CA1255670A

CA1255670A - 2-substituted 4-amino-6,7-dimethoxyquinolines

Info

Publication number: CA1255670A
Application number: CA000433023A
Authority: CA
Inventors: Simon F. Campbell; John D. Hardstone
Original assignee: Pfizer Corp
Current assignee: Pfizer Corp
Priority date: 1982-07-24
Filing date: 1983-07-22
Publication date: 1989-06-13
Also published as: SG6489G; AU548036B2; US4686228A; IL69311A; PL139498B1; CS247073B2; KR880001315B1; JPH0219112B2; JPS5933264A; NZ204996A; ES524320A0; IE55798B1; PL243131A1; NO171594C; NO171594B; KR840005428A; FI78296C; US4758568A; YU157283A; DK337383A

Abstract

Abstract 2-Substituted 4-Amino-6,7-Dimethoxyquinolines Novel derivatives of 4-amino-6,7-dimethoxyquinoline are disclosed as regulators of the cardiovascular system, in particular as antihypertensive agents, which have the formula:

Description

7~

-2- 69387-44 This invention relates to therapeutic agents which are novel derivatives of 4-amino-6,7-dimethoxyquinoline. Such com-pounds are useful as regulators of the cardiovascular system and, in particular, in the treatment of hypertension.
The novel compounds accordlng to the invention are those having the formula:

CH ~ ~ Nf~/ R ( I ) and their pharmaceutically acceptable acid addition salts, wherein R is -N(Cl-C~ alkyl)2, piperidino, 6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinol-2-yl or a group of the formula -N ~ -Y where Y is H, Cl-C6 alkyl, aryl or Cl-C4 alkyl substituted by aryl, or Y is se].ected from (a) -CORl where Rl is Cl-C6 alkyl, Cl-C4 alkyl substituted by aryl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)methyl, aryl, styryl, 2-Euryl, 2-tetrahydrofuryl, 2-benzo-1,4-dioxanyl, 2-chromanyl, 5-methylthio-2-(1,3,4-oxadiazolyl) or 2-quinolyl group;
(b) -CONHR2 where R2 is Cl-C6 alkyl, aryl, Cl-C4 alkyl sub-stituted by aryl, (C2-C4 alkenyl)methyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl)methyl; and ~5~'7~3

-3- 69387-44 (c) -CooR3 where R3 is Cl-C6 alkyl, Cl-C4 alkyl substituted by aryl, C2-C4 alkyl substituted other than on an ~-carbon atom by hydroxy/ C3-C6 cycloalkyl, (C3-C6 cycloalkyl)methyl, (C2-C4 alkenyl)methyl, or aryl; aryl, wherever it occurs, meaning phenyl, naphthyl or phenyl substituted by 1 or 2 substituents each selected from halo, CF3, Cl-C4 alkyl and Cl-C4 alkoxy, or by a single methylenedioxy group.
"Halo" means F, Cl, Br or I.
Alkyl, alkoxy and alkenyl groups can be straight or, when appropriate, branched chain. Preferred alkyl groups have 1 to 4 carbon atoms.
Pharmaceutically acceptable acid addition salts of the compounds of the invention are those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, succinate, lactate, tartrate, citrate, gluconate and p-toluenesulphonate salts.

~s~

-4- 69387-44 Examples of R include _~0~ ~/0~

N N

~ CH\2 ~ ~ S CH3 phenyl, ~-fluorophenyl, methyl, cyclopropylmethyl, cyclopentyl, styryl, 2-naphthyl and 2-quinolyl.
Examples of R2 include phenyl, cyclopropylmethyl, benzyl, n-propyl and allyl.
Examples of R3 include ethyl, -CH2CH(CH3)2, -CH2C(CH3)2(OH), cyclopropylmethyl, ~-fluorophenyl, benzyl and -CH2-C(CH3)=CH2-r, ~.z~S6~

The compounds of the formula (I), can be prepared asfollows:-~1) An N-(lR-substituted-ethylidene)-2-cyano-4,5-dimethoxy-aniline ~II) may be cyclised to form the corresponding substituted 4-amino-6,7-dimethoxyquinoline (I):-C~130 / ~ N ~ R ~13 ~ / ~ ~ R

(II) (I) The cyclisation can be carried out using a Lewis acid, e.g.zinc chloride, or a base, e.g. lithium diisopropylamide (LDA). Zinc chloride is preferred when R is said tetrahydroisoquinolyl group or an N-aralkyl-piperazino group. The reaction with zinc chloride is typically carried out by heating the reactants, preferably at reflux, in a suitable organic solvent, e.g. dimethylacetamide, for up to about 4 hours. The reaction with LDA is typically carried out at low temperature (e.g. -70C) in à suitable organic solvent, e.g. tetrahydrofuran, following which the reaction mixture is allow-ed to warm to room temperature. In some cases using LDA, heating may be necessary to complete the reaction. The product can then be isolated and purified conventionally.

~.S~6'7~

The compounds (II) are obtainable conventionally as is illustrated in the following Preparations. Typical methods are outlined as follows:-(a) For compounds where R is as defined above except for unsubstituted piperazinyl (Y = H):-3 ~ R.cocH3/Pocl3 Compound (II) ~ reflux in \ CHC13.
(known) CH3C(OC2H5)3, ~ R.H, c.150 C CH30 ~ ~ OC2H5 / H ~ , c.150C.

