CA1131636A - Quinazoline antihypertensives - Google Patents
Quinazoline antihypertensivesInfo
- Publication number
- CA1131636A CA1131636A CA344,714A CA344714A CA1131636A CA 1131636 A CA1131636 A CA 1131636A CA 344714 A CA344714 A CA 344714A CA 1131636 A CA1131636 A CA 1131636A
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- alkyl
- formula
- ethoxy
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
ABSTRACT
Title: "Quinazoline Antihypertensives"
Quinazoline antihypertensives of the formula:
--- (I) and their pharmaceutically acceptable acid addition salts, wherein R is C1-C4 alXyl, benzyl or (C3-C6 cycloalkyl)methyl, R is C1-C4 alkyl, X is -CH2CH2- substltuted by a phenyl group and optianally by 1 or 2 methyl groups;
and R2 is hydrogen, C1-C4 alkyl, or phenyl optionally substituted by 1 or 2 substltuents selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, CF3, -CONR3R4 and -SO2NR3R4 wherein R3 and R4 each represent hydrogen or Cl-C4 alkyl;
and processes for preparing the compounds of the formula (I);
and pharmaceutical compositions containing them.
Title: "Quinazoline Antihypertensives"
Quinazoline antihypertensives of the formula:
--- (I) and their pharmaceutically acceptable acid addition salts, wherein R is C1-C4 alXyl, benzyl or (C3-C6 cycloalkyl)methyl, R is C1-C4 alkyl, X is -CH2CH2- substltuted by a phenyl group and optianally by 1 or 2 methyl groups;
and R2 is hydrogen, C1-C4 alkyl, or phenyl optionally substituted by 1 or 2 substltuents selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, CF3, -CONR3R4 and -SO2NR3R4 wherein R3 and R4 each represent hydrogen or Cl-C4 alkyl;
and processes for preparing the compounds of the formula (I);
and pharmaceutical compositions containing them.
Description
3L13~3~;
The lnvention relates to therapeutic agents which are novel derivatlves of 4-amino-2-plperldlnoqulnazoline, and 19 partlcularly concerned with d~rivatives having a substituted alkoxy group in the 4- positlon o~ tha plperidino ring. Such compou~ds S are useful a~ re~ulator~ of the cardiovascular syste~ and, in partlcular, in the treabment of hypertensio~.
Th~ novel compounds o~ the invention are tho~e hav~ng the general form ~a:-,N3 0 X CX2 N~
. NE~2 10 wherein R i9 Cl-C4 alkyl, benzyl or(C3-C6 cycloalky~methyl; R is C~-C4 X i9 -C~2C~2- substituted by a phenyl group and optionally by 1 or 2 methyl groups;
. , .
and- R Ls hydrogen, Cl-C4 alkyl, or phenyl optionally su~stltuted by one or two substituents selected from 15 Cl-C4 alkyl, Cl-C4 alkoxy, halogen, CF3, -CONR R and -S02MR R
: 3 4 wherein R and R each represent hydrogen or Cl-C4 alkyl;
and the pharmaceutically accept~ble acid additlon salts thereo~.
~, .
',' ~ (RLC. 290) , ..
~L3~3~
Pharmaceutically acceptable acid addition salts ~e those formed from acids whi~h form non-toxic acid-addition salts contain~
ing pharmaceutlcally acceptable anions such a3 the hydrochloride hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, ac~tate, maleats, fumarat~, lactate, tartrate, citrate, g~uconate, s ccharatc or p-toluQ~esulphonate salts.
Th~ cDmpounds of the inventlon cont~ining one or more a3ymmetric centre~ will exist as one or re palrs of enantiomer~, and such pairs or individual enantiomer~ may be separabl~ by physical method , e.g. by fractional crystRllisation of suitable q~lts.
The invention lncludes the separated pairs as well a~ mi~ture~
thereof, as rac~mic mi~tures or as separated d- and l- optloaIly active isomeric forms.
"~alogen" means fluorine, chlorin~, bromine or lodine C3 and C4 alkyl and alX~ ~ groups may be straight or branched chain.
In one aspect o the invention R is Cl-C4 alkyl_ R is preferably C~3, C2~5, ben~yl or cyclopropylmet~yl.
R i~ preferably CH30 R is prefexably H, methyl, ethyl or phenyl.
~ i~ pref2rably -C~(phenyl)C~2-, -C~2C~(phenyl)- or {:~2C(CE~3) (phenyl)---~ The preferred individual compound3 are those of Examples 1 and 3.
~; 25 The compounds o~ the in~ention can be prepared by the following routes:
(PLC. 290 ~31~36 ~1) The compounds of the inv~ntion ln which R is Cl-C4 alkyl or benzyl can be prepared by the following ~cheme:
~ ~ 3 x o~2 ~N~--X ~112 N N
~II) ~III) (I~
R, Rl, R and~X re as de~ined above and Q repre~ents a facile leaving group such as chloro, bromol iodo, (Cl-C4 aLkyl)thio or ~Cl-C4 alk~L) sulphDnyl.
Q ls preferably Cl or Br.
.
. ' ~ .
In a typical procedure the react~nts are heated t~gether, e.g. at a temperature o~ from 70 to 130 C, preferably under refIux, in an inert organic sol~ent, e.g. n butan~l, for periods of up to about 48 houxs. The product can be lsolated and puxified by con-ventional pr~cedur2~.
The intermedlate o~ the fo~m~la (II) and ~III) are ei~her knwwn co~pounds or can be prepared by procedures a`nalogous to those of the prior art. The preparation of many intermediates of the fonmula ~III) is in fact illu~trated in the Preparatlons given herein~after.
~LC. 290) .~ .
, - _ 5 _
The lnvention relates to therapeutic agents which are novel derivatlves of 4-amino-2-plperldlnoqulnazoline, and 19 partlcularly concerned with d~rivatives having a substituted alkoxy group in the 4- positlon o~ tha plperidino ring. Such compou~ds S are useful a~ re~ulator~ of the cardiovascular syste~ and, in partlcular, in the treabment of hypertensio~.
Th~ novel compounds o~ the invention are tho~e hav~ng the general form ~a:-,N3 0 X CX2 N~
. NE~2 10 wherein R i9 Cl-C4 alkyl, benzyl or(C3-C6 cycloalky~methyl; R is C~-C4 X i9 -C~2C~2- substituted by a phenyl group and optionally by 1 or 2 methyl groups;
. , .
and- R Ls hydrogen, Cl-C4 alkyl, or phenyl optionally su~stltuted by one or two substituents selected from 15 Cl-C4 alkyl, Cl-C4 alkoxy, halogen, CF3, -CONR R and -S02MR R
: 3 4 wherein R and R each represent hydrogen or Cl-C4 alkyl;
and the pharmaceutically accept~ble acid additlon salts thereo~.
~, .
',' ~ (RLC. 290) , ..
~L3~3~
Pharmaceutically acceptable acid addition salts ~e those formed from acids whi~h form non-toxic acid-addition salts contain~
ing pharmaceutlcally acceptable anions such a3 the hydrochloride hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, ac~tate, maleats, fumarat~, lactate, tartrate, citrate, g~uconate, s ccharatc or p-toluQ~esulphonate salts.
Th~ cDmpounds of the inventlon cont~ining one or more a3ymmetric centre~ will exist as one or re palrs of enantiomer~, and such pairs or individual enantiomer~ may be separabl~ by physical method , e.g. by fractional crystRllisation of suitable q~lts.
The invention lncludes the separated pairs as well a~ mi~ture~
thereof, as rac~mic mi~tures or as separated d- and l- optloaIly active isomeric forms.
"~alogen" means fluorine, chlorin~, bromine or lodine C3 and C4 alkyl and alX~ ~ groups may be straight or branched chain.
In one aspect o the invention R is Cl-C4 alkyl_ R is preferably C~3, C2~5, ben~yl or cyclopropylmet~yl.
R i~ preferably CH30 R is prefexably H, methyl, ethyl or phenyl.
~ i~ pref2rably -C~(phenyl)C~2-, -C~2C~(phenyl)- or {:~2C(CE~3) (phenyl)---~ The preferred individual compound3 are those of Examples 1 and 3.
~; 25 The compounds o~ the in~ention can be prepared by the following routes:
(PLC. 290 ~31~36 ~1) The compounds of the inv~ntion ln which R is Cl-C4 alkyl or benzyl can be prepared by the following ~cheme:
~ ~ 3 x o~2 ~N~--X ~112 N N
~II) ~III) (I~
R, Rl, R and~X re as de~ined above and Q repre~ents a facile leaving group such as chloro, bromol iodo, (Cl-C4 aLkyl)thio or ~Cl-C4 alk~L) sulphDnyl.
Q ls preferably Cl or Br.
.
. ' ~ .
