CA1230875A - Bicyclic nitrogen heterocyclic ethers and thioethers, and their pharmaceutical uses - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to a class of bicyclic nitrogen heterocyclic ether and thioether compounds having the general formula:

wherein:
W1 is CH, CH2, CHR or CR;
W2 and W3 are independently CH, CH2, CHR3 or CR3;
X is N or CH, or (CH)3-d, when Y is (CH)d;
Y is O, S, or NR4, or (CH)d, when X is (CH)3-d;
Z is O, S, , , or CH2;
and wherein:
R is alkyl, halo, alkoxy, hydroxy, hydroxy alkyl, halo alkyl, -(CH2)n-NR8R9,, or ;
R1 is H, alkyl, acyl, haloalkyl, alkoxy alkyl, hydroxyalkyl, aminoalkyl, mono- and di-alkylamino alkyl, or together with W1 forms a carbon-nitrogen double bond;
R2 is selected from the group consisting of NH2, , , , , , and ;

R3 is alkyl, halo, alkoxy, hydroxy, hydroxy alkyl, haloalkyl, aminoalkyl, mono- and di-alkylamino alkyl, amino, alkylamino, or dialkylamino;
R4 is H, alkyl, or acyl;
R5 is H or alkyl;
R6 is H, alkyl or acyl;
R8 and R9 are each independently hydrogen, alkyl, or both together with the nitrogen to which they are attached form a 5, 6 or 7-membered ring which may in-clude one to three additional hetero atoms of N, O or S;
and wherein:
a is 0 or 1;
b is 1 or 2;
c is 0, 1 or 2;
d is 0, 1, 2 or 3;
e is 1 or 2;
f is 1, 2, 3, or 4;
n is 0, 1, 2, or 3;

and the acid addition salts thereof. These compounds exhibit physiological activity in mammals including anti-secretory activity, histamine H2-receptor antagonist activity, anti-ulcer activity and cytoprotective activity.

Description

~X~(~875 Field of the Invention This invention relates to a class of bicyclic heterocyclic compounds characterized by an ether or thither substituent on the bicyclic ring system and methods for the treatment of physiological disorders, including gastrointestinal disorders, such as peptic ulcer, in humans and other mammals.

Retorted Developments Gastrointestinal hyperacid secretion, stomach and intestinal ulceration, and ghostwrites are major gas-trointestinal disorders observed in the general adult populations of industrialized societies. Many factors, including the production of excess gastric acid and the weakening of the lining of the stomach and gastrointestinal tract against such acid are implicated as causes of these disorders. Traditional treatment of these disorders has involved the administration of antacids to neutralize the excess gastric acid and the I

administration of anti secretory drugs which generally reduce the production of all gastric secretions.
In the last few years, the treatment of gastrointestinal disorders such as peptic ulcer has changed to include the use of anti-secretory drugs which selectively block the production of gastric acid.
These drugs are believed to interfere with the body's physiological pathway responsible for the production of gastric acid by blocking the action of histamine.
Histamine production is induced in the body by a number of stimuli, including stress, allergic reaction, etc., and acts to increase gastric secretion, dilate blood vessels and stimulate smooth muscle tissue. Histamine is believed to function by way of interaction with histamine receptors in the body. The subdivision of these receptors into two groups, the Hi- and H2-receptors, was proposed by Ash and Child (Bruit. J.
Pharmacol. Chemother, 1966, 27, 427) and Black et at (Nature 1972, 236, 385). The Hl-receptor is involved in the bronchial and gastrointestinal smooth muscle stimulative action of histamine. Drugs which block this action are labeled "antihistamines" (erg.
mepyramine).
Black et at, cited above, described the group of substances which act at histamine receptors other than the Hl-receptor as H2-receptor agonists/antagonists.
Blocking the action of histamine at the H2-receptors will selectively block histamine's stimulative action on gastric acid secretion and heart rate. Burimamide was the first clinically effective H2-receptor ant ago-nit inhibiting gastric secretion in man; but Burimam-ides oral absorptivity is poor. Subsequent studies developed the orally active Metiamide, the side effects of which limited clinical use, and Cimetidine which has 1~30~375 been marketed as an anti-ulcer drug. A number of classes of heterocyclic chemical compounds have been reported as H2-receptor antagonists, for example, those disclosed in US. Pat. Nos. 4,104,381, 4,279,819, 4,323,566, and British published patent application GO
AYE.

Another method for the prevention or treatment of gastric ulcer comprises the use of drugs which neither neutralize nor inhibit the secretion of gastric acid. These drugs constitute a class of anti-ulcer compounds which function to enhance the normal defense mechanisms of the body, rather than to reduce normal body secretions, and are described as "cytoprotective"
agents. It has been proposed that such agents act to strengthen the mucosal lining of the gastrointestinal system by one or more mechanisms, thereby preventing any damage which could result from the action of strong gastric acid. Prostaglandins have bee implicate in the mechanism of cytoprotection by a number Ox wormers in the field. See, the discussion of cytop~ote_tion I
Robert, Andre, "Prosta~lar.di~s art Digestive Diseases", Advances in Prostaqlandin an Thromboxane ~ese2rch, Vol. 8 (raven Press, NAY. 1980), and Robert et at, "Cytopro~ection by Prostaglandins in Rats", Gastroenteroloqv, 77, 433-443 (1979). Drugs, other than prostaglandins, which exhibit cytoprotective activity include carbenoxolone sodium, reported to exhibit undesirable side effects, such as edema, diastolic hypertension or hypokalemia, and the thiazol-

2-yl-carbamoylcarboxylic acids, esters and immediacy described in US. Pat. No 4,321,372.

4 12;~375 The compounds of the present invention are a class of novel bicyclic heterocyclics which exhibit cytoprotective, anti-secretory, H2-receptor antagonist and anti-ulcer activity.

Summary of the Invention This invention comprises a class of compounds according to Formula I

Waco We -X
, (Shea - Z - (showoff -- R2 Al I y /
(Wallaby wherein:
We is OH, SHEA, CUR or OR;
We and We are independently OH, SHEA, CRY or CRY;
X is N or OH, or (Chad, when Y is Chad;
Y is 0, S, or NR4, or (Chad, when X is Chad;
Z is 0, S, I, So , or SHEA;
O O O
and wherein:
R is alkyd, halo, alkoxy, hydroxy, hydroxy alkyd, NH o halo alkyd, -~CH2)n-NRgRg, -C-NRgRg, or -C-NRgRg;
Al is H, alkyd, azalea, haloalkyl, alkoxy alkyd, hydroxyalkyl, aminoalkyl, moo- and di-alkylamino alkyd, or together with We forms a carbon-nitrogen double bond;
R2 is selected from the group consisting of NH2, -C-NH2, -ON, ~230~3~5 N - ON N - ON
-NH -C - NOR 5, -NH -C - S -a lay l, \\ if NH N-- NOR 6, -NH -C - NOR 5, N So alkaryl N , and 3 -NH -NH N
No H

R3 it alkyd, halo, alkoxy, hydroxy, hydroxy alkyd, haloalkyl, aminoalkyl, moo- and di-alkylamino alkyd, amino, alkylamino, or dialkylamino;
R4 is H, alkyd, or azalea;
Us is H or alkyd;
R6 is H, alkyd or azalea;
R8 and Rug are each independently hydrogen, alkyd, or both together with the nitrogen to which they are attached form a 5, 6 or 7-membered ring which Jay in-elude one to three additional hotter atoms of N, O or S;
and wherein:
a is O or l;
b is 1 or 2;
c is 0, 1 or 2;
d is 0, 1, 2 or 3;
e is 1 or 2;
f is 1, 2, 3, or 4;
n is 0, 1, 2, or 3;

and the acid addition salts thereof.
Compounds within the scope of Formula I exhibit physiological activity in mammals including anti-secre-tory activity, histamine H2-receptor antagonist anti-viny, anti-ulcer activity, and cytoprotective activity.
This invention also relates to methods for the treatment and prevention of gastrointestinal hyperacidity and ulcerogenic disorders in humans and owner mammals comprising administering to a patient an effective amount of a compound with the description of Formula I.

Detailed Description of the Invention Preferred classes of compounds are described with respect to Formula I as follows:
PA) Wherein:
We, We and We are OH;
b and c are l; and Al together with I forms a double bond;
or (B) Wherein:
We is CUR or SHEA; and We and We are SHEA;
or (C) Wherein either A or B above apply, and X is (Chad;
Y is (Chad;
Z is O; and a is zero;
or 7 38'7S

(D) Wherein either A or B above apply, and X is N or I
Y it o, S or NR4;
z is S; and a is 1.

A most preferred class of compounds within the scope of Formula I comprises the isoquinoline and the dip and tetrahydroisoquinoline compounds. Of this class, the compounds of Formulae II and III are of particular interest.

R3 (R when the 1-position is substituted) N III

Al R R7 CH2CH2C~2-R2 In Formulae II and III, R, R2 and R3 are as defined above; Al is H, alkyd, substituted alkyd, azalea or loge-then with R7 forms a carbon-nitrogen double bond; and R7 is H or together with Al forms a carbon-nitrogen double bond; provided that in Formula III when Al and R7 form a double bond then R is other than alkyd, halo, alkoxy, hydroxy, hydroxy alkyd or halo ~lkyl. In Forum-ice II and III~ the R2 propoxy substituent may be sub-stituted at the 5, 6, 7 or 8 position.

8 ~Z3(~ s Another preferred embodiment of this invention comprises the bicyclic compounds including a heteroatom in both rings and including a thither ring substitu-en as defined herein. This embodiment includes the compounds of Formulae IV and V

R3 (R when the l-position is substituted) (SHEA I

CH2-S-CH2CH~R2 V
/ (Wallaby Al wherein We is CRY when b is 1 or SHEA when b is 2, and R, Al, R2, R7, X, Y, b and c are as defined above.
A particularly interesting class of compounds according to Formula V comprises those compounds where-in Y is oxygen and b and c are 1.
The compounds of Formulae I to V may also form hydrates and exhibit tautomerism. Formula I is intent dyed to encompass all hydrates and tautomers, as well as any diastereomer~ and optical enantiomers.
As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Alkyd" means a saturated aliphatic hydrocarbon which may be either straight- or branched-chained.
Preferred alkyd groups have no more than about 6 carbon ~2;30~3~5 atoms and may be methyl, ethyl and structural isomers of propel, bottle, ponytail, and Huxley.
Lower alkyd" means an alkyd group as adore, having 1 to about 4 carbon atoms. Examples of lower alkyd groups are methyl, ethyl, n-propyl, isopropyl, bottle, sec-butyl, and tert-butyl.
The term "halo includes all four halogens;
namely, fluorine, chlorine, bromide and iodine.
Fluorine and chlorine are preferred.
The "azalea radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group such as acutely, propionyl, 3-carboxy propionyl, bouncily, etc. Preferred azalea radicals are radicals of lower alkyd organic acids.
"Substituted alkyd" means an alkyd group substituted by a halo, alkoxy, hydroxy, amino, moo- or di-alkylamino group.
"Haloalkyl" means an alkyd group substituted by a halo group. The haloalkyls include groups having one or more halo substituents which may be the same or different, such as trifluoromethyl.
Alkoxy" means the ox radical of an alkyd group, preferably a lower alkyd group, such as methoxy, ethics, n-propoxy, and i-propoxy.
"Alkoxy alkyd" means an alkyd group substituted by an alkoxy group as defined above.
"Hydroxy alkyd" means an alkyd group substituted by a hydroxy group.
"Amino alkyd" means an alkyd group substituted by an amino group.
"Moo- or di-alkylamino alkyd" means an alkyd group substituted by an alkyd- or di-alkyl-substituted amino group.

0~3~75 "Alkylamino" means a primary or secondary alkyd-substituted amino group.
Representative examples of compounds of this invention are listed below in Tables A, B, C and D.

I 37~
TABLE A

wherein substitution may be at the 5,6,7 or 8 position _ . _ NHCN

NON

IClHNO2 NHCN
If I
-NH -C-NHCH 3 No NON
If Jo --NH -C--NH 2 No 12 123~375 TABLE A

OC82c82c~2R2 wherein substitution may be at the 5,6,7 or 8 position NUN

NUN

-NH-C-S-CH3 N~CH3)2 NUN
-NH -C -S -OH 3 -No,>

NUN
-NH-C-S-CH 3 -No 13 .5 TABLE A

wherein substitution may be at the 5,6,7 or 8 position .