(b) For compounds in which R is unsubstituted piperazinyl:-C 3 ~ ~ NH2 CH3C-N W-COCF3/POCl T 11 ~ ~ 3CH ~ N~C~N N-COCF3 3 CN re-Elux in CHC13. ~ CN CH3 ~laOH/CH30H, room temperature \ /r~
CH 0~ ~ ~ ,, N NH

. -- , ~2~56i~

(2) The Compound in which R is -N ~ NN can also be prepared by debenzylation o~ the corresponding 4-benzylpiperazin-1-yl compound, itself preparable via route (l~ above. This can be carried ou~ conventionally using, e.g., H2 over a Pd/C ca~alyst.
~3) Compounds in which Y i5 ~C0Rl can be prepared,as follows:-C~3O ~ N C33O ~ N ~ COR
N~,, ~ NH2 Q is a facile leaving group, preferably Cl~
The reaction can be carried out conventionally. When Q is Cl, the presence of a tertiary amine acid acceptor such as eriethylamine is desirable. Generally, heating is unnecessary.
Typically the reactan~s are stirred together in a suitable organic solvent, e.g. chloroorm, at 5-10C for 1-2 hours. The reaction mixture can then be allowed to attain room temperature and the product isolated conventionally.
(4) Co~pounds in which Y is -CONHR2 can be prepared as follo~s:-C~3 ~ R .NCO C~3O N /'~~~-CONHR2 c~3o or C~3O
N~2 R .NHCOCl P~C 351C

When an isocyanatP R2.NCO is used, the reaction can again be carried out conventionally, e.g. by stirring the reactants together for a few hours (e.g. 3-6 hours) in a suitable organic ~olvent, e.g. chloroform. Heating ls agaln generally unnece~sary;
the product can be isolated routinely.
~hen a carbamoyl chloride R2.~HCOCl~is used, thi~ may be generated in situ by the action of phosgene on the amine R2.N~2 as ics hydrochloride salt in the presence of an acid acceptor such as ~riethylamine in a dry, cooled organic solvent, such as chloroform at 40. After allowing this to warm to ambient temperature and re~oving e~cess phosgene, a solution of the piperazino-quinoline in the same solvent is added slowly with cooling, the mixture stirred until reaction is complete and the product isola~ed rou~inely.
lS IS) Compounds in which Y is -CooR3 can be prepared as follows:-CH30 ,~ N N N~
C~30 i ~ _ ~ ~ ~ N-C-o~

where Q is a facile leaving group9 preferably Cl. Typically the reaction is carr ed out by stirring ~he reactants together for a few hours in a suitable organic solvent such as chloroform, preferably, when Q is Cl, in the presence of an acld acceptor such as triethylamine-. Heating is no~ generally necessary, and ~he product e-Rn be isolated in a routine manner.
PLC 35lC

~;2 SS6~0 Certain compounds oE the invention can be converted to other compounds of the invention by conventional means, e.g. a chlorine substituent on an aromatic heterocyclic group Y can be replaced by a phenoxy group or an amino group by reaction with phenol or an amine, respectively, under conditions well known in the art, and an alkenyl-methyl group R3 can be converted to a hydroxyalkyl-methyl group by treatment with concentrated sulphuric acid, as is also well known in the art.
The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) can be prepared by conventional procedures, e.g. by reacting the free base with the appropriate acid in an inert organic solvent, and collecting the resulting precipitate oE the salt by filtration or by evaporation of the reaction mixture. If necessary, the product may then be recrystallised to purify it.

~z~

When the compounds o~ the invention contain an asymmetric centre, the in~ention includes both the resolved and unresolved forms. Resolution of optically active isomers can be carried out accordlng to co~ventional prior art methods.
The antihypertensive activi.y of the compounds of the formula (I~ is shown by their abillty to lot~er the blood pressure of conscious spontaneously hyper~ensive rats and consciou~ renally hypertensive dogs, ~hen administered orally at doses of up to 5 mglkg .
The compounds of the formula (I) and their salts can be administered alone, but will generally be administered in admixture wi.th a pharmaceutical carrier selected t~i~h regard to the intended route o administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing s~-ch excipients as starch or lactose, or in capsules ei~her alone or in admixture ~ith exc pients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They can be injected parenterally, for e~ample, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best use~ in the form of a sterile aqueous solution which may contain other solutes, for example, enough salt or slucose to make the solution isotonic.
Thus the in~ention also pro~ides a pharmaceutical composition comprising a compound of t'ne formula (I) or pharmaceutically acceptable acid additlon salt thereof togeeher wlth ~ pharntaceutically acceptable diluent or carrier.