In a typical procedure the react~nts are heated t~gether, e.g. at a temperature o~ from 70 to 130 C, preferably under refIux, in an inert organic sol~ent, e.g. n butan~l, for periods of up to about 48 houxs. The product can be lsolated and puxified by con-ventional pr~cedur2~.
The intermedlate o~ the fo~m~la (II) and ~III) are ei~her knwwn co~pounds or can be prepared by procedures a`nalogous to those of the prior art. The preparation of many intermediates of the fonmula ~III) is in fact illu~trated in the Preparatlons given herein~after.
~LC. 290) .~ .
, - _ 5 _
(2) The CCmpOUndB in which R i8 Cl-C4 alXyl or(C3-C6 cyclo-alky ~ ethyl can be prepared v~a the following reaction sche~e:
.
R;l ~ N ~ N ~ o - X - QR2 PhC~20 ~ N
(IA) 2 ydkogena ~ Pd/C 2 R O ~ N ~ N ~ O - X - OR
~O ~ N
V) ~.Q~Q i~ a fac~le leaving group, preferably.Cl, se ~ B,r or I) R10 ~ N ~ N ~ O - X - OR
RO
~; (I9~ 2 The hydrogenation may be ca~ried out by conventlonal procedures, e.g. by hydrogenat~,ng th~ compound of the formula (Ia) -` ~ in a suitable solvQnt, aOg. ethanol, over a Pd/C catalyst, typically ', at r~om t~perature and 15 p.s.i. for a few hourq.
'`~ 10 ~he hydroxy~comEound (IV) can then be react2d with ~he ,~ , compound o~ th~ formula RQ in a suitabLe solvent, e.g. dimethyl-form1mide, in the pxesence of a base, e.g. sodium hydroxide, ~ , and under a nitrogen at~osphere. Generally long reaction times are, '- nece6~ary, e.g. up to 24 hours. The product may be isolat~d and ",~ 15 purified by con~ent1onal procedure .
.~ The starting matexials of the fonmula tIA~ may be prepared vLa route (.) ~bove, .
, ~ ~3~3~
,, - -. .
. .
.
~ ( ~ The phanmaceutic~lly acceptable acid addition salts of .~ . the c~mpounds of th~ formula (I) can be prepared by conventlonal , pro~edures, e.g. by:mixi~g ths free base witX the appropriate acid in a suitable solvent, e.g~ iso-propanol, filterlng, and i~
nace3sary, recry3tallising the thu~-produced salt to purity. Often of course the product of route (1) wlll.b~ in the fDrm o~ an acid addition salt.
The antihyperte~sive acti~lty of the compounds of the invention is shown by.thair abllity to lower the blood preqsure of conscious ~pontaneously hypertensive rat3 and conscious renPlly hypertensive dogs, when admini~tered orally a~ doses o~ up to 5 mg/kg.
The compounds of the in~ention can be administered alone, but will generally be administered in adm~ture with a pharmaceutical carrler ~elect~d with regard bo the intend2d route of adm~ni tratio~
and st~ndard pharmaceu~ical practice.
.
,:
::
(PLC. 290) .
.
For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents.
S They can be in~ected parenterally, for example, intramuscularly, lntravenously or subcutaneously. For parenteral administration, they are best used in the fonm of a sterile aqueous solution which may contain other solutes, for example, enough salLs or glucose to make the solution isotonic.
Thus the invention also provides a pharmaceutical compo-sition comprising a compound of the formula ~I) or a pharmaceutically acceptable addition salt thereof together with a pharmaceutically acceptable diluent or carrier.
The compounds of the invention can be administered to humans for the treabment of hypertension by either the oral or parenteral routes, and can be administered orally at dosage le~els approximately within the range 1 to 50 mg/day for an average adult patient (70 kg), given in a single dose or up to 3 divided doses.
Intravenous dosage levels would be expected to be ab~ut -5th to-lOth ~; 20 of the daily oral dose. Thus for an average adult patient, individual oral doses in ta~let or capsule form will~enerally be in the range from 1 to 50 mg of the active compound. Variations ; will necessarily occur depending on the weight and condition of the sub~ect being treated and the particular route of administration chosen as will be known to those skilled in the art.
(PLC. 290) ~.3 3~
~ he invention yet further provides a method of trea~ing an animal, including a human being, having hypertension, which comprises administering to the animal an antihypertensive amount oE a compound of the formula (I) or pharmaceutically acceptable acid addition salt thereof or pharmaceutlcal composition as defined above.
The following Examples illustrate the invention:-;~ .
:
(PLC. 290) : --
.
R;l ~ N ~ N ~ o - X - QR2 PhC~20 ~ N
(IA) 2 ydkogena ~ Pd/C 2 R O ~ N ~ N ~ O - X - OR
~O ~ N
V) ~.Q~Q i~ a fac~le leaving group, preferably.Cl, se ~ B,r or I) R10 ~ N ~ N ~ O - X - OR
RO
~; (I9~ 2 The hydrogenation may be ca~ried out by conventlonal procedures, e.g. by hydrogenat~,ng th~ compound of the formula (Ia) -` ~ in a suitable solvQnt, aOg. ethanol, over a Pd/C catalyst, typically ', at r~om t~perature and 15 p.s.i. for a few hourq.
'`~ 10 ~he hydroxy~comEound (IV) can then be react2d with ~he ,~ , compound o~ th~ formula RQ in a suitabLe solvent, e.g. dimethyl-form1mide, in the pxesence of a base, e.g. sodium hydroxide, ~ , and under a nitrogen at~osphere. Generally long reaction times are, '- nece6~ary, e.g. up to 24 hours. The product may be isolat~d and ",~ 15 purified by con~ent1onal procedure .
.~ The starting matexials of the fonmula tIA~ may be prepared vLa route (.) ~bove, .
, ~ ~3~3~
,, - -. .
. .
.
~ ( ~ The phanmaceutic~lly acceptable acid addition salts of .~ . the c~mpounds of th~ formula (I) can be prepared by conventlonal , pro~edures, e.g. by:mixi~g ths free base witX the appropriate acid in a suitable solvent, e.g~ iso-propanol, filterlng, and i~
nace3sary, recry3tallising the thu~-produced salt to purity. Often of course the product of route (1) wlll.b~ in the fDrm o~ an acid addition salt.
The antihyperte~sive acti~lty of the compounds of the invention is shown by.thair abllity to lower the blood preqsure of conscious ~pontaneously hypertensive rat3 and conscious renPlly hypertensive dogs, when admini~tered orally a~ doses o~ up to 5 mg/kg.
The compounds of the in~ention can be administered alone, but will generally be administered in adm~ture with a pharmaceutical carrler ~elect~d with regard bo the intend2d route of adm~ni tratio~
and st~ndard pharmaceu~ical practice.
.
,:
::
(PLC. 290) .
.
For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents.
S They can be in~ected parenterally, for example, intramuscularly, lntravenously or subcutaneously. For parenteral administration, they are best used in the fonm of a sterile aqueous solution which may contain other solutes, for example, enough salLs or glucose to make the solution isotonic.
Thus the invention also provides a pharmaceutical compo-sition comprising a compound of the formula ~I) or a pharmaceutically acceptable addition salt thereof together with a pharmaceutically acceptable diluent or carrier.
The compounds of the invention can be administered to humans for the treabment of hypertension by either the oral or parenteral routes, and can be administered orally at dosage le~els approximately within the range 1 to 50 mg/day for an average adult patient (70 kg), given in a single dose or up to 3 divided doses.
Intravenous dosage levels would be expected to be ab~ut -5th to-lOth ~; 20 of the daily oral dose. Thus for an average adult patient, individual oral doses in ta~let or capsule form will~enerally be in the range from 1 to 50 mg of the active compound. Variations ; will necessarily occur depending on the weight and condition of the sub~ect being treated and the particular route of administration chosen as will be known to those skilled in the art.
(PLC. 290) ~.3 3~
~ he invention yet further provides a method of trea~ing an animal, including a human being, having hypertension, which comprises administering to the animal an antihypertensive amount oE a compound of the formula (I) or pharmaceutically acceptable acid addition salt thereof or pharmaceutlcal composition as defined above.
The following Examples illustrate the invention:-;~ .
:
(PLC. 290) : --
3~L31~3~
E2~MPLE 1 Preparation of 4-Amino-6,7-dimethoxy-2-/4-(2-ethoxy-1-phenylethoxy) . . , . _ . _ . , _ _ piperidino7quinazoline hydrochloride 3~Cl C ~N ~
C}13 N~2 _ ~ ~ ~ N 2 2 5
E2~MPLE 1 Preparation of 4-Amino-6,7-dimethoxy-2-/4-(2-ethoxy-1-phenylethoxy) . . , . _ . _ . , _ _ piperidino7quinazoline hydrochloride 3~Cl C ~N ~
C}13 N~2 _ ~ ~ ~ N 2 2 5
4-~mino-2-chloro-6,7-~methoxyquinazol~ne ~2.6 g) and 4-~2-eth~xy-1-phenyleth~xy)piperidine (3.0 g) in n-butanol (100 ml) ~; w~re heated undQr reflux for 22 hours. The ~olution wa9 then cooled, f1.ltered and the filtrate evaporated in va~uo. The residue was trituxated with diethylather and recrystallised twice from iscpropanol to give ~
; ethoxy)piperidino7quinazoline hydrochloride (2~0 g), m.p. 229 -230.