NUN I C~2 I NHCH3 --NH N O

O SHEA
HO SHEA

-NH No 2 I, N ON SHEA

// \\ H
N N
S
o TABLE A

OC~2cH2cH2R2 wherein substitution may be at the 5,6,7 or 8 position If I\ -N
N N
S

SHEA
N - N

SHEA

SHEA\
N N I
-N

~l~3087~';

TABLE A

, oCH2CH2CH2R2 wherein substitution may be at the 5,6,7 or 8 position SHEA

--NH N NH 2 No SHEA
NUN
No -NH No NH2 \_/

SHEA
NUN
// \\ -N g SHEA
NUN NH
// \\ --C -NH 2 SHEA
N N O

I\

TABLE: A

No_, OX H SUE SHEA OR 2 wherein substitution may be at the 5, 6, 7 or 8 position SHEA
N N

I\ -C~2-NH2 SHEA
NUN
// \\ CON
--NH No NH2 SHEA
N N
-NF~CH3 SHEA
NUN
N(CH3) 2 17 ~2301375 TABLE A

No oCH2CH2CH2R2 wherein substitution may be at the 5,6,7 or position SHEA
N N
--CHINOOK

SHEA
N -N
I -CHIN ( OH 3 ) 2 SHEA
NUN NH
C -N ( OH 3 ) 2 SHEA
N - N NH

Et NUN
Jo -H

assay TABLE A

OCH~CH2CH2R2 wherein substitution may be at the 5,6,7 or 8 position ON -N

-NH N N~CH3 NSO2N~2 NO 2 NH 2 /--\

NO 2 NH 2 Jo Insane 19 ~23~ 75 TABLE A

wherein substitution may be at the 5,6,7 or 8 position .

--C-NH 2 No ,N,SO2NH2 NH
-C-NH 2 -'C-~3 2 NS02NH2 o -C -NH 2 -N ( C H 3 ) 2 -C -NH 2 -CEIL 2NHC En 3 ~L2~375 TABLE A

OCR2CRzCl~zRz wherein substitution may be at the 5,6,7 or 8 position ~NS02NH2 --C-NH2 -SHEEHAN SHEA ) 2 INSANE NH
-C -NH 2 -C -N ( OH 3 ) 2 ~N~S02NH2 NH

21' TABLE B

OCH2cH2cH2~2 Al R R7 wherein substitution may be at the 5, 6, 7 or 8 position Al R2 R R7 _ NON

Dublin OH 2 I double bond I l SHEA bond with R7 -NH O with Al double HO SHEA double bond NHCH 3 bond with R7 -NH N N SHEA with R

double HO SHEA double bond N bond with R7 -NH N ON SHEA with R

double // \\ Nat double bond No N bond with R7 S with R

22 12~ 375 TABLE s N ocH2cH2cK2R2 Al R R7 wherein substitution may be at the 5,6,7 or 8 position Al R2 R R7 .. . .

-NH \ NH2 double NH2double bond N N bond with R7 S with R

-NH NH2 Jo double -N double bond No ON bond with R7 S with R

SHEA H H
I

SHEA H H
S

I

23 8~5 TABLE B
-~_ocH2cE~2cH2R2 N

Al R R7 wherein substitution may be at the 5,6,7 or 8 position Al R2 R R7 .
C~2 l l HO I
SHEA I H H

O SHEA

-NH 1 > H H

SHEA
NUN
Et I H H

CjHNO 2 Et -NH-C-NH 2 H H

NON

NUN
If n-propyl -NH-C-NHCH3 H H

lo 5 TABLE B

No} OUCH SHEA SHEA OR 2 Al R R7 wherein substitution may be at the 5, 5, 7 or 8 position Al R2 R I
. . . _ SHEA\
double N -\ double bond -N bond with R7-HN N NH2 with R

SHEA\
double N N double bond -N 3 bond with R7 -HO N NH2 with R

double N - double bond -N bond with R7 -HO N NH2 \~/ with R

SHEA
double N - N double bond -N S bond with R7 -HO N NH2 \--/ with R

SHEA
double N N. double bond -N J bond with R7 OHM N NO with R

..

~L23~375 TABLE B

OCH2CH2cH2R2 Al R R7 wherein substitution may be at the 5,6,7 or 8 position Al R2 R R7 SHEA
Dublin N double bond -CH2-N~2bond with R7 -HO N NH2 with R

OH I
double N double bond -CHINCH bond with R7 - HO N NH2 with R

SHEA
double -N double bond Al \\ -SHEEHAN bond with R7 -HO "-ON ~`~NH2 With R

SHEA
double - N double bond -SHEEHAN 3 bond with R7 -HO N NH2 with R

SHEA
double -N double bond -CH2-N(CH3)2bond with R7 -HO N NH2 with R

~3~)~75 TABLE B

I_ OCH2cEl2cH2R2 Al R R7 wherein substitution may be at the 5, 6, 7 or 8 position Al R2 R R7 . .
SHEA
double N N NH double bond -C-NH2 bond with R7 - HO N NH2 with R

SHEA\
double N -N NH double bond -NHCH3 bond with R7-HN N NH2 with R

SHEA
double N N NH double bond -~-N(CH3)2bond with R7 -HO N NH2 with R

double double bond NISSAN bond wit t h R 7 -C -NH 2 NH 2 wit t h R

double double bond IlS02NH2 bond with R7 -C--NH2 NHCH3 with R

double double bond NO 2NH2 bond with R7 -C-NH2 NH(CH3)2with Al ~30~7~i TABLE B

f ~-OCH2CH2CH2R2 N

Al R R7 wherein substitution may be at the 5,6,7 or 8 position Al R2 R R7 double double bond I~S02NH2 -N bond with R7 -C-NH2 with R

double double bond INSANE -No bond with R7 -C-NH2 with R

double double bond llS2NH2 -N O bond with R7 -C-NH2 with R

double double bond INSANE -N S bond with R7 -C-NH2 with R

double double bond INSANE -N J bond with R7 -C-NH2 with R

double double bond SNOW bond with R7 ~C-NH2 SHEEHAN we to R

28 ~2~0~3~S
TABLE B

No OUCH SHEA 2C~ OR 2 Al R R7 wherein substitution may be at the 5,6,7 or 8 position .
double double bond ~N~so2NH2 bond with R7 -C-NH2 -CHINCH with R

double double bond IlS02NH2 bond with R7 -C-NH2-CH2N(CH3)2 with R

double double bond ~NISo2NH2CH2N bond with R7 -C-NH2 with R

double double bond NS02NH2 bond with R7 -C-NH2 CHIN with R

double double bond NISSAN NH bond with R7 -C-NH2 -C-NHCH3 with R

double double bond INSANE NH bond with R7 -C-NH2 -C-NH2 with R

29 ~3~375 TABLE B

N oC~2CH2CH2R2 Al R R7 wherein substitution may be at the 5,6,7 or 8 position Al R2 R R7 .
dub to duo b to bond NS2NH2 1l bond With R7 --IC-NH2 -C-NHCH3 With R1 double double bond NS02NH2 o bond Wit t h R7 -C-NH2 -C-N(CH3)2 wit t h R 1 double NH double bond ~NS02NH2 -C-N/ bond with R7 -C-NH2 wit to R1 NISSAN

~N~so2NH2 NISSAN
OH 3 -C-NH 2 -OH ON ( I 3 ) 2 H

OH 3 -C-NH 2 OH ON ) H

~230~
TABLE B

No OcH2cH2cH~R2 Al R R7 wherein substitution may be at the 5, 6, 7 or 8 position Al R2 R R7 Inlays 2NH 2 NH

llS2NH2 NH

OH 3 -C-NH 2-C -N ( OH 3 ) 2 En OH 3 -C-NH 2 -C -N I) H

TABLE C

>_ CH2SCH2CH2R2 Y may be oxygen or sulfur NHCN

NON
NH-C-NH2 c~3 SHEEHAN

SHEEHAN

NUN

HO SHEA O

-NH N O> NHCH3 32 12;3~
TABLE C

CE~2SCH2C~2R2 N Y

Y may be oxygen or sulfur > -N 3 NHCN

NHCN
-N~-C-NHCH3 -SHEA-O SHEA

-NH N N SHEA

S SUE

.~.

33 23~375 TABLE C

R I- CH2SCH2C~2R2 Y may be oxygen or sulfur -NH ~NHC H 3 // Jo H
N` N
S

I

SHEA
N No SHEA
NUN O

SHEA
N - N
-Chinese 3 ~30~

TABLE C

N I/ y R

Y may be oxygen or sulfur SHEA
N N.
SHEEHAN S C~3 2 Et No Jo H
-NH N /J~NHC H 3 HO ON
I\ H
-NH Jo No NHCH 3 SHEA
NUN

SHEA
N N

TABLE C

OH 2 SUCH 2C~ OR 2 Y may be oxygen or sulfur SHEA
N N \

-NH N No /--\

SHEA
NUN ,/--~
~<~ -N I

SHEA
N N NH

TABLE C

CH2SC~2CH2R2 Y may be oxygen or sulfur _ .
SHEA
N NH
CON
--NH N Ho SHEA
N - N NH
<\ -C -NHCH 3 Ions 2NH 2 NO 2NH 2 /--\\
--C--NH2 -N Jo INSANE
--C--NH 2 -No) I [)~375 TABLE C

No Y
R

Y may be oxygen or sulfur NS2~H2 NISSAN NH

NISSAN

INSANE

NS02NH2 /--\

Taste D

f CH~SCH2CH2R2 / N O
Al R R7 .. . . . _ NICK

SHEEHAN

double SHEA 0 double bond > SHEA bond with R7 -NH N O with R

double HO SHEA double bond NHCH3 bond with R7 -NH N N SHEA with -NH \ NH2 double N(F,t)2 double bond N \ / N bond with R7 S with R

double ~NH2 double bond N ON bond with R7 S with R

~23~S

TAB LYE

N O
Pal R R7 Al R2 R R7 .

SHEA H H
/

--Nil NHC H 3 SHEA H H
S

o O SHEA

I H H

p SHEA

an I owe H

SHEA
N N
Et I H H

I I
TABLE D

/ N O
Al R R7 Al R2 R R7 .
SHEEHAN
Et-NH-C-NH2 H H

NON
CHINOOKS SHEA H

NUN
n-propyl -NH-C-NHCH3 H H

SHEA
N N NH
SHEA -C-NH2 En SHEA\
N N NH

SHEA\
N - N NH
-C-N H

SHEA\
N -N NH

-NH N No 2 41 lo TABLE D

Al R R7 Al R2 R R7 OH I
N N o SHEA I Ho H

OH 3\
N- N
SHEA SHEEHAN H

SHEA\

SHEEHAN No NH2 -SHEEHAN H

SHEA
N N
SHEA Jo -CHINCH H

SHEA\
double N N ~--~ double bond -N I> bond with R7-NH N NH2 with R

_, 42 1'~3C)~75 TALE D

. / N O
Al R R7 Al R2 R R7 :
SHEA
double N N double bond -N bond With R7--NH N NH2 with R

OH I
double N N I double bond -N J bond with R7 -NH N NH2 with R

SHEA
double --N double bond -N O bond with R7 NO N NH2 \ J with R

double N N double bond N S bond with R7 -NH N NH2 with R

SHEA
double N - N NH double bond -C-NH2 bond with R7 -NH N NH2 with R

43 12~ 5 TABLE D

No CH2ScH2cH2R2 Al R R7 Al R2 R R7 .
SHEA
double N --N NH double bond -C-NHCH3bond with R7-NH N NH2 with R

double N NH /_--\ double bond \ -C-N bond with R7-NH N NHz with R

Kiwi double - N NH double bond -C-N J bond with R7-NH N NH2 with R

double - N Al double bond -C-NH2 bond with R7-NH N NH2 with R

SHEA
double N N double bond I -SHEA bond with R7-NH N NH2 with R

s TABLE D

O
Al R R7 Al R2 R R7 . .
SHEA
double N N double bond -SHEEHAN bond with R7-NH N NH2 with R

SHEA
double N N double bond -CHINCH bond with R7 -NH N NH2 with R

double double bond INSANE -N bond with R7 -C!-NH2 with R

double double bond IIS2NH2 -N bond with R7 -C NH2 with R

double double bond NS2NH2 -N ¦ bond with R7 -~-NH2 with R

double double bond NISSAN -N O bond with R7 -C-NH2 with R

~l23~3~75 TABLE D

CH2SCH2C~2R2 N O
Al R 7 Al R2 R R7 double double bondIN~S2NH2 -N S bond with R7-C-NH2 with R

double double bondINIS2NH2 NH bond with R7-C-NH2 -C-NH2 with double double bondINIS2NH2 NH bond with R7-C-NH2 -C-NHCH3 with R

IIS2NH2 NH /---\ bond SHEA -C-NH2 -C-N with R

double double bond~N~S02NH2 NH bond with R7-C-NH2 -C -No Wit to R

double double withNS02NH2 o bond with R7-C-NH2 -C-NH2 with R

double double bond~NISO2NH2 SHEEHAN bond with R7-C-NH2 with TABLE D

C~2SCH2CH2R2 double r double bond INSINUATION bond with R7 -C-NH2 / with R
double double bond 1 152NH2-CH2NHCH3 bond with R7 -C-NH2 with R
-~3~8~

The compounds of this invention may be prepared by one of the following general synthetic schemes.
When the bicyclic heterocyclic portion of the compound is directly attached to the Z component of Formula I, these compounds may be prepared from an art-matte hydroxy (or they'll) precursor either obtained from a commercially available source or prepared according to procedures known in the art. If the tetrahydrobicy-die compound is desired, the qua ternary or acid add-lion salt of the aromatic precursor is partially hydra-jointed. (Scheme 1) R R