12S56~ -It also provides a compound of the formula (I), or a pharmaceutically acceptable acid addition salt thereof, for use in treating hypertension in a human being.
The compounds of the formula (I) and their salts can be administered t~ humans for the treatment of hypertension by either ehe oral or parenteral routes, and will pe administered orally at dosage levels 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 will be 1/5th to l/lOth of the daily oral dose. Thus for an average adult patient, individual oral doses in tablet or capsule form will be appro~imately in the range from 1 to 25 ~g of the active compound. It should however be stated that variations will necessarily occur depending on the weight and condition of ehe sub~ect being treated and the particular route of administration chosen as will be known to those skilled in the art.
The invention yet further provides a method of treating a human belng having hypertension, which comprises administering to the human an antihypertensive amount of a compound of the formula (I) or pharmaceutically acceptable acid addition salt thereof or pharmaceutical composition as defined above.
The following Examples illustrate the invention. All ee~peratures are in C:-7~) ~`~, ~H 3 0~ N ~ o A solution of l/g-benzodioxan-2-carbonyl chloride (0.75 g) in chloroform (10 ml) was added dropwise to a stirred solution of 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (l.0 g) in chloro-form (50 ml) with triethylamine (1.06 g) at 5-10. The reaction was stirred at 5-10 for one hour, then allowed to attain room temperature and stirred overnight. The mixture was then exaporated ln vacuo and the residue partitioned between chloroform (50 ml) and sodium carbonate solution (10%, 50 ml). The chloroform layer was separated, the aqueous phase extracted with chloroform (2 x 50 ml), the extracts combined, washed with brine, dried (Na2SO4) and evaporated ln vacuo. The residue was then taken up in chloroform and chromatographed On silica (Merck 9385, 60 g) eluting with chloroform/methanol (100:0 -~ 97:3). A solution of the purified product in chloroform was treated with ethereal hydrogen chloride, evaporated in vacuo and the residue recrystallised from isopropanol to give 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinoline hydrochloride hydrate (0.28 g), m.p. 201.

~2~S~

Found:C,56.7; H,5.4; N,llØ
Calculated for C24H26N405'HCl'H2 ~ . ~
The follo~ing compounds were prepared slmilarly ~o Example 1, searting from the same quinollne and the appropriate acid chloride as indicated. After chromatography, the product was crystallised from the solvent shown in each case.

CH30 ~ ~ N ~ _y 7~

~ ~ _ , I ' _ _~ u~ ~ r- a~ ~ u~ ~ O ~
VZ ~ ~ ~ ~ ~ _~ ~ ~1 ~
a~
~ u~ r~O u~ r~o o,~
~ , O r~ r_ C~ C'l C~ ~O `D O O C~ _i C~ ~ _~
_ ~ ~O ~D ~ u~ u~

c ~ _ _ ~ ~ _ _ a ~ ~ ~ o ~ ~ ~ ~C ~ ~.

.~ ~ ~1 ~ 5 ~ - _ tJ 1~ ~1 ~ o - - - - ~ - -;~o ~o ~o O ~ ~ O ~ 1 O r-~ ~
~ ~ ~ s~ ~o ~ l q ~ o l tS~ ~ ~ r ~ ~, --- ~ - - ~ - - -~. ~1 ~ o Qol~o , . ~
, ~
~ _ ~ _ ~:r _ I

~LZ5~7~

~ _ _ .
~:Z ~ ,1 ~ ~ ~o ~'~ss Lrl ~ u~ u~ u~ ~ u~ U~

E~C~ ~J ~ u~ u~ ~ u~ u~
. C~., .__ ~ :~
a ~ , O ~ o ~,~ ~o~ ~ oai . ~a) ~ ~ c~ O ~S s::~ ~
~ ~ ~ ~ ~ ~ u ~S ~ ,~
P~ ~) c~ ~- ~ o~ u ~1 o. u Q~¦ C) H
~ _ __ __ ~
~ ~ O ~ ~I ~ ........... , ~,0"
~ ~d ~ ~ ~ .~
_ _, __ '`- __ ~1 ~ 0 ~:0~ 0 __ __ __ _ ~ _ ~Z .' _ ~ _ _ 0~ , ~s~

_ ~n c~
a) ~ ,i .-i _l V'~
q~ J
h ~ ~ r~
,~
~ U~ U~
___ ~
~ O ~
. t~l W
~,;a o ~ 0,~
._ a~
~d ~ C~
O p~ ..o t~ 1 ~i rl O 1:~
~ ~ ~R~
_ ~

_ .

~LZ~67~

CH3O ~ N N NH
~ --/ + C6H5NC ~

3 ~--\ H
NH2 3 ~ N ~ N N ~ NC6H5.

~ O

Phenylisocyanate (1.1 g) was added to a stirred suspension of 4~amino-6,7-dimethoxy-2-lpiperazin-1-yl)quinoline (0.72 g) in chloroform (25 ml) at room temperature and the reaction mixture was stirred for 4 hours. The mixture was evaporated ln vacuo, the residue taken up in methanol-chloroform and treated with ethereal hydrogen chloride. The crude product was purified by chromato-graphy on silica gel eluting with methylene chloride followed by chloroform/methanol and then recrystallised from methanol/ether to give 4-amino-6,7-dimethoxy-2-[4-(N-phenylcarbamoyl)piperazin-l-yl]-quinoline dihydrochloride (0.18 g), m.p. 235.
Analysis ~:-Found: C,55.1; H,5.7; N,14.7 Calculated for C22H25N5O32HCl: C,55-.0; H,5.7; N,14.6.

~'

5~

The following compounds were prepared similarly to Example 12, using the appropriate isocyanate R2.NCO as indicated, and the product crystal,lised frnm the solvene shown in each case.

NH2.

In Example 13 chromatography was not necessary, while in Examples 14 and 15 the reaction mixtures were purified as in Example 16, i.e. chromatographed as the ~ree base and (in the case of Example 14) then converted to the hydrochloride.

