines can be prepared by reacting 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., 7 63935 R "R" ' R "R" '

II I I

OCH-CH OCH-CH

rV “_> λ ^ L J (i) NaH / DMF L.

^ N I ^ N ^ j (ii) R I, Rnär |

Prot. or R10SO2CH3 Prot.

Removing a protection group \ / R "R '"

I I

OCH-CH

OR 1

B

(Prot. And R "denote as above and R" "is hydrogen or lower alkyl).

f) 4- (2-Aryloxyalkoxy) -piperidines can be prepared: I) By reacting the N-acetyl-4- (2-hydroxyalkoxy) -piperidine obtained above with an appropriately substituted phenol in the presence of triphenylphosphine and diethyl azodicarboxylate ("D.E.A.D."):

OH

TT tS r 2

OCH-CH-OH | OCH-CH-O (R

X. / S

I R2 [\ Ph ^ P / D.E.A.D., I TKF C = 0

C = 0 I

I CH-. hydrolysis (acid or base) ca3 * V R.n \ N /

B

8 2 63935 (R "and R '" have the same meaning as above and R is methoxy or halogen).

II) Alternatively, 4- (2-aryloxyalkoxy) piperidines can be prepared from the N-suppressed 4- (2-hydroxyalkoxy) piperidine and fluorobenzene obtained above or substituted fluorobenzene in the presence of NaH and DMF: R "R" 'R "R" ·

li II

rS _> ry O

^ N NaH / D.M.F. \ N ^

I I

c = o F ^ ~ ° CH3 I, 100 ° c ^ 3 hydrolysis VR "R '" I I --v OCH-CH fj \ Λ' * 0 k (R "and R1" have the same meaning as above).

2) Pharmaceutically acceptable acid addition salts of compounds of formula I may be prepared by conventional methods, e.g. by mixing the free base and a suitable acid in a suitable solvent, e.g. isopropanol, filtering and, if necessary, purifying the product thus prepared by recrystallization. Often the product of reaction method 1) is in the form of an acid addition salt.

The invention also relates to pharmaceutically acceptable bioprecursors of the compounds of formula I and their salts. In pharmaceutical chemistry, the aim is generally to remove an undesired physical or chemical property of the drug by converting the drug to a chemical derivative that has lost the undesired property, but which, however, is converted back to the parent compound upon administration to an animal or human. If, for example, when the drug is administered orally to an animal or patient

II

63935 is not well absorbed, it can be converted to a chemical derivative that is well absorbed and converted back to the parent compound in blood or tissues. On the other hand, if the drug is unstable in solution, a chemical derivative can be prepared which is stable and can be administered as a solution, but is converted back in the body to the parent compound.

In this patent application, the phrase "pharmaceutically acceptable bioprecursor" of a compound of formula I means a compound having a structural formula different from that of the compounds of formula I, but which, upon administration to an animal or human, is converted to a compound of formula I.

The antihypertensive effect of the compounds of the invention can be demonstrated by their ability to lower blood pressure in rats with hypertension and in dogs with renal hypertension when administered orally at a dose of up to 5 mg / kg.

The therapeutic properties of the compounds known from SE Publication No. 342,454 and the compounds of the present application were compared by examining the reduction in blood pressure caused by the compounds in hypertensive rats. The results are shown in the following table. The last two compounds in the table are those according to said SE-Ad publication. The results show a stronger activity of the compounds of the present application compared to the compounds known from SE-Announcement 342,454.

10 63935

Results of therapeutic comparative trials

Decrease in blood pressure Max. , CH3 -0CH ~ C0Et 4 56 1

^ I

CH.

