CA1144163A - Sulfur-containing isoquinoline derivatives, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

ABSTRACT
The invention concerns new sulfur-containing isoquinoline derivatives.
More particularly, the invention relates to isoquinoline derivatives of the gen-eral formula (I) (I) wherein R independently represents hydrogen, hydroxyl or alkoxy having 1 to 4 carbon atoms, R1 is hydrogen, alkyl having 1 to 4 carbon atoms and optionally substituted with phenyl, phenyl optionally substituted with one or more halogen or alkoxy group, cyano or carbamoyl, R2 is phenyl optionally substituted with one or more halogen, alkoxy or carboxyl, or a group of the general formula A

Description

114~63 Sulfur-oontainin~ i~oauinoline derivati~
prooee~ ~or the preparation thereo~ and pharma-¢eutical composition~ containi~e them This invention relates to new ~ulfur-- and salts and cyclic acid amide~ thereof containing l~oquinoline deri~atives~. More p~rticularly, the invention conoern~ ne~ suliur-containing i~oquinoline derivativea of the g~neral formula tI) ~ 2 R - CH - S - R

~herei~
R independently repre~ents hgdrogen, h~droxyl or alkoxy havi~g 1 to 4 carbon atoms, Rl is hydrogen, alkyl having 1 to 4 carbon-atome ~nd optionally sub~t~tuted with phe~yl, phenyl optionally substituted with one or more halogen or alkoxy group, cya~o or carbamoyl, R2 i~ phenyl optio~ally substituted ~ith o~e ~r more halogen, alkoxy or carboxyl, or a.grDUp o~ the general formula A

¦-CH ~ C~2 ~ R4 A
A1~4~ S3~JGM

~4~L63 wherein R is hydrogen, a straight or branched chain alkyl having 1 to 4 carbon atoms or phenyl; m and n independently represent 0, 1 or 2, with the proviso that m + n is at least l; R is hydrogen, phenyl, hydroxyl, acyloxy, carboxyl, alkoxycarbonyl having 1 to 6 carbon atoms, carbamoyl, carbazoyl or dialkylamino containing 1 to 6 carbon atoms in the alkyl moieties; or R is a straight or branched chain alkenyl group having 2 to 6 carbon atoms, and the dotted line stands for a further carbon-carbon bond or hydrogen atoms in the 3- and 4-positions of the ring, or a pharmaceutically acceptable salt thereof, or a cyclic amide of formula VII

R ~ N - \ (VII) (CIH2)n Rl _ C (CH - R )m S /
wherein R, R , R , n and m and the dotted line are as defined above, or a cyclic amide of formula VIII

~ ~ (VIII) :wherein R, R and the dotted line are as defined above.
According to a further aspect of the invention there is provided a process for the preparation of these compounds.
According to the present invention there are also provided pharmaceu-: tical compositions containing as active ingredient a compound of the general : - 2 -formula I in admixture with one or more conventional pharmaceutical carriers.
It is known that isoquinoline derivatives which have an analogous structure but contain a heterocyclic R in the general formula I are potent spasmolytic and vasodilating substances (see Published - 2a -, . .. .

Japane~e Patent Applicatione No~. 76,32,569;
76,80,867~ 76,86,478 and 76,86,477) These analogeoue compounde were prepared b~ reacting l-halomethyl--ieoquinoline derivatives ~ith heterocyclic compound~
containing a sulfhydrile group in a manner known per _ We have ~urprieingly found that the ne~ ieo-quinoline derivativee of the general formula (I) have ~aluable pharmaceutical propertiee. P~ore parti¢ularly, they promote the production of proetaglandine-E2 from arachidonic a¢id and therefore ahow diuretic, anti-a~th~atic, antii~flammatory and hypoten~ive aoti~ity.
Ao¢ording to the invention ne~ i~oquinoli~e derivative~ o~ the general formula tI) are prepared by the following method~:
a) The compound3 of the ge~eral formula (I) in whioh R i3 hydrogen or alk~x~ having 1 to 4 carbon atom~, Rl, R2 and-the dotted line sre ae defined above, ars prepared by reacti~g i~oquinoline derivative~ oi the general formula tII) 8 ~ N ~II) Rl - CH - Hal ~herein R i~ a~ de~ined immediately hereinabove, R
and the dotted line are as defined above, and Hal repreeent~ halogen, ~44~63 -- 4 _ ~lth thiole of the g~neral forfflula tIII) R2 _ SH tIII) ~herein R i8 a~ deiined above.
b) ~he compound~ of the generaL formula (I~
~n whioh R i~ hydrogen or ~n alkyL harin~ L to 4 carbo~
atomo, Rl a~d the dotted line are a~ defined above, a~d R2 repre~enta a group of the general fDrmula A, in ~hioh ~3, R , m and n are a~ defiued above, are pre-pared b~ hydroly~ing isothiuronium salt~ of the general formula ~IV) , ~
IR 1~ ~
. Rl - CH - S - C - ~H2 in ~hioh R 1~ as deiined immediately hereinabove, R
~d the dotted line are ae defined nbove, and X~ repre~e~ts one equi~ale~t of a~ organi¢ or in-organio anio~, i~ ~n alkaline medium, and sub~equ~ntly reaoting the thiolate~ oi the ge~eral formula (V) ~R ~3 R~ S
obt~ined, wherêin R, Rl and the dotted line are aa .
deii~sd herei~above and ,:

Ye+ represe~ts Dne equivalent of a~ organi¢ or inorgan~o cation, with halideo of the ge~ral formula tVI) R2 _ Hal tVI) ~herein R2 ha~ the ~ame me~ing a~ defined above a~d Hal etande ~or a h~logen atom.
If desired, the iaoquinoLine derlvativea oi the general ~ormula (I), wherein Rl, R2 and the do~ted line are a~ de~ined above, and ~ i9 alkoxy having 1 to 4 carbon atom~, ¢an be deDalkylated i~to oompound~ of the ~e~ersl formula tI) i~ which R i9 a hydroxyl group s~d Rl, R2 and the dotted li~e sxe as defined above.
If deoired, the oompounds of the general .
formul~ ~I), in which R repre~ents a group of the general ~ormula A, R3, m end n are as here~nbe~ore defi~ed and * i~ hgdrQxyl can be co~verted into deriYative~ which eontain a~ a~yloxy group in place o~ * by a¢ylation.
The ieoquinoli~e derivativee of the ge~eral formula (I) i~ which R2 stand~ for a group of the g~ral formula A, R3, m and n are ae de~ d ~bove, aud R4 le ¢arboxyl or carbalkoxy whiLe R, Rl ~nd the dotted lil~e are ae hereinbefore defined, ca~ be

2 5 conv~rted l~to othsr i~oqui~oline derivatives of the ge~eral formula ~I), in uh~ch R2 i9 a group of th~
general formula A, in which R, Rl, R3, m, n a~d the .

~4~63 dotted line are as defined above, and R4 is an alkoxycarbonyl group having 1 to 6 carbon atoms, carbamoyl or carbazoyl group, by esterification, amidation and formation of a hydrazide, respectively. The same starting compounds can be converted into cyclic acid amides of the general formula (VII~

~CH2)n ¦ (VII) Rl _ C j CH-R3) wherein R, Rl, R3 and the dotted line are as defined above, by using a suitable dehydrating agent.
The isoquinoline derivatives of the general formula (I), in which R2 stands for a 2-carboxyphenyl group, and R, Rl and the dotted line are as here-inbefore defined, can be converted into cyclic acid amides of the general for-mula (VIII) R ~ (Vlll~