PLC 35lC

~.~25S6~

_ ~ ~
^Z ,_ ~ ~o`

a~ , c~ ~ ~ ~ O

~ ~ ~ ~ ~ ~ a~
_ ~ _ ~ ~ ~. ' 'i ~ u~ ~

~ C A ~O O CO ~

., _L

S~

E _ COCl 2 ~ ~ NHCCCl ~--\

C330 ~ N ~3 N~2 0 C~

~Aminomethyl)cyclopropane hydrochloride (0.25 g) and triethylamine (0.61 g) in P~05-dried chloroform (15 ml) was added dropwise to a stirred solution of phosgene in toluene (12.5%, 2.6 ml) a~ -40. The reaction mixture was allowed to warm ~o room temperature and stirred for 0.5 hours. Excesæ phosgene was removed in a steam of nitrogen then a solution of 4-amlno-

6,7-dimethoxy-2-(piperaz~n-1-yl)qu~noline (0.3 g) in P205-dried chloroform (30 ml) was added drop~ise at 10 and the reaction mixture stirred at room temperature for 1.5 hours. Sodium carbonate solution (lOZ, 10 ml) W8S then added and the chloroform layer separated. The aqueous phase was extracted wieh chloroform, the organic phases combined, washed with water, dried (MgS04) and PLC 351 c ~ Z55;~7~

evaporated in vacuo. The residue was then taken up in methylene chloride and chromaeographed on s$1ica (Merck 9385, 85 g) eluting with methylene chloride/methanol (100:0-~ 85:15). A solut$on of the purified product in methylene chloride was treated with S ethereal hydrogen chloride, evaporatPd in vacuo and the residue recrystallised from isopropanol to give 4-amino-2-~4-(N-cyclo-propylmethylcarbamoyl)piperazin-l-yl]-6,7-dimethoxyquinoline hydrochloride hemihydrate (165 mg), m.p. 220-223 (d).

~ ~ , Found: C,55.6; H,6.5; N,16.4 20H27N503. HCl,O.S H20: C,55.7; H,6.8; N,16.3 'i~

3 ~ N NH ~ N(CH3)2 N~12 N ~ N(CH3) ~ ~ 3 N O~

4-Amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (1.26 g~
and 2~chloro-4-dimethylaminopyrimidine (0.76 g) in n-bu~anol (60 ml) ~ere heated under reflux for 16 hours. The mixture ~as then evaporated in vacuo, the residue partitioned between chloroform and sodium carbonate solutlon (10~) and thP aqueous phase PLC 351c extracted with chloroform. The combined extracts were washed with water, dried (Na2S04), evaporated in vacuo and the residue chronatogsaphed on silica gel (Merck 9385). Elution with chloroform-methanol (100:0 -j~ 95.5) followed by treatment of the product with ethereal hydrogen chloride and recrys~allisa~$on from me~hanol gave 4-amlno-6,7~dimethoxy-2~[4 (4-dimethylamino-pyrimidin 2-yl)piperazin-1-yl]quinoline dihydrochloride dihydrate (0.19 g), m.p. 260-263.

~:--Found: C,48.4; E,5.8; N,18.9.
Calculated for C21H27N72 ZHcl-2H2o C,48.7; H,6.4; ~,18.9.

~A~IP~ES 18 T0 26 The following compounds were prepared similarly to Example 18, using the approprlate halogenaeed heterocyclic compound Y~ as indicated, and the product crystallised from the solvene shown in each case. In Example 20 chromatography was not necessary.

3 ~ N ~ 3-Y

N~2 PLC 35lC

~LZ~S6~

~ ~ ~ ~ U~ ~
Z ~ ~ I_ r~.r~ r~ ~ c~
,1 ~ ,1 ~~ ~ ,~
u~ O~ ~ co u~ , 3~ u~ ~ ~ ~ u~
~ , V ~ r- O ~ c~
~ U~ U~ ~ ~ , e~l U~ U~
_ Ul D~ .,.......... ..... ~ ~ U~ _~ _ ~ ~ ~ I
. ~ l ~ ~ , ~
O ~1 N :~: E i ~ -rt ~ rl C`l I
_I ~ :~ I ~ I ~ I
h ~ O '~ 1' ~ O r-l O _~ O ~ O ~
tl~ U~ ~1 ~ ~I ~ ~ -l ~ N
A . ~.1 J.l O~ C O ,C ~ ~a t~ I ~¢ I ~1 ~J I ~ ~ I ~ 1.1 c~ O c~ ~ 1 __ ~ _ _ P~ :~ ~ oo o o Lf~ o ~ ~ ~ ~ ,~ I ~ o ~o O ~ ~ C~
~t~ ~ ~`I -~
. _ z~ O ~ ~r r . . . . _ a~ a~ ~ o ~Z

i67~
-- 2d~ _ . _ ~ _ _ _ , ~q v~ ~ ~00 a~ o~ ~
Z; ~ ~ ~ ~ ~

~c ~ ~ C~l ~ ~ U~ C~ ~ ,U~ ~
3~ ~o ~o u~ u~ u~ u~ ~ ~o ~ ~ .
O ~ r~ ~ u, ~ I_ ~ ~
E~ ~ ~ ~ ~ ~ O O
'~ ~ .~
5S`- ~ ~ ~ O
~ ~r ô ~ V V

~ I ~ JJ ~ ~ ,C ~
~C~ ~ ~ 1~ I ~
__ _ .
~C~ O .
O ~ U~ ~ ~`LO C~ 0;~
e ~ c~ ~ ~ ~D ~ c~
o ~:: ~ ~o :~ ~r ~ C`J C~ ~ C`J
. \, J r~ zOI UU~I U z;F\

z æ ~;~J ~ ~z - o _ _ . __ ~0 ~ C~ ~. U~
.~ _ ~ _ _ _ _ _ .