-OCH CH 0 \ 5 77 1 * ^ ch3 -0CH2CH2O- o 7 67 1

= CH

-OCH, CH 8 113 1 * ^ OCH3 -O'V-OH 9 48 4 -O ^ N ^ Q - ^^ - F 11 6 3 6 -Q ^ O-QoCH3 12 9 2 4 -OCH2CH2OCH3 18 171 1 - OCH2CH2OPh 19 81 1 / H 3 -OCH2CH-OH 20 95 1 / ^ 3 -OCH, CH 21 135 1 Z XOEt ch3 -OCH2C-OCH3 22 72 1 ch3 -OCH, 40 1'-OC2H5 4 0 1 drop in blood pressure of the test compound -

Blood pressure reduction <%> = -tea?> -An-t - ?. m.isen j ^ to <mm) -χ 100 rat blood pressure before test compound administration (mm) -130 (mm) 11 63935

In general, the compounds of the invention will 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 as elixirs or suspensions containing flavoring and coloring agents. They can be injected parenterally, e.g. intramuscularly, intravenously or subcutaneously. For parenteral administration, the best use is a sterile aqueous solution which may contain other solutes, e.g., enough salts or glucose to make the solution isotonic.

The compounds of the invention may be administered to a human for the treatment of hypertension either orally or parenterally. For oral administration, the dose is approximately 1-20 mg / day for the average adult (70 kg) patient in a single dose or in up to three single doses.

The intravenous injection dose can be expected to be from about one-fifth to one-tenth of the oral dose. Thus, for a moderate adult patient, a single oral dose of a tablet or capsule is about 5 to 100 mg of active ingredient. These amounts can be varied by one skilled in the art depending on the weight and condition of the patient and the desired route of administration.

The following examples illustrate the invention.

Example 1 Preparation of 4-amino-6,7-dimethoxy-2- [1- (2-ethoxyethoxy) -piperidino] -quinazoline hydrochloride OCHOCH-, OCOH-CH3-CH-O M Cl JL OH n ^ m '\ N ^ _ ^ -och2ch2oc2h5

CU./ y '„ch3c5 ^ T

NH2 NH2

4.3 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 10 ml of triethylamine in 400 ml of n-butanol were heated under reflux overnight under nitrogen. The mixture was then cooled, evaporated in vacuo, the residue basified (aqueous Na 2 CO 3) and extracted three times with chloroform. The combined chloroform extracts were evaporated and the residue was chromatographed on neutral alumina (150 g, step 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 hydrochloric acid in ethanol. The hydrochloride was recrystallized from ethanol-isopropanol to give 3.4 g of 4-amino-6,7-dimethoxy-2- [N- (2-ethoxyethoxy) -piperidine-7-quinazoline hydrochloride, m.p. 219-220 ° C.

Analysis%

Found: C, 55.4; H 7.2; N 13.5

Calcd for c 18 H 28 N 4 O 4 .HCl: C, 55.3; H 7.1; N 13.6

Examples 2-7

The following quinazolines were prepared according to Example 1 starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and appropriately substituted piperidine and isolated as reported.

13 63935 r- Γ '· * σ »σ> * -» γμ ζ ». . . . .

CN (Ν ^ CM CM

Ύ- ^ τΗ * - <* - <· - <ψ— «« 3

rH

3 ιο LO in m r- to rn · · · ·. · R ** · r · ** r- r ^ · r · * r-

O

dfi>

• H TO CO

I i s 2 S in CM O 10 c ^ o Ö r · '- r-% - <o un v in in vd in in Λ f1 —— + r

J I * „U

IoU So, | fc || o / Γ λ s h «j> I j. fis * V * a-R & 3 ss & g s r ΓΓ

o 'O

m m 5 6 U in

I. K

d I <n

I U

O CC m O m

v ng m O rn 33 I E

· * · K s: I 33 u— υ - υ u u —0 —o 1

ΓΊ CN CN

ffi X K

. υ u y 000 1 1 1 g CM ΓΟ rj · • H 0 W ··

W G

14 6 3 9 3 5 co o äo sr v 2 · * · · · ·

m ^ CM «—i CM <N

* * —I * —I * - (r-H «—4 * w m d 'd r-' r ~ -« a> vo cn «j · r- t" vd φ r ~ r »