wherein R, R and the dotted line are as defined i~44~L~3 7 _ above, by treating with ~uitable dehydrsting age~t~.
If deaired, the compounds c~ the general formula (I) ~hioh oontain a carboxyl group can be converted i~to their ~alt~.
The pro¢es~ variant a) can b~ accompli8~ed in an org~nic, prefer~bly in an alcoholic medium, in the pre~ence of ~oid binding agents. As acid bindi~g agente alkali metal alcoholate~, hydro~dea or oarbonate~ c~ be used. ~he reation i~ carried out a~ a temperature between O C and 120 C, pre- -~erably at the boiling temperature of the sDlvent employed. In the ca~e o~ o~idation-~eneitive ¢ompoundo the prooe~s i~ performed under i~ert atmosphere. A~
an inert ga~ nitrogen or argon can adva~tageoualy be u~ed. According to a pre~erred embodiment o~ the procese is~quinoline derivatiYee of the general ~ormula (II) or the solution~ thereof are added intD
a ~olution of thiols of the general formula ~III) and the dehgdrating agent. A re~ersed order is, ~owever, equally po~ible.
Isoquinoline derivatives o~ the general formula (II) uaed as startin~ material~ are either kuown or can be prepared by literature known method~
~DOS No. 2,426,?67, J. Chem. Soc., 1931, 36~ and Arch. Pharm. t 277, 177 /1939/).
The alkaline hgdroLysie aocording to pro~ess variant b) i~ preferably carried out with alkali ~1~4~63 met~l hydro~ide~, in a mixture of water-mi~cible orE~nio ~olvent~ a~d water. The reactio~ i~ prefersb-ly socompli~hed in aqueou~ alcohol~. It i~ preferred to promote the prQgre~ of hydrolyei0 by heating the reaoti~n mixture, e.g. by boiling ror 1 or 2 hour~. ~he thiolate~ o~ the general formula (V) produced b~ hydroly~io ~ee~ not be ~eparated from the reaction ~ixture, the halides of the g~eral formula tVI) oan direotly be added into the hydroly~is mixturo.
~o complete the reaotion the reaction mi~ture i8 pre-~erably bo~led also in thi~ reactio~ ~tep. ~o aroid oxidation ~ide-reaotiona the reaction i~ preferably performed under inort gas atmo~phere. ~he i~othiuro-~ium ~alt~ of the generai formula (IV) u~ed as atart-ing oompou~ds are prepared by reaoting isoquinoline deri~atives of the ge~ral formula (II) with thi~ures.
~he oonver~ion of the R alkoxy gr~ups into hydrox~ groupe is oarried out by ~no~n desalkylati~g ~ethods, ~or example by an a¢idic reactant, such as pyridine hydroohloride u~der heati~g.
The R hydroxyl group ¢an be a¢ylated by reao.ti~e c~rboxylio acid derirativec. Su¢h derirative~ i~cludo for e~mple acid anhydrideo and acid halides. The 'res.¢tio~ i~ perforlDed ln a~ i~ert organi¢ 801VeD.t, or in Qsoe~a o~ the acyLati~g age~t.
~he R4 carboxyl group can be e3terified by ~ own method~, or ¢an be con~erted into carbamoyl or ¢ar~azoyl group~ b~r rea¢tion w~th ammonia and hydrazi~e, ~4~63 re~pectively. The e~ter~ are preferably prepared in an alcoholic medium, by boiling the reaction mixture, The acid amide~ and acid hydr~zide~ are preferably obtained through the oorre~ponding e~tere, ~hio~ are reacted ~ith ammonia or hydrazine.
~he cyolic amides of the general formula (VII) and tVIII) are preferably prepared by reacting i~o-qul~oline derivatives of the general formula (I), i~
which R ie carboxyl with dehydrating agent~, e.g.
aoid a~hydride~, pre~erably acetic ac~d a~hydride or di¢yclohe~yl-carbodiimide. ~he cyclio amide~ ca~ be reconverted into the corre~ponding carbQ~ylic acid by hydrDlyei~.
The isoquinolyl derivatives of the ge~eral ~ormula (I), which oontain a group capable of ~ormi~g ~alte, aan be converted into the correspDnding salts by reacting with basio and aaide, resprectively, in a man~er known per se.
The isoquinoline derivative~ of the g~neral rormula (I) ~btained can be i~olated by know~ techniquee, ~uch aa filtratio~, evaporation, cry~tallization, e~traotlo~, and can be puri~ied by typioal purifica-tion technique~ of organic ¢hemi~try, for example re-ory~tsllization. The preparatio~ of salt~ can be u~ed al~o ~or purification.
The termo "alkyl" or "alkQsy" having 1 to 4 or 1 to 6 oarbon atom~ re~er to ~traight or branohed chained hydrocarbon groups which are attached to the adjacent moiety through an optional carbon atom thereof. These groups include alkyl groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, n- and isopropyl, n-, iso- and sec.-and tert.- butyl-groups. Alkyl groups having 1 to 6 carbon atoms also include pentyl and hexyl groups. The corresponding alkoxy groups can be derived from the alkyl groups listed above.
The term "halogen" refers to fluorine, chlorine, bromine and iodine atoms.
The term "organic or inorganic basis and acids'~ is used to refer to hydroxides containing alkalimetal, alkali earth metal J ammonium and various substituted ammonium ions; halohydrogenic acids, inorganic oxiacids, organic aliphatic and aromatic carboxylic acids. The cations and anions, which can be derived therefrom are Me cations and X anions. Preferred representatives of said bases are sodium, potassiumj and calcium hydroxides, ammonium hydroxide;
preferred acids are hydrochloric acid, sulfuric acid, phosphoric acid, benzoic acid, oxalic acid, tartaric acid and the cations and anions are preferably de-rived from the above-listed bases and acids.
The effect of the compounds of the general formula (I) on the bio-synthesis of prostaglandins was determined by a known technique (J. Biol. Chem., 246, 6700 /1971/). As an enzyme source a homogenizate of spermatocele of sheeps and as a substrate arachidonic acid were used. The transformation of the substrate, which involves oxygen consumption, was monitored on the basis of the change of the concentration of dissolved oxygen, which was measured by a Clark electrode. During the measurements the concentration of the active compounds, which involved a 50% and 100%, respectively increase in the oxygen consumption were determined. The concentrations were expressed in ~M/lit.
The results obtained are contained in the Table below.
Table The effect of the compounds of the general formula (I) on the activity of cyclic oxygenase Substrate: arachidonic acid Example No. AC50% 100%

3 100 200

4 70 140 ~: i - 12 _ The diuretio activity of the oomp~u~d~ of the general formula (I) ~as tested o~ rat~. The qu~ntity of the urine pa~ed in 4 hour~ a~d o~ the diecharged Na+ snd K~ ions ~ere determi~ed by kno~n methode ~Arz~eimitt. For~oh. 27, 559 /1978/)~ The s~tiinrlammatory aoti~ity ~aa te~ted i~ pa~ oedema 9~ rat~. The oedema was i~duced by oarrage~ee~ a~d the i~hibition ~a~ Qxpres~ed in ~0.
Accordi~g to a te~t oarried out o~ i~ol~ted traohea of guinea pig~ (J~ Pharm. Pharmac. 31, 798 /1979/) the ¢ompou~d~ prepared aocordi~g to the i~re~-tio~ have a relaxant activity. The compounde prepsred i~ Example 9 hae the ~ame actirity a~ theophylline ~hile the compou~d of Exampl2 4 ~ho~ a fire-time~
--hieher aotivlty tha~ theophylli~e related t~ a 95 to 100 % relasation~ A 1 ~ gJml. do~e of the produot Or Example 4 i~ five-times more effe¢tive tha~ theo-phylline but the compound of E~ample 9 ha~ only halP
of it~ effect. The acti~ity of the compounde obtai~od , in E~ample 4 ie ~ignifioant also at a doee of 0.1 ~ g~ml.
0~ ileum of guinea pige the compounds aooord-ing to the in~entiou eho~ a~ antagoni~tic actiYity ~gai~et acotylcoline and hi~tamine (Turner, R., 8ereening ~ethoda ~n Pharmacolog~, Aoademy Pre~o, . 25 ~o~ York, 1965~ p. 42-43). When u~ed in a 50 /ug/ml.
antagonietic dose againet acetylcoline theophylli~e re~ult~ i~ a 16 % i~hi~ition. ~he compDund of Example 1~44163 9 ha~ the same activity, while the product of E~ample 4 i~ eix-time~ more ac~ive. The maximum inhibition in the ca~e of theophylli~e ia 30 % (at ~ do~e of 200 /ug/ml.), of the ¢ompou~d of E~ample 4 ~ ic 100 % (in a do~e of 50 /ug/ml.), in the oa~e of the compound obtained in Example 9 i~ 55 ~ (in a doee of 100 ~ g/ml.).
When used in a 50 ~ g/ml. antagoni~tic dose theophylline causes a 18 % inhibition again~t histami~eO
The compound of Example 9 ha~ the same effect ao theo-phylline. The compound obtai~ed in Example 4 ie six-time~ more potent. Tha maximum inhibition for theo-phglline i~ 37 % (in a do~e of 200 ~ /ml.~, for the produ¢t of Example 4 ie 100 ~ (50 ~ g/ml.) ior the compou~d oi Example 9 is 26 % (100 ~ g/ml.).
The eeroto~ine a~tagoni~tic e~fect o~ the compound~ according to the inve~tion was examined o~
a gaatri¢ fundu~ ~trip of rats (8r. J. Pharm. 12, 344-349 /1957/). A 10 p g/ml. anta~oni~tic do~e of theop~ylline pr~ced a 8 ~, that of the compound of Example 8 a 8 ~, bhat of the compound oi E~smple 6 a 16 ~ and thst of the compound obtsi~ed in Example 4 a 80 % i~hibitio~.
Compounds of the genersl formula (I) can be u~ed in the therapy in the form of oompo~itiona co~tai~ing the active lngredient~ alo~g with inert, ~olid or llquid, orgs~ic or inorganic carrier~. The ~ ", 1~44~63 compositions are prepared by conventional techniques o pharmaceutical industry.
The compositions can be formulated as formulations suitable for oral, parenteral administra-tion or for inspiration. Suitable formulations include for example tablets, dragées, capsules, lozenges, powder mixtures, aerosol sprays, aqueous suspensions or solutions, injectable solutions or syrups. The formulations can contain suitable solid diluents or carriers, a sterile aqueous solvent or a non-toxic organic solvent. The formulations prepared for oral administration also contain conventional sweetening and aroma agents.
As a carrier of tablets for oral administra-tion for example lactose, sodium citrate, calcium carbonate and disintegrating substances for example starch, alginic acid; lubricants, for example talc, sodium-lauryl sulfate, magnesium stearate can be used.
Typical carriers for capsules are lactose and polyethylene glycol. The aqueous suspensions can also contain emulsifying or suspensing agents. In the suspensions prepared with organic diluents for example ethanol, glycerine and chloroform can be used.
The compositions suitable for parenteral administration or inspiration are suitable solutions or suspensions of the active ingredient. Suitable solvents, or diluents are for example peanut oil, sesame oil, polypropylene glycol or water. The injection formulations can be administered intra-venously, intramuscularly or subcutaneously.
The injection solutions are preferably produced with water and the pH is adjusted to a suitable value. Isotonic salt or glucose solutions can also be prepared.
If the compositions are to be used for curing asthma, they are administrated through inspiration by the conventional inhalating and inspirating equipments.
The pharmaceutical compositions can contain 0,005 to 90% of active ingredient. The effective daily dose can be varied within a wide range depend-ing on the state, age, weight of the patient, on the formulation used and on the activity of the specific active ingredient used.
In the case of oral administration the daily dose generally is 0,05 to 15 mg/kg~ and if the ad-ministration is effected by inspiration or intra-venously, the compounds can be administered in a 0.001 to 5 mg/kg. dose once or more times a day.
The above data are for orientation only and in concrete cases amendments in both directions are allowed.
Capsules containing 40 mg. of active ingredient can for example be prepared as follows:

~.~.g,4iL63 400.0 g. o a compound of the general formula (I) 1590.0 g. of lactose and 10 0 g. of magnesium stearate are admixed homogenously and filled into hard gelatine capsules in 200.0 mg. portions. 10,000 pieces of capsules containing 40 mg. of active ingredient are prepared.
Further details of the invention are to be found in the following Examples which illustrate but do not limit the invention.
Example 1 To 8.0 g. of [a-cyano-a-6,7-dimethoxy-3,4-dihydro-l-isoquinolyl]-methyl-isothiuronium bromide 80 ml. of a 96% alcohol and 24 ml. of a 10% aqueous sodium hydroxide solution are added and the reaction mixture is refluxed for two hours. 2 ml. of ethyl iodide in 20 ml. of alcohol are then added and the mixture is refluxed for further six hours. The solvent is evaporated in vacuo and to the residue water is added. 5.6 g. of a-(ethylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 113 to 115C after crystallization from absolute ethanol.
Analysis for cl5H18N202S (290-38):
calculated: C 62.04%, H 6.25%, N 9.65%, S 11.04%
found: C 62.00%, H 6.10%, N 9.73%, S 11.15%.

, Example 2 Starting from 8.0 g S-(-cyano-~ 6,7-dimethoxy-3,4-dihydro-isoquinolyl)~methyl-isothiuronium bromide and 2.5 ml. of allyl bromide and following the procedure described in Example 1 5.1 g. of -(allyl-mercapto)-6,7-dimethoxy-3,4-dihydro-isoquinolyl-acetonitrile are obtained, melting at 146 to 147 C
after recrystallization from absolute ethanol.
Analysis for C16H18N2O2S (302-35):
calculated: C 63.56% H 6.00% N 9.27%
found: C 63.77% H 6.25% N 9.54%.
Example 3 Starting from 8.0 g. of S-(-cyano-~-6,7-di-methoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide and 1.7 g. of ethylene chlorohydrine and following the procedure described in Example 1 6.3 g.
of -(2-hydroxy-ethylmercapto)-6,7-dimethoxy-3,4-di-hydro-l-isoquinolyl-acetonitrile are obtained, melting at 138 to 140 C after recrystallization from a 50%
aqueous ethanol solution.
Analysis for C15H18N2O3S (306.38):
calculated: C 58.80% H 5.92% N 9.14% S 10.47%
found: C 59.07% H 5.67% N 9.08% S 10.18%.
DL > 500 mg/kg. per os on mice. A 100 mg/kg. dose of the compound on rats in paw oedema test resulted in ` a 20% inhibition.

:

~,7.

Example 4 Starting from 8.0 g. of S-(a-cyano-a-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-iso-thiuronium bromide and 2.0 g. of 3-chloropropanol and following the procedure described in Example 1 6.2 g. of a-(3-hydroxy-propylmercapto)-6,7-di-methoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 155 to 156 C after recrystal-lization from absolute ethanol.
Analysis for C16H20N2O3S (320-41):
calculated: C 59.98% H 6.29% N 8.74% S 10.01%
found: C 59.96% H 6.33% N 8.89% S 10.39%.
LD50 ~ 500 mg/kg. p.o. on mice. A 100 mg/kg. p.o. dose of the compound on rats in paw oedema test resulted in a 20% inhibition.
Example 5 To 10.0 g. of S-(a-cyano-a-3,4-dihydro-1-iso-quinolyl)-methyl-isothiuronium bromide 200 ml. of a 96% alcohol and 40 ml. of a 10% aqueous sodium hydroxide solution are added and the reaction mixture is refluxed for two hours. A solution of 2.9 g. of chloroacetic acid in 30 ml. of alcohol is then added and the mixture is refluxed for further four hours. The solvent is evaporated in vacuo and 25 ml. of water are added to the residue. The solu-tion is decoloured by charcoal, filtered and its pH is adjusted to 4 with concentrated hydrochloric ' ' ~4~63 acid. 4.9 g. of ~carboxy-methyl-mercapto-3,4-di-hydro-ieoquinolyl-acetotlitrile are obtained, melting `at 159-160 C after recry~tallization ~rom ab~oLute ethanol.
Analyeia fDr C13H12N202 c~lculateds C 59.98 ~0 H 4.65 ~ N 10.76 % S 12.32 %
$ound : C 59.77 % H 4.72 ~ N 10~53 % S 11.94 %.
E~ample 6 Following the procedure of Example 5 but ~tarting from 19.2 g. oî S-(a-cya~o-c~6~7-dim~thoxg--3,4-dihydro~ oquino~rl)-methyl-icothiuronium bromide aQd 4.7 g. of chloroacetic acid 13.3 g. of cc-carbo~y-methyl-mercapto-6,7-dimethoxy-3,4-dihydro-1-i~oquinol~l--aoeton~trile are obtained, melting at 173 to 175 C
after recry~tallization from abcolute etha~ol.
Analy8i~ ~oX C15H16~24 ~3 37) oalculateds C 56.23 X H 5.03 % N 8.75 % S 10.01 %
fou~d : C 65.22 % H 4.89 % N 8.87 % S 10.04 %.
I~1)50 > 500 mg/kg. p.o. on mice. A 2 mg/l~g. do~e of the oompound increa~ed the qua~tity of the urine seoret~d to the eame extent ae a 2 mg/kg. p.~. dose of Hypo-thiazid.
Example 7 , Eollo~sing the procedure de~cribed in ~sample

5 but etarting from 2.5 g. OI S~ ieoquinol~rl-methgl)--i~othiuroniu~ chloride and 0.9 g. of chloroacetio aoid 1.3 g. of S-(l-ieoquinolyl-methyl~-thioglycoli¢

