BICYCLIC NITROGEN HETEROCYCLIC ETHERS AND THIOETHERS, AND THEIR PHARMACEUTICAL USES

(THIO)ETHERS DE COMPOSES BICYCLIQUES N-HETERO- CYCLIQUES ET APPLICATIONS PHARMACEUTIQUES

English Abstract

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

Image

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, Image, Image, or CH2;
and wherein:
R is alkyl, halo, alkoxy, hydroxy, hydroxy alkyl,
halo alkyl, -(CH2)n-NR8R9,Image, or Image;
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,
Image




Image , Image ,


Image , Image,

Image , and Image ;



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.

Claims

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

Image




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, Image, Image or CH2;
O O O
and wherein:
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower

alkyl, halo lower alkyl, Image, Image 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;
100

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



Image




wherein Pr is a base insensitive amine protecting group, with a
reagent which removes said protecting group;
or
2) reacting a compound of formula



Image




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



Image


101

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, Image, Image or CH2;

and wherein:
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower

alkyl, halo lower alkyl, Image , Image, 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;


102

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



Image


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, Image, Image, 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


103

1) reacting a compound of the formula


Image



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

Image


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, Image, Image, 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,

104

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



Image




wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower

alkyl, halo lower alkyl, Image, Image, 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



Image




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


Image

105

wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower

alkyl, halo lower alkyl, Image, Image, 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



Image




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, Image, Image, or -(CH2)n-NR8R9;
R7 is H or together with R1 forms a carbon-nitrogen
double bond;
106

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

Image


with a) Cl(CH2)3CN;
or 2) reacting a compound of the formula



Image




with hydrazine.

8. A compound of the formula



Image


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:


107

R2 is NH2 or CN;

R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower

alkyl, halo lower alkyl, Image, Image, 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



Image


wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower

alkyl, halo lower alkyl, Image, Image, 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;

108

or pharmaceutically acceptable salt thereof,
comprising
1) reacting a compound of the formula



Image




with Cl(CH2)3CN;
or
2) reacting a compound of the formula



Image


with hydrazine.

10. A compound of the formula



Image


wherein:
R2 is NH2 or CN;
R is lower alkyl, halo, alkoxy, hydroxy, hydroxy lower


alkyl, halo lower alkyl, Image, Image, 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;

109

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-

110

(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.




111

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


123087S

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,
NS2NH2
-C-NH2, -ON,

~230~3~5


N - ON N - ON
-NH -C - NOR 5, -NH -C - S -a lay l,

R5
N N OH - NO 2
\\ 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;

6 I

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.

OCH2CH2CH2-R2 II

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

N CH2-S-CH2CH2R2 IV

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

N OCH2CH2CH2R2


wherein substitution may be at the 5,6,7 or 8 position
R2 R
_ . _

NHCN
-NH-C-NHCH3 H

NON
-NH -C-NH 2 OH 3

IClHNO2
-NH-C-NHCH 3 H

SHEEHAN 2
-NH-C-NH 2 NH 2

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
R2 R

NUN
-NH-C-S-CH3 H

7-CN
-NH-C-S-CH3 SHEA

NUN
-NH-C-S-CH3 NR2

7-CN
-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

OUCH SHEA SHEA OR 2


wherein substitution may be at the 5,6,7 or 8 position
R2 R
.


NUN I C~2 I NHCH3

--NH N O

O SHEA
HO SHEA


-NH No 2
I,
N ON SHEA


-NH NHC H 3
// \\ H
N N
S
o

14 I
TABLE A

OC~2cH2cH2R2


wherein substitution may be at the 5,6,7 or 8 position
R2 R

-NH NH2
If I\ -N
N N
S

SHEA
N - N

-NH N NH2 NH2

SHEA

-ND N NH2 -N

SHEA\
N N I
-N
-NH N NH2

~l~3087~';