G

Φ

G

c #> -H + J H -P

sL3) en in * -nt "~ en m; _i oo * - <oor ^ oo X (3 $ '-o vo vo ιο in in 1-yl - l_p - 1_ * d' d Z i ω -h -B

V—- -d Ό | O 0 0 O O

/ 2 e * r ^ o3 sr «-H ro f — i iH

Λ .V CM: ¾ CJ co ^ cm ^ h 'J V§ «2 ° ΐ i 7 B 7

z / · ΗΟ · O O ^ N Ό O

\ / W3 & fCon> i CN> 1 i — I

\ / W 1 m> <H ffi CN S3 CN

9 o 'o

ro CO

5 6

ET, Q

X «" vO

y υ T

o o o

CN m I CN

33 BX 33 a u— υ u

CN CN CN

eat

0 O O

1 i I

• ift vO r- I s

M C

15 63935

The following small changes in the method of Example 1 should be mentioned. In Example 3, the product from chromatographic purification was recrystallized directly without first being converted to the hydrochloride salt. In Examples 5 and 7, silica was used for chromatographic purification. In Example 6, the evaporation residue of the original reaction mixture (which was the hydrochloride salt) was recrystallized from dimethylformamide and then chromatographed directly on silica.

Example 8 4-Amino-6,7-dimethoxy-2- [3- (2-methoxy-n-propoxy) piperidino] quinazoline hydrochloride

3.6 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 3.0 g of 4- (2-methoxy-n-propoxy) piperidine and 1.5 g of triethylamine in n-butanol were heated under reflux for 30 hours. The solvent was evaporated in vacuo, the residue and diethyl ether were stirred, the solid was isolated, recrystallized twice from isopropanol to give 2.8 g of 4-amino-6,7-dimethoxy-2-β- (2-methoxy-n-propoxy) -. piperidinq7 * -quinazoline hydrochloride, m.p. 239-241 ° C.

Analysis%

Found: C, 55.1; H 7.2; N 13.6

Calculated for HCl: C 55.2; H 7.1; N 13.6

Examples 9-16

The following quinazolines were prepared according to Example 8 starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and appropriately substituted piperidine and isolated as reported.

16 6 3 9 3 5 -------

<0— H N Op -HO

(/) Z · '· «t 1

to (N H I—! I — I

• H <—I I — I ΓH H

3

I-I

3 03

Q

(u 33 co r ~~ σν <Ti oq in

g CO VO mm CD CD

* 5

• H -P

03 03

^ S CO CO vor "CO VO

m 8 u ^ J vd νό G mm m m mm Λ ^ TLT-! ΐΐ -p ^ 'd s. J 03 d {§% p ° r- t · Λθ λ__ Sqou I 1 | Ά -8 A' «Ι8Λ i! \ λ a g & a I &. ££ \ s ^ 1 · ^

° - ° - J \ JL

s s I il ill

-, V V

o

CM o O

33 CM, CN

U 33 33

CM o U

33 CM CM

y 33 33? 8 8

t I

t ---------

O 1-H

£ - · <-h • H O 03 ··

W G

17 63935 I Π I 1

^ - »O

55 2 ^ 'a ·' • CO 1-4 * -4 d! 3 δ> O 00 ro in vd i H 4-> tn m ^ S 00 ™ d Q υ m '^ g J-j ui in <3 ^ “-: --- 3 s I -H ™

CO P

-H «3 O I

L E -η <Hi _ /: E o M o -P O O p ™

\ tn + j S fM

y ~ \ s ml_ z y — 2 \}

O O

m

5 o X

m

K

U

O

(OF

2

U

CM

S

0

. <n

• S O

en ·· w e 6 6 9 3 5 18 ί ------- O m cm r * r- lo co co ^ $ ojrsi mm cncn c \ im

1 ♦ - «rH r-t * —I» -H iH * —4 tH

I-i

3 to Affi Ί3γο γ ~~ r- ~ <n ιn n ™ co to co co r- r- Γ'Γ '