~LZ~S~7~3 .
~n , ~
1~ Z t~ t ~ ,~ ~

,~ U~
'c ~ ,~
¢~

O , ~ r~
~7 ", ~, ,n tr, e ~
~J~ _I C
o tD O .
/ ~U O

_ .... - .
t~ _~ .. o ~-H~ O,~ C
t t :1 e ~ r~3 ~

~0 e~ ~ ~ _, iit~D

EXAMPLE 2j Cl ~ N ~ OH
CN3 ~ N ~ N

anh. x2Co3 C'~30 C~3O ~ ~ ~

~2 4-Amino-2-[4-(2-chloropyrimidin-4-yl)piperazin-1-yl]-6,7-dimethoxyquinoline hemihydrate (0.32 g), phenol (0.15 g), anhydrous potas~ium carbonate (0.22 g) and potassium iodide (catalytic ~race) in 4-methyl-2-pentanone (125 ml) were stirred under reflu~ for 13 hours. Further portions of phenol, anhydrous potassium carbonate and potassium iodide were then added thrice at L0 8 hour lnter~als, followed by a final 18 hours re~luxing. After cooling, methylene chloride (50 ml) and ~ethanol (20 ml) were added and ~he reaction mixture filtered. The filtrate was evaporated in vacuo and the residue dissolved in methylene chloride, washed with water, dried (MgS04) and evaporated in l~ vacuo. Chro~atography on silica (Merck 9385, 40 g) eluting with . ~ .
P~C 35~

- ~2S56'7~

methylene chloride/methanol (100:0 ~88:12) followed by treatment of the product wlth ethereal hydrogen chloride and r~crystallisation from isopropanol gave 4-amino-6,7-dimethoxy-2-[4-(2-phenoxypyrimidin-~yl)piperazin-i-yl]quinoline dihydro-chloride (0.26 g), m.p. 199-201~ (d).

%:-Found: C,56.1; H, 5.2; N,15.7 CalculaCed f r 25 26 6 3 C~56.5; H,5.3; N,15.8.

EXA~JPLE 28 Cl C~130 ~ ~ ~ ~ ~ + ~ C~

~ C~3 eBuON C33O ~ N ~ N

NE~2 ~z~

4-Amino~2-[4 (2-chloropyrimidin-4-yl)piperazin-1-yl]-6,7-dimethoxyquinoline hemihydrate (0.2 g) and N-methylcyclopentyl-amine (0.17 g) in n-butanol (20 ml) were stirred under reflux for 60 hours. The mlxture was then evaporated in vacuo, the resldue partitloned be~ween cnloroform and sodium carbonate solution (10%) and the aqueous phase extracted with chloroform. The combined ex~racts ~ere ~ashed with water, dried (MgS04), evaporated in vacuo and the residue chromatographed on silica gel (Merck 9385, 50 g). Elution with methylene chloride/methanol (100.0 ~ 35:15) follo~ed by treatment of the product with ethereal hydrogen chlorlde and recrystallisation from isopropanol/ether gave 4~amino-6,7-dimethoxy-2 [4-~2-N-methylcyclopentylaminopyrimidin-4-yl)piperazin-1-yl]quinoline dihydrochloride sesquihydrate (0.06 g), m.p. 248-250.

Analysis %:-Found: C,53.6; H,6.5; N,17.2 Calculated for C25H33N70~.2HCl.1.5H20: C,53.3; H,6.8; N,17.4.

CH30 ~ N ~ N NC6H5 L A ,~

/~
3 ~ p ~ ~ N-C H

~. NH2 ~ - 29 -N~[1-(4~Phenylpiperazin-l-yl)ethylidene]-2-cyano-4,5-dimethoxyaniline (2.5 g) in tetrahydrofuran (35 ml) was added to a stirred solution of lithium diisopropylamide [from n-butyl lithium 1~3~ in hexane (6.44 ml) and diisopropylamine (1.44 ml)] in teerahydrofuran (5 ml) at -70. The resulting solution w~s stirred at 70 for 4 hours then allowed to attain roo~
temperature overnight. The mixture was poured into ice-water (100 ~1), extracted with chloform (3 x 200 ml), the combined extracts ~a hed with water, dried (~a2S04) and evaporated in vacuo. The residue was taken up in chloroform~methanol, treated with ethereal hydrogen chloride and recrystallised from methanol to give 4-~mino 6,7-dimethoxy-2-[4-phenylpiperazin-l~yl]quinoline dihydrochloride hemihydrate (0.82 g) m.p. 288-290.

~: -Found: C,56.9; H,6.0; N,12.7 Calc la C21 24 4 2 ~ 2 C956.5; H,6.1; N,12.6.

- ~Z5~0 E.YAMPLES 30 T0 32 The following compounds were prepared by the same general route as in Example?~ , using the appropriate substituted ethylidene compound of formula tII), except that in Example 3~ the reaction was completed by heaeing on a stea~ ba~h. In Lxamples 30 and 3~, the crude product was purified by column chromatography.