~ ,, acid are obtaincd, meltirlg at 186 to 187 C after reorystallization from absolute ethanol.
Analyeie for C12HllN02S (233.29):
calculated~ C 61.78 % H 4.75 ~0 N 6.01 % S 13.75 ~
found : C 61.96 % H 4.89 % N 6.01 ~0 S 14.10 %.
Example 8 Following the procedure described in Example 5 but ~tarting from 10.0 g. o~ S~ cyano-o_ -3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide and 3.4 e. o~ 3-chloropropionic acid, 5.4 g. of ~,(2--carboxyethyl)-mercapto~3,4-dihydro-1-i~oquinolgl--acetonitrile are obtained, melting at 149 to 150 C
a~ter recry~tallization from absolute ethQnol.
Analy~i8 for C14H14N202S (274.34~:
¢alculated: C 61.29 % H 5.14 % N 10.21 % S 11.69 ~
found : C 61.58 % H 5.30 % N 10.20 % S 11.97 %.
Example 9 Follo~ing the prooedure described in E~ample 5 but starting from 8.0 g. o~ S~ ¢yano-~6,7-di-methoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide and 2.3 g. of 3-ohloropropionic acid 5.5 g.
of a~t2-csrboxyethyl)-mercapto-6~7-dimetho~y-l-iso-quinolyl-acetonitrile are obtained~ melting at 169 to 170 C after recrystallization from absolute etha~ol.
A~alY~i8 for C16H18 2 4 calculated: C 57.47 % H 5.43 ~0 N 8038 ,oO S 9 . 59 ~0 found : C 57.l~4 % H 5.49 o~ N 8.34 % S 9.70 ~.

~i49~63 LD50 > 500 mg/kg. p.o. on mioe. A 2 mg/kg. dose of the compound increa~ed the quantitg OI the urine secreted to the ~ame exte~t aa a 2 mg/kg.
p.o. do~e of Hypothiazid.
Example 10 Following the procedure des¢ribed i~
Example 5 but starting from 10.0 g. of S-(c~cyano-~6,7-diethoxy-3,4-dih~dro-1-i~oqu~nolyl~-methyl--isothiuronium bromide a~d 2.6 g. of 3-chloroprDpionic acid, 6.0 g. o~ ~(2-carba~yethyl)-mercapto-6,7-di-ethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 106 to 108 C after rec~y~talliza-tion from a 50 % o~ an ~ueou~ ~:ohol solution.
Al~aly8i~ ~or ~18H22N245 (352.45):
calculated: S 8.85 fou~d : S 9.04 %.
Example 11 .
~ollowing the procedure de~cribed ir~
Ea~ample 5 but starting from 15.0 gO o~ S-tl-i~o-~uinolyLmethyl)-iaothiuronium chloride and 6.4 g.
oî 3-chloro-propionio acid, 8.0 g. o~ S-(l-iao-quinolyl-methyl)-3-mercapto-propionic acid are obtained, melting at 126 to 130 C aftel recryatalli~a~
tion ~rom abaolute ethanol.
A~aly8i~ for C13H13~02S (247.31):
calculateds S 12.97 %
fcund : S 12.65 %.

~14~63 am~e 12 Followi~g the prooedure de~cribed in Example 5 but ~tarting from 8.0 g. o~ S~ ¢ya~ora-

-6, 7-dimethoxy-3 ,4-dihydro~ oquinolyl)-methyl--isothiuronium bromide and 2,3 g. of 2-ohloropropionic a¢id, 5.1. g. of ~(1-carboxy-1-eth~l)-m~rcapto-6,7-~dimethoxy-3,~-dihydro~ oqui~olyl-acetonitrile are obtained, melting at 155 to 158 C after recry~talli . zation from ethyl acetate.
n Y 16 18 2 4 (334 39):
oalculateds S 9.59 ~h ~ou~d : S 9.22 %.
~xample 13 I Followi~ the procedure de~cribed in Example 5 but ~tarting from 15.0 g. of S-(l-i~oqui~olyl-methyl)--i~othiuronium chloride and 6.4 g. of 2;chloropropiouic aoid, 7.1 g. o~ S~(l-inoquinolyl-methy1)-2-mercapto-propionio acid are obtained, melting at 1~3 to 156 C
~ter re¢ry~talli~ation from a 96 % ethanol.
A~aly~i~ rOr C13HL3 2 ( 47 31):
oa~oulatod: C 63.13 % H 5.3~ o~ ~ 5.66 oh s 12.97 ~
i~Dl~ld s C 63.~0 ~0 H 5.6~ ~ ~A 5.33 ~ S t2.52 ~.
xa~ple 14 ~c 8.0 g. O~ ~-(~cybn~6~dimethoxg~-3~4 25. ~dih~rdr~ oquinolyl)-m0t~ othiuro~ium br~mide 80 ml. ~i a 96 h ethan~l and 24 ml. of` a 10 ~ aqueou~
aodium hydroxide 901utio~l are add~d and th~ rea¢tio~

mi~ture 1~ refluxed for 20 minute~. Into the boili~g colutio~ a eolution o~ 3.6 g. o~ 2~diethy1-amino--ethyl-chlorid~ hydro¢hloride in 10 ml. of water ie added drop~ioe. After atirring ~or ~urther three hour~ the ~olvent i~ evaporated in vacuo, the mixture i~ decoloured with charooal, ~iltered and acidified ~ith an alooholic hydrochloric acid solution. ~rom the ~olution 6.4 g. of a_(2-dieth~laminoethyl)-mercaptD--6,7-dimethox~-3,4-dihydro-1-i~oquinolyl-acetonitrile ; 10 ~ydrochloride are precipitated, melting at 169 to 172 C after recrystalllzatio~ ~rom aboolute ethanol.
~naly~i~ for ClgH28N302SC1 ~397.96):
calculated: C 57.34 ~ ~ 7.09 % N 10.56 ~ S 8006 %
Cl 8.91 %
?5 found : C 57.37-% H 7.05 ~ N 10.09 ~ S 7.83 %
Cl g.OO ~.
; Example 15 Following the procedure described in Example 14 but etarting ~rom 8.0 g. of S-(o~cyano--~6,7-dimethoxy-3,4-dihydro-1-ieoquinolyl)-methyl--ieothiuronium bromide a~d 3.0 g. o~ 2-dimethylamino--ethyl-chloride hgdrochlorlde, 6.6 ~. of ~-(2-di-m~thylaminoethyl)-mer¢apto-6,7-dimethoxy-3,4-dihydro-iaoqui~olyl-acetonitrile hydrochloride are obtainsd, melting ~t 210 to 212 C after recry~tallization from ab~olute alcohQl.

~."

ll~gS63 An81y~i~ for C17H 4N302SCl (369.91):
calculated: N 11.36 ~0 S 8.67 % Cl 9.59 %
found : N 11.21 % S 8.69 % Cl 9.78 %.
Example 16 Into a ~odium ethylate eolution prepared irom 0.46 g. of sodium and 50 ml. of ab~olute alcohol 1,54 g. of thio~alyoilic scid are added. The reactiDn mlxture i~ brought to the boil and into the boiling solution a ~olution o~ 3.1 g. of ~bromo-l-cyano-methyl--6,7-dimethoxy-3,4-dihydro-i~Dqui~oline i~ 100 ml. of absolute etha~ol i~ added dropwise. The mixture i8 boiled for further half an hour, and the 301vent ie evaporated i~ vacuo. To the evaporation residue 50 ml.
of water and a few dropc of a 10 % aqueous ~odium hgdroxide ~olution are added, the solutio~ i~ de~oured wlth ¢harcoal while hot and filtered. The pH of the filtrate i~ adjusted to 4 with concentrated hgdro-chlorio acid. 1.6 g. of ~,(2-carboxyphenyl)-mer¢apto--6,7-dimethoxy-3,4-dihydro~ oquinolyl-aceto~itrile are obtained, m~ing at 245 to 247 C after recrystall~za-tlon from a l:l mixture of DM~ and water.
Analyei~ ior C20Hl8N24S t382-43) ca~Gulsted: C 62.81 % H 4.74 ~0 ~ 7.33 ~
found : C 63.03 ,~ H 4.85 Y0 N 7.05 %.
Example 17 Following the procedure de~cribed i~ Example 16 but ~tarting from 1.8 g. of l-chloromethyl-i~o-quinoline and 1. 54 g. of thio~alycilic acid, 1.1 g.
of S~ isoquinolyl-meth~ 2-mercapto be~zoio acid are obtained, melting at 170 to 172 C.
Analy9i9 for C17H13N02S (295.35):
calculated: S 10.86 ~O
found : S 1~.50 ~.
E~ample 18 I