S

<#> C

H + J

to -P

RHP. tn o> (O O CO —I On ro n υ........

c φ en σ> mm mm vo vd <J 4J m ld mm in lo tn in Λ ———-

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\ —Z s I | s // \ sT * § 0U 3 3 i 3 ™ 2 2 E · Η · Η · Η · Η ^ / m · Li i_l Li Lr \ / -d fi op 00 op o \ / EtOiHrOiHVOrHOOr-l / - \ - PO (N P-PCslQ-PtNp / \ »Hl H -PIH -PI Ö / \ -ho μ to <0 tn tj to r- το \ v // H> im> i (0 ^ 1 *> -i 03 »H> i \\ // W KOJ KPfNKPtNffi O onn K aua

X

n m

ffi K

co (N n υ υκ o k o u cm n O n i n O n

K KK KK K · K

u u —u u —u u — u — u

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u u y u

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1 i i i geo "jt tn cd

P Ή iH rH ι — I

to ··

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II

i9 6 3935

The following examples illustrate the preparation of some of the starting materials used in the previous examples.

Example A

Preparation of 4- (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 11.26 g of sodium hydride (50% dispersion in mineral oil) in 300 ml of dimethylformamide under nitrogen gas. The reaction temperature was kept below 30 ° C by cooling, and after the addition was complete, stirring was continued for 1 1/4 hours. A solution of 32.6 g of 1-bromo-2-methoxyethane in 100 ml of dimethylformamide was added dropwise with cooling, and the resulting clear solution was stirred at room temperature overnight. The reaction mixture was then evaporated in vacuo, the residue was partitioned between water and chloroform, the organic extracts dried (NaSO 4), evaporated to give 16.1 g of crude residue. The above aqueous phase was saturated with sodium chloride, further extracted with chloroform, the organic phase dried (Na 2 SO 4), evaporated to give an additional 9.2 g of residue. This and the previous residue were combined and heated in a water bath overnight in 243 mL of 2N hydrochloric acid. The reaction mixture was extracted with chloroform to remove mineral oil residues, the aqueous phase was concentrated, basified with sodium hydroxide (pH 12) and re-extracted with chloroform. The organic extracts were washed with brine, dried (Na 2 SO 4), evaporated to give 8.3 g of 4- (2-methoxyethoxy) piperidine. A sample of this product in ethyl acetate was converted to the oxalate salt by the addition of an ethereal solution of oxalic acid and recrystallized from ethanol, m.p. 86-88 ° C.

Analysis%

Found: C, 48.1; H 7.6; N 5.6

Calcd for C 9 H 17 NO 2 · (CO 2 H) 2: C, 48.2; H 7.7; N 5.6

The following piperidine derivatives were prepared according to the methods of Example A starting from N-acetyl-4-hydroxypiperidine and the appropriate bromide. The hydrolysis of the N-acetylated intermediates of Examples B and D was performed with dilute sodium hydroxide instead of dilute hydrochloric acid.

20 6 3 9 3 5

HN \ __ Y

v_y

Eg Y Isolation- Analysis% n forms and (theoretical value in parentheses)

° C c H N

B -OCH_CH OC Hr Oxalate 58.5 6.8 4.3 J 144-145 ° (57.9 6.8 4.5) C -ocnOCH_o-nc.hq Oxalate- 52.4 8.4 4.8 1 1 * 4 y hemihydrate (52.0 8.7 4.7) 86-88 ° D -OCH Cl ! OC-H Oxalate 50.5 8.2 5.2 93_g50 (50.2 8.0 5.3)

Example E

Preparation of N-acetyl-4-allyloxypiperidine

A solution of 100 g of N-acetyl-4-hydroxypiperidine in 250 ml of dimethylformamide was added dropwise under nitrogen to 38 g of sodium hydride (50% mineral oil dispersion). The mixture was stirred for two hours and 93 g of allyl bromide was added slowly keeping the reaction temperature at 25 ° C with cooling. The mixture was 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-allyl-oxypiperidine, b.p. 128 ° C / 2 mm Hg, was identified spectroscopically.