~: ~
~ound:C, 61.0; ~, 6~9; N, 11.5 C25~32N44O~C1: C, 61.4; ~, 6.8; N, 11~5.
(PLC..290) .
~L~3~63~ .
-- 1o-- _, EX~MPLE 2 PreE~ration of 4-Amlno-6,7-Dimethoxy-2-~4-~2-phenoxy-1-phenylethoxy2 ~ , . .
piparldlno7quinazoiine hydrochloride hydrate ~33 ~ ~ 33O =
C~ ~ ~ ~ N ~ 2 2 3 N~2 \=/-4-Am.~no-2-chloro-6,7-dlmethoxyqyinazoline (1.44 g) and 4-(2-phenoxy~ henylethoxy)piperidine (2.0 g2 in n-~utanol (100 ml) were heat~d und~r reflux for 20 hours. The solvent was then evaporated in ~acuo~ the re~idue triturated with ether and crystal-lised ~rom ~ ropanol. The solid was partitioned between chlorofvrm : 10 and aqueous sodium carbonate sDlution, the chlorofonm extract dried (MgSO ~ and the ~olvent e~aporated ~n vacuo. Ihe residue wa3 4 ~ _ chromatographed on ~ilica (100 g2 eluti~g with chloroform ollowed by chlorofo ~ metha 1 (20:1). Fractions containing the product were oom~ined, the ~D}Vent ~vapora~ed in vacuo and the resldue converted to the hydrochloride salt by treatment of a chloroform solution wlth ethereal h~drogen chloride.
, (PLC. 290) 3~
The sol'~d hydrochloride salt was collected and recrystallised from isopropanol to give 4-amino-6,7-dimethoxy-2-/4-~2-phenoxy-1-phenyl-ethoxy)piperidino7quinazol~ne, hydrochloride hydrate, ~0.85~ -m.p. 202 -204.
Analysis ~:-Found: C, 62.8; H, 6.1; N, 10.0 alculated for C29H32N4O4.HCl.H2O: C, 62.8; H, 6.4; N, 10-1-EXAMPLES 3 ~ro 6 The following compounds were prepared similarly to the previous Examples, starting from 4-amino-2-chloro-6,7-dimethoxy-quinazol~ne and the appropriate plperidine, viz., the product of Example 3 was prepared similarly to Example 1, and the products of Examples 4, 5 and 6 were prepared similarly to Example 2, but the ~ product of Example 5 was not converted to a hydrochloride salt.
:' ; ' :;:
,';
~ (PLC.,290) ` ' , .
.
~L~3~;3~i :
-- ~ 2 -- .
~- ' '.
~ ~ . ~ U ~ , :~ b~ ~ ~-~ ~ 3~ 3~
~;~ . ' .
(RLC: 290 ~L~3~;3~i ~ ~, ', z ~o~ a) ~ ~
U ~
(PLC: 290) - ~ ' ~L~3~;3ti Preparation of 4-Amino-6-cyclopropylmethoxy-2-/4-(2-ethoxy-1-phenylethoxy)piperidino7~7-methoxy qulnazoline, D(+) tartrate 4-Amino 2-/4-(2-ethoxy-1-phenylethox~)piperidin~-6-hydroxy-7-methoxyquinazoline hydrochloride (0.75 g) in dimethyl-formamide (50 ml) and sodium hydroxide solution (1 ml, 5N) was stirred at room temperature under an atmosphere of nitrogen for 40 minutes in the dark. Cyclopropylmethyl bromide (0.27 g) was then added and the solution stirred under N2 fox 20 hours. Potassium iodide (5 mgs) followed by further cyclopropylme~hyl bromide (0.27 g) were added and stirring was continued for 2 hours at room temperature.
The solvent was evaporated in vacuo, and ~he ~esidue was ~aken up in H2O (50 ml), kasified to p~ l2 with 2N sodium hydroxide, and extracted -~ with ~hloroform ~3 x 100 ml). The combined chlorofonm la~ers were dried (Na2SO4) and the solvent evaporated in vauco to give a semi-solid. The product was chromatographed on silica (7 g) eluting with chloroform. Fractions containing the product were combined and the solvent evaporated in vacuo. The residùe was converted to the tartrate salt by treatment of a chloroform solution with a solution of D(~) tartaric acid in ether. The resulting solid was filtered off, washed with ether and dried under reduced pressure to give 4-amino-6-cyclopropylmethoxy-2-/4-(2-ethoxy-1-phenylethoxy)piperidino7 (115 mg), m.p. 142 - 145.
Analysis %:-25 Found: C, 59.8; ~, 6.5; N, 8.9.
Calaulated for C28336N44 C4d66 ,~ .
~' ' ' ~3~3~ ' -. . .
ExAMæLE 8 Pr ~ o~ 4-Amino-6-ethoxy-2-/4-(2-ethoxy-1-pheny}ethoxy) piperldi~o7-7-methoxyquinaæollne h~droiodide ~he tltle compound wa~ prepared similarly to E$ample 7 ¦ -starting from 4-amino-2-/4-(2-eth~xy-1-phenylethoxy)piperidino7-6-hydroxy-7 methoxy~inazoline and ethyl iodide in the presence of sodium hydroxide,and had a m.p. of 227 - 228. t Anal~sls Found: C, 52.1, ~, 5.8, N, 9.
Calculated f~r C26~34N44 ~I - C, 52.5, ~, 5.9, ~, 904.
~j~
Preparation o~ 4-Amino-6-~enzyloxy-2-/4-(2-ethoxy-1-phenylethoxy) ~--~ I
- piperidin~ th~ ~line, hydrochloride 4-Amlno-6-benzyloxy-2-chloro-7-methoxyquinazoline (0.72 g) /J. Med. Chem. 1977, 20, 1467 and 4-(2-ethoxy-1-phenylethoxy) -piperidine (0.57 g) i~ n-butanol (~0 ml) were heated undier re lux for 30 hours. The solvent wac evapRrated in ~ -and the residue t~-- turated wlth ether to give a solid whlch was recrystalllcied ~rom _ -p~opa~ol/dilsopropylether to give 4 ~ hydro~hloride (7~0 mg). A sample recry~itallised from ethanol had a m.p. of 238 -240.
Anal ~ ~ :-Found: C, 65.5; ~, 6.5; N, 10.0 Calculated or C31~36N44-aCl C, 65.9; ~, 6.6; N, 9.9.
~1.3~
-lG-The following Preparations illustrate the preparatlon of certain of the starting materials:- -Preparation A
Preparation o~ 4-(2-hydro yphenethyloxy)piperidine N-~cetyl-4-hydroxypiperidine (5.0 g) in tetrahydrofuran (THF)(50 ml) was added to a stirred suspension of sodium hydride (1.84 g, 50~ dispersion in mineral oil) in tetrahydrofuran (THF) (25 ml) under an atmosphere of nitrogen. When effervescence had ceased, styrene oxide (4.6 g) in THF (25 ml) was added, then the reaction mixture was diluted with dimethylformamide (DMF)(25 ml) and stirred at 60 C for 18 hours. After addition of isopropanol to the cooled solution, the solvent was removed in vacuo, the residue ~reated with water, ad~usted to pH 4 with 2N hydrochloric ~; ac~d, and extracted withcHoroform. The chloroorm extract was dried (Na2SO4) and the solvent evaporated in vacuo to give N-acetyl-4-(2-hydroxypheneth~loxy)piperidine. This product in ethanol (50 ml) and 5N sodium hydroxide solution (100 ml) was heated under reflux for 3 hours. The solvent was then removed in vacuo, the residue taken up in water, extracted with chloroform, dried and the solvent evaporated in vacuov The product in chloroform was con-verted to the hydrochloride salt by treatment with ethereal hydrogen chloride and evaporation of the solvent.
., ''~
:
~ (PLC. 2~0) .~.................................. .
, , ' ,'~, ' .
.
~3~3t;
The residue wa~ taken up in me~hanol, ~reated with ether, the precipitated solid separated and recrystallised from isopropanol _ to give 4-(2-hydrox~phenethyloxy)~iperidine h~drochloride tO.6 g), m.p. 174 - 175C.
Analysis ~:-Found. C, 60.1~~, 7.8; N, 5.2 Calculated ~or C13~19N02.HCl: C, 60.6; ~, 708; N, 5.4.
. ~ .