~o 3.2 g. of ~-carboxymethyl-meroapto-6,7--dimethoxy-3,4-dihydro-1-i~oquinolyl-acetonitril~
50 ml. of ab~olute alcohol a~d 0.3 ml. o~ c~centrated sulfuric acid are added. The reactiou mixture i~
xefluxed for ~ix hour~. ~he ~olution i~ evaporated to hal~ of its volume in vacuo. Upon cooling 1.7 g.
of o_(ethoxycarbonyl)-methyl-mercapto-6,7-dimethogy--3~4-dihydro~ oqui~ol~l -acetonitrile are obtained, melting at 128 to 130 C after recry~tallization from 96 % ethanol.
A~aly~i9 fQr Cl7H20 24 (3 cal¢ulated: C 58.60 % H 5.79 % N 8.04 ~ S 9.20 ~
found : C 59.02 % H 5.70 % N 8.37 % S 9.28 %.
ample l9 ~o 1.6 g. of ~,carboxymethyl-mercapto-6,7--di~ethosy-3,4-dihydro-1-isoquinolyl-s¢etonitrile 5 ml. of i~obuta~lol, 50 ml. o~ benzene and 3 drops o~ coRoentrated ~ulfuric acid are addedO ~he mixture i~ refluxed for 3 hours a~d then is eraporated to dryne~. The re~idue i~ cry~tallized by adding ~1~4~63 -- ~6 abeolute ethanol. 0.7 g. Df ~,12-butoxycarbonyl)--l~ethyl-mercapto-6,7-dimethoxy-3,4-dihydro~ oquinolyl-aceto nitrilé are obtained, me~ting at 113 to 114 C
after recry~tallization from absolute ethanol.
Analy~i~ for ClgH24N204S
calculated: C 60.61 % H 6.42 % N 7.44 y~ S 8.52 %
found : C 60.33 Y0 H 6.21 ~0 ~ 7.46 C/o S 8.30 G~o ExampLe 20 Following the procedure de~cribed in Exsmple 19 but starting ~rom 1.67 g. of ~-(2-csrboxyethyl)-msrcapto--6,7-dimethnxy-3,4-dihydro-isoqui~olyl-acetonitrile and 5 mL. of ieobutan~l 1.4 g. o~ a_~2-(2-butexycarbD~yl)--ethyl~-mercapto-6,7-dimethoxy-3~'l dihydro- 1-i8 oqui~olyl--acetonitrile are obtained, melti~g at 120 C after re-S cry~tallization from ab~olute etha~ol.20 26 2 4 ~al¢ulated: C 61.51 % H 6.71 % N 7.17 % S 8.21 ~
found : C 61.14 % H 6.70 % N 7.35 G~o S 8.48 %.
Example 21 ~llowi~g the procedure de~cribed i~ Example 19 but ~tarting from 1.67 g. of ~(2-csrboxyethyl)-mercapto--6,7-dimethoxy-3,4-dihydro-1-i~oquinvlyl-acetonitrile and 5 ml. of isoamyl alcohol, 1.7 g. of ~C2-t3-methyl--butoxycarbonyl)-ethyl~-mercapto-6,7-dimethoxy-3,4-di-hydro-l-isoquinolyl-acetonitrile are obtained, melti~g at 120 C after recrystallization from isopropanol.
Analy~i~ for C21H2 ~ 204S ( 404.52):
calculated: N 6.93 % S 7.93 Y~
~ound : ~ 7-93 ~o S 7.73 ~o-114g~163 -- 27 _ Examp e 22 To 3.5 g. oi ~tetho~YcarbonYl)~ethYl--mercapto-6,7-dimetho~y-3,4-dihydro-1-iaoquinolyl--acetonitrile 0.7 g. of hydrazine hydrate and 70 ml.
of ab~olute etha~ol are added and the reaction mixture i~ refluxed for 6 hours. Upon ~Goli~g 3.2 g.
of o~(ca*x~ydrazido-methyl)-mer¢apto-6,7-dimethoxy--394-dihydro~ oquinolyl-acetonitrile are cbtained a~ a ory~talline product melting at 192 to 194 C
a~ter recry~tallization from ab~olute e~hQnol.
Y 15H18~43S ~334-39) calculated: C 53.87 o~O H 5.42 % N 16.76 % S 9.59 %
found : a 54.22 % H 5.26 % N 16.30 ~0 S 9.89 %.
Example 23 To 1.0 g. o~ o_~2-hydroxyethylmercapto~-6,7--dimethoxy-3,4-dihgdro-1-i~oquinolyl-aceto~itrile 5 ml. of acetio anhydride and 15 ml. oi be~zene are added a~d the reacticn mixture i8 re~luxed for 4 hours.
The mixture i~ then evaporated to drynee3 a~d to the reoidue carbon tetrachloride i~ added. o.6 g.
or~2-acetoxyethyl-mercapto)-6,7_dimethoxy-3,4_ -dih~dro-l-i~oquinolyl-acetonitrile are obtai~ed, melting at l57 C a*tsr recry~tallizatio~ from butflnol.
A~alysis for C17H2oN~04S (348-41):
caloulated: C 58.60 % H 5.79 % N 8.04 % S 9~20 ~
~ound s C 58.62 % H 5.45 ~ N 8.46 % S 8.92 %.

.. ,~ ,, - 28 _ Example 24 ~o a pyridine ~olution of 3.2 gO o~ ~
-tcarbo~ymethyl-mercapto)-6,7-dimethoxy-3,4;dihydro-~ oquinolyl-aceto~itrile 2.1 g. of dioyclohexyl--carbodiimide are added. The reaction mixture i8 allo~ed to stand at room temperature for t~o day~.
~he ~olvont i~ evaporated in vacuo and the re~idue .
i~ re¢rystallized from buta~ol. 1.9 g. Df l-eyano--9,10-dimethoxy-3,4,6,7-tetrahydro-1,4-thiazi~o~3,4-~ iso~
quinoline-4-~ne are obtained, melting at 186 to 187 C
a~ter recrg~tallizatio~ ~rom buta~ol.
Analy8i~ for Cl5Hl4N2o3s (302-33)s oalculated: C 59.59 % H 4.66 % N 9.27 ~0 S 10.61 %
found s C 59013 ~ H 4.60 % N 8.93 % S 10.74 %.
Example 25 To 3.2 g. of ~carbo~ymethyl-mercapto~6,7--dimethoxy-3,4-dihydro~ oquin~lyl-aoetonitrile 15 ml.
of pyridine a~d 15 ml. of acetic anhydride are added.
~he 801utio~ i3 allowed to ~tand at roo~ temperature ior two dayc. 2.8 g~ o~ 1-Cyano-9,10-dimethoxy-3,4,6,7--tetrahydro-1,4-thiazinoL3,4-ali~Dquinoli~e-40ne are obtained in a cry~talli~e form. The product i~ identic~l with th~ product of Example 24.
Example 26 FD110Wing the procedure ds~cribed i~ Example 25 but ~tarting from 3.3 g. of ~tl-carbDxy-l-ethyl)--meroapto-6,7-dimethoxy-3,4-dihydro~ oquinolyl-aoeto-nitrlle, 2.5 g. of 1-cyano-3-methyl-9,10-dimethoxy ~3,4,6,7-tetrahydro-1,4-thiszino~3,4-aJisoquinolins--4-one are obtained, melting at 170 to 171 C after recry~tallization ~rom absolute ethanol.
n y~i for C16H16N203S (316.38)s oalculated: C 60.74 % H 5.10 % N 8.86 % S 10.14 %
found : C 60.32 % H 5.14 ~0 N 8.79 % S 10.14 %.
Example 27 Following the procedure de~cribed in Example 25 ~ut starting from 3.3 g. of ~-(2-carboxyethyl)--mer¢spto-6,7-dimethoxy-3,4-dih~dro-1-isoquinolyl--acetonitrile, 1.9 g. of l-cyano-10,11-dimetho~y--314,~-tetrahydro-5H-l,4-thiazepino~3,4-al i80-quinoline-5-one are obtained, melting at 192 to 194 C after recry~tallization from butanol.
Analysis for C16H16N203S
calculated: C 60.74 % H 5.10 % N 8.86 % S ~o-L4 ~
found : C 61~18 % H 5.41 % N 8.83 % S 10.30 %.
Example 28 ~ollowing the procedure described in Example 24 but starting from 2.3 g. o~ S-(l-isDquinolyl--methyl)-thioglycolic acid, 1.1 g. of 3,4-dihydro--1,4-thiazino~3,4-alisoquinolins-4-one are obtained, melting at 104 to 106 C after recry~tallizatio~
from absolute ethanol.
A~alysi~ for C12HgNOB t215.27):

..0,~.