Example F

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

A solution of 6.4 g of N-acetyl-4-allyloxypiperidine in 10 ml of anhydrous ethanol was added dropwise at room temperature to a stirred suspension of 11.5 g of mercuric acetate in 50 ml of ethanol. After twenty minutes, the mercuric acetate had dissolved and the mixture was stirred for a further 40 minutes, cooled in ice water and 20 ml of 5N sodium hydroxide were added. A yellow precipitate formed during the addition. A solution of 1.3 g of sodium borohydride in 20 ml of 5N sodium hydroxide was added, the mixture was stirred for 10 minutes and acetic acid was added to pH 6. The precipitated mercury was removed by filtration, the ethanol was evaporated in vacuo and the resulting aqueous phase was extracted with chloroform. The organic extracts were dried (Na 2 SO 4), evaporated in vacuo, the resulting 7.5 g of crude residue was dissolved in 50 ml of ethanol and this solution, 20 ml of 5N sodium hydroxide solution and 20 ml of water were heated under reflux overnight. Most of the ethanol was removed in vacuo, the aqueous layer was extracted with ether, the extracts dried (Na 2 SO 4), evaporated to give 5 g of residue. Thin layer chromatography showed that the hydrolysis of the acetyl group had been incomplete, so the residue was treated with 20 ml of 2N hydrochloric acid and heated on a water bath for 10 hours. The mixture was then washed with ether, the aqueous phase basified (^ 2003), extracted with ether, the organic extract dried (Na 2 SO 4), evaporated to give 4.3 g of residue. Distillation gave 3.0 g of 4- (2-ethoxy-n-propoxy) -piperidine, b.p. 112-116 ° C / 10 mm Hg from which the sesquioxalate salt was prepared by reacting an ethereal solution of piperidine with an ethereal solution of oxalic acid. It was then recrystallized from ethyl acetate, m.p. 68-70 ° C.

Analysis%

Found: C, 48.3; H 7.5; N 4.7

Calculated for C 10 H 21 NO 2 1.5 (CCl 2 H) 2: He: C, 48.4; H 7.5; N 4.4

Example G

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

18 g of N-acetyl-4-allyloxypiperidine in 30 ml of tetrahydrofuran were added dropwise to a stirred yellow suspension of 34 g of mercuric acetate in a 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, 70 ml of 5N sodium hydroxide was added while cooling in ice water. The intermediate thus obtained was reduced by adding 2 g of sodium borohydride in 40 ml of 5N sodium hydroxide. After ten minutes, the excess hydride was destroyed with glacial acetic acid. The liquid phase was isolated by decantation, 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 (NaSO 4), evaporated in vacuo to give 23 g of a colorless oil.

This oil and 5N sodium hydroxide were stirred at room temperature for 16 hours and then at 100 ° C for two hours. The solution was extracted four times with chloroform, the combined extracts dried (Na 2 SO 4), evaporated in vacuo to give 16.1 g of crude crystalline product. This was dissolved in methylene chloride, filtered, evaporated, the residue triturated in petroleum ether (b.p. 40-60 ° C) to give 11.0 g of 4- (2-hydroxy-n-propoxy) piperidine, m.p. 55-57 ° C.

Its oxalate salt was prepared according to Example F and recrystallized from isopropanol, m.p. 104-105 ° C.