N y OH Rex + C Jo OH Jo OH
R Al X Al Scheme I
When R is other than hydrogen, for example when an amino group is present in the l-position, the Dow-drocompound may be prepared by an electrophilic cyclic ration of a 2~N-formyl)ethyl aromatic compound.
(Scheme II) H 2 ,~NHCHO

Pro Pro PUKE

N < HNR8R9 ON
Pro No Pro Of R8 Rug Scheme II
The protecting group, PRY may be methyl, bouncily or the ~-phthalimido propel as described below. If the protecting group is chosen to be other than the N-phthalimido propel, the protecting group is removed according to methods known in the art, and the formation of the ether linkage is accomplished by treat in the hydroxy compound with a protected N-propylbro-mode in the presence of base such as sodium methoxide.
Ether coupling reagents other than a base and a bromide may also be used. (Scheme III) By N
Al O R o N Jo OH B- N Jo O-CH2CH2CH2N

R Al o Scheme III

The nitrogen protecting group is preferably phthalimido but can be any protecting group insensitive to the ether formation reaction conditions, such as a base insensitive group.
The amine compound is obtained by the removal of the protecting group, for example, the phthalimido group is removed with hydrazine hydrate. (Scheme IV) R Al No -0 NH2NH2 No Jo NH2 Al R
. Scheme IV

A preferred route to the 3,4-dihydroisoquino-lines within the scope of Formula I comprises the pro-parathion of the 3-aminop~opoxy derivative of a l-amino-49 3L23~)1375

3,4-dihydroisoquinoline intermediate by means of the partial hydrogenation of an isoquinolone followed by the transformation of the l-carbonyl to the desired substituent. Scheme V, below, details an exemplary preparation of the 5-(3-aminopropoxy) intermediate.
OH. OH O
H 2 ox ox o o o o Ol(CH2)3N O(CH2)3N

H SCHICK
OOZE
- OR -(C~2 ) ON
,/ O
r No \ /
N
O
ouch) 3NH2 SHEA) ON

n HEN NH2 I
N N
/ \ /\
R 8 R g R R g Scheme V

Compounds within the scope of Formula I where R

...

I 1~308~75 NH O
(Sheehan N~8Rg, -C-NR8Rg, or -C-NR8Rg and n is greater than zero, may be prepared by the addition of one or more carbon units a the 1-position of the star-tying bicyciic heterocyclic compound. An exemplary react lion sequence involving the isoquinoline ring system is shown in Scheme VI, below. The isoquinoline l-position may be functionalized by treatment with an arylsulfonyl halide in the presence of cyanide. Preferred reagents for this reaction are benzenesulfonylchloride and poles-slum cyanide in ethylene chloride. The resulting sulk fonamide adduce is aromatized and the cyan intermedi-ate may then be hydrolyzed to the carboxylic acid or aside or transformed into an amidine by treatment with alcoholic Hal followed by a desired amine.

51 ~2~0~

OH OUR OUR
clue Nay /
PRO I/
Jo ON
OWE or H+/ \ HO 1 I/ H 2 ROW \ OUR

llC~) No COO I
HO OR
1. SEIKO OH
2- R8RgNH NR8Rg , OUR / OUR
OWE I

// \ R8 // \
O N HO NR8Rg erg LO
/ I PRY
Ox OH Scheme VI

NR8Rg 52 ~23~375 The 5-hydroxy group shown in Scheme VI, above, may be protected by one or more protecting groups during this synthetic sequence. Scheme VII, below, depicts the use of a methyl group follower by the use of the N-phthalimido propel protected group.
OH OUCH

N SHEA N CON >
Shea OUCH
Nay > Hvdrol. _ 0 S2 Ox O J tacit or base) CON CON
OUCH OUCH

COO I \ N R8 R

OUCH OH O
N SCHICK N O Brush SHEA ITCH

N N
/ \ / \
R8 Rug R8 Rug OUCH o~CH2)3N~2 ON No N N
/\ /\
R8 Rug R8 Rug Scheme VII
It should be noted that the phthalimido propel group may be introduced at the outset of the sequence and removed at the last step as long as the hydrolytic conditions chosen to transform the nitrite group to an acid group do not remove the phthalimido group.
Compounds within the scope of Formula I and having a methyleneoxy or methylenethio substituent ( awl ) on the bicyclic portion of the compound may be prepared by one of the reaction sequences described below.
The methyleneoxy or methylenethio ether may be prepared from the coupling of a 2-thioethylamine with the ethylene hydroxy ring system according to Scheme VIII.

N SHEA + HSCH2CH2NH3Cl Al YO-YO
R H+

I \>--CH2-scH2cH2N~

R Scheme VIII

The foreign or thinly bicyclic systems may be prepared by one of many pathways including reaction sequences which build the Furman or thiophene ring about the preformed nitrogen-containing ring or which start with the Furman or thiophene rings. Exemplary synthetic pathways are described below in Schemes IX to XI.

o 5~-=C-CH20Pr + Li-C-C-CH2-OPr lo]

-Shapiro -C-CH20Pr `

-Pry ¢~_ C H OWE

Scheme IX

Scheme IX starts with a preformed nitrogen-containing ring kitten which is either commercially available or prepared by procedures known in the literature. The kitten is reacted with an acetylenic I ~230B75 nucleophile having a protected alcohol group in a solvent system below room temperature. The alcoholic addition product is readily dehydrated to form the conjugated triple double bond system by treatment with mild acid. Selective oxidation of the double bond with a peroxide forms the epoxide which under acidic conditions rearranges to form the Furman moiety. The alcohol is then deprotected. Compounds having symmetrical substituents in the 5- and 7- positions of the bicyclic ring (counting the foreign oxygen as the l-position and the pyridinyl nitrogen as the 6-position) may be prepared by this route.
Aromatic bicyclics may be prepared by cyclizing an appropriately substituted 3-hydroxy-4-(3'-hydroxy-1-propynyl)-pyridine prepared according to Scheme X.

I OR + CROSSCHECKS R3~
N ¦ / C--C-CH20H
R 3 No H+
\
C=-S-CH20H

SHEA B

Scheme X

Treatment of a 5-alkoxy oxaæole with a vinyl hydroxymethyl acetylene (the hydroxy group may or may not be protected) at elevated temperature and/or pressure results in the ox bridled ring Diels-Alder product. Treatment of the bridged ring system with mild acid forms the 3-hydroxy, 4-oxymethylacetylenic 56 ~L~3Q8~5 pardon which upon treatment with base forms the 2-oxymethyl-furano[2,3-c~pyridine.
Another route to this ring system proceeds by way of the 2-methyl Furman as the starting point, as shown in Scheme XI.

Hal 1. Rex SHEA ECHO \ SHEA 2. base SHEA
HO Run L___CO2R I -COREY

lNaOH, 2 [O] I SHEA
" ,~\ I\
r Jo Shea ` l ¦ SHEA Al O / N - Kiwi Al Al Scheme XI

Exemplary reaction conditions for the synthetic sequence of Scheme XI are described by Metes, J Or.
Chum, 33, 133 (1968). The veto function is removed by reduction, hydrogenation or the like to obtain the tetrahydro compound. The hydroxy methyl group then is introduced by the oxidation of the 2-methyl group by methods known in the art.
In the case where R2 is other than amino, one method of preparing the terminal R2 group comprises treating the amine with an R2 end group precursor unit including those groups listed in Scheme XII. The preparation of the precursors of the R2 groups and the reaction conditions under which they are coupled to the primary amine are fully described in US. Patent Nos.

I I

4,104,381, 4,279,819, 4,323,566 and GO AYE.

1 ) alkaline\ 1 ) phony C=CH--N02 ~/\~ NHalkyl OH 3 S lo or_ / NH 2 I\
2 ) CH30~0CH3 , ~H2-- No ON + NH3 -Tony O I

3 ) alkalis\ 3 ) NUN
C=N-CN ~O~/~,)Nh-C-S-alkyl . alkalis ~;~ \
\

NH2-alk~ ~R5-NH~H2 0V~.;H ,R5 I/\ NH- -Allah \
N -ON N N

No Scheme IT

Treatment of the Sulkily compound with a primary amine results in the N-cyano, N-alkyl guanidine analog.
If a hydrazine compound is substituted for the primary amine, the triazole analog results.
When R2 is ON, or sulfonyl amid-, the reaction sequence may be slightly modified as shown below in Scheme XIII. reaction of the finlike intermediate with Jo 1~30B75 a cyano-substituted alkylating agent such as 3-cyanoprop-ylchloride in the presence of a base produces the cyan ether compound. Reduction of the cyan group with a hydrides such as lithium aluminum hydrides results in the amino compound. Treatment of the cyan compound with an hydrous methanolic Hal yields an imitate intermediate which is converted to the sulfonyl amidine by treatment with sulfamide in methanol. For a complete discussion of this preparatory sequence, see US. Patent Jo.
4,283,408.

R / base ON (C~2)3CN

ashy. SHEA/
Hal 2Nh2 ~)( SHEA ) SHEA

Al 50~( Ho o(CH2)3-C-0CH3 Scheme XIII

The analogous mercaptan compounds may be prepared by reacting a cyan mercaptan with the appropriate halo-ethylene intermediate as shown in Scheme XIV below The amino sulfonyl amidine compound is prepared by reaction sequences similar to those described above.

~H2H SEIKO shekel R I Per 3 -By N-S02N~2 base ~2ScH2cH2-c-NH2 1. anhv. HCl/MeOH CH2S-CH2CH2CN
ON 2. Sue /
l /\ SHEA Al /\

Scheme XIV

The compounds of this invention may be readily converted to their non-toxic acid addition salts by customary methods in the art. The nontoxic salts of this invention are those salts the acid component ox which is pharmacologically acceptable in the intended dosages, including those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and from organic acids such as methane sulfonic acid, benzenesulfonic acid, acetic acid, prop ionic acid, mafia acid, oxalic acid, succinic acid, glycolic acid, lactic acid, salicylic acid, b~nzoic acid, nicotinic acid, phthalic acid, Starkey acid, oleic acid, abietic acid, etc.

1~3~75 The following are selected examples of the pro-parathion of the compounds according to this invention.

THE PREPARATION OF l-CYANO-3-13-(5-IsO-QUINOLYLOXY)PROPYL~-2-METRYL-PSEUDOTHIOUREA

Step 1. 5-(3-Phthalimido)Pro~oxY isoquinoline

5-hydroxyisoquinoline (39.3 g) is dissolved in dimethylformamide (350 ml). The solution is purged with nitrogen for several minutes. An hydrous potassium carbonate (41.2 g) and N-(3-bromopropyl~ phthalimide (72.7 g) are added to the solution and the reaction mixture is stirred for four days at RUT under No. The mixture is poured into l liter of HO, stirred for l-l/2 hours and filtered. The resulting solid is washed with HO and partially dried in air. The wet solid is added to C~Cl3 (l-l/2 liters) and the mixture is slowly filtered and rinsed with Shekel (500 ml). The layers are separate, the chloroform layer dried over Nazi, filtered and the filtrate evaporated in vacua to yield the phthalimido iso~uinoline as a solid.

Step 2. 5-t3-AminoPropoxY)isoquinoline The dark purple solid of Step l is added to 750 ml of absolute ethanol. 17 ml of an 85% solution of hydrazine hydrate are added to the solution. The react lion mixture is stirred under reflex for 3 hours, lit-toned and the dark red filtrate evaporated in vacua.
The residue is dissolved in 750 ml of concentrated Hal, stirred for 1 hour and filtered, and the filtered solid rinsed with a I clue solution. The dark filtrate is alkalinized with a 50~ aqueous Noah solution and stirred with 500 ml ethylene chloride. The layers are separated and the aqueous layer extracted with methyl Lo 5 tone chloride. The ethylene chloride extract is washed with saturated Nail solution and cried over Nazi. The dried extract is filtered and the filtrate evaporated in vacua yielding a dark red oil. The oil is distilled under vacuum and the distillate fraction cling up to a temperature of approximately 205C at 1 mm Hug is collected. The distillate is a mixture of the aminopropoxyisoquinoline as a viscous yellow oil and a smaller amount of a gel. The major portion of the oil is decanted from the gel and dissolved in methanol.
Methanesulfonic acid (98% solution) is added to the methanol solution and the mixture evaporated in vacua.
The residue is dissolved in absolute ethanol causing the precipitation of crystals. The precipitate is lit-toned, and the solid washed with ethanol, deathly ether and dried under house vacuum at approximately 70C for 2 his, yielding the methanesulfonic acid salt of the aminopropoxyisoquinoline as a powder, MOP. 180-182~C.

Step 3. 1-CYano-3-[3-(5-isoauinolYloxy3 Droopily-methyl-pseudothiourea 8 g of the aminopropoxy isoquinoline of Step 2 in 10 ml isopropanol is added to a solution of 5.78 g of S,S-dimethyl-N-cyaniminodithiocarbonimidate dissolved in isopropanol. A white precipitate forms immediately and the reaction mixture is stirred overnight at RUT
under nitrogen. The mixture is slowly filtered and the solid washed with isopropanol and deathly ether and then dried in air yielding the pseudothiourea as a solid, MOP. 164-165C.