Prepar~tion of 4-(2-othoxyphenethyloxy)piperidlne 10 N-Acetyl-4-(2-hydroxyphenethy.toxy)piperidine (8.0 g), prepared as in Preparation A,and 1,2-dimethDxyethane (0.3 g) in dry DMF (50 ml) were added dropwise to a stirred suspension of sodium hydride (2.96 g, 50~ disper.~ion in minerat oil) in dry DMF (50 ml).
The suspension wa~ stirred at room temperature for 3.5 h~ur~, cooled to 0-5 C then a solution of ethyl iodide (9.6 g) in D~F
~25 ml) added dropwise. The mixture was allowed to warm to room temperatur~ ~20C.), then st~rred at room temperature for 2 hours.
Isopropanol ~75 ml) wa added, the solvent rqmoved in vacuo and the residue partitioned between chloro~orm and water. The chloro-form layer was dried and the solYent evaporated in vacuo to giveN-acetyl-4-(2-ethoxyphenethyloxy)piperldine ~5.2 g).
(PLC. 290) . . .
~3~i3~
This product ln ethanol ~50 ml) and sodium hydroxide solution (50 ml, 5N) was heated under reflux for 3.5 hours. The organic solvent was removed in vacuo and the aqueous residue extracted with chloroform. The organic extract was dried (Na2SO4), evaporated in vacuo, then the residue partitioned between 2N
hydrochloric acid solution and ether. The aqueous phase was then basified with sodium carbonate solution and extracted with chloro-form. The chloroform extract was dried (Na2SO4), the solvent evaporated in vacuo, then the residue was taken up in ether and converted to the oxalate salt. Recrystallisation from isopropanol gave 4-(2-ethoxyphene hyloxy)piperidine~oxalate salt (1.6 g), m.p. 136 - 137C.
Analysis %:-Found: C, 60.3; E, 7.4; N, 4.1 CalcUlated for C15E23NO2-C2 2 4 C, 60.2; H, 7.4; N, 4.1.
(PLC. 290) :~3~
~ ~ Prep~ration C
-- Preparation of 4-(2-etho ~ h ny~ethoxy~piperidine , 1. Na~ ~
~ ~ ~ f ~02C2~S
~ ~ J 3~ ~-b~ L~Lo ~~~ ~~ ~rJ
f o ~o C~3 C~3 Li~El,g OC2~5 ~ c~2 N 3~ NaO~/C~3o~ ~
~ ~ C~ O
... .. . .. .... .... .. . . -- , .. -- ..
(i) ~[y =~ , .
.~. - N-Acetyl-~-hYdro~ypiperidlne (27.5 g) in dry DMF (100 ml) wa.~ added 510wly to a stirred suspension o~ sodium hydride ~25 g, 50~ di persion in mineral oil) in D~F (150 ml) and 1,2-dimethoxyethane ( 1 0 m~
"~
. (PLC. 290) :
- . .
, ' ~ ' ' ~
:
~L3~
~he ~uspenslon was stirred at room temperature for 3 hours.
CC -BromophenyLacetic acid t45 g) in DMF ~250 mL) was then added slowly with ice/water cooling. The miKture was stlrred at room temperature for 20 hour~, then isopropanol added and the solvent avaporated in vacuo. The rssidue wa~ taken up ln water, ~cldlfied to pH 1 with 2N hydrochlorlc acid and e~tracted four times with chloroform (300 mL). The combined chLoroform eKtracts wre washed with watec and brine, dried (MgS04) and the solvent evaporatea ln vacuo. The resldue in anhydrous etha~ol (450 ml) with concen-trated sulphuric acid (9 ml) wa~ heated und ¢ reflux for B ~ours.
The cooled solution was cautiously neutralised with aqueou~ sDdium carbonate solution and the organlc solvent evaporat~d in vacuo.
The aqueou~ residue wa~ ad~usted to pH 10 with sodium carbonate solution and extracted twice with chlorofo D . The c~bined chlo m - -
; ethoxy)piperidino7quinazoline hydrochloride (2~0 g), m.p. 229 -230.
~: ~
~ound:C, 61.0; ~, 6~9; N, 11.5 C25~32N44O~C1: C, 61.4; ~, 6.8; N, 11~5.
(PLC..290) .
~L~3~63~ .
-- 1o-- _, EX~MPLE 2 PreE~ration of 4-Amlno-6,7-Dimethoxy-2-~4-~2-phenoxy-1-phenylethoxy2 ~ , . .
piparldlno7quinazoiine hydrochloride hydrate ~33 ~ ~ 33O =
C~ ~ ~ ~ N ~ 2 2 3 N~2 \=/-4-Am.~no-2-chloro-6,7-dlmethoxyqyinazoline (1.44 g) and 4-(2-phenoxy~ henylethoxy)piperidine (2.0 g2 in n-~utanol (100 ml) were heat~d und~r reflux for 20 hours. The solvent was then evaporated in ~acuo~ the re~idue triturated with ether and crystal-lised ~rom ~ ropanol. The solid was partitioned between chlorofvrm : 10 and aqueous sodium carbonate sDlution, the chlorofonm extract dried (MgSO ~ and the ~olvent e~aporated ~n vacuo. Ihe residue wa3 4 ~ _ chromatographed on ~ilica (100 g2 eluti~g with chloroform ollowed by chlorofo ~ metha 1 (20:1). Fractions containing the product were oom~ined, the ~D}Vent ~vapora~ed in vacuo and the resldue converted to the hydrochloride salt by treatment of a chloroform solution wlth ethereal h~drogen chloride.
, (PLC. 290) 3~
The sol'~d hydrochloride salt was collected and recrystallised from isopropanol to give 4-amino-6,7-dimethoxy-2-/4-~2-phenoxy-1-phenyl-ethoxy)piperidino7quinazol~ne, hydrochloride hydrate, ~0.85~ -m.p. 202 -204.
Analysis ~:-Found: C, 62.8; H, 6.1; N, 10.0 alculated for C29H32N4O4.HCl.H2O: C, 62.8; H, 6.4; N, 10-1-EXAMPLES 3 ~ro 6 The following compounds were prepared similarly to the previous Examples, starting from 4-amino-2-chloro-6,7-dimethoxy-quinazol~ne and the appropriate plperidine, viz., the product of Example 3 was prepared similarly to Example 1, and the products of Examples 4, 5 and 6 were prepared similarly to Example 2, but the ~ product of Example 5 was not converted to a hydrochloride salt.
:' ; ' :;:
,';
~ (PLC.,290) ` ' , .
.
~L~3~;3~i :
-- ~ 2 -- .
~- ' '.
~ ~ . ~ U ~ , :~ b~ ~ ~-~ ~ 3~ 3~
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(RLC: 290 ~L~3~;3~i ~ ~, ', z ~o~ a) ~ ~
U ~
(PLC: 290) - ~ ' ~L~3~;3ti Preparation of 4-Amino-6-cyclopropylmethoxy-2-/4-(2-ethoxy-1-phenylethoxy)piperidino7~7-methoxy qulnazoline, D(+) tartrate 4-Amino 2-/4-(2-ethoxy-1-phenylethox~)piperidin~-6-hydroxy-7-methoxyquinazoline hydrochloride (0.75 g) in dimethyl-formamide (50 ml) and sodium hydroxide solution (1 ml, 5N) was stirred at room temperature under an atmosphere of nitrogen for 40 minutes in the dark. Cyclopropylmethyl bromide (0.27 g) was then added and the solution stirred under N2 fox 20 hours. Potassium iodide (5 mgs) followed by further cyclopropylme~hyl bromide (0.27 g) were added and stirring was continued for 2 hours at room temperature.
The solvent was evaporated in vacuo, and ~he ~esidue was ~aken up in H2O (50 ml), kasified to p~ l2 with 2N sodium hydroxide, and extracted -~ with ~hloroform ~3 x 100 ml). The combined chlorofonm la~ers were dried (Na2SO4) and the solvent evaporated in vauco to give a semi-solid. The product was chromatographed on silica (7 g) eluting with chloroform. Fractions containing the product were combined and the solvent evaporated in vacuo. The residùe was converted to the tartrate salt by treatment of a chloroform solution with a solution of D(~) tartaric acid in ether. The resulting solid was filtered off, washed with ether and dried under reduced pressure to give 4-amino-6-cyclopropylmethoxy-2-/4-(2-ethoxy-1-phenylethoxy)piperidino7 (115 mg), m.p. 142 - 145.
Analysis %:-25 Found: C, 59.8; ~, 6.5; N, 8.9.
Calaulated for C28336N44 C4d66 ,~ .
~' ' ' ~3~3~ ' -. . .