Analysis%

Found: C, 48.2; H 7.7 and N 5.6

Calculated for 08Η1 ?ΝO2 (CO2H) 2: C, 48.2; H 7.7; N 5.6

Example H

Preparation of N-acetyl-4- (2-methylallyloxy) -piperidine This compound was prepared according to Example E starting from N-acetyl-4-hydroxypiperidine and 2-methylallyl chloride and distilled and used directly in the next step. Sen kp. was 123 ° C / 1 mm Hg.

Example I

Preparation of 4- (2-methoxy-2-methyl-n-propoxy) -piperidine This compound was prepared according to Example F starting from N-acetyl-4- (2-methylallyloxy) -piperidine and mercuric acetate-methanol. The compound was identified as the hemioxalate salt, m.p. 208-210 ° C.

Analysis%

Found: C, 56.7; H 9.5; N 5.9

Calculated for c 1 (H) NO 2 .1 / 2 (CO 2 H) 2: C, 56.9; H 9.6; N 6.0

Example J

Preparation of 4- (2-hydroxy-2,2-methyl-n-propoxy) -piperidine This compound, m.p. 80-82 ° C, was prepared according to Example G starting from N-acetyl-4- (2-methylallyloxy) -piperidine and mercuric acetate in a mixture of water and tetrahydrofuran.

Analysis%

Found: C, 62.2; H 11.1; N 8.3

Calcd for C 9 H 19 N 2 O 2: C 62.4; H 11.1; N 3.1 li 23 6 3 9 3 5

Example K

Preparation of 4- (2-ethoxy-2-methyl-n-propoxy) -piperidine This compound was prepared according to Example F starting from N-acetyl-4- (2-methylallyloxy) -piperidine and mercuric acetate-t-ethanol and removing the N-acetyl group by base hydrolysis. . The sample was converted to the hemioxalate salt, which was recrystallized from ethyl acetate-methanol, m.p. 184-185 ° C.

Analysis%

Found: C, 58.6; H 9.7; N 5.8

Calcd for C11H23NO2.1 / 2Cl2H2O4: C, 58.5; H 9.8; N 5.7

Example L

Preparation of 4- (2-isopropoxyethoxy) piperidine This compound was prepared according to Example A from N-acetyl-4-hydroxypipridine and 1-bromo-2-isopropoxyethane. The compound was identified by spectroscopic methods.

Example M

Preparation of 4- (2-methoxy-n-propoxy) -piperidine This compound was prepared according to Example F starting from N-acetyl-4-allyloxypiperidine and mercuric acetate in methanol. To improve the conversion, the mercuric acetate-methanol treatment was repeated twice to give N-acetyl-4- (2-methoxy-n-propoxy) -piperidine, which was hydrolyzed in a methanolic solution of sodium hydroxide to give 4- (2-methoxy-n-propoxy) -piperidine. The sample was identified as the oxalate salt, m.p. 89-91 ° C.

Analysis%

Found: C, 49.6; H 7.9; N 5.3

Calculated for C 9 H 19 NO 2 .C 2 H 2 O 4: C 50.2; H 8.1; N 5.3

Example N

Preparation of 4- (2-phenoxy-n-propoxy) -piperidine

At 60-70 ° C under nitrogen, 12 g of N-acetyl-4- (2-hydroxy-n-propoxy) piperidine in 50 ml of dry DMF were added dropwise to a stirred suspension of 5.0 g of sodium hydride ( 50% dispersion in mineral oil) in 50 ml DMF. The suspension was stirred for three hours, 6.4 g of fluorobenzene in 50 ml of DMF were added dropwise and the suspension was stirred at 100 ° C for 50 hours. The cooled solution was treated with 20 mL of isopropanol and 200 mL of water and extracted with 3 x 200 mL of petroleum ether and 3 x 200 mL of chloroform. The combined chloroform extracts were dried (Na 2 SO 4) and the solvent 24 639 3 5 evaporated in vacuo. A solution of 9.0 g of the residue in 20 ml of 5N sodium hydroxide solution and 20 ml of methanol was heated under reflux for 5 hours. The methanol was evaporated, the residue was diluted with water and extracted with 3 x 50 ml of chloroform. The combined chloroform extracts were washed with 3 x 30 mL of 2N hydrochloric acid, the combined aqueous extracts were basified to pH 12 with sodium hydroxide solution and extracted with 3 x 50 mL of chloroform. The combined chloroform layers were dried (Na 2 SO 4), the solvent evaporated in vacuo, the residue triturated with ether and filtered. The filtrate was concentrated and distilled to give 0.5 g of 4- (2-phenoxy-n-propoxy) -piperidine, b.p. 118-122 ° C / 0.3 mm Hg, was identified spectroscopically.