~4S63 caloulated: C 66.95 ~ H 4.21 % N 6.52 ~ S 14.90 found : C 66.64 % H 4.44 % N 6.48 ~ S 15.06 ample 29 Pollowine the procedure des¢ribed in Ex~mpla 24 but etarting from 2.47 g. of S~ oquinolyl--methyl)-2-mercapto-prDpio~ic acid, 1.~ g. of 3--methgl-3,4-dihydro-1,4-thiazino~3,4-a~ieoquinoline--4-one are obtai~ed, melting at 67 to 68 C after recryetalliæation ~ro~ ab~olute etha~ol.
Analy~is for C13~Ll~OS ~229.30):
¢~bulated: C 68.09 % H 4.84 % N 6011 % S 13.99 ~
found : C 68.01 % H 4.9~ ~ N 6.13 ~ S 13.97 ~ -ExampLe 30 ~ollowi~g the prooedure ~scribed in E~ample 25 but ~tarting from 3.8 g. of ort2-carboxyphenyl)-meroapt -6,7-dimetho~y-3,4-dihydro-1 iso~ui~olyl-acetonitrlle, 2.7 g. of 1-cya~o-12,13-dimetho~y-9,10-dihydro-7H--be~zo~ -1,4-thia~epino[3,4-aJiooqzinoline-7-o~e are obtained, melting at 233 to 236 C a~ter re-cry~tallization from butanol.
Analy~ for C20Hl6N23 t364-42)s calculated: a 65.91 % H 4.43 % N 7.69 ~ S 8.80 %
found : C 65.60 % H 4.32 % N 7.61 % S 8.55 %.
E~ample 31 Following the procedure desGribed in ExampLe 25 but ~tarting from 2.95 g. of S-(l-isoquinolyl-~ethyl)--2-meroapto-benzoio acid, 2.1 g. of 7H-benzo~fl-1,4-~4~63 -- 3~ ---thiazepinoL3,4-aJ i30quinolille-7-one Rre obtained, melti~g at 178 to 180 C after recry~tallization from butanol.
Analy~io for C17Hl}NOS (277.33):
¢al¢ulated: N 5.05 ~ S 11; 56 S~
found : 151 5.00 ~ S 11.82 S~
Example 32 To 1.0 g. of 1-o~ano-12,13~dimethoxy-9,10--dihydro~ be~zo~ -1,4-thiqzepino~3,4~ o-quinoline-7-one 10 ml. of a 10 % aqueou~ ~odiulD
hydro~ide ~olution snd 20 ml. of alcohol are added.
The reaotion mixture is refLuxed for 8 hour~, where-upon i8 evaporated. The residue is dissolvsd irl water, the ~olution ia deooloured with charcoal, filtered ~nd acidified with a 5 ~ aqueous hydrochloric acid solution, 0.8 g. of c~(2-~arbo~yphenyl)-mercapto-- -6,7-dimethoxy-3,4-di~gdro-1-i~oquinoLyl-acetonitrile are obtained, which is identical with the produot of Example 16.
Example 33 To a sodium methylste ~olution prepsred from 0.46 g. of eodium and 50 ml. of ab~olute ethanol 1.1 g. o~ thiophenol sre added. The reaction mixture i8 brought to the boil and a eoLution o~ 3.1 g. of o~bromo-1-cyanomethyl-6,7-dimethoxy-3,4-dihydro-iso-quinoli~e in 100 ml. of ab~olute ethanol i~ added to the boiling ~olution. The mixture i~ boiled ior further 4 to 6 hour~ whereupon the ~olvent ie evaporated in vacuo. To the re~idue 20 ml. of ab~olut~ ethanol are added, the ~olution i~ deooloured with charcoal and filtered. 2.8 g. of c~p~enyl-~mer¢apto-6,7-dimethoxy-3,4-dihydro~ oquinolyl--acstonitrile are obtained in a crystQlline ~orm, melting at 160 to 161 C after recry~tallization from abeolute ethanol.
AnaLy~i8 for Cl9H18N22S (338-42) cal¢ulated: C 67.43 % H 5.36 % N 8.28 G~o S 9.48 ~o found : C 66.83 % H 5.49 % N 8.39 ~0 S 9.39 ~.
Example 34 ~ollowing the procedure described in ExampLe 33 but starting from 3.4 g. of ~bromo-1-cyan~methyl-6,7--diethoxy-3,4-dihydro-i~oquinoline and 1.1 g. o~ thio-phenol, 2.4 g. of ~,phenyl-mercapto-6,7-diethoxy-3,4--dihydro~ oquinolyl-a¢etonitrile are obtained, melting at ll8 to 119 C after recrystallization from abEolute ethanol.
Analy~i~ for C21H2 ~ 2 2 (3 7) calculateds C 68.82 % H 6.05 % ~ 7.65 % S 8.75 %
~ound s C 68.81 % H 6.51 % N 7.34 % S 8.62 ~.
Example 35 ~o 5.25 g. o~ ethoxycarbonylD-methyl-mercapto--6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile 20 ml~ of cool ab~olute ethanol and 20 ml. of a cool 25 % aqueous ammonia solution are added. ~he mixture ~4~63 i~ allo~ed to ~tand at room t~mperature ~or one dag.
The precipitated product in filtered off and d~ied to yield 3.9 g. o~ ~,(carboxamidomethyl)-mercapto--6,7-dimethoxy-3,4-dihydro-1-isoqui~olyl-acetonitrile, melting at 167 to 168 C after recrystallization from ab~olute ethanol.
Analy~i~ for C15H1 ~ 303S ~ (3 calculated: C 56.41 ~ H 5.37 % N 13.16 % S 10.04 %
~ound s C 56.59 ~ ~ 5.49 % ~ 13021 ~ S 9.91 ~.
Example 36 ~c 1.7 g. of ~-(l-carboxy-l-ethyl)-mercapto--6,7-dimethoxy-3,4-dihydro-l-i0oquinolyl-acetonitrile 10 ml. o~ abeoLute etha~ol and 0.2 ml. of concentrated eulfurio acid are added. The reaction mi~ure is re-fluxed ~cr 10 hours. UpDn cDoling 1.6 g. of ~
-ethoxycarbonyl-l-ethyl)-mercspto-6,7-dimethoxy-3,4--dihydro-l-i~oquinolyl-aceto~itriLe cry~tallize~ out from the rea¢tion mixture. Melting poi~t: 163 to 165 C a~ter recrystallizatio~ from a 75 ~0 aqueou~
eth~nol ~olutio~.
Analy~i~ for C18H2 ~ 204S (362.45):
oalculated: C 59.64 ~ H 6.12 % ~ 7.73 ~ S 8.85 %
~ound s C 59.24 % H 5.88 % ~ 7.93 % S 9.21 %.
Example 37 Followi~g the pro¢edure de~cribed in Example 33 but starting ~rom 3.1 g. of ~bromo-l-oya~omethyl--6,7-dimethoxy-3,4-dihydroxy-i~oqui~oline and 1.5 g of 4-chloro-thiophenol, 3.5 g. of ~4-chloro-phe~yl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-iao quinolyl-acetonitrile are obtained, melting at 135 to 136 C after recrystallization from ethgl aoetate.
AnalY~ or Cl9H17N22~Cl (372-87) oaloulated: a 61.20 ~ H 4.60 % ~ 7.51 % S 8.60 %
Cl 9.51 %
~ound : C 60.99 % H 4.65 % N 7.60 % S 8.70 %
Cl 9.71 ~0.