ExAMæLE 8 Pr ~ o~ 4-Amino-6-ethoxy-2-/4-(2-ethoxy-1-pheny}ethoxy) piperldi~o7-7-methoxyquinaæollne h~droiodide ~he tltle compound wa~ prepared similarly to E$ample 7 ¦ -starting from 4-amino-2-/4-(2-eth~xy-1-phenylethoxy)piperidino7-6-hydroxy-7 methoxy~inazoline and ethyl iodide in the presence of sodium hydroxide,and had a m.p. of 227 - 228. t Anal~sls Found: C, 52.1, ~, 5.8, N, 9.
Calculated f~r C26~34N44 ~I - C, 52.5, ~, 5.9, ~, 904.
~j~
Preparation o~ 4-Amino-6-~enzyloxy-2-/4-(2-ethoxy-1-phenylethoxy) ~--~ I
- piperidin~ th~ ~line, hydrochloride 4-Amlno-6-benzyloxy-2-chloro-7-methoxyquinazoline (0.72 g) /J. Med. Chem. 1977, 20, 1467 and 4-(2-ethoxy-1-phenylethoxy) -piperidine (0.57 g) i~ n-butanol (~0 ml) were heated undier re lux for 30 hours. The solvent wac evapRrated in ~ -and the residue t~-- turated wlth ether to give a solid whlch was recrystalllcied ~rom _ -p~opa~ol/dilsopropylether to give 4 ~ hydro~hloride (7~0 mg). A sample recry~itallised from ethanol had a m.p. of 238 -240.
Anal ~ ~ :-Found: C, 65.5; ~, 6.5; N, 10.0 Calculated or C31~36N44-aCl C, 65.9; ~, 6.6; N, 9.9.
~1.3~
-lG-The following Preparations illustrate the preparatlon of certain of the starting materials:- -Preparation A
Preparation o~ 4-(2-hydro yphenethyloxy)piperidine N-~cetyl-4-hydroxypiperidine (5.0 g) in tetrahydrofuran (THF)(50 ml) was added to a stirred suspension of sodium hydride (1.84 g, 50~ dispersion in mineral oil) in tetrahydrofuran (THF) (25 ml) under an atmosphere of nitrogen. When effervescence had ceased, styrene oxide (4.6 g) in THF (25 ml) was added, then the reaction mixture was diluted with dimethylformamide (DMF)(25 ml) and stirred at 60 C for 18 hours. After addition of isopropanol to the cooled solution, the solvent was removed in vacuo, the residue ~reated with water, ad~usted to pH 4 with 2N hydrochloric ~; ac~d, and extracted withcHoroform. The chloroorm extract was dried (Na2SO4) and the solvent evaporated in vacuo to give N-acetyl-4-(2-hydroxypheneth~loxy)piperidine. This product in ethanol (50 ml) and 5N sodium hydroxide solution (100 ml) was heated under reflux for 3 hours. The solvent was then removed in vacuo, the residue taken up in water, extracted with chloroform, dried and the solvent evaporated in vacuov The product in chloroform was con-verted to the hydrochloride salt by treatment with ethereal hydrogen chloride and evaporation of the solvent.
., ''~
:
~ (PLC. 2~0) .~.................................. .
, , ' ,'~, ' .
.
~3~3t;
The residue wa~ taken up in me~hanol, ~reated with ether, the precipitated solid separated and recrystallised from isopropanol _ to give 4-(2-hydrox~phenethyloxy)~iperidine h~drochloride tO.6 g), m.p. 174 - 175C.
Analysis ~:-Found. C, 60.1~~, 7.8; N, 5.2 Calculated ~or C13~19N02.HCl: C, 60.6; ~, 708; N, 5.4.
. ~ .
Prepar~tion of 4-(2-othoxyphenethyloxy)piperidlne 10 N-Acetyl-4-(2-hydroxyphenethy.toxy)piperidine (8.0 g), prepared as in Preparation A,and 1,2-dimethDxyethane (0.3 g) in dry DMF (50 ml) were added dropwise to a stirred suspension of sodium hydride (2.96 g, 50~ disper.~ion in minerat oil) in dry DMF (50 ml).
The suspension wa~ stirred at room temperature for 3.5 h~ur~, cooled to 0-5 C then a solution of ethyl iodide (9.6 g) in D~F
~25 ml) added dropwise. The mixture was allowed to warm to room temperatur~ ~20C.), then st~rred at room temperature for 2 hours.
Isopropanol ~75 ml) wa added, the solvent rqmoved in vacuo and the residue partitioned between chloro~orm and water. The chloro-form layer was dried and the solYent evaporated in vacuo to giveN-acetyl-4-(2-ethoxyphenethyloxy)piperldine ~5.2 g).
(PLC. 290) . . .
~3~i3~
This product ln ethanol ~50 ml) and sodium hydroxide solution (50 ml, 5N) was heated under reflux for 3.5 hours. The organic solvent was removed in vacuo and the aqueous residue extracted with chloroform. The organic extract was dried (Na2SO4), evaporated in vacuo, then the residue partitioned between 2N
hydrochloric acid solution and ether. The aqueous phase was then basified with sodium carbonate solution and extracted with chloro-form. The chloroform extract was dried (Na2SO4), the solvent evaporated in vacuo, then the residue was taken up in ether and converted to the oxalate salt. Recrystallisation from isopropanol gave 4-(2-ethoxyphene hyloxy)piperidine~oxalate salt (1.6 g), m.p. 136 - 137C.
Analysis %:-Found: C, 60.3; E, 7.4; N, 4.1 CalcUlated for C15E23NO2-C2 2 4 C, 60.2; H, 7.4; N, 4.1.
(PLC. 290) :~3~
~ ~ Prep~ration C
-- Preparation of 4-(2-etho ~ h ny~ethoxy~piperidine , 1. Na~ ~
~ ~ ~ f ~02C2~S
~ ~ J 3~ ~-b~ L~Lo ~~~ ~~ ~rJ
f o ~o C~3 C~3 Li~El,g OC2~5 ~ c~2 N 3~ NaO~/C~3o~ ~
~ ~ C~ O
... .. . .. .... .... .. . . -- , .. -- ..
(i) ~[y =~ , .
.~. - N-Acetyl-~-hYdro~ypiperidlne (27.5 g) in dry DMF (100 ml) wa.~ added 510wly to a stirred suspension o~ sodium hydride ~25 g, 50~ di persion in mineral oil) in D~F (150 ml) and 1,2-dimethoxyethane ( 1 0 m~
"~
. (PLC. 290) :
- . .
, ' ~ ' ' ~
:
~L3~
~he ~uspenslon was stirred at room temperature for 3 hours.
CC -BromophenyLacetic acid t45 g) in DMF ~250 mL) was then added slowly with ice/water cooling. The miKture was stlrred at room temperature for 20 hour~, then isopropanol added and the solvent avaporated in vacuo. The rssidue wa~ taken up ln water, ~cldlfied to pH 1 with 2N hydrochlorlc acid and e~tracted four times with chloroform (300 mL). The combined chLoroform eKtracts wre washed with watec and brine, dried (MgS04) and the solvent evaporatea ln vacuo. The resldue in anhydrous etha~ol (450 ml) with concen-trated sulphuric acid (9 ml) wa~ heated und ¢ reflux for B ~ours.
The cooled solution was cautiously neutralised with aqueou~ sDdium carbonate solution and the organlc solvent evaporat~d in vacuo.
The aqueou~ residue wa~ ad~usted to pH 10 with sodium carbonate solution and extracted twice with chlorofo D . The c~bined chlo m - -
5 form extr~cts were dried (MgSD ), and evaporated in vacuo.----Distillation of the residue gave ~C-(N-acety~-4-piper~dinoxy) _ _ _ . _ phenylacetlc acid, ethyl ester (3/.2 g), b.p. 190 - 194C/0.18 mm.
A~.y8i!3 %:--Found: C, 66.4; H, 7.8; N, 4.5 Cal~ulated for C17H23N04: C, 66.9; ~, 7.6p N, 4.6.
.
(~LC. 290) ~3~
~., (ii) N-Acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine Llthium borohydride (3.24 g) was added portionwise to a solution of ~C -~N-acetyl-4-piperidinoxy)~phenylacetic acid, ethyl ester (11.2 g) in dry THF (200 ml). When the hydrogen evolution had subslded the reaction mixture was heated under reflux for 4 hours. Water was added to the cooled solution, the solvent evaporated _ vacuo, then the residue taken up in chloroform (200 ml) and washed with dilute hydrochloric acid, water and brine. The chloroform extract was dried (MgS04) and the solvent evaporated in vacuo. Thin layer chromatographic analysis of the product indicated that reduction was incomplete~ therefore the product in THF (100 ml) was treated with a further quantity of lithium boro-hydride (3.24 g) and heated under reflux for 4 hours. The reaction mixture was treated as above to give N-acetyl-4-(2-hydroxy-1-phenyl-ethoxy)piperidine (9.5 g) as an oil which solidified on standing.A sample crystallised from ether and had a m.p. of 92 - 94 C.