Example 0 A) Preparation of N-acetyl-4- (2,2-diethoxyethoxy) piperidine

57.2 g of N-acetyl-4-hydroxypiperidine in 250 ml of dry DMF were added dropwise to a stirred suspension of 23.2 g of sodium hydride (50% dispersion in mineral oil) in 200 ml of dry DMF under nitrogen gas and under cooling. in an ice-water bath. The suspension was allowed to warm to room temperature and stirred for five hours. 94.7 g of bromoacetaldehyde diethyl acetal was slowly added to the stirred reaction mixture under cooling, and the mixture was stirred at room temperature for 18 hours. An additional 23.2 g of sodium hydride was added portionwise and stirring was continued until effervescence ceased. An additional 100 mL of dry DMF was added, the mixture was cooled in an ice-water bath, and a second portion, 94.7 g of bromoacetaldehyde diethyl acetal, was slowly added. The mixture was stirred for three hours at room temperature and then 150 ml of isopropanol was added to destroy the excess sodium hydride. The suspension was filtered, the filtrate was evaporated in vacuo, the residue was dissolved in water and extracted with chloroform. The chloroform extract was dried (NaSO 4), the solvent was evaporated in vacuo, the residue was distilled to give 61.5 g of N-acetyl-4- (2,2-diethoxyethoxy) piperidine, b.p.

142-145 ° C / 3 mm Hg, identified by NMR.

B) Preparation of N-acetyl-4- (2-hydroxyethoxy) -piperidine

12 g of N-acetyl-4- (2,2-diethoxyethoxy) piperidine 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 (500 ml in total). The chloroform extract was dried (Na 2 SO 4) and the solvent was evaporated in vacuo at a bath temperature below 30 C. 9.8 g of the aldehyde aldehyde were formed, which was immediately reduced with 0.75 g of sodium borohydride in 75 ml of ethanol at pH 6. at room temperature. 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, extracted with 10 x 30 ml of chloroform, the combined chloroform extracts dried (Na 2 SO 4) and the solvent evaporated in vacuo. The residue was dissolved in 70 ml of water and washed with 2 x 10 ml of petroleum ether. The aqueous phase was evaporated to give 6.9 g of N-acetyl-4- (2-hydroxyethoxy) -piperidine, identified by spectroscopic. Dist. Of the distilled sample was 139-140 ° C / 0.3 mm Hg.

Analysis%

Found: C, 57.5; H 9.1; N 7.6

Calcd for C 9 H 11 NO 3: C, 57.8; H 9.1; N 7.5 C) 4- (2-cyclopentyloxyethoxy) -piperidine

5.0 g of N-acetyl-4- (2-hydroxyethoxy) -piperidine in 25 ml of DMF were added dropwise under nitrogen to a stirred suspension of 1.28 g of sodium hydride (50% dispersion in mineral oil) in 50 ml of dry DMF. After the effervescence ceased, 4.4 g of cyclopentyl mesylate (Tetrahedron, 1972, 28, 2469) in 10 ml of DMF were slowly added and the mixture was stirred at room temperature for 40 hours. An additional 0.64 g of sodium hydride and then 2.2 g of cyclopentyl mesylate were added and the mixture was stirred for seven hours at 60 ° C and room temperature for 64 hours. Isopropanol was added, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was heated under reflux for three hours in 30 ml of ethanol and 30 ml of 5N sodium hydroxide solution. The ethanol was removed in vacuo, the residue was diluted with water and extracted with chloroform. The chloroform extract was dried (Na 3 SO 4), the solvent was evaporated in vacuo and the residue in chloroform was treated with ethereal hydrogen chloride solution. The solvent was removed by decantation, 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 as such.