~2308~5 The Methanesulfonic Salt of 1-Cyano-3-[3-~5-isoquino-lyloxv)propyll 2-methyl-pseudothiourea 1.13 ml of a solution of methanesulfonic acid (98%) are added to a solution of 3.4 g of the pseudo-Thor dissolved in 100 ml of methanol. The result tying solution is evaporated in vacua. The solid nest-due is triturated in 40 ml absolute ethanol, the result tying solution filtered, the solid washed with ethanol and deathly ether, dried in air, stored in a vacuum dissector overnight, and dried under house vacuum for 2 his, yielding the methanesulfonic acid salt as a powder, MOP. 190-191C.

THE PREPARATION OF 2-CYANO-1-[3-(5-ISOQUINO-LYLOXY)PROPYL~-3-METHYL GUANIDINE HYDROCHLORIDE

A solution of 14.3 g an hydrous methyl amine in 75 ml absolute ethanol is added to a solution of 7.0 g of the pseudothiourea compound obtained in Step 3 dissolved in 100 ml methanol. The reaction mixture is stirred with nitrogen purge overnight. While cooling in an ice bath, approximately 22 g methyl amine is bubbled into the reaction mixture. The reaction mixture is allowed to warm to RUT while stirring is continued and then heated to reflex for 1 hr. After cooling, the solution is filtered and the resulting solid washed with ethanol, deathly ether and dried in air, yielding the desired guanidine as a white solid.
The solid is suspended in methanol and the pi adjusted to 3-4 with m~thanolic Hal. This solution is filtered and the filtrate evaporated in vacua. The residue is triturated in ethyl acetate, filtered and the solid washed with ethyl acetate and deathly ether. The solid is dried and stored in a vacuum dissector, yielding the hydrochloride salt of the desired guanidine as a powder, MOP. 177-179C.

TV

THE PREPARATION OF N-METHYL-N'-[3-[5-(2-MET~YL-1~2~3~4-TETRAHyDRolsoQuINoLyLoxy)] PROPEL]-2-NITRO-l,l-DIAMINOETHENE

Step 1. ~-Hydroxy-2-methyl-isoquinolenium iodide 24.7 g of 5-hydroxyquinoline (technical grade) is dissolved in boiling absolute ethanol (350 ml). The resulting solution is filtered and washed with hot ethanol. Iodomethane (50 g) is added to the solution, which is stirred under reflex for 2-1/2 hours. The mixture is cooled, filtered and the precipitate washed with absolute ethanol, an hydrous deathly ether, and dried in air, yielding the isoquinolenium iodide as a solid, MOP. 236-237~C.

Step 2. 5-~ydroxv-2-methyl-1,2,3,4-tetrahvdroiso-quinoline The isoquinolenium methiodide of Step 1 (31 g) is dissolved in 650 ml of a 10% water in methanol (w/v) solution. Sodium bordered (17. 2 g) is added to the solution under a blanket of nitrogen, over a period of 15 minutes, while the mixture is heated to boiling.
After completing the addition, the mixture is reflexed for ten minutes. Acetone ~250 ml) is added and the resulting mixture allowed to cool and evaporated in vacua. The residue is shaken with 375 ml of a OWE
sodium carbonate solution. The resulting slurry is filtered, the solid washed with 200 ml water and dried on a Buchner overnight, yielding the tetrahydroiso-quinoline as a powder, MOP. 183.5C.

Step 3. 2-Methyl-5-[3-(N-phthalimido)-propoxy]-1,2,3,4-tetrahydroisoquinoline 41.5 g of the tetrahydroisoquinoline are mixed with 500 ml of methanol, 13.7 g sodium methoxide added to the stirred mixture and the solution evaporated in vacua. The residue is dissolved in dimethylformamide, 68.1 g of N-(3-bromopropyl)phthalimide added and the mixture stirred at RUT for 20 hours. The reaction mix-lure is partitioned between water and ethyl acetate.
The layers are separated and the aqueous layer extract ted with ethyl acetate The combined organic extract is washed with water, saturated sodium chloride, dried over sodium sulfate, filtered, and the filtrate evapo-rated in vacua yielding a light brown solid. The solid is dissolved in hot absolute ethanol, the solution lit-toned, the solid rinsed with hot ethanol and the lit-irate cooled at RUT and in an ice bath. The resulting mixture is filtered, the solid washed with cold ethanol and dried in air, yielding the phthalimido product as a solid, MOP. 111-112C.

Step 4. 2-MethYl-5-(3-amino~ropoxv)-1,2,3,~-tetra-hydroisoquinoline 34.2 g of the phthalimido compound is mixed in 350 ml of absolute ethanol. 6.9 ml of a 85~ hydrazine hydrate solution it added and the mixture heated to reflex for three hours. The mixture is cooled, filtered and the filtrate evaporated in vacua. The residue is triturated with a 5% Hal solution and the slurry is slowly filtered. The clear filtrate is alkalinized by adding a 50~ Noah solution. The resulting oily precipi-late is extracted with deathly ether, washed with sat-rated Nail, dried over Nazi, filtered and evaporated in vacua yielding the aminopropoxy compound as a fight vet-low oil, which crystallizes on standing.

us 12~0875 Step 5. N-MethYl-N'-[3-[5-(2-methyl-1,2,3,4-tetra-hydroisoquinolyloxy)]propyl]-2-nitro-l~l-diaminoetthese 5.47 g of the aminopropoxy compound of Step 4 and 3.68 g of 1-nitro-2-methylamino-2-methylthioethene are mixed in 50 ml of absolute ethanol and heated to reflex with stirring for an hour and 15 minutes. The reaction mixture is cooled and evaporated in vacua. The residue is triturated with hot ethyl acetate, stirred in ethyl acetate and filtered. The filtered solid is washed with ethyl acetate and dried, yielding the Damon ethene as a white powder, MOP. 133-135C, which is recrystallized from acetone, MOP. 136.8C.

THE PREPARATION OF 2-CYANo-l-METHYL-3-~3-15-( 2-METHYL-1,2,3,4-TETRAHYDRO-ISOQUI~OLYLOXY)~PROPYL~ GUANIDINE

Step 1. 1-Cyano-2-methyl-3-13-15-(2-methyl-1,2,3,4-tetrahydroisoquinolyloxy)]~ropYl]~seudothiourea 60 g of S,S-dimethyl-N-cyanoiminodithiocarbonimi-date is dissolved in 75 ml isopropanol and the mixture stirred at RUT while purging with No. 9.0 g of methyl-amine in 20 ml isopropanol is added to the mixture and stirring is continued overnight. Isopropanol is added to the solidified mixture and the thick slurry lit-toned, washed with isopropanol, deathly ether and air-dried, yielding the pseudothiourea as a white solid, MOP. 135.6C.
The pseudothiourea is dissolved in methanol, acidified with methanol/HCl and evaporated to dryness.
The solid is triturated in absolute ethanol, stirred in ethanol and filtered. The resulting solid is washed with ethanol, deathly ether, dried in air and under house vacuum, yielding the hydrochloride salt as a white solid, MOP. 170-172C.

.

66 I )8~5 Step 2. 2-cyano-l-methvl-3-t3-[5-(2-methvl-1,2,3t4-tetrahydroisoquinolyloxy)~pro~vl] quanidine

6.0 g of the S-methyl compound is dissolved in 120 ml of warm absolute ethanol. 12.2 g of an hydrous methyl amine in 50 ml absolute ethanol are added to the cooled ethanolic solution and stirred at RUT overnight.
The reaction mixture is filtered and the solid washed with ethanol, deathly ether and dried in air, yielding the desired guanidine as a white powder, MOP. 90-96DC.
This powder is suspended in 50 ml methanol and slightly acidified with methanol~HCl. The solution is filtered and the filtrate evaporated in vacua resulting in a clear oil and foam which is dissolved in absolute ethanol and recrystallized twice yielding the hydra-chloride guanidine salt, MOP. 170-172C.

THE PREPARATION OF AMMAN-METHYL-1,2,3,4-TETRAHYDROI SOQUINOLYLOXY ) ]
PROPYLAMINO~-l-METHYL-1~-1,2,4-T~IAZOLE

Methyl hydrazine (2.9 g) is added to a stirred solution of l-cyano-2-methyl-3-[3-[5-(2-methyl-1,2,3,4-tetrahydroisoquinolyloxy)] propyl~pseudothiourea (4.0 g) dissolved in 40 ml of dim ethyl formamide and stirring is continued at 40C for 20 his. The reaction mixture is evaporated resulting in an oil which crystallizes on standing. The crystalline product is dissolved in hot acetonitrile, filtered, washed with acetonitrile and deathly ether, dried in a vacuum dissector, recrystal-lived from ethanol and dried at elevated temperature, affording the desired triazole product, Pi 150-152C, with shrinkage beginning at 140C. Elemental analysis indicates the presence of a 1~10 mole percent quantity of ethanol.

67 ~.230875 THE PREPARATION OF 2-cyANo-l-[3-(7-IsoQuIN
LYLOXY)PROPYL]-3-METHYL GUANIDINE

Step 1. 7-[3-(N-phthalimido)DropoXY]isooUinoline Sodium methoxide (11.6 g) is added to a mixture of 7-hydroxyisoquinoline (31.1 g) in 400 ml methanol.
The reaction mixture is evaporated in vacua and the residue dissolved in dimethylformamide. No Brigham-propyl)phthalimide (57.6 g) is added to the solution and stirred overnight at RUT. The reaction mixture is poured into HO, creating a yellow precipitate. The suspension is stirred for 1 hour, filtered, the solid washed with HO. The moist solid is stirred in also-lute ethanol for 1 hour, filtered and washed with ethanol (1:1) and dried in air. The phthalimido compound is obtained by recrystallizing the yellow solid from boiling absolute ethanol.

Step 2. 7-(3-Aminopropoxy)isoquinoline Hydrazine hydrate (8 ml of an 85~ solution) is added to a stirred suspension of the phthalimido come pound of Step 1 (37.4 g) in absolute ethanol and the reaction mixture is heated to reflex for 3 hours, cooled and filtered. The resulting solid is washed with ethanol and the filtrate evaporated in vacua. The evaporated residue is triturated in 250 ml of a I Hal solution, slowly filtered and the filtrate stored in the refrigerator overnight. The next day the solution is washed with ethylene chloride and alkalinized with a 50~ aqueous sodium hydroxide solution, giving an oily precipitate. The aqueous layer is extracted with methyl tone chloride and the combined organic extracts washed with saturated sodium chloride solution and dried over sodium sulfate. After filtering the resulting mixture, I
~23~)~37S

the filtrate is evaporated in vacua to give the amino pro-proxy compound as an amber oil. The dihydrochloride acid salt of the aminopropoxy compound is prepared by the addition of a methanolic Hal solution to a methanol soul-lion of the amber oil, and after drying the salt under vacuum, yields a light yellow powder, MOP. 212-215C;
the methanesulfonic acid salt is a white powder, MOP.
182-183~C.

Step 3. Sweeney 7-isoquinolyloxy)propvl]-2-methyl-pseudothiourea 11.0 g of 7-(3-aminopropoxy)isoquinoline in 20 ml isopropanol is added to a solution of S,S-dimethyl-N-cyanoiminodithiocarbonimidate (7.2 q) in 90 ml isopro-panel. The reaction mixture is stirred at RUT for 2 hours. The mixture is filtered, the resulting solid washed with isopropanol, deathly ether, and dried in air, yielding the desired pseudothiourea as a white powder, MOP. 112-114C. The methanesulfonic acid salt of the pseudothiourea crystallizes from methanol as a solid, MOP. 202-204C.

Step 4. 2-Cyano-1-[3-(7-isoquinol~loxy)~ropyl]-3-methyl quanidine A solution of an hydrous methyl amine (18.2 g) in 90 ml of absolute ethanol is added to a stirred suspend soon of the psuedothiourea (8.4 g) obtained in Step 3 in 17S ml methanol. The reaction mixture is stirred at RUT overnight, filtered, the resulting so id washed with ethanol and deathly ether, and dried in air, yielding the desired isoquinolyloxy guanidine as a white flurry powder, MOP. 175-177C. The methanesulfonic acid salt 69 1~3~375 of the guanidine is recrystallized twice from ethanol and methanol to give a powder, MOP. 162.5-164~C.

THE PREPARATION OF 2-CYANO-l-METHYL-METHYL, 4-TETRAHYDRO-ISOQUINOLYLOXY)]PROPYL GUANIDINE

Step 1. 7-Hydroxy-2-methylisoquinolenium iodide 153 g of iodomethane is added to a suspension of

7-hydroxyisoquinoline (78.2 g) in 1 liver absolute ethanol. The mixture is stirred at reflex for two hours, cooled, and filtered. The solid is washed with ethanol and deathly ether and dried in air, yielding the methyl iodide salt of the isoquinoline as a crystal-line material, MOP. SKYE.