Analysis %:-Found: C, 68.1; ~, 8.1; N, 5.7 Calculated ~or C15H21N03: C, 68.4; H, 8.1; N, 5.3.
' :
,~
:' " .
(PLC. 290) . , ',' ,, , ' ` ~3~6 (iii) 4-(2-Ethoxy-l-phenylethoxy)piperidine This compound was prepared similarly to Preparation B, starting from N-acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine (prepared as ln part (ii) above) and ethyl iodide, followed by basic hydrolysis of the N-acetyl group. A sample was characterised as the oxalate salt, m.p. 137 - 139C.
Analysis ~:-Found: C, 59.9; H, 7.4; N, 4.0 Calculated for C15~23NO2-C2R2O4 C, 60.2; H, 7.4; N, 4.1.
Preparation D
4-(2-Phenoxy-l-phenyleth~xy)piperidine .
N-.~cetyl-4-(2-hydroxy-1-phenylethoxy)piperidine (5.25 g) (prepared as in Preparation C ~i~diethyl azodicarboxylate (4.2 g), triphenylphosphine (6.3 g) and phenol (2.25 g) in dry tetrahydro-furan (100 ml) were stirred at 0C for 2 hours then left at room temperature for 48 hours. The solvent was evaporated in vacuo, the residue taken up in refluxing diethyl ether (50 ml) and left in a refrigerator overnight. The precipitated hiproducts were removed by filtration and the filtrate evaporated to dryness. The residue wasagain taken up in ether, set aside to cool and the ~ precipitated solid fil~ered off. The ether filtrate was evaporated ~~ to dryness and the residue in me~hanol (50 ml) and sodium hydroxide solution (30 ml, 5N) was heated under reflux for 5 hours.
(PLC. ~90 .~
. :
. ~
~, ' .
,. . .
:;
3 ~ ~ 3 The organlc 301vsnt wa~ r~moved in vacu , the aqueous residue l -acidified to p~ 3 with 2N hydrochloric acld and extracted.twice with ether, the organic extract3 being di~carded. The aqueou~ pha3e wa~
ad~uqted to p~ 12 wlth sodlum hydroxlde solutlon, extracted with ether (3 x S 100 ml), the ether extract~ comhined,drled ~MgS04),and the solvent evaporate:
in vacuo to give 4-t2-phen~xy-1-~heny.lethoxy)piperidinQ ~3.55 g) as ..
an oil. A sample wa-~ converted to the oxalate salt which was recrystallised from isopropanol and had a m.p. of 170 - 172C.
Analysi3 ~:-.10 Found: C, 64.9~ ~, 6.6; N, 3.8 CalcUlated for C19~23N~2-C2~2 4 C, 6501;. ~, 6.5; N, 3_6.
:
, ~PLC. 290) :~
: .
- 2~r-Preparation E
Preparation of 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine 2 3rC32 ~ ~ 3g(0~) O N2C - 03 ' ~ 3 N~ON/
`CH3OH N
= IC= o H
(i) N-Acetyl-4-(2-ahenylallv~oxy)piperidine N-Acetyl-4-hydroxypiperidine (13.6 g) in DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (10 g, 50~ dispersion in mineral oil) in DMF (50 ml) under nitrogen. The - mixture was stirred at room temperat~re for 3 hours then ~-(bromo-methyl)styrene (20 g) in DMF (50 ml) was added dropwise. The - 10 mixture was stirred at room temperature for 4 hoarsj then diluted with water and extracted with chloroform (3 x 200 ml). The combined chloroform extracts were dried (Na2S04), evaporated in vacuo, and distilled to give N-acety~-4-(2-phenylallyloxy)Iiperidine (25 g), b.p. 170 - 180C/0.3 mm with an n.m.r. spectrum in accordance with this structure.
,-`~
' , (PLC. 290) , ., ,......... - .
.:
.
, 3~
(ii) 4-(2-~ydroxy-2-phenyl-n-propoxy)piperidine N-Acetyl-4-~2-phenylallyloxy)piperidine (4.0 g) in dry THF (60 ml) was added dropwise to a stirred solution of mercuric acetate (6.35 g) in water (60 ml) and the solution stirred at room temperature for 1 hour. Sodium hydroxide solution (40 ml, ; 3N) and sodi~ borohydride (0.75 g) in sodium hydroxide solution (40 ml, 3N) were then added dropwise to the stirred solution at 0C.
The grey suspension was stirred at 0C for 1 hour, glacial acetic acid was added to pH 6, then the suspension iltered and the filtrate extracted with chloroform (3 x 150 ml). The combined chloroform extracts were dried (Na2SO4) and evaporated in vacuo to give N-acetyl-4-(2-hydroxy-2-phenyl-n-propo~y)piperidine (2.1 g).
This product in methanol (30 ml) and sodium hydroxide solution (20 ml, 5N) uas heated under reflux for 4 hours. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3 x 20 ml), dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (1.8 g) as an oil. A sample was characterised as the oxalate salt which recrystallised from ethyl acetate and had a m.p. of 132 - 13~ C.
Analysis %:-Found: C, 58.8; ~, 7.1; N, 4.8 Calculated for C14H21NO2-C2 2 4 C, 59.1; H, 7.1; N, 4.3.
~ .
(PLC. 293) :
. ' :
Preparation F
Preparation of 4-(2-ethoxy-2-phenyl-n-propoxy)piperidine _~ .
N-Acetyl-4-(2-phenylallyloxy)piperidine (7.0 g)(prepared as ln Preparation E) in ethanol (10 ml) was added to a stirred suspension of mercuric acetate (9.2 g) in ethanol (50 ml) at room temperature. The mixture was stirred at room temperature for 1 hour then cooled to 0C. Sodium hydroxide solution (20 ml, 5N) followed by sodium borohydride (1.03 g) in sodium hydroxide solution (20 ml, 5N) were added to the stirred suspension and after 10 minutes glacial acetic acid was added to p~ 6. The suspension was filtered, the filtrate concentrated and the residue partitioned between chlorofoxm and water. The organic layer was dried (Na2S04) and the solvent evaporated in vacuo. Gas-liquid chromatographic (GLC) analysis of the product indicated incomplete conversion to the desired product therefore the oxymercura~ion process was repeated as ahove to giYe N-acetyl-4-(2-ethoxy~2-phenyl-n-propoxy)piperidine (7.4 g), 84% pure by GLC. The product in ethanol (100 ml) and sodium hydroxide solution (30 ml) was heated under reflux for 11 hours. The organic solvent was evaporated and the aqueous solution was extracted with chloroform (3 x 30 ml). The combined chloroform extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give ~ as an oil (3.8 g).
A sample was converted to the oxalate salt which was recrystallised twice ~rom ethyl acetate then acetone and had a m.p. of 126 - 127 C.
~PLC. 290) Analysis ~:-Found: C, 60.4; H, 7.6; N, 4.1 Calculated for C16H25N02-C2 2 4 4 2 Preparation G
Preparation of 4-Amino-2-/4-~2-ethoxy-1-phenylethoxy)piperidino7-6-_ hydroxy-7-methoxyquinazoline, hydrochloride hydrate 4-Amino-6-benzyloxy-2-/4-(2-ethoxy-1-phsnylethoxy)piperidino7 -7-methoxy-quinazoline, hydrochloride (0.9 g) in dry ethanol (150 ml) was hydrogenated over 5% Pd/~. at room temperature and 15 p.s.i. for 2 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness in vacuo. The residue was triturated with ether to give a white solid (0.S5 g). A sample (200 mg) was recrystal-lisad from isopropanol to give 4-ami -2-/4-(2-ethoxy~ henylethoxy) piperidino7-6~hydroxy-7-methoxyquinazoline, hydrochloride hydrate (71 mg). m.p. 141 - 144.
Analysis %:-, Found: C, 58.0; ~, 6.5; N, 11.5.
Calculated for C24H30N44 ~Cl ~2 (PLC. 290)
A~.y8i!3 %:--Found: C, 66.4; H, 7.8; N, 4.5 Cal~ulated for C17H23N04: C, 66.9; ~, 7.6p N, 4.6.
.
(~LC. 290) ~3~
~., (ii) N-Acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine Llthium borohydride (3.24 g) was added portionwise to a solution of ~C -~N-acetyl-4-piperidinoxy)~phenylacetic acid, ethyl ester (11.2 g) in dry THF (200 ml). When the hydrogen evolution had subslded the reaction mixture was heated under reflux for 4 hours. Water was added to the cooled solution, the solvent evaporated _ vacuo, then the residue taken up in chloroform (200 ml) and washed with dilute hydrochloric acid, water and brine. The chloroform extract was dried (MgS04) and the solvent evaporated in vacuo. Thin layer chromatographic analysis of the product indicated that reduction was incomplete~ therefore the product in THF (100 ml) was treated with a further quantity of lithium boro-hydride (3.24 g) and heated under reflux for 4 hours. The reaction mixture was treated as above to give N-acetyl-4-(2-hydroxy-1-phenyl-ethoxy)piperidine (9.5 g) as an oil which solidified on standing.A sample crystallised from ether and had a m.p. of 92 - 94 C.