Followi~g the procedure deocribed in Example 33 but etarting from 3.1 g. of ~_bromo-l-cyanomethyl--6,7-diethoxy-3,4-dihydroiooquinoline a~d 1.5 g. of 4-chloro-thiophenol, 2,9 g. of ~-(4-chlor~phenyl)--mercapto-6~7-diethoxy-3,4-dihydro-1-i~oquinolyl--a~etonitrile are obtained, melting at 157 to 160 C
after recryatallization from absolute ethanol.
Analy0i~ for C21H21~202SCl (400.92):
oal~ulateds C 62.91 96 H 5.28 % N 6.99 g~ S 7.90 %
Cl 8.84 %
~ou~d s C 62.43 % H 5.26 ~ N 7.10 % S 7.56 %
Cl 8.81 %
Example 3~
8.3 g. of S~ ayano~o~6,7-diethoxy-3,4-di-h~rdro~ oquinolyl)-methgl-i00thiuro~ium bromide are dieeol~ed in 80 ml. o~ a 96 ~ ethanol ~Glution ~14~63 and 24 ml. of a 10 ~0 aqueous ~Gdium hydr~xide ~olutio~
under heating. The reaction mixture i~ reflu~ed for t~e hour~, whereupon a ~olution of 4.1 mL. ~f ethglene-- -chlorohgdrine in 20 ml. of ab~olute ethanol are added dropwise and the r~Dtion mixture i9 refluxed for fuxther four hours. ~he solvent i~ evaporated in vacuo and 40 ml. of water are added to the re~idue. 5.4 gO
of ~-(2-hydroxyethyl-mercapto)-6,7-diethoxy-3,4-di-hydro-l-i~oquinolylacetonitrile are sbtained in a cry~talliue fo~m, melting at 94 to 96 C after re-cry~tallization from ethyl acetate.
Analyei~ for C17H2 ~ 203S (334-44) oalculateds C 61.05 % H 6.63 % N 8.38 % S 9.59 ~0 fou~d : C 60.76 ~0 H 6.58 ~0 N 8.21 % S 9.70 ~0.
ample 40 Following the proced~re of Exampla 39 but ~tarti~g from 8.3 g. of S-(o~cyano-~-6,7-dietho~y--3,4-dihydro-1-i~oqui~olyL)-methyl-i~othiuronium bro~ide and 4.2 ml. sf 3-chloro-propanol, 3.5 g. of ~rt3-bgdr~3y-propyl-m~rcapto)-6,7-diethoxy-3,4-dibydro-1-isoquinolyl--acetonitrile are obtained, melting at 100 t lQ5 C
after re¢ryatallization from absolute ethanol.
Analy~iB for C18H24N23S (348.4Ç)~
cal~ulated: C 62.04 ~ H 6.94 % ~ 8.04 % S 9.20 %
fou~d : C 61.73 % H 6.54 % N 8.34 % S 8.80 %~

Claims (43)

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

1. A process for the preparation of an isoquinoline derivative of the general formula (I) (I) wherein R independently represents hydrogen, hydroxyl or alkoxy having 1 to 4 carbon atoms, R1 is hydrogen, alkyl having 1 to 4 carbon atoms and optionally substituted with phenyl, phenyl optionally substituted with one or more halogen, or alkoxy group, cyano or carbamoyl, R2 is phenyl optionally substituted with one or more halogen, alkoxy or carboxyl, or a group of the general formula A

(A) wherein R3 is hydrogen, a straight or branched chain alkyl having 1 to 4 carbon atoms or phenyl, m and n independently represent 0, 1 or 2, with the proviso that m + n is at least 1, R4 is hydrogen, phenyl, hydroxyl, acyloxy, carboxyl, alkoxycarbonyl having 1 to 6 carbon atoms, carbamoyl, carbazoyl or dialkylamino containing 1 to 6 carbon atoms in the alkyl moieties, or R2 is a straight or branched chain alkenyl group having 2 to 6 carbon atoms, and the dotted line stands for a further carbon-carbon bond or hydrogen atoms in the 3- and 4-positions of the ring, or a pharmaceutically acceptable salt thereof, or a cyclic amide of formula VII
(VII) wherein R, R1, R3, n and m and the dotted line are as defined above, or a cyclic amide of formula (VIII) (VIII) wherein R, R1 and the dotted line are as defined above, which process comprises a) to prepare an isoquinoline derivative of the general formula (I) in which R is hydrogen or alkoxy having 1 to 4 carbon atoms and R1, R2 and the dotted line are as defined above, reacting an isoquinoline derivative of the general formula (II) (II) wherein R is hydrogen or alkoxy having 1 to 4 carbon atoms, and the dotted line have the meaning defined above, and Hal represents a halogen atom, with a thiol of the general formula (III) R2 - SH (III) wherein R2 is as defined above; or b) to prepare a compound of the general formula (I), in which R is hydrogen or alkoxy having 1 to 4 carbon atoms, and the dotted line are as defined above, and R2 represents a group of the formula (A), wherein R3, R4, m and n are as defined above, hydrolysing an isothiuronium salt of the general formula (IV) (IV) wherein R, R1 and the dotted line are as defined above, and X- is one equivalent of an organic or inorganic anion, in an alkaline medium and subsequently reacting the thiolate of the general formula (V) (V) wherein R, R1 and the dotted line are as defined above and Me+ is one equivalent of an organic or inorganic cation, with a halide of the general formula (VI) R2 - Hal (VI) wherein R2 is as defined above, and Hal represents halogen, without isolation, and if required, desalkylating an obtained compound of the general formula (I), in which R is alkoxy having 1 to 4 carbon atoms and R1, R2 and the dotted line are as defined above to obtain an isoquinoline derivative of the general formula (I), in which R represents hydroxyl, and R1, R2 and the dotted line are as defined above; or, if required, acylating an obtained isoquinoline compound of the general formula (I), in which R2 represents a group of the formula A, wherein R3, m and n are as defined above, and R4 is hydroxyl, R, R1 and the dotted line are as defined above, to obtain a corresponding derivative of the general formula (I), in which R4 represents an acyloxy group; or, if required, converting an obtained isoquinoline compound of the general formula (I) in which R2 represents a group of the general formula A, in which R3, m and n are as defined above and R4 is a carboxyl or carbalkoxy group, and R, R1 and the dotted line are as defined above, into the corresponding compound of the general formula (I), in which R2 represents a group of the general formula (A), wherein R3, m and n are as defined above, R and R1 and the dotted line are as defined above and R4 is alkoxycarbonyl having 1 to 6 carbon atoms, carbamoyl or carbazoyl by esterification, amidation or hydrazide formation, respectively, or into a cyclic acid amide of the general formula (VII) (VII) wherein R, R1, m, n and the dotted line are as defined above, by treatment with a dehydrating agent; or converting an obtained isoquinoline compound of the general formula (I) in which R2 is 2-carboxyphenyl and R, R1 and the dotted line are as defined above, into a cyclic amide of the general formula (VIII) (VIII) wherein R, R1 and the dotted line are as defined above, by treatment with a dehydrating agent, or if required, converting an isoquinoline compound of the general formula (I) in which R, R1, R2 and the dotted line are as defined above, into a pharmaceutically acceptable salt thereof.

2. A process according to claim 1(a), wherein the reaction is carried out in an organic solvent and in the presence of a base.

3. A process according to claim 1(b) wherein the reaction is carried out in a mixture of water-miscible organic solvent and water and in the presence of an alkali metal hydroxide.

4. A process according to claim 1, 2 or 3 for the preparation of a compound of the general formula (I) in which R
is hydroxyl and R1, R2 and the dotted line are as defined in claim 1, which includes the step of desalkylating a compound of formula I in which R is alkoxy having 1 to 4 carbon atoms with pyridine hydrochloride at a temperature of 100 to 250°C.

5. A process according to claim 1, 2 or 3 for the preparation of a compound of the general formula (I), in which R2 is a group of the general formula (A), in which R4 is an acyloxy group and R3, m and n are as defined in claim 1, and R, R1 and the dotted line are as defined in claim 1, which includes the step of acylating a compound of the general formula (I) in which R2 represents a group of the general formula (A), in which R4 is hydroxyl and R3, m and n are as defined above, R, R1 and the dotted line are as defined above, with an acid anhydride or acid halide.

6. A process according to claim 1, 2 or 3 for the preparation of a compound of the general formula (I) in which R represents a group of the general formula (A), in which R is alkoxycarbonyl having 1 to 6 carbon atoms, R3, m, n, R, R1 and the dotted line are as defined in claim 1, which includes the step of esterifying a compound of the general formula (I) in which R2 represents a group of the general formula A, in which R4 is carboxyl and R3, m, n, R, R1 and the dotted line are as defined above, in an alkanol having 1 to 6 carbon atoms, in the presence of an acid catalyst, under reflux.