Example P

Preparation of 4- (2-p-fluorophenoxylethoxy) -piperidine 26 6 39 35

A solution of 5.0 g of N-acetyl-4- (2-hydroxyethoxy) piperidine, 8.4 g of triphenylphosphine, 5.6 g of diethylazodicarboxylate and 3.36 g of p-fluorophenol in 75 ml of ice was stirred for two hours in an ice bath. distilled tetrahydrofuran, and the mixture was allowed to stand at room temperature for 48 hours. The solvent was evaporated in vacuo, the residue was dissolved in chloroform, washed twice with 1N sodium hydroxide solution and twice with water, dried (Na 2 SO 4) and the solvent was evaporated in vacuo. The residue was dissolved in a minimum amount of ether at reflux and then allowed to cool in a refrigerator. The precipitated solid was isolated, the filtrate was evaporated and the residue was extracted with 3 x 100 ml of refluxing petroleum ether (60-80 ° C). The solvent was evaporated in vacuo, the residue in 50 ml of ethanol and 50 ml of sodium hydroxide solution were heated under reflux for 5 hours, neutralized with 2N hydrochloric acid and the organic solvent was evaporated. The pH of the aqueous residue was adjusted to 2 with 2N hydrochloric acid and extracted twice with ether. The aqueous phase was basified to pH 12 with 2N sodium hydroxide solution and extracted with 3 x 100 ml of chloroform. The combined chloroform extracts were dried (Na 2 SO 4), 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, m.p. 144-145 ° C.

Analysis%

Found; C 56.1; H 6.8; N 5.5

Calculated for c13H18FNO2.HCl: C, 56.6; H 6.9; N 5.1

Example Q

The following piperidine derivative was prepared according to Example P starting from N-acetyl-4- (2-hydroxyethoxy) -piperidine and the appropriate phenol.

Il 27 I - * - 63935

_ or cR

23 * * - · ^

S

w Ή d

r-I

δ

! L

γ- ~ r- § <#> -rj • H + J m φ

& I

"ra aj rn · & <- U CO 00 m in?, 3

S «N W« 3 U

• d · η OO

g rH oo tf f $ ° u i? ο ή d · dr »jl age ·

kg J

8 • f o «

$ H

Claims (2)

23 63935 An analogous process for the preparation of 4-amino-6,7-dimethoxy-2- (4- / Substituted alkoxy7, piperidino) quinazolines of the formula I or their pharmaceutically acceptable acid addition salts as antihypertensive agents, in which: X is a group of the formula -OCH-CH-OR 1, 1. 1 -OCH 2 CH (CH 3) OR or -OCH 2 C (CH 3) 2 OR, and R is hydrogen, C 1-4 alkyl, cyclopentyl or phenyl optionally para substituted by a methoxy group or a halogen atom, characterized in that a compound of formula II i i ai) CH3 ° f nh2 in which Q is a readily leaving group such as chlorine, bromine, iodine, lower alkoxy, lower alkylthio or lower alkylsulfonyl is reacted with formula III with piperidine according to Λ dll) H wherein X is as defined above, after which the compound of formula I is optionally converted into a pharmaceutically acceptable acid addition salt by reacting it with a non-toxic acid. Process according to Claim 1, characterized in that compounds of the formula I in which X is -OCl 2 Cf 2 OR 1 in which R 1 is C 2 H 5 or C 6 H 5 · 63935