Analysis %:-Found: C, 68.1; ~, 8.1; N, 5.7 Calculated ~or C15H21N03: C, 68.4; H, 8.1; N, 5.3.
' :
,~
:' " .
(PLC. 290) . , ',' ,, , ' ` ~3~6 (iii) 4-(2-Ethoxy-l-phenylethoxy)piperidine This compound was prepared similarly to Preparation B, starting from N-acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine (prepared as ln part (ii) above) and ethyl iodide, followed by basic hydrolysis of the N-acetyl group. A sample was characterised as the oxalate salt, m.p. 137 - 139C.
Analysis ~:-Found: C, 59.9; H, 7.4; N, 4.0 Calculated for C15~23NO2-C2R2O4 C, 60.2; H, 7.4; N, 4.1.
Preparation D
4-(2-Phenoxy-l-phenyleth~xy)piperidine .
N-.~cetyl-4-(2-hydroxy-1-phenylethoxy)piperidine (5.25 g) (prepared as in Preparation C ~i~diethyl azodicarboxylate (4.2 g), triphenylphosphine (6.3 g) and phenol (2.25 g) in dry tetrahydro-furan (100 ml) were stirred at 0C for 2 hours then left at room temperature for 48 hours. The solvent was evaporated in vacuo, the residue taken up in refluxing diethyl ether (50 ml) and left in a refrigerator overnight. The precipitated hiproducts were removed by filtration and the filtrate evaporated to dryness. The residue wasagain taken up in ether, set aside to cool and the ~ precipitated solid fil~ered off. The ether filtrate was evaporated ~~ to dryness and the residue in me~hanol (50 ml) and sodium hydroxide solution (30 ml, 5N) was heated under reflux for 5 hours.
(PLC. ~90 .~
. :
. ~
~, ' .
,. . .
:;
3 ~ ~ 3 The organlc 301vsnt wa~ r~moved in vacu , the aqueous residue l -acidified to p~ 3 with 2N hydrochloric acld and extracted.twice with ether, the organic extract3 being di~carded. The aqueou~ pha3e wa~
ad~uqted to p~ 12 wlth sodlum hydroxlde solutlon, extracted with ether (3 x S 100 ml), the ether extract~ comhined,drled ~MgS04),and the solvent evaporate:
in vacuo to give 4-t2-phen~xy-1-~heny.lethoxy)piperidinQ ~3.55 g) as ..
an oil. A sample wa-~ converted to the oxalate salt which was recrystallised from isopropanol and had a m.p. of 170 - 172C.
Analysi3 ~:-.10 Found: C, 64.9~ ~, 6.6; N, 3.8 CalcUlated for C19~23N~2-C2~2 4 C, 6501;. ~, 6.5; N, 3_6.
:
, ~PLC. 290) :~
: .
- 2~r-Preparation E
Preparation of 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine 2 3rC32 ~ ~ 3g(0~) O N2C - 03 ' ~ 3 N~ON/
`CH3OH N
= IC= o H
(i) N-Acetyl-4-(2-ahenylallv~oxy)piperidine N-Acetyl-4-hydroxypiperidine (13.6 g) in DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (10 g, 50~ dispersion in mineral oil) in DMF (50 ml) under nitrogen. The - mixture was stirred at room temperat~re for 3 hours then ~-(bromo-methyl)styrene (20 g) in DMF (50 ml) was added dropwise. The - 10 mixture was stirred at room temperature for 4 hoarsj then diluted with water and extracted with chloroform (3 x 200 ml). The combined chloroform extracts were dried (Na2S04), evaporated in vacuo, and distilled to give N-acety~-4-(2-phenylallyloxy)Iiperidine (25 g), b.p. 170 - 180C/0.3 mm with an n.m.r. spectrum in accordance with this structure.
,-`~
' , (PLC. 290) , ., ,......... - .
.:
.
, 3~
(ii) 4-(2-~ydroxy-2-phenyl-n-propoxy)piperidine N-Acetyl-4-~2-phenylallyloxy)piperidine (4.0 g) in dry THF (60 ml) was added dropwise to a stirred solution of mercuric acetate (6.35 g) in water (60 ml) and the solution stirred at room temperature for 1 hour. Sodium hydroxide solution (40 ml, ; 3N) and sodi~ borohydride (0.75 g) in sodium hydroxide solution (40 ml, 3N) were then added dropwise to the stirred solution at 0C.
The grey suspension was stirred at 0C for 1 hour, glacial acetic acid was added to pH 6, then the suspension iltered and the filtrate extracted with chloroform (3 x 150 ml). The combined chloroform extracts were dried (Na2SO4) and evaporated in vacuo to give N-acetyl-4-(2-hydroxy-2-phenyl-n-propo~y)piperidine (2.1 g).
This product in methanol (30 ml) and sodium hydroxide solution (20 ml, 5N) uas heated under reflux for 4 hours. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3 x 20 ml), dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (1.8 g) as an oil. A sample was characterised as the oxalate salt which recrystallised from ethyl acetate and had a m.p. of 132 - 13~ C.
Analysis %:-Found: C, 58.8; ~, 7.1; N, 4.8 Calculated for C14H21NO2-C2 2 4 C, 59.1; H, 7.1; N, 4.3.
~ .
(PLC. 293) :
. ' :
Preparation F
Preparation of 4-(2-ethoxy-2-phenyl-n-propoxy)piperidine _~ .
N-Acetyl-4-(2-phenylallyloxy)piperidine (7.0 g)(prepared as ln Preparation E) in ethanol (10 ml) was added to a stirred suspension of mercuric acetate (9.2 g) in ethanol (50 ml) at room temperature. The mixture was stirred at room temperature for 1 hour then cooled to 0C. Sodium hydroxide solution (20 ml, 5N) followed by sodium borohydride (1.03 g) in sodium hydroxide solution (20 ml, 5N) were added to the stirred suspension and after 10 minutes glacial acetic acid was added to p~ 6. The suspension was filtered, the filtrate concentrated and the residue partitioned between chlorofoxm and water. The organic layer was dried (Na2S04) and the solvent evaporated in vacuo. Gas-liquid chromatographic (GLC) analysis of the product indicated incomplete conversion to the desired product therefore the oxymercura~ion process was repeated as ahove to giYe N-acetyl-4-(2-ethoxy~2-phenyl-n-propoxy)piperidine (7.4 g), 84% pure by GLC. The product in ethanol (100 ml) and sodium hydroxide solution (30 ml) was heated under reflux for 11 hours. The organic solvent was evaporated and the aqueous solution was extracted with chloroform (3 x 30 ml). The combined chloroform extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give ~ as an oil (3.8 g).
A sample was converted to the oxalate salt which was recrystallised twice ~rom ethyl acetate then acetone and had a m.p. of 126 - 127 C.
~PLC. 290) Analysis ~:-Found: C, 60.4; H, 7.6; N, 4.1 Calculated for C16H25N02-C2 2 4 4 2 Preparation G
Preparation of 4-Amino-2-/4-~2-ethoxy-1-phenylethoxy)piperidino7-6-_ hydroxy-7-methoxyquinazoline, hydrochloride hydrate 4-Amino-6-benzyloxy-2-/4-(2-ethoxy-1-phsnylethoxy)piperidino7 -7-methoxy-quinazoline, hydrochloride (0.9 g) in dry ethanol (150 ml) was hydrogenated over 5% Pd/~. at room temperature and 15 p.s.i. for 2 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness in vacuo. The residue was triturated with ether to give a white solid (0.S5 g). A sample (200 mg) was recrystal-lisad from isopropanol to give 4-ami -2-/4-(2-ethoxy~ henylethoxy) piperidino7-6~hydroxy-7-methoxyquinazoline, hydrochloride hydrate (71 mg). m.p. 141 - 144.
Analysis %:-, Found: C, 58.0; ~, 6.5; N, 11.5.
Calculated for C24H30N44 ~Cl ~2 (PLC. 290)
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a quinazoline of the formula:
--- (I) wherein R is C1-C4 alkyl, benzyl or (C3-C6 cycloalkyl)methyl;
R1 is C1-C4 alkyl, X is -CH2CH2- substituted by a phenyl group and optionally by 1 or 2 methyl groups; and R2 is hydrogen, C1-C4 alkyl or phenyl optionally substituted by one or two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, CF3, -CONR3R4 and -SO2NR3R4 wherein R3 and R4 each represent hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable acid addition salt thereof; character-ised by reacting a quinazoline of the formula:
--- (II) wherein R and Rl are as defined above and Q is a facile leaving group with a piperidine of the formula:
--- (III) wherein X and R2 are as defined above, followed, where required, by conversion of the product of the formula (I) into a pharmaceutically acceptable acid addition salt thereof.