;H30 _ __ _ _ E~ample R Form lsolated Analysis % (Theoretical No. m.p. in brackets) _ _ _ -N 3 HCl, 58.9 6.9 13.1 272-27S (59.3 6.9 13.0) . _. _ ~
31 /CH3 , HC~ H2o53.8 6.3 14.6 L________ ~ ~ 153.3 6.5 14.4) 32 -N NH 2HCl.~H2O47.8 6.0 15.1 ~ 260 (47.5 6.4 14.8) __ _ _ _ PLC 35lC

_ 3~ 2 ~5 6 7 ~

ZnC12 3 ~ N ~ N~CH 2 C 6 H 5 DMA

3 ~ \___/CH2C6H5 N- [1- (4-Benzylpiperazin-l-yl)ethylidene]-2-cyano-4,5-dimethoxyaniline (13.5 g) and zinc chloride (4.86 g) in dimethyl-acetamide (90 ml) were stirred under reflux for 2~ hours; further zinc chloride (0.5, 0.2 g) was added after ~ and 1~ hours respect-ively. The mixture was cooled, treated with ether (700 ml, 2 X 100 ml) and the supernatant discarded each time. The residual tar was then treated with sodium hydroxide solution (2N, 100 ml) and methylene chloride (100 ml) and the mixture was stirred at room temperature for 5 minutes. The organic layer was separated, the aqueous phase extracted with methylene chloride and the total organic extracts washed with waterO The dried (Na2S04) extracts were evaporated ln vacuo and the brown residue (~ 13 g) purified by chromatography on silica gel (~erck 9385, 250 g) eluting with chloroform-methanol (100:0 ~ 88:12). A sample of the pure product (6.95 g) was taken up in ethanol, treated with ethereal hydrogen chloride and evaporated ln vacuo. The residue was recrystallised from methanol to give 4-amino-6,7-dimethoxy-2(4-benzylpiperazin-1-yl)quinoline dihydrochloride sesquihydrate, m.p. 260-263.

." ~

i67~

Analysis %:-Found: C,54.9; H,5.9; N,11.5.
Calculated for C22EI26N42 2HCl l~EI2 C,55.2; H~6.5; N,11.7.

4-Amino-6,7-dimethoxy-2-[6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinol-2-yl]quinoline, m.p. 226-227 was prepared in the same general manner as the previous Example using the corresponding 1-[6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl]ethylidene compound except that the crude reaction residue was recrystallised from isopropanol.
Analysis_ %:-Found: C,66.0; El,6.3; N,lO.9 Calculated for C22H25N3 4 r~ O
C 3 ~ N N ~H ll ~ J + Cl-c.ocH2cH(cH3)2 CH3 ~ ~ N N ~ 0 A solution of isobutylchloroformate (0.11 g) in chloroform (5 ml) was added dropwice to a stirred solution of 4-amino-o,7-dimethoxy-2-[piperazin-1-yl]quinoline (0.21 g) in chloroform (15 ml) with triethylamine (0.22 g) at 10. The solution was then s~irred at roo~ temperature for 1 hour and sodium carbonate solution (10~, 10 ml) added. The organic phase was separated, tne aqueouc solution extracted with chloroform (2 x 15 mL) and the total combined extracts dried (Na2SO4) and evaporated in vacuo.
The resldue ~as purified by chromatography on silica gel (Merck 9385, 25 g) eluting ~ith methylene chloride methanol (100:0-~
93:7), followed by treatment of the product with ethereal hydrogenchloride and recrystallisatiorl from isopropanol to give 4-amino 6,7 dimethoxy-2-[4 (isobutoxycarbonyl)- piperazin-l-yl]
quinoline hydrochloride sesquihydrate, m.p. 254-256 (0.065 g).

Found: C,52.8; H,6.9; N,12.2 Calculated for C20H28N44'~C~ 2 C,53.2, H,7.1; N,12.4 P~C 351C

~s~

T-ne following compounds were prepared similarly to Example 35, using the appropriate chloroformate ClCOOR3 as indicated, the product being crystallised from the solvent shown in each case~
The compound of ~xample 38 was obtained as a bi-product from Example 37, ethyl chloroformate having ~een formed in situ due to traces of ethanol in the chloroform reaction solvent.

; 3 ~ N NCOOR3 PLC 35lC

~z~ss~

_ _ _~ _ _~
0 Z; ~ 0~ O ~ ~ O
2~ C~l ~ ~ ~ ~ ~ C~l :~ '' e; '`' ' ~ u) ~ c~ oo C~
~o ~ ~ ~o U~ U~ U~ ~o h c c.~o~ Irl Il~ Crl ~ r-l C`l CO
E-J ~ ~~ ~7 `4 ~_ i_ ~D
_~ U~ U'l____ U7 U') U~
_ ~ ~ .~ . .
S:: ~ _1 . Oe ~0 ~ O .~ ~ ~ O
.~ ~ ~ O ~ ~ o ,_~
O ~ OJ S~ o _l ~
. ~ ~ ~c~! e ~: ,, O ~ d h ~ U I ~ ~~ O P~ I ~ ~ ~ O
~ ~ ~ 1~ 1 ~ ~4~
_ .
~C~ ~ O 0 C~ ~ ~ rr~
~n ~ô~ u~ ~ co O
~ es~ ' o ' ~ ' o C ~ ~o ~ ~o a~ ~ ~ ~ ~ ~
t ~ ,, . 5~ q q ~1 . ~ _ ~1 ~J
Z ~ ~ , o . .