7. A process according to claim 1 for the preparation of a compound of the general formula (I) in which R2 represents a group of the general formula (A), in which R4 is carbamoyl or carbazoyl, R3, m, n, R, R1 and the dotted line are as defined in claim 1, which includes the step of converting a compound of the general formula (I) in which R2 represents a group of the general formula (A), in which R4 is alkoxycarbonyl having 1 to 6 carbon atoms, R3, m, n, R, R1 and the dotted line are as defined in claim 1 into the corresponding acid amide or acid hydrazide, respectively in an organic solvent.

8. A process according to claim 7 wherein the reaction is carried out in an alkanol at a temperature between 0°C and 130°C.

9. A process according to claim 1, 2 or 3 for the preparation of a pharmaceutically acceptable salt of a compound of the general formula (I), which includes the step of reacting the compound of general formula (I), in a mixture of water and a water-miscible organic solvent, with an alkali metal hydroxide, at a temperature between 0°C and 130°C.

10. A process according to claim 1, 2 or 3 wherein the two R's are the same and are both hydrogen, methoxy or ethoxy, is hydrogen or cyano, R2 is ethyl, allyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 2-diethylamino-ethyl, 2-dimethylaminoethyl, 2-carboxyphenyl, ethoxycarbonyl-methyl, 2-butoxycarbonyl-methyl, 2-(2-butoxycarbonyl)-ethyl, 2-(3-methyl-1-butoxycarbonyl)-ethyl, carbazoylmethyl, 2-acetoxyethyl, phenyl, carboxamido-methyl or 4-chlorophenyl and the dotted line stands for further hydrogen atoms.

11. A process according to claim 1, 2 or 3 wherein the two R's are the same and are both hydrogen or methoxy, R1 is hydrogen or cyano, the dotted line stands for further hydrogen atoms, R2 is a group of formula (A) in which R is hydrogen or methyl, m is I
and n is zero or 1 and the process includes the step of treatment with a dehydrating agent to obtain a cyclic amide of formula (VII).

12. A process according to claim 1, 2 or 3 wherein the two R's are the same and are both hydrogen or methoxy, R1 is hydrogen or cyano and R2 is 2-carboxyphenyl and the process includes the step of treatment with a dehydrating agent to obtain a cyclic amide of formula (VIII).

13. An isoquinoline compound of formula (I) or a cyclic amide of formula (VII) or (VIII) or a pharmaceutically acceptable salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

14. A process according to claim 1, 2 or 3 wherein both R's are methoxy, R1 is cyano, R2 is 2-hydroxyethyl and the dotted line represents further hydrogen atoms.

15. A process for preparing .alpha. -(2-hydroxy-ethylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile which comprises hydrolysing S-(.alpha. -cyano-.alpha.-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide with aqueous sodium hydroxide and reacting the product with ethylene chlorohydrin.

16. The compound .alpha. -(2-hydroxy-ethylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile when prepared by a process according to claim 15 or an obvious chemical equivalent thereof.

17. A process according to claim 1, 2 or 3 wherein both R's are methoxy, Rl is cyano, R2 is 3-hydroxypropyl and the dotted line represents further hydrogen atoms.

18. A process for preparing .alpha. -(3-hydroxy-propylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile which comprises hydrolysing S-(.alpha. -cyanol-.alpha.-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide with aqueous sodium hydroxide and reacting the product with 3-chloropropanol.

19. The compound .alpha. -(3-hydroxy-propylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile when prepared by a process according to claim 18 or an obvious chemical equivalent thereof.

20. A process according to claim 1, 2 or 3 wherein both R's are hydrogen, R1 is cyano, R2 is carboxy-methyl and the dotted line represents further hydrogen atoms.

21. A process for preparing .alpha. -carboxy-methyl-mercapto-3,4-dihydro-isoquinolyl-acetonitrile which comprises hydrolysing S-(.alpha.-cyano-.alpha.-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide with aqueous sodium hydroxide and reacting the product with chloroacetic acid.

22. The compound .alpha.-carboxy-methyl-mercapto-3,4-dihydro-isoquinolyl-acetonitrile when prepared by a process according to claim 21 or an obvious chemical equivalent thereof.

23. A process according to claim 1, 2 or 3 wherein both R's are methoxy, R1 is cyano, R2 is carboxymethyl and the dotted line represents further hydrogen atoms.

24. A process for preparing .alpha.-carboxy-methyl-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile which comprises hydrolysing S-(.alpha.-cyano-.alpha.-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-methyl-isothiuronium bromide and reacting the product with chloroacetic acid.

25. The compound .alpha. -carboxymethyl-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile when prepared by a process according to claim 24 or an obvious chemical equivalent thereof.

26. A process according to claim 1, 2 or 3 wherein both R's are hydrogen, Rl is cyano, R2 is 2-carboxyethyl and the dotted line represents further hydrogen atoms.

27. A process for preparing .alpha.-(2-carboxyethyl)-mercapto-3,4-dihydro-1-isoquinolyl-acetonitrile which comprises hydrolysing S-(.alpha.-cyano-.alpha.-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide with aqueous sodium hydroxide and reacting the product with 3-chloropropionic acid.

28. The compound .alpha.-(2-carboxyethyl)-mercapto-3,4-dihydro-l-isoquinolyl-acetonitrile when prepared by the process according to claim 27 or an obvious chemical equivalent thereof.

29. A process according to claim 1, 2 or 3 wherein both R's are methoxy, Rl is cyano, R2 is 1-carboxyethyl and the dotted line represents further hydrogen atoms.

30. A process for preparing .alpha.-(1-carboxy-1-ethyl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile which comprises hydrolysing S-(.alpha.-cyano-.alpha.-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide with aqueous sodium hydroxide and reacting the product with 2-chloropropionic acid.

36. The compound .alpha.-(1-carboxy-1-ethyl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile when prepared by a process according to claim 30 or an obvious chemical equivalent thereof.

32. A process according to claim 1, 2 or 3 wherein both R's are methoxy, R1 is cyano, R2 is 2-diethylaminoethyl and the dotted line represents further hydrogen atoms.

33. A process for preparing .alpha.-(2-diethylaminoethyl)-mercapto-6,7-aimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile or its hydrochloride salt which comp-ises hydrolysing S-(.alpha. -cyanoi-.alpha.-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide with aqueous sodium hydroxide reacting the product with 2-diethylamino-ethyl-chloride hydrochloride to obtain the hydrochloride salt and, if required, converting the hydrochloride salt to the free base.

34. The compound .alpha. -(2-diethylaminoethyl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile or its hydrochloride salt when prepared by a process according to claim 33 or an obvious chemical equivalent thereof.

35. A process according to claim 1, 2 or 3 wherein both R's are methoxy, R1 is cyano, R2 is 2-dimethylaminoethyl and the dotted line represents further hydrogen atoms.

36. A process for preparing .alpha.-(2-dimethylaminoethyl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile or its hydrochloride salt which comprises hydrolysing S-(.alpha.-cyano-.alpha.-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuronium bromide with aqueous sodium hydroxide, reacting the product with 2-dimethylaminoethyl-chloride hydrochloride to obtain the hydrochloride salt and, if required, converting the hydrochloride salt to the free base.

37. The compound .alpha.-(2-dimethylaminoethyl)-mercapto-6,7 dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile or its hydrochloride salt when prepared by a process according to claim 36 or an obvious chemical equivalent thereof.

38. A process according to claim 1, 2 or 3 wherein both R's are methoxy, R1 is cyano, R2 is ethoxycarbonylmethyl and the dotted line represents further hydrogen atoms.

39. A process for preparing .alpha.-(ethoxycarbonyl)-methyl-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile which comprises subjecting .alpha.-carboxymethyl-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile, prepared by a process according to claim 24 or an obvious chemical equivalent thereof, to esterification with ethanol.

40. The compound .alpha.-(ethoxycarbonyl)-methyl-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile when prepared by a process according to claim 39 or an obvious chemical equivalent thereof.

41. A process according to claim 1, 2 or 3 wherein both R's are methoxy, R1 is cyano, R2 is carbohydrazido-methyl and the dotted line represents further hydrogen atoms.

42. A process for preparing .alpha.-(carbohydrazido-methyl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile which comprises reacting .alpha.-(ethoxycarbonyl)-methyl-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile, prepared by a process according to claim 39 or an obvious chemical equivalent thereof, with hydrazine hydrate.

43. The compound .alpha.-(carbohydrazido-methyl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile when prepared by a process according to claim 42 or an obvious chemical equivalent thereof.