Step 2. 7-Hydroxy-2-methvl-1,2,3,4-tetrahYdro-isoquinoline 41.6 g of Nub are slowly added over a period of 30 minutes to a stirred solution of the methiodlde of Step 1 (75.0 9) in 1550 ml of 103 HO in methanol under a stream of nitrogen. After the addition is complete, the mixture is kept at reflex for 20 minutes, after which 700 ml acetone are added, Audi the mixture is cooled and evaporated in vacua. The residue is shaken with a 3.5~ sodium carbonate solution, filtered and the solid washes with HO and dried in air over-night, giving the desired tetrahydroisoquinoline as a powder, MOP. 167-169C.

US

Step 3. 2-Met~yl-7-[3-(N-phthalimido)propoxy~-1,2,3,4-tetrahYdroisoquinoline 10.1 g of sodium methoxide is added to a soul-lion of the tetrahydroisoquinoline of Step 2 (30.7 g) in methanol and the resulting mixture evaporated in vacua. The oily residue is dissolved in dimethylform-aside and 50.4 g of N-(3-bromopropyl) phthalimide added to the solution. The reaction mixture is stirred at RUT
for 21 hours and partitioned between HO and ethyl ace-late. The layers are separated and the aqueous layer extracted with ethyl acetate. The combined organic extract is washed with HO and saturated Nail solution, dried over sodium sulfate, filtered, and the filtrate evaporated in vacua to give the desired product as a solid.

Step 4. 7-~3-AminoDropoxv)-2-methYl-1,2,3,4-tetra-hYdroiso~uinoline 6.6 ml of an 85% hydrazine hydrate solution are added to a stirred suspension of the phthalimido is-quinoline of Step 3 (34.4 g) in 350 ml absolute ethanol.
The reaction mixture is heated to reflex for 3 hours, allowed to cool and evaporated in vacua. The residue is triturated with 250 ml 5% HC1 and filtered. The clear filtrate is stored in the refrigerator overnight, extracted with ethylene chloride, alkalinized with 50 sodium hydroxide solution, and extracted again with ethylene chloride. The combined organic extract is washed with saturated Nail solution, dried over sodium sulfate, filtered, and the filtrate evaporated in vacua, giving the desired aminopro2oxy compound as a light amber oil.

I 37~;

The MindWrite of the dihydrochloride acid salt of the tetrahydroisoquinoline compound is a white solid, MOP. 120-123C.

Step 5. 1-Cyano-2-methyl-3-[3-[7-(2-methyl-1,2~3,4-tetrahydroisoquinolyloxy)]propyl]pseudothiourea A suspension of the aminopropoxytetrahydroiso-quinoline of Step 4 (701 g) in isopropanol is added to a solution Go S,S-dimethyl-N-cyanoiminodithiocarbon-imitate (4.7 g) in 60 ml isopropanol. The reaction mixture is stirred at RUT for 1-1/2 hours, filtered, the resulting solid washed with isopropanol and deathly ether and dried in air, giving the desired pseudothio-urea as a white powder, MOP. 147-149C.

Step 6. 2-Cyano-1-methyl-3-[3-[7-(2-methvl-1,2,3,4_ tetrahydroisoquinolyloxY)]propyl] quanidine A solution of an hydrous methyl amine (9.8 g) in 50 ml absolute ethanol is added to a suspension of the pseudothiourea of Step 5 (4.5 g) in 50 ml methanol.
The mixture is stirred overnight at RUT and the result tying clear solution is evaporated Lo vacua. Two nest-due is dissolved in 75 ml hot isopropanol, filtered, cooled, and stirred for 2 hours. The suspension is filtered and the solid washed with isopropanol and deathly ether and dried in air, giving the desired isoquinolyloxy guanidine as a white powder, MOP.
142-144C.

,~.

s THE PREPARATION OF AMMAN-METHYL-1,2,3,4-TETRAHYDROISOQUINOLYLOXY)]
PROPYLAMINO]-1,2, 5 -THIADIAZOLE-l OXIDE

A solution of 5.0 g of 5-(3-aminopropoxy)-2-methyl-1,2,3,4 tetrahydroisoquinoline in 50 ml of methane of is added, over a one-hour period, to a stirred soul-lion of 3.68 g of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide in 200 ml methanol while maintaining the tempera-lure at approximately 0C. After stirring the mixture in an ice bath for 1-1/2 hours, an hydrous ammonia (18 3 9) is bubbled in over a period of 10 minutes and stirring is continued at RUT for l-lJ2 hour. The reaction mixture is evaporated in vacua and the residue (light foam/glass) is triturated in an hydrous ether. The resulting solid material is filtered, the solid washed with ether and dried in air, giving a white powder, melting with decompo-session at 166-171C. The powder is dissolved in 10%
methanol in ethylene chloride, filtered and the i~puri-ties separated on a silica gel column. The purified free-lions are evaporated in vacua and the resulting foam in-turated in ether, filtered, the solid washed with ether and dried in air, giving the desired thiadiazole-l-oxide as a white solid, MOP. 172-174C.

~0~375 THE PREPARATION OF 3-AMINO-4-[3-[7-(2-METHYL-1,2,3,4-TETRAHYD~OISOQUINOLYLOXY)]PROPYL~MINO3-1,2,5-THIADIAZOLE-l-OXIDE

A solution of 7-(3-aminopropoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline (5.43 g) in methanol (70 ml) is slowly added over a period of 45 minutes to a stirred solution of 3,4-dimetho~-1,2,5-thiadiazole-1-oxide (3.68 g) in 375 ml of methanol at a temperature of 3C. The reaction mixture is stirred for an additional one hour and 25.0 g an hydrous ammonia is bubbled in over a period of 10 minutes. The resulting mixture is warmed to RUT
with stirring and the solution is evaporated in vacua.
The near-white solid residue is dissolved in hot 95~
ethanol, filtered hot and rinsed with hot ethanol. The solution is cooled with stirring, then stirred in an ice bath for 30 minutes and filtered. The resulting solid is washed with cold ethanol and deathly ether and dried in air, giving the desired tetrahydroisoquinoline thud-zole-l-oxide as a white powder, MOP. 193-194C.

74 1.~30~37~i THE PREPARATION OF 3-AMINO-l-METHYL-5-r 3-(l-pIpERIDINo-s-IsoQuINoLyLoxy) PROPYLAMINO]-lH-1,2,4-TRIAZOLE

Step 1. 5-HYdroxY-1~2-dihYdro-1-(2H)-isoquinolone 300 g of isoquinoline-5-sulfonic acid are slowly added to a reaction vessel containing 500 g of sodium hydroxide and 574 g of potassium hydroxide pellets, stirred at a temperature of 238~C. When the addition is completed, the mixture is stirred at 250-268C for 30 minutes, after which the mixture it cooled to 135~C, followed by the addition of 2 liters of HO. the aqueous mixture is poured into a second liter of HO
and the reaction vessel washed with a third liter of HO. The combined aqueous mixtures are filtered and the filtrate added to an ice bath adjusted to pi of about 7. The chilled mixture is filtered and resultant solid stirred with 2 liters of ON aqueous clue. The acidic mixture is filtered, the solid washed with HO
and dried, yielding 212 g of the desired product as a solid, MOP. 170-172C.

Step 2. 5-(3-Phthalimido-proPoxY)-l-h~droxY-isoquinoline N-(3-Bromopropyl) phthalimide (164 g) is added to a stirred solution of 5-hydroxy-1,2-dihydr~ (OH)-isoquinolone (96.7 g) and anhvdrous R2CO3 (91.2 g) in 750 ml of DMF. The reaction mixture is stirred at room temperature for one week, diluted with 3 liters of HO
and stirring continued at RUT for an additional 30 minutes. The reaction mixture is filtered and the solid resuspended in 2 liters of HO and stirred at RUT

1~3~37S

for an additional 1-1/2 hours. The suspension is filtered and the solid dried in air. The dried solid is broken up, suspended in 750 ml of chloroform and stirred vigorously at RUT for 1 hour. The suspension is filtered and the solid dried. The crude product (95.8 g) is dissolved in 2.5 liters in boiling glacial acetic acid. The resulting dark solution is concentrated and cooled. The crystalline precipitate is collected and dried, washed with deathly ether, resuspended in deathly ether, stirred at RUT for 30 minutes, filtered and dried _ vacua overnight, yielding 59~3 g of the desired product, MOP. >300C.

Step 3. 1-Chloro-5-(3-~-phthalimido-propoxy) isoquinoline A mixture of 5-(3-N-phthalimido-prop~xy)-l-hydroxy isoquinoline (59.2 g) and PUKE (340 ml) is stirred under reflex for 4 days. The reaction mixture is cooled to RUT and the volatile material removed under reduced pressure. The residue is suspended in HO (850 ml) and the aqueous mixture poured into 1.7 liters of ethylene chloride. The aqueous layer is made alkaline with solid sodium bicarbonate and the organic phase separated. The aqueous layer is extracted with methyl tone chloride and the organic extracts combined and dried over sodium sulfate. The extract is filtered and evaporated, yielding 61.~ g of crude product, which is dissolved is boiling ethyl acetate and filtered through Elite, the filtrate concentrated, cooled. The crystal-line precipitate is collected, washed with ethyl ace-late and dried, affording 51.6 g of the desired come pound as a crystalline product, MOP. 173-175~C.

Step 4. 5-(3-Phthali~idopropoxy)-l-Piperidino-isoq~inolinee Piperidine (12.4 ml) is added to a stirred suspend soon of l-chloro-5-(3-N-phthalimido-propoxy)-isoquinoline (18.3 g) in 100 ml of pardon. The reaction mixture is heated to reflex for 3 days, cooled and evaporated under reduced pressure. The resulting dark residue is suspend dyed in ethylene chloride and washed with 5% aqueous Hal, saturated aqueous sodium bicarbonate, and ~2 The organ-to phase is dried over sodium sulfate, filtered and evapo-rated in vacua. The resulting solid is stirred in also-lute ethanol at RUT for 30 minutes and cooled in an ice bath. The solid is collected, washed with absolute ethanol and dried Lo vacua overnight, yielding 16.5 g of the desired product as a powder, MOP. 146-147~C.

Step 5. 5-(3-Aminopropoxy)-l-DiDeridino-isoquinoline succinate 85% hydrazine hydrate (23.5 ml) is added to a stirred suspension of 5-(~-N-phthalimidopropoxy)-l-piper-idino-isoquinoline (33.2 g) in 800 ml of absolute ethanol.
The reaction mixture is heated under reflex for 72 hours, after which the solvent is removed under vacua and the residue triturated with ethylene chloride. The ethylene chloride mixture is stirred at RUT for 30 minutes and filtered. The solid is washed with ethylene chloride and the filtrate is evaporated under reduced pressure. The residue is dried in vacua overnight. The residue is a dark oil which is dissolved in isopropanol.
9.45 g of succinic acid is added to the stirred isopropanol solution heated to reflex until all the succinic acid is dissolved. The reaction mixture is cooled and stirred in an ice bath. The resultant precipitate is collected, washed with isopropanol and dried in vacua overnight, yielding the desired product as a powder, MOP. 167-168C.

77 ,~3~37~i Step 6. Senate piperidino-5-isoqUinolyloXV)-propyl]-2-methylpseudothiourea 50% aqueous sodium hydroxide is added to a stirred solution of 5-(aminopropoxy)~ piperidino-isoquinoline succinate (18.~ g) in 400 ml of Ho until the reaction mixture is strongly alkaline. The reaction mixture is extracted with ethylene chloride, the extract dried over sodium sulfate, filtered and evaporated under vacua, viol-ding 12.25 g of a brown oil. The oil is dissolved in isopropanol and the alcoholic solution added drops to a vigorously stirred solution of S,S-dimethyl-N-cyano-iminodithiocarbonimidate (6.58 go in iscpropanol (90 ml).
The reaction mixture is stirred at RUT overnight. The precipitate is collected and washed thoroughly with isopropanol. The crude product is dissolved in boiling acetonitrile, the hot solution treated with charcoal and filtered through Elite. The filtrate is concentrated and cooled in an ice bath. The resulting precipitate is collected, washed with acetonitrile and dried, affording 10.2 g of the desired product as a solid, MOP. 186-187C.

Step 7. 3-Amino-l-methyl-5-[3-(1-piperidino-5-isoquino-YUCCA) propvlamino]-lH-1,2,4-triazole Methyl hydrazine (5.7 ml) is added to a stirred suspension of l-cyano-3-~3-(1-piperidino-5-isoquinolyl-oxy)propyl]-2-methylpseudothiourea t7.77 go in 62 ml of DMF under nitrogen. The reaction mixture is stirred at 40C under nitrogen for 24 hours, cooled to KIT, evaporated under vacua and the residue dissolved in warm absolute ethanol. The resulting precipitate is collected, washed with absolute ethanol and dried in air.
The filtrate is evaporated on vacua and the residue crystallized f rum acetonitrile and dried overnight, yielding S . 3 g of the crude product as an of f -white solid, MOP. 173-175C. The crude product is placed on a silica gel column and eluded with ethylene chloride/me~h-anon. The combined pure fractions are evaporated and recrystallized from acetonitrile, yielding the desired product, MOP. 181-182C.