- 36 - ~SS~'7~

2-Methylallyl 4-[4-amino-6,7-dimethoxyquinolin-2-yl]-piperazine-l-carboxylate (0.21 g) was added to a stirred solution of concentrated sulphuric acid (2 ml) and H2O (2 ml) at 10-15 and stirring maintained at 10-15 for 3 hours. The reaction mixture was basified with sodium hydroxide solution (5N) whilst maintaining temperature below 15 and then extracted with methylene chloride.
The combined extracts were washed with water, dried (MgSO4) and evaporated _ vacuo. Chromatography on silica (Merck 9385, 100 g) eluting with methylene chloride/methanol (100:0 ~ 85:15) followed by treatment of the product with ethereal hydrogen chloride and recrystallisation from isopropanol gave 2-methyl-2-hydroxypropyl 4-[4-amino-6,7-dimethoxyquinolin-2-yl]piperazine-1-carboxylate hydrochloride hemihydrate (0.05 g), m.p. 280.
Analysis %:-Found: C,53.6; H,6.6; N,12.7 Calculated for C2oH28N4O5.HClØ5 H2O: C,53.4; H,6.7; N,12-5-CH30 N N-~H2C6H5 H2 CH3O ~ N NH

Pd/C CH30 ~ss~o 4-Amino-6,7-dimethoxy-2~4-benzylpiperazin-1-yl)quinoline (6.2 g) in ethanol (300 ml) with 5% Pd/C catalyst was stlrred at 50 under an atmosphere of hydrogen (50 p.s.i.) for 20 hours. The mixture was cooled, chloroform (100 ml) added and the solution fil~ered through "Solkafloc". The solid was washed with chloroform~ethanol (1:1, 4 x 100 ml) a~d the combined filtrates evaporated in vacuo. The residue was partitioned between chloroform~sodium carbonate solution (10%), ehe organic layer removed, the aqueous phase saturated with salt and further extracted with chloroform. The combined organic extracts were washed with brine, drled (Na2S04) and evaporated in vacuo to yield 4 amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (2.42 g).
Spectroscopy showed this product to be the same as that of Example 32.
The following Preparations illustrate the preperation of certain starting materials.

~ ation 1 C~30 ~ N~2 ~CH3)2NCOCH3/POC13 ",CH3 PLC 351c ~S67~

Phosphorous oxychloride (1.0 ml) was added to a stirred solution of dimethylacetamide (2.8 ml) in chloroform (10 ml) at room cemperature. The mix~ure was stirred for 5 minutes, 2 cyano-4,5-dime~hoxyaniline (1.78 g) added and the reaction stirred under reflux for 4 hours. The mixture was cooled, poured onto ice and extracted with chloroform and the organic phase discardedc The aqueous layer was basiied (solid NaOH) extracted wi~h chloroform, the combined extracts washed with ~ater, dried (Na2S04~ and evaporated in vacuo. A sample of the brown oily residue (2 g) was crystallised from diisopropylether ~o give N,N-dimethyl-N'-(2-cyano-4,5-dimethoxyphenyl)acetamidine, m.p.

g4- 96 .

_alysis Z:-Found: C,63.3; H,6.9; N,17.2 Calculated for C13H17N302: C,63.1; H,6.9; N,17Ø

The following compounds were prepared by the same general method as Preparation 1, starting from the appropriate acetyl derivative of the formula R.COCH3. In Preparation 2 the crude product was purified by column chromatography.

3 ~ N
CH30 CN C~3 ~2~67(~

___,. ~. . , I
~, æ ~ ~ ,_ ~ o o `~ ~:~ `D `O . `O `O
~ ~ 7 .
~C~ .c~P~ CS~
_~

__~__ 1-. _ _ ~
d~ o .. _. _~

C
,_L_

7~

PreDaration 6 NaOH

3 ~ ~ ~ ~

3 ~ N 3 A solution of N-[1-(4-trifluoroacetylplperazin-1-yl)ethyl-idene]-2-cyano-4,S-dimechoxyaniline (29.5 g) in mechanol (400 ml) and sodium hydroxide ~2N, 100 ml) was stirred at room temperature for 3 hours. l`he mixture was ~hen evaporated in vacuo, the residue taken up in chloroform (350 ml) washed with water and dried (Na2S04). The solution was evaporated in vacuo and the crude N~ [piperazin-l-yl]ethylidene)-2-cyano-4,5-dimethoxy-aniline (23 g), used without further purification.

Preparation 7 CH30 ~ N~2 CH30 ~ ~`~C2H5 + CH3C (oEt3) ~' ~
CH3 CN 3 C~ CH3 PLC 351c ~Z~S~;7~

2-Cyano-4,5-dimethoxyaniline (20 g), a trace of the corresponding hydrogen chloride sal~ (200 mg) and triethylorthoacetate (40 ml) were stlrred at 150 for 1 hour, with removal of ethanol by distillation. The mixture was then evaporated in vacuo and the crude residue of ethyl N-(2-cyano~4,5-dimethoxyphenyl)acetimidate (27.95 g) used directly.

Preparation 8 C 3 ~ ~ ~ C2 5 CH3 C~ CH3 ~ 3N NCH2C6~s - -CH3 ~ N ~ ~ NCH2C6 5 CH30 C~

The crude product (26.9 g) from the previous Preparation, N-benzylpiperazine (21 g) and p-toluenesulphonic acid (100 mg) were stirred together at 150 for 2 hours under a slight pressure reduction. On cooling, the residùè was taken up in methylene chloride and extracted with dilute hydrochloric acid (2N, 2 x 200 ml). The acid layer ~as adjusted to pH4 (5N NaOH), extracted with methylene chloride (2 x 200 ml) and the combined extracts discarded. The aqueous phase was then basified to pH9, extracted with methylene chloride (3 x 200 ~1), the combined extracts washed with brine, dried (Na SO4) and evaporated in vacuo. The residue was purified by column chromatography (Merck 9385 sillca, 400 g) ~Z5~6~7~

eluting with methylene chloride/methanol (100:0 -~98:2) and a sample of the product (11.68 g) was taken up in ethyl acetate-methanol and treated with ethereal hydrogen chloride. The solid ~as treated with ether and dried to give N-[1-(4-benzyl-piperazin-1-yl)ethylidene]-2-cyano-4,5-dimethoxyaniline -dihydrochloride hydrate 9 m.p. 181-182.