--- (I) wherein R is C1-C4 alkyl, benzyl or (C3-C6 cycloalkyl)methyl;
R1 is C1-C4 alkyl, X is -CH2CH2- substituted by a phenyl group and optionally by 1 or 2 methyl groups; and R2 is hydrogen, C1-C4 alkyl or phenyl optionally substituted by one or two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, CF3, -CONR3R4 and -SO2NR3R4 wherein R3 and R4 each represent hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable acid addition salt thereof; character-ised by reacting a quinazoline of the formula:
--- (II) wherein R and Rl are as defined above and Q is a facile leaving group with a piperidine of the formula:
--- (III) wherein X and R2 are as defined above, followed, where required, by conversion of the product of the formula (I) into a pharmaceutically acceptable acid addition salt thereof.
2. A process according to claim 1 characterised in that a product in which R is benzyl is converted into a compound in which R is hydrogen by hydro-genation, followed by conversion of the compound in which R is hydrogen into a compound of the formula (I) in which R is C1-C4 alkyl or (C3-C6 cycloalkyl) methyl by reaction with a compound of the formula R.Q wherein R is C1-C4 alkyl or (C3-C6 cycloalkyl) methyl and Q is a facile leaving group.
3. A process according to claim 1, characterised in that in the starting materials R is CH3, C2H5, benzyl or cyclopropylmethyl; R1 is CH3;
R2 is H, methyl, ethyl or phenyl; and X is -CH(phenyl)CH2-, -CH2CH(phenyl)- or -CH2C(CH3)(phenyl)-.
R2 is H, methyl, ethyl or phenyl; and X is -CH(phenyl)CH2-, -CH2CH(phenyl)- or -CH2C(CH3)(phenyl)-.
4. A process according to claim 2, characterised in that a product in which R is benzyl, R1 is CH3; R2 is H, methyl; ethyl or phenyl; and X is -CH(phenyl)CH2-, -CH2CH(phenyl)- or -CH2C(CH3) (phenyl)- is converted into a compound in which R is hydrogen by hydrogenation, followed by conversion of the compound in which R is hydrogen into a compound of the formula (I) in l~hich R is CH3, C2H5 or cyclopropylmethyl.
5. A process according to claim 3, characterised in that in the start-ing materials R and Rl are both CH3, X is -CH(phenyl)CH2- and R2 is C2H5.
6. A process according to claim 3, characterised in that in the start-ing materials R and R1 are both C3, X is -CH2CH(phenyl)- and R2 is H.
7. A process for the preparation of 4-amino-6,7-dimethoxyy-2-[4-(2-ethoxy-l-phenylethoxy)piperidino]quinazoline hydrochloride which comprises reacting 4-amino-2-chloro-6,7-dimethoxyquinazoline with 4-(2-ethoxy-1-phenyl-ethoxy)piperidino.
8. A process for the preparation of 4-amino-6,7-dimethoxy-2-[4-(2-hydroxy-2-phenylethoxy)piperidino]quinazoline hydrochloride which comprises reacting 4-amino-2-chloro-6,7-dimethoxyquinazoline with 4-(2-hydroxy-2-phenyl-ethoxy)piperidine.
9. Compounds of formula (I) defined in claim 1, and their pharmaceuti-cally acceptable acid addition salts, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
10. 4-Amino-6,7-dimethoxy-2-[4-(2-ethoxy-1-phenylethoxy)piperidino]
quinazoline hydrochloride, when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
quinazoline hydrochloride, when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
11. 4-Amino-6,7-dimethoxy-2-[4-(2-hydroxy-2-phenylethoxy)piperidino]
quinazoline hydrochloride, when prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
quinazoline hydrochloride, when prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7903398 | 1979-01-31 | ||
| GB7903398 | 1979-01-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1131636A true CA1131636A (en) | 1982-09-14 |
Family
ID=10502852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA344,714A Expired CA1131636A (en) | 1979-01-31 | 1980-01-30 | Quinazoline antihypertensives |
Country Status (28)
| Country | Link |
|---|---|
| JP (1) | JPS55104278A (en) |
| AR (1) | AR222208A1 (en) |
| AT (1) | AT373595B (en) |
| BE (1) | BE881448A (en) |
| CA (1) | CA1131636A (en) |
| CS (1) | CS231970B2 (en) |
| DD (1) | DD148720A5 (en) |
| DE (1) | DE3003323A1 (en) |
| DK (1) | DK540879A (en) |
| ES (1) | ES488129A0 (en) |
| FI (1) | FI63936C (en) |
| FR (1) | FR2447919A1 (en) |
| GR (1) | GR73626B (en) |
| HU (1) | HU184233B (en) |
| IE (1) | IE800178L (en) |
| IL (1) | IL59252A (en) |
| IT (1) | IT1149902B (en) |
| LU (1) | LU82115A1 (en) |
| NL (1) | NL8000571A (en) |
| NO (1) | NO800230L (en) |
| NZ (1) | NZ192744A (en) |
| PH (1) | PH15436A (en) |
| PL (1) | PL121890B1 (en) |
| PT (1) | PT70749A (en) |
| SE (1) | SE8000699L (en) |
| SU (1) | SU895291A3 (en) |
| YU (1) | YU22980A (en) |
| ZA (1) | ZA80557B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2483920A1 (en) * | 1980-06-09 | 1981-12-11 | Synthelabo | Antihypertensive piperidino quinazoline(s) - prepd. from benzyloxy piperidine and a 2:halo-4:amino 6,7-di:methoxy quinazoline |
| ES515338A0 (en) * | 1981-09-09 | 1983-11-01 | Orion Yhtymae Oy | "METHOD FOR THE PREPARATION OF SUBSTITUTED PIPERIDINYLQUINAZOLIDINES". |
| US5280032A (en) * | 1989-02-14 | 1994-01-18 | Toyama Chemical Co., Ltd. | 1,2-ethanediol derivative and salt thereof, process for producing the same, and cerebral function-improving agent comprising the same |
| US9458131B2 (en) * | 2011-11-08 | 2016-10-04 | Emory University | Compounds and compositions used to epigenetically transform cells and methods related thereto |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1088068A (en) * | 1977-11-16 | 1980-10-21 | Simon F. Campbell | Piperidino-quinazolines |
| GB2021108B (en) * | 1978-05-18 | 1982-07-21 | Pfizer Ltd | 6,7 - di - 4 - amino - 2 - quinazolines |
-
1979
- 1979-01-30 IE IE800178A patent/IE800178L/en unknown
- 1979-12-18 DK DK540879A patent/DK540879A/en not_active Application Discontinuation
-
1980
- 1980-01-28 PH PH23559A patent/PH15436A/en unknown
- 1980-01-29 FI FI800252A patent/FI63936C/en not_active IP Right Cessation
- 1980-01-29 AT AT0046980A patent/AT373595B/en not_active IP Right Cessation
- 1980-01-29 YU YU00229/80A patent/YU22980A/en unknown
- 1980-01-29 SE SE8000699A patent/SE8000699L/en not_active Application Discontinuation
- 1980-01-29 CS CS80607A patent/CS231970B2/en unknown
- 1980-01-29 NZ NZ192744A patent/NZ192744A/en unknown
- 1980-01-29 IL IL59252A patent/IL59252A/en unknown
- 1980-01-29 IT IT19537/80A patent/IT1149902B/en active
- 1980-01-30 PL PL1980221683A patent/PL121890B1/en unknown
- 1980-01-30 CA CA344,714A patent/CA1131636A/en not_active Expired
- 1980-01-30 NO NO800230A patent/NO800230L/en unknown
- 1980-01-30 FR FR8002012A patent/FR2447919A1/en active Granted
- 1980-01-30 SU SU802877159A patent/SU895291A3/en active
- 1980-01-30 PT PT70749A patent/PT70749A/en unknown
- 1980-01-30 BE BE0/199187A patent/BE881448A/en not_active IP Right Cessation
- 1980-01-30 NL NL8000571A patent/NL8000571A/en not_active Application Discontinuation
- 1980-01-30 HU HU80202A patent/HU184233B/en unknown
- 1980-01-30 ZA ZA00800557A patent/ZA80557B/en unknown
- 1980-01-30 JP JP990580A patent/JPS55104278A/en active Granted
- 1980-01-30 DE DE19803003323 patent/DE3003323A1/en not_active Ceased
- 1980-01-30 AR AR279793A patent/AR222208A1/en active
- 1980-01-31 ES ES488129A patent/ES488129A0/en active Granted
- 1980-01-31 LU LU82115A patent/LU82115A1/en unknown
- 1980-01-31 DD DD80218769A patent/DD148720A5/en unknown
- 1980-02-11 GR GR61081A patent/GR73626B/el unknown
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