THE PREPARATION OF 3-AMINO-4-[3-(1-PIPERIDINO-5-ISOQUINOLYLOXY) PROPYLAMINO]-1,2,5-THIADIAZOLE-l-OXIDE HYDRATE

Sodium methoxide (2.70 g) is added slowly to a stirred solution of 5-(3-aminopropoxy)-1-piperidino-iso-quinoline Saxon (10.09 g) in 200 ml of methanol. The reaction mixture is stirred at RUT for 30 minutes and the solvent evaporated under reduced pressure. The residual solid is broken up and stirred with ethylene chloride overnight. The reaction mixture is filtered and the solid washed with ethylene chloride. The filtrate is evaporated under reduced pressure affording 1.5 g of a tan powder which is the desired base material. The insoluble material is recombined with the tan powder in a mixture of water and ethylene chloride and reacted with a 50% aqueous sodium hydroxide solution. The aqueous phase is separated and extracted with ethylene chloride and deathly ether. The combined organic extracts are dried, filtered and evaporated, affording 6.9 g of a brown oil which is dissolved in methanol.
The methanol solution is added drops to a stirred ice cold solution of 3,4-dimethoxy-1,2,5-tria-diazole-l-oxide t4.05 g) in methanol (425 ml) under nitrogen over a period of 2-1/2 his and stirring continued at RUT for 2 his. The reaction mixture is cooled to ice bath temperature, saturated with ammonia, stirred at RUT overnight and evaporated in vacua. The 12~3~8~

residue is reprecipitated with methanol and ethylene chloride, and the resulting solid collected, washed with methanol and dried in air. The resulting brown solid is applied to a silica gel column (100-200 mesh; 200 g; 4x30 cm) and successively eluded with ethanol/ethylacetate, 95% ethanol. The purest fractions containing the desired material are combined an concentrated, affording a powder, MOP. 209-211C with decomposition. Elemental analysis indicates tune product exists as a hemihydrate.

THE PREPARATION OF l-CYANO-2-~E~HYL-3-[3-tl-MORPHOLINo-5-Iso-~UINOLYLOXY)PROPYL] PSEUDOTHIOUREA

Step 1. 5-(3-Aminoproeoxv)-l-morpholinoisoouinoline succinate 1-1~2 hydrate Hydrazine hydrate (85~) (85.5 ml) is added to a stirred solution of l-morpholino-5-(3-phthalimido propcxy)-isoquinolin- (121.1 g) in absolute ethanol t2.9 1). The stirrer reaction mixture is heated to boiling and reflexed for 72 h s. After cooling to RUT, the reaction mixture is evaporated and the residue stirred in ethylene chloride. The mixture is filtered and the solids washed with ethylene chloride. The filtrate is evaporated under in assay and the residual oil is dissolved in isopropanol and heated to boiling. Succinic acid (24.8 g) is added to the boiling solution followed by the addition of Marco G-60. The boiling mixture is filtered through Solute cooler and the solid collected, washed with isopro2anol and dried n vacua. The solid is stirred in I aqueous Hal and the mixture filtered. The insoluble material is washed with H20 and dried, result tying in the desired succinate as a powder, MOP. 159-161C.

Jo 1~3~875 Step 2. 1-C~ano-2-methyl-3-[3-~1-morpholino-5-isoquino-lvloxY)Propyl] pseudothiourea A solution of 5-~3-aminopropoxy)-1-morpholino-isoquinoline ~24.3 g) in 600 ml of HO is made strongly alkaline with 50% aqueous sodium hydroxide. The reaction mixture is extracted with ethylene chloride and the extracts are dried, filtered and evaporated in vacua, affording 13.1 g of a dark oil which is dissolved in 60 ml of isopropanol. The isopropanol solution is added drops to a stirred solution of S,S-dimethyl-N-cyano-dithiocarbonimidate ~8.77 g) in 120 ml of isopropanol and the resulting reaction mixture stirred at RUT for 2 days.
The reaction precipitate is collected, washed with isopro-panel and dried in air, resulting in crude product which is dissolved in boiling acetonitrile. The acetonitrile solution is treated with Marco G-60, filtered through Elite, partially evaporated and cooled affording the desired pseudothiourea as a solid, MOP. 160-161C.

THE PREPARATION OF 3-AMINO-l-METHYL-5-[3-(1-MORPHOLINO-5-ISOQUINOLYLOXY) PROPYLAMINO]-lH-1,2,4-TRIAZOLE

Methyl hydrazine (7.3 g) is added to a stirred suspension of 1-cyano-2-methyl-3-13-(1-morpholino-5-iso-quinolyloxy) propel] pseudothiourea (11.56 g) in DMF
(91.5 ml). The reaction mixture is stirred at 40C under nitrogen for 24 his and evaporated in vacua resulting in a red oil which partially crystallizes on standing. The residue is dissolved in boiling acetonitrile (150 ml) and the hot solution treated with Marco G-60, filtered through Elite, concentrated and cooled. The precipitate is collected, washed with acetonitrile and dried in vacua 81 ~3~)~75 at elevated temperature. The dried precipitate is recrystallized from absolute ethanol, dried in vacua at 75C affording the desired product as a powder, MOP. 178-180C. Elemental analysis indicates the product as a 1/4 hydrate.

THE PREPARATION OF AMMAN-~l-MORPHOLINO-5-ISOQUINOLYL OX) PROPYLAMINO]-1,2,5-THIADIAZOLE-l-OXIDE

A solution of 5-(3-aminopropoxy)-1-morpholinoiso-quinoline (19.46 g) in HO (480 ml) is made strongly alkaline with 50~ aqueous sodium hydroxide and extracted with ethylene chloride. The organic extract is dried over sodium sulfate, filtered and evaporated in vacua.
The residue is dissolved in 150 ml of methanol and the methanolic solution added drops to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (7.78 g) in methanol (825 ml) maintained at -10 to 0C. The addition takes about 5 his, after which the reaction mixture is stirred overnight and allowed to warm slowly to RUT. The reaction mixture is cooled again to -10 to 0C and the cooled solution saturated with an hydrous ammonia. The solution is allowed to reach RUT over a period of 2 his and then stirred at RUT under nitrogen for a period of 3 days. The reaction mixture is filtered and the resultant solid dried in vacua, affording the desired product as a powder, MOP. 222-224C, with Dick.

I ~L2~87~

THE PREPARATION OF l-CYANO--I 3- ( lucks, DODDER -ISOQUINOLYLOXY )--PROPEL METHYL PSEUDOTHIOUREA

Step 1. 5-(3-Aminopropoxy)-1,2-dihydro-1-(2H) i Seiko i no lone hydrochloride Hydrazine hydrate ~85~: 17.2 g) is added to a stirred suspension of So 3-phthalimidopropoxy)-1,2-dihedral isoquinolone (34.84 g) in absolute ethanol (550 ml). The reaction mixture is heated to boiling and stirred under reflex for 60 his, after which the reaction mixture is cooled to RUT and evaporated in vacua. The residue is suspended in HO and the suspension evaporated in vacua. The residue is resuspended in methanol and acidified with methanolic Hal. The suspension is again evaporated in awoke and the residue suspended in HO and stirring is continued at RUT overnight, aster which the slurry is filtered and the filtered solid washed with HO and dried. The filtrate is evaporated in vacua, until a precipitate begins to form. The aqueous mixture is heated to boiling, treated with Marco G-60 and filtered while hot. The filtrate is partially evaporated and cooled in an ice bath. The resulting crystalline precipitate is collected, washed with cold ~2 absolute ethanol and dried in vacua at Luke overnight, affording the desired product as a crystalline solid, MOP. >300~C.

3C~5 Step 2. 1-Cvano-3-[ 3-(l-oxo-l,2-dihvdro-5-isoquino-lilacs) propvl3-2-methyl pseudothiourea 5-(3-aminopropoxy)-l,2-dihydro-l-(2H)isoquinolone hydrochloride (15.28 g) is added to a stirred solution under nitrogen of S,S-dimethyl-N-cyanoiminodithiocarbon-imitate (8.77 g) in 150 ml of isopropanol. Triethylamine (16.7 ml) is ceded to the reaction mixture which is stirred at RUT while a flow of nitrogen flushes evolved methyl mercaptan into a chlorox trap. The reaction mixture is stirred at RUT for 18 his followed by slowly heating the reaction mixture to boiling and refluxing for an additional hour. The reaction mixture is cooled to RUT, filtered and the resulting white solid washed with isopropanol. The crude product is dissolved in boiling glacial acetic acid and the resulting pale yellow solution cooled. The precipitate is collected, dried and the product suspended in deathly ether. The suspension is stirred at RUT for an hour, filtered and the solid dried in vacua at 100C for 4 his, resulting in the desired pseudothiourea product as a white powder, MOP. 244-245C.

THE PREPARATION OF 3-~INO-l-METHYL-5-[3-( l-oxo-l,2-DIHYDRO-5-ISOQUINOLYLOXY)PROPYLAMINO)-lH-l, 2, 4-TRIAZOLE HYDROCHLORIDE SESQUIHYDRATE

Methyl hydrazine (5.7 ml) is added to a stirred suspension of l-cyano-3-[3-(l-oxo-1,2-dihydro-5-isoquino-lilacs) propyl]-2-methylthiopseudourea (6.3 9) in DMF (61 ml). The reaction mixture is stirred at 40C for 24 his, cooled to RUT and evaporated in vacua. The residue is triturated in absolute ethanol and the mixture stirred at RUT overnight. The reaction mixture is filtered, and the filtered solid washed with absolute ethanol and dried in i~30~37~;

air, affording the desired triazole as a white solid, MOP. 276-278C. The triazole is suspended in 150 ml of methanol and methanolic Hal added. After stirring the suspension at RUT for 15 minutes, the solution is filtered through Elite and the filtrate evaporated in vacua. The residue is triturated in absolute ethanol and the solid is filtered, washed with absolute ethanol and dried in air, resulting in a white powder, MOP. 252-254C, identified as the hydrochloride sesquihydrate of the triazole.

[3-(1 - ox - 1, 2-DIHYDRO-5-ISOQUINOLYLOXY3-PROPYLAMINO]-1,2,5-THIADIAZOLE-l-OXIDE

Over a period of 5 his, 5.65 g of 5-(3-aminopro-poxy)-1,2-dihydro 1-(2H) isoquinolone are added portion-wise to a stirred solution of 3,4-dimethoxy-1,2,5-thia-diazole-l-oxide (4.22 g) in absolute methanol (520 ml) under nitrogen at C. The reaction mixture is allowed to warm to RUT and is stirred at RUT under nitrogen overnight. The reaction mixture is again cooled to ice bath temperature and is saturated with an hydrous ammonia over a period of 1 hr. The reaction mixture is allowed to warm slowly to RUT and stirred at RUT for 2 his. The stirred reaction mixture is again cooled to ice bath temperature and saturated with ammonia over a period of 2 his and stirred overnight. concentrated in vacua and the solid filtered, washed with methanol and dried. The filtered solid is dissolved in hot DMF and the hot solution filtered using Marco G-60. The filtrate is cooled and diluted with HO. The resultant precipitate is collected, washed with HO, absolute ethanol and dried in vacua at 75C overnight. The resulting tan solid is suspended in methanol and the mixture heated to boiling ~2308~
and reflexed for 2 his. The mixture is filtered while hot and the resulting tan solid washed with methanol and dried in vacua overnight, yielding the desired product as a powder, MOP. 235C w/dec.

The following exemplifies intermediates useful in the preparation of the compounds of Formula I.

THE PREPARATION OF DODDERS-QUININES ACCORDING TO FORMULA I

Step 1. 5-Hydroxy-1,2,3,4-tetrahydro-1-(2H) isoquinolone A mixture of 5-hydroxy-1,2-dihydro~ OH) isoquinO-lone ~141 g) and 20 g of 10% Pd/C in absolute ethanol (1.5 1) is heated to about 50~C under hydrogen with shaking until a total of 120 pi of hydrogen is consumed.
The reaction mixture is cooled, evacuated, filtered and evaporated in vacua. The residue is triturated in asset-nitrite which affords, after drying, the desired isoquino-lone as a white solid, MOP. 187-190C

Step 2. 5-(3-PhthalimidoPro~oxY)-1,2,3,4-tetrahvdro-1-(OH) isoquinolone An hydrous K2CO3 (47.13 g), N-(3-bro~opropyl) phthalimide ~87.27 g) and HO ~39 ml) are added to a stirred solution of s-hydroxy-l~2l3~4-tetrahydro-l-(2H)-isoquinolone (50.59 g) in DMF (388 ml) and stirred at RUT
for 5 days. 2.5 1 of HO are added to the reaction mixture which is stirred for an additional 1-1/2 his and then filtered. The filtered white solid is washed with HO, dried and suspended in THY. The suspension is stirred at RUT for 1-1/2 his, filtered, and the filtered solid washed with THY and dried, affording the desired lZ3~)~375 product as a white powder, MOP. 219-221C. The powder is is recrystallized from boiling glacial acetic acid and dried in vacua at 100C, resulting in white crystals of the desired product having a melting point of 221-222C.