Found: C,56.6; H,6.7; N,11.9 Calculated for C22H26N4022HCl.H20: C,56.3; H,6.4; N,ll.9.

Pl,C 351C

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula:

(I) or a pharmaceutically acceptable acid addition salt thereof, where-in R is -N(C1-C4 alkyl)2, piperidino, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl or a group of the formula where Y is H, C1-C6 alkyl, aryl or C1-C4 alkyl substituted by aryl or Y is seleeted from (a) -COR1 where R1 is a C1-C6 alkyl, C1-C4 alkyl substituted by aryl, (C3-C6 cycloalkyl)methyl, aryl, styryl, 2-furyl, 2-tetra-hydrofuryl, 2-benzo-1,4-dioxanyl, 2-chromanyl, 5-methylthio-2-(1,3,4-oxadiazolyl) or 2-quinolyl group;
(b) -CONHR2 where R2 is C1-C6 alkyl, aryl, C1-C4 alkyl sub-stituted by aryl, (C2-C4 alkenyl)methyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl)methyl; and (e) -COOR3 where R3 is C1-C6 alkyl, C1-C4 alkyl substituted by aryl, C2-C4 alkyl substituted other than on an .alpha.-carbon atom by hydroxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)methyl, (C2-C4 alkenyl)methyl, or aryl; aryl, wherever it occurs, meaning phenyl, naphthyl or phenyl substituted by 1 or 2 substituents each selected from halo, CF3, C1-C4 alkyl and C1-C4 alkoxy, or by a single methylenedioxy group.

2. A compound according to claim 1, in which R is , Y is -COR1 and R1 is 2-furyl, benzodioxan-2-yl, chroman-2-yl, phenyl, p-fluorophenyl, 3,4-methylenedioxyphenyl, methyl, cyclopropylmethyl, cyclopentyl, styryl, 2-naphthyl or 2-quinolyl.

3. A compound according to claim 1, in which R is , Y is -CONHR2 and R2 is phenyl, cyclopropylmethyl, benzyl, n-propyl or allyl.

4. A compound according to claim 1, in which R is , Y is COOR3 and R3 is ethyl, isobutyl, 2-hydroxy-2-methylpropyl, cyclopropylmethyl, p-fluorophenyl, benzyl or 2-methylallyl.

5. 4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxy-quinoline and its pharmaceutically acceptable acid addition salts.

6. 4-Amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinoline and its pharmaceutically acceptable acid addition salts.

7. 4-Amino-6,7-dimethoxy-2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline and its pharmaceutically acceptable acid addition salts.

8. A process for preparing a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, which comprises cyclising a compound of the formula:

wherein R is as defined in claim 1; then, if necessary, carry-ing out any one or more of the following steps:
(i) debenzylating a product of formula (I) in which R
is 4-benzyl-piperazin-2-yl to form a compound in which R is piperazino;
(ii) acylating a product of formula (I) in which R is piperazino, with a compound of the formula R1COQ in which R1 is as defined in claim 1 and Q is a facile leaving group, to form a compound in which R is ;

(iii) reacting a product of formula (I) in which R is piperazino, with an isocyanate of the formula R2?NCO or a carbamoyl chloride of the formula R2?NHCOCl, in which R2 is as defined in claim 1, to form a compound in which R is ;

(iv) reacting a product of formula (I) in which R is piperazino, with a compound of the formula R3OCOQ in which R3 is as defined in claim 1 and Q is a facile leaving group, to form a compound in which R is and then, if required, converting the product to a pharmaceutic-ally acceptable acid addition salt thereof.

9. A process according to claim 8 including step (ii), in which R is piperazino or 4-benzyl-piperazin-1-yl and R1 is a 2-furyl group.

10. A process according to claim 8 including step (ii), in which R is piperazino or 4-benzyl-piperazin-1-yl and R1 is a benzo-1,4-dioxan-2-yl group.

11. A process according to claim 8 including step (iv), in which R is piperazino or 4-benzyl-piperazin-1-yl and R3 is an alkenyl-methyl group, wherein the product is further reacted with concentrated sulphuric acid to form a compound in which R3 is a hydroxyalkyl-methyl group, and then, if required, con-verting the product to a pharmaceutica]ly acceptable acid addition salt.

12. A process according to claim 8 wherein R is a 4-(2-furoyl)piperazin-1-yl group.

13. A process according to claim 8 wherein R is 4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl group.

14. A process according to claim 8 wherein R is a (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)quinoline group.

15. A pharmaceutical composition comprising a compound as claimed in claim 1, 2 or 3 and a pharmaceutically acceptable carrier material.

16. A pharmaceutical composition comprising a compound as claimed in claim 5, 6 or 7 and a pharmaceutically acceptable carrier material.

17. A process for preparing a pharmaceutical composition for use in treating hypertension, which process comprises incorporating a compound as claimed in claim 1, 2 or 3 as active ingredient in the composition, together with a pharmaceutically acceptable carrier material.

18. A process for preparing a pharmaceutical composition for use in treating hypertension, which process comprises incorporating a compound as claimed in claim 5, 6 or 7 as active ingredient in the composition, together with a pharmaceutically acceptable carrier material.