Step 3. 1-Chloro-3,4-dihydro-5-~3-phthalimidopropQxy)-isoquinoline hydrochloride 5-~3-Phthalimidopropoxy)-1,2,3,4-tetrahydro-1~(2H))-isoquinolone (7 g) is added to a stirred solution of phosgene (25 g) in ethylene chloride (200 ml) while maintaining a reaction temperature of -10C. The stirred reaction mixture is allowed to warm slowly to RUT
and stirring is continued at RUT overnight. The reaction mixture is heated to reflex, stirred at reflex for 2 his.
Excess phosgene is removed by adding Tulane to the residue twice and evaporating the suspension. The resulting residue is the desired l-chloro product. NOR
spectrum (100 MMz) (CF3-COOD) 2.32~ (m,2H), 3.28~ (try 4.06~ (t,2H), 4.15~ (m,4H), 7.4-7.9~ (m,7H).

Step 4. 1-Ethoxy-3,4-dihydro-5-(3-phthalimidopropoxy)-isoquinoline 5-(3-Phthalimidopropoxy)-1,2,3,4-tetrahydro-1-(2H))-isoquinolone I g) is added to a stirred solution of phosgene (25 g) in ethylene chloride ~200 ml) while maintaining a reaction temperature of -10C. The reaction mixture is stirred and allowed to warm slowly to RUT and stirring is continued at RUT for an hour. The reaction mixture is evaporated in vacua and the residue suspended in ethylene chloride, cooled to -10C and treated with absolute ethanol (25 ml). The reaction mixture is stirred for 30 minutes, allowed to reach RUT
and stirred overnight. the reaction mixture is evapo-rated in vacua affording the desired l-ethoxy product as ~30~3~5 a solid. NOR spectrum (100 MHz) (CDC13/CD30D~ 1.3 (t,3H), 2.2~ (m,2H), 2.6~ to 3.48~ (t,2H), 3.8-4.3 (m7H).
Treatment of the l-chloro dihydroisoquinolinium salt with an amine such as piperidine instead of ethanol results in the desired l-amino intermediate. Subsequent removal of the phthalimido group with hydrazine and elaboration of the propylamino side chain according to the reaction sequence discussed above results in the formation of the 3,4-dihydroisoquinoline compounds according to Formula I.

THE PREPARATION OF CHAIN EXTENDED
COMPOUNDS ACCORDING TO FORMULA I

Step 1. 5-Methoxy isoquinoline Potassium t-butoxide ~122 g) is added over a period of 5 minutes to a solution of 5-hydroxyisoquinoline (150 g) in DMF (1.5 1) while maintaining a temperature of 15-20C under nitrogen. The reaction temperature is dropped to 10C and iodomethane (67 ml) in DMF (KIWI ml) is added to the reaction mixture over a period of 20 minutes, while maintaining the reaction temperature at less than 20C. The reaction mixture is stirred at RUT
overnight, after which a mixture of H20 and ethyl acetate is added. The organic phase is separated and washed with 5% sodium hydroxide solution and ice cold 53 aqueous hydrochloric acid. The hydrochloric acid extract is made strongly alkaline, resulting in the formation of a precipitate. The precipitate is extracted into ethyl acetate and the ethyl acetate extract washed with Eye and saturated chloride solution and dried over sodium sulfate.
The dried extract is filtered and the filtrate evaporated in vacua, affording a dark red oil. Vacuum distillation 88 ~23~
results in the desired methoxy compound as a clear colorless oil, BY 98-103C (0.5 mm Hug).

Step 2. 1-Cyano-2-benzenesulfonyl-5-methoxv-1,~-dihydro-isoquinoline Benzylsulfonyl chloride (125 ml) is added over a period of 2 his to a stirred reaction mixture of S-methoxy isoquinoline (78 g) and potassium cyanide (98 g) in ethylene chloride (650 ml) under nitrogen while maintaining the temperature below 23C. After the addition is complete, stirring at RUT is continued for 4 his. The reaction mixture is partitioned between HO and ethylene chloride. The organic extract is separated, washed with H20 and stirred with 10% hydrochloric acid.
The layers are separated and the organic layers washed with HO, 5% sodium hydroxide solution and dried over sodium sulfate. The dried extract is filtered and the filtrate evaporated in vacua, affording a yellow solid which is triturated with hexanes. The triturated solid is filtered, dried, dissolved in hot absolute ethanol, filtered while hot, and allowed to cool, forming a precipitate. The precipitate is filtered, washed with ethanol and dried, yielding the desired cyanobenzenesul-phenol compound as a white crystalline solid, MOP. 152.5-154C.

Step 3. 1-Cyano-5-methoxvisoquinoline Sodium hydrides (1.2 g of 60~ in mineral oil) is added to a stirred suspension of l-cyano-2-benzenesul-fonyl-1,2-dihydro-5-methoxyisoquinoline (10 grin zillion (100 ml). The reaction mixture is reflexed under nitrogen for 3 his, cooled to RUT, stirred for an additional hour, and filtered. The filtered solid is washed with zillions. The filtrate is evaporated in vacua.

~'~3087S

The filtered solid is stirred with ethylene chloride and aqueous I sodium hydroxide solution. The ethylene chloride phase is combined with the residue from the evaporated filtrate and the combined extracts are washed with 5% sodium hydroxide solution, HO and dried over sodium sulfate. The dried extract is filtered and the filtrate evaporated in vacua, affording a moist solid which is triturated in hexanes. The triturated solid is filtered, washed with hexanes, and dried, affording a fluffy orange solid, MOP. 166-175C. The crude product is dissolved in ethyl acetate, treated with charcoal, filtered and recrystallized from ethyl acetate, affording the desired cyanoisoquinoline as a crystalline solid, MOP. 180-182~C.
Hydrolysis of the cyan group followed by amidation and hydrides reduction affords the chain extended amine.
Deprotection of the foxy group followed by the addition of the R2-propylene chain according to the reactor sequences described above results in the chain extended compounds of Formula I.

go )8~7S

The compounds of Formula I have been found to be histamine wrester antagonists by the results obtained in the following H2-antagonist tests.

A. Isolated Guinea Pig Aria The H2-receptor antagonist activity of the compounds of Formula I is measured by observing the beat raze response versus compound concentration in isolated guinea pig aria. A discussion of criteria to evaluate these dose response curves may be found in, EDGY. Anions, GOUGE. vans, ARM. Simmons, and TAM. van Possum, "A Molecular Approach to General Pharmacology", Sections AYE, lob, and 111, Molecular Pharmacology:
The Mode of Action of Biologically Active Compound.
Vol. 1, Academic Press (1964).

1. Tissue Bath A fifty ml jacketed tissue bath is maintained at 30C. The bath consists of a Krebs-Henseleit buffer aerated with 95% 2 5% COY, (pi 7.4). The buffer is prepared by mixing: 4 ml of an aqueous (distilled deionized) solution of Cook OWE ~0.37 g/ml); 4 ml of an aqueous (distilled deionized) solution of McCoy OWE ~0.29 g/ml); 7.2 g of glucose; and, 2 liters of aqueous (distilled deionized) solution containing Nail (28 g), Nikko (8.4 g), Clue (1.4 g) and KH2PO4 (0-6 g).

I Z~3~87 2. Preparation of Aria Male albino guinea pigs (400-700 g, preferably 500-600 g) are killed by a blow to the back of the head and exsanguinate by cutting jugular veins and carotid arteries. The thoracic skin is opened from this neck cut and the rib cage exposed. Both sides of the rib cage and the diaphragm are cut and laid back, exposing the heart. The heart is removed by cutting through the vessels above and behind it while it is slightly elevated with forceps holding the ventricle tip. The heart is immediately placed in warm, aerated buffer and further dissected in a large putter dish of the same buffer. Since the pericardium is removed, it is possible to slip iris scissors between the aria and ventricles while holding the aorta and vessels with tweezers and cut off the aria. The aria are then dissected from any remaining tissue and vessels and suspended in the bath using small, curved taper-point needles formed into hooks and tied to an S-shaped hook and the L-shaped lower support with 00 silk.
A Beckman Type 9308 Strain Gauge Coupler connects a Beckman cardiotachometer to a Grass FT03C
strain gauge supported in a rook and pinion clamp. The upper hook of the strain gauge is placed in the edge of the left atrium and the lower hook in the tip of the right atrium. The lower support is clamped in a femur clamp and the upper hook is suspended from the strain gauge lug. The strain gauge is raised until the resting tension on the tissue is 1 gram. The tissue is allowed to stabilize for about one hour with several buffer washings and tension adjustments before the addition of the test compounds 3. Test Procedure A control dose-response curve using cumulative, approximately tripling doses is obtained in all three running from Owl to 30.0 M histamine (Owl, 0.3, lo, 3.0, etc.) In order to minimize volume changes when adding drugs to the bath, small volumes of concentrated solutions are used. It is convenient to make up a 0.5M
solution and dilute it to give 50, 5 and 0.5 my solutions.
Data recorded consists of the initial baseline rate and the stable plateau rate after each addition.
Histamine is then washed out and the tissues are allowed to stabilize again near the initial baseline rate; this may take several rinses and l hr. The test compound is then added at the same cumulative doses and rates again recorded. If the compound behaves as an agonist and stimulates, then the dose is increased until the rate plateaus or the concentration is lo my.
If, however, no agonistic activity is observed when the concentrations has reached loo M then its antagonistic activity is assessed by repeating the histamine curve without washing out the test compound. Reversibility of effect is assessed by attempting to wash out the test compound and/or histamine and repeat the histamine curve. Erratic or irregular beating or any other abnormal behavior at any time is noted. Calculations consist of the change in rate from base line and that change as a percentage of the maximum rate obtained in the initial control curve. The mean of those percentages I+ SEMI is plotted as a function of agonist concentration (either histamine or test compound) to evaluate the type of response.

By Lumen Perfused Rat Stomach - Effect on the Gastric Secretion Male Sprague-Dawley rats weighing between 350 and 500 gym are housed individually according to standard animal husbandry procedures and are deprived of food twenty-four hours prior to testing. The rats are anesthetized by an intraperitoneal injection of 25 solution of urethane (0.5 to 0.7 ml/100 g of body weight). Once anesthetized, the trachea is exposed and cannulated with PI 100 tubing. The jugular vein is exposed and cannulated with PI 50 tubing beveled at the tip. The abdomen is opened through a midline incision, and the esophagus is isolated excluding the vague nerve. PI 190 tubing, with a flange on one end, is passed down the rat's mouth through the esophagus and into the stomach. The esophagus is tied off and the tubing checked to make sure that it is securely in the stomach. The duodenum is then identified and a small cut made about 1 cm below the pyloric sphincter.
A piece of PI 320 tubing (flanged at one end) is inserted through the cut and into the stomach. It is secured firmly by tying a ligature around the pullers.
Using a 50 ml syringe, the stomach is flushed out with 0.4 my Noah through the esophageal tube until the perfusate emerging from the pyloric tube is clear. The animal is placed on a tilted table covered with a Gordon-Rupp water blanket Model 'K' to maintain the rat's body temperature at 30~C. The tube going into the esophagus is attached to a Sage Peristaltic Pump and 0.4 my aye (pi - 10.0) is perfused and collected in 30 ml beakers. The beakers are changed every 10 or 15 minutes and the pi of these samples are recorded. Once 94 :~230875 the pi has stabilized around 6.5-7.5, drugs that affect gastric secretion are given intravenously. The effectiveness of a compound is based on its ability to prevent a drop in pi initiated by a gastric stimulant, such as histamine. See, Gosh, MEN. and Child, HO., Bruit. J. Pharmacol., 13: 54 (1958).
Compounds within the scope of Formula I have also been determined to exhibit anti-ulcer activity.
The anti-ulcer properties of these compounds can be evaluated using an anti-ulcer assay in which aspirin or another nonsteroidal anti-inflammatory agent is used to induce gastric ulcers in the ray according to the following test procedure.
See, Cornell, T., "Interaction of Salicylates and other Non-steroidal Anti-inflammatory Agents in Rats as Shown by Gastro-ulcerogenic and Anti-inflammatory Activities, and Plasma Concentrations", Act.
Pharmacology et. Toxicology, 45, 225-231 (1979).
Male Sprague-Dawley rats 140-170 g are housed according to standard animal husbandry procedures. The rats are fasted twenty-four hours prior to testing. On the test day, rats are divided into groups of S or 10, with one group serving as controls and receiving vow-ale for example, distilled water or a 0.1% Tweet 80 solution). The test compounds, using logarithmic doses, are administered at a dose volume of 10 ml/kg.
Thirty minutes post-drug, the rats are orally ad minis-toned ~10 ml/kg) aspirin or indomethacin suspended in 0.1% Tweet 80 at a dose of 150.0 or 20.0 mg/kg, respect lively. Four hours following indomethacin administer-lion five hours after aspirin administration) animals are sacrificed via cervical dislocation; their stomachs are removed, opened along the greater curvature, and gently rinsed and examined for lesions with a 10X
magnifying glass; the following scale is employed:

, Grade Description 0 No lesions 1 5 lesions, all < 2 em 2 5 lesions, at least 1 > 2 mm 3 5-10 lesions, all < 2 mm 4 5-10 lesions, at least 1 2 mm 10 lesions, all < 2 mm 6 10 lesions r at least 1 > 2 mm 7 Perforation The average ulcer severity (+ SUE for each group of animals is calculated. The percent inhibition for each test compound is calculated as follows:

% inhibition =

Mean value for control - Mean value for exDerimenta] x 100 Mean value for control The compounds of Formula I have also been determined to exhibit cytoprotective activity.
The cytoprotective effectiveness of the compounds of Formula I is evaluated according to the following test procedure.
Male Sprague-Dawley rats 150-200 g are housed according to standard animal husbandry procedures. The rats are fasted twenty-four hours prior to testing. On the test day, rats are divided into groups of 6, with one group serving as controls and receiving vehicle (for example, distilled water or a 0.5% Methuselah soul-lion). The test compounds, using logarithmically spaced doses, are administered at a dose volume of 5 ml/kg. Ten minutes post-drug, the rats are orally ~23C~875 administered 1 ml of absolute alcohol, 0.2N Noah I ml) or 0.6N Hal (1 ml), regardless of body weight. One hour after administration animals are sacrificed by cervical dislocation, their stomachs are removed, opened along the greater curvature, rinsed under running tap water and examined for lesions with a 2X-10X magnifying glass.
The reduction of lesion count, lesion severity score and ulcer index as compared to similar measure-mints made in the controls was expressed as a percent tare. Measurement of statistical significance of the results was done by standard methods.
The average ulcer severity (+ SUE.) for each group of animals is calculated. The percent inhibition for each test compound is calculated as follows:

% inhibition =

Mean value for control - Mean value for experimental x 100 Mean value for control he results of the anti-secretory, anti-ulcer and cytoprotective assays, detailed above, establish the anti-secretory activity, the H2-receptor antagonist activity, the anti-ulcer activity, the cytoprotective activity, and the utility of the compounds of the pro-sent invention in the treatment of peptic ulcers in mammals, including humans. These compounds both aid in the healing of such ulcers and also prevent their or-motion.
A preferred cytoprotective compound is l-cyano-3-l3-~S-isoquinolyloxy)propyl~-2-methyl-pseudothiourfee which is 100% effective in the above described cytopro-tective tests at doses of less than 25 mg/kg.

.

97 1'~30~375 Other preferred cytoprotective compounds include Sweeney 3-(5-isoquinolyloxy)propyl]-3-methylguanidine and 5-~3-aminopropoxy) isoquinoline.
A preferred H2-antagonist compound is 3-amino-1-methyl-5-~3-(1-piperidino-5-isoquinolyloxy) propel-amino]-lH-1,2,4-triazole.
In particular, the compounds according to Forum-ice I to V are useful: in the treatment and prevention of hyperacidity and gastrointestinal ulceration; for decreasing gastrointestinal acid secretion in mammals;
and for enhancing the gastrointestinal resistance to gastrointestinal irritants in humans and other mammals.
For all these purposes, the compounds of this invention can be normally administered orally or parent tonally. Oral administration is preferred.
The compounds according to the invention, preferably in the form of a salt, may be formulated for administration in any convenient way, and the invention includes within its scope pharmaceutical compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Such compositions may also contain if required other active ingredients, for example, Hl-antagonists, or known antacids such as aluminum hydroxide, magnesium hydroxide, magnesium trisilicate, aluminum glycinate, or calcium carbonate.
Suitable carriers include delineates or fillers, sterile aqueous media and various non-toxic organic solvents.
The compositions may be formulated in the form of tablets, capsules, lozenges, torches, hard candies, powders, aqueous suspensions, or solutions, injectable solutions, elixirs, syrups and the live and may contain 98 ~X30~

one or more agents selected from the group including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a pharmaceutically acceptable preparation.
The particular carrier and the ratio of active compound to carrier are determined by the volubility and chemical properties of the compounds, the particular mode of administration and standard pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate and various disintegrants such as starch, alginic acid and certain complex silicates, together with lubricating agents such as magnesium Stewart, sodium laurel sulfite and talc, can be used in producing tablets. For a capsule form, lactose and high molecular weight polyethylene glycols are among the preferred pharmaceutically acceptable carriers.
Where aqueous suspensions for oral use are formulated, the carrier can be emulsifying or suspending agents.
Delineates such as ethanol, propylene glycol, glycerin and chloroform and their combinations can be employed as well as other materials.
For parenteral administration, solutions or suspensions of these compounds in sesame or peanut oil or aqueous propylene glycol solutions, as well as sterile aqueous solutions of the soluble pharmaceutically acceptable salts described herein can be employed. Solutions of the salts of these compounds are especially suited for intramuscular and subcutaneous injection purposes. The aqueous solutions, including those of the salts dissolved in pure distilled water, are also useful for intravenous injection purposes, provided that their pi is properly adjusted, suitably buffered, and made isotonic with sufficient saline or glucose.

~'~30B75 The dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief. Thus, in general, the dosages are those that are therapeutically effective in the treatment of gastrointestinal disease conditions or symptoms, such as duodenal and peptic ulcer. In general, the dose can be between about 0.1 mg/kg and 100 mg/kg (preferably in the range of 1 to 20 mg/kg), bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, age, and other factors which may influence response to the drug. The daily dose can range from 1 to 4 times a Jay.
This application is a division of Canadian Apply-cation SUN. 432,915 filed on July 21, 1983.

Claims (22)

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 a compound of the formula wherein:
W1 is CH, CH2, CHR or CR;
W2 and W3 are independently CH, CH2, CHR3 or CR3;
X is N or CH, or (CH)3-d, when Y is (CH)d;
Y is O, S, or NR4, or (CH)d, when X is (CH)3-d;
Z is O, S, , or CH2;
O O O
and wherein:
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , or -(CH2)n -NR8R9;
R1 is H, lower alkyl, lower alkyl acyl, halo lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, or together with W1 forms a carbon-nitrogen double bond;

R2 is NH2 or CN;
R3 is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, amino, lower alkylamino, or di-lower alkylamino;
R4 is H, lower alkyl, or lower alkyl acyl;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;

and wherein:
a is 0 or 1;
b is 1 or 2;
e is 0, 1 or 2;
d is 0, 1, 2 or 3;
f is 1, 2, 3 or 4;
n is 0, 1, 2 or 3;
comprising 1) reacting a compound of formula wherein Pr is a base insensitive amine protecting group, with a reagent which removes said protecting group;
or 2) reacting a compound of formula with a) cyano substituted alkylating agent in the presence of base;
or b) an acid salt of HS-(CH2)?-NH2;
or e) a halogenating agent; and d) reacting the product of step c) with HS-(CH2)?CN.

2. A compound of the formula wherein:
W1 is CH, CH2, CHR or CR;
W2 and W3 are independently CH, CH2, CHR3 or CR3;
X is N or CH, or (CH)3-d, when Y is (CH)d;
Y is O, S, or NR4, or (CH)d, when X is (CH)3-d;
Z is O, S, , or CH2;

and wherein:
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2 )n -NR8R9;
R1 is H, lower alkyl, lower alkyl acyl, halo lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, or together with W1 forms a carbon-nitrogen double bond;
R2 is NH2 or CN;
R3 is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, amino, lower alkylamino, or di-lower alkylamino;
R4 is H, lower alkyl, or lower alkyl acyl;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;
and wherein:
a is 0 or 1;
b is 1 or 2;
c is 0, 1 or 2;
d is 0, 1, 2 or 3;
f is 1, 2, 3 or 4;
n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

3. A process for the preparation of a compound of the formula wherein:
b is 1 or 2;
c is 0, 1 or 2;
W1 is CRR7, when b is 1, or CH2, when b is 2;
Y is O, S or NR4;
R1 is H, lower alkyl, lower alkyl acyl, halo lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, or together with R7 forms a carbon-nitrogen double bond;
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n -NR8R9;
R4 is H, lower alkyl, or lower alkyl acyl;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;

n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, comprising 1) reacting a compound of the formula with a) HS(CH2)2NH3+Cl;
or b) a halogenating agent; and c) reacting the product of step b) with HS(CH2)2CN.

4. A compound of the formula wherein:
b is 1 or 2;
c is 0, 1 or 2;
W1 is CRR7, when b is 1, or CH2, when b is 2;
Y is O, S or NR4;
R1 is H, lower alkyl, lower alkyl acyl, halo lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, or together with R7 forms a carbon-nitrogen double bond;
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n-NR8R9;
R4 is H, lower alkyl, or lower alkyl acyl;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

5. A process for the preparation of a compound of the formula wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n-NR8R9;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;
n is 0, 1, 2 or 3;
comprising reacting a compound of the formula with a) HS(CH2)2NH3+Cl:
or b) a halogenating agent; and c) reacting the product of step b) with HS(CH2)2CN;
or a pharmaceutically acceptable salt thereof.

6. A compound of the formula wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n-NR8R9;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

7. A process for the preparation of a compound of the formula wherein:
R1 is H, lower alkyl, lower alkyl acyl, halo lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, or together with R7 forms a carbon-nitrogen double bond;

R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n-NR8R9;
R7 is H or together with R1 forms a carbon-nitrogen double bond;

R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, comprising 1) reacting a compound of formula with a) Cl(CH2)3CN;
or 2) reacting a compound of the formula with hydrazine.

8. A compound of the formula wherein:
R1 is H, lower alkyl, lower alkyl acyl, halo lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono- and di-lower alkylamino lower alkyl, or together with R7 forms a carbon-nitrogen double bond:

R2 is NH2 or CN;

R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n-NR8R9;
R7 is H or together with R1 forms a carbon-nitrogen double bond;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.

9. A process for the preparation of a compound of the formula wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n-NR8R9;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;
n is 0, 1, 2 or 3;

or pharmaceutically acceptable salt thereof, comprising 1) reacting a compound of the formula with Cl(CH2)3CN;
or 2) reacting a compound of the formula with hydrazine.

10. A compound of the formula wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower alkyl, halo lower alkyl, , , or -(CH2)n-NR8R9;
R8 and R9 are each independently H or lower alkyl or together with the nitrogen atom to which they are attached form a 5, 6 or 7 member ring which may include an additional heteroatom of N, O or S;

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof, when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.

11. A process for the preparation of 5-(3-aminopropoxy)isoquinoline comprising the reaction of 5-(3-phthalimido)propoxy isoquinoline with hydrazine.

12. 5-(3-aminopropoxy)isoquinoline or a pharmaceutically acceptable salt thereof when prepared by the process defined in Claim 11 or an obvious chemical equivalent.

13. A process for the preparation of 5-(3-aminopropoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline by reacting 5-[3-(N-phthalimido)propoxy]-2-methyl-1,2,3,4-tetrahydroisoquinoline with hydrazine.

14. 5-(3-aminopropoxy)-2-methyl-1,2,3,4-tetrahydro-isoquinoline or a pharmaceutically acceptable salt thereof when prepared by the process defined in Claim 13 or an obvious chemical equivalent.

15. A process for the preparation of 7-(3-aminopropoxy)-isoquinoline by reacting 7-[3-(N-phthalimido)propoxy]-isoquinoline with hydrazine.

16. 7-(3-aminopropoxy)isoquinoline or a pharmaceutically acceptable salt thereof when prepared by the process defined in Claim 15 or an obvious chemical equivalent.

17. A process for the preparation of 7-(3-aminopropoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline by reacting 2-methyl-7-[3-(1 phthalimido)propoxy]-1,2,3,4-tetrahydroisoquinoline with hydrazine.

18. 7-(3-aminopropoxy)-2-methyl-1,2,3,4-tetrahydro-isoquinoline or a pharmaceutically acceptable salt thereof when prepared by the process defined in Claim 17 or an obvious chemical equivalent.

19. A process for the preparation of 5-(3-aminopropoxy)-1-piperidino-isoquinoline by reacting 5-(3-phthalimidopropoxy)-1-piperidinoisoquinoline with hydrazine.

20. 5-(3-aminopropoxy)-1-piperidinoisoquinoline or a pharmaceutically acceptable salt thereof when prepared by the process defined in Claim 19 or an obvious chemical equivalent.

21. A process for the preparation of 5-(3-aminopropoxy)-1-morpholinoisoquinoline by reacting 1-morpholino-5-(3-phthalimido-propoxy)isoquinoline with hydrazine.

22. 5-(3-aminopropoxy)-1-morpholinoisoquinoline or a pharmaceutically acceptable salt thereof when prepared by the process defined in Claim 21 or an obvious chemical equivalent.