TABLE A

, oCH2CH2CH2R2


wherein substitution may be at the 5,6,7 or 8 position
R2 R

SHEA

--NH N NH 2 No

SHEA
NUN
No
-NH No NH2 \_/

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

SHEA
NUN NH
// \\ --C -NH 2
-NH N NH2

SHEA
N N O
I -C-NH2
I\
--NH N NH 2

1230B75
16
TABLE: A

No_, OX H SUE SHEA OR 2


wherein substitution may be at the 5, 6, 7 or 8 position
R2 R


SHEA
N N

I\ -C~2-NH2
-NH N NH 2

SHEA
NUN
// \\ CON
--NH No NH2

SHEA
N N
-NF~CH3
-NH N NH 2

SHEA
NUN
N(CH3) 2
-NH N NH 2

17 ~2301375
TABLE A

No oCH2CH2CH2R2


wherein substitution may be at the 5,6,7 or position
R2 R

SHEA
N N
--CHINOOK
--NH N NH 2

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

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

SHEA
N - N NH
-C-NHCH3
-NH N NH 2

Et
NUN
Jo -H
-NH N NHCH3

assay
18
TABLE A

OCH~CH2CH2R2


wherein substitution may be at the 5,6,7 or 8 position
R2 R


ON -N
1 -H
-NH N N~CH3

NSO2NH2
--C -NH 2 -NEW 2

NSO2N~2
-C-NH2 -H

NSO2NH

--C--NH2 V
NO 2 NH 2 /--\
-C-NH 2 NO

NO 2 NH 2 Jo
- C - NH 2 -N

Insane
-C-NH 2 -N O

19 ~23~ 75
TABLE A

OCR SHEA SHEA OR 2


wherein substitution may be at the 5,6,7 or 8 position
R2 R
.

NS02NH2 I
--C-NH 2 No

,N,SO2NH2 NH
-C-NH 2 -'C-~3 2

NS02NH2 o
-C -NH 2 -C -NH 2

NO 2 NH 2
-C -NH 2 -SUE 2NH 2

NS2NH2
--C-NH2 SHEA

NS2 NH 2
-C -NH 2 -NAZI 3

NO 2 NEW 2
-C -NH 2 -N ( C H 3 ) 2

NS02NH2
-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
R2 R

~NS02NH2
--C-NH2 -SHEEHAN SHEA ) 2

INSANE NH
-C -NH 2 -C -N ( OH 3 ) 2

~N~S02NH2 NH
-C -NH 2 -I -NHC H 3

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
OH 3--NH--C -NHCH 3 H H

SHEEHAN 2
SHEA -NH-C-NHCH3 SHEA - H

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

-NH NH 2
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
2

-NH NH2 Jo
double -N double
bond No ON bond
with R7 S with R
2

-NH NH2
SHEA H H
I




2

-NH NHCH3
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
-NH N N C H 3

O SHEA

-NH 1 > H H

SHEA
NUN
Et I H H
-HO N NHCH3

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

NON
SHEA -NH-C-SCH3 SHEA H

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

lo 5
24
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
26
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
27
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
I R2 R R7
.
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
OH 3 --C -NH 2 OH 2NH 2 H

~N~so2NH2
SHEA -C-NH2 -CHINCH H

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

NO 2NH 2 I
OH 3 -C-NH 2 OH ON ) H

NO 2NH 2
OH 3 -C-NH 2 -OH 2N3 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
OH 3 --C -NH 2 - --C--NHCH 3 H

llS2NH2 NH
OH 3 -C -NH 2 -C--NH2 H

NO 2NH 2
SHEA -C-NH2 --C-NHCH3 H

NO 2 NH 2
OH 3 -C-NH 2-C -N ( OH 3 ) 2 En

INTO 2NH 2 NH
OH 3 -C-NH 2 -C -N I) H

37S
31
TABLE C

>_ CH2SCH2CH2R2


Y may be oxygen or sulfur
2 R
NHCN
-NH-C-NHCH3 H

NON
NH-C-NH2 c~3

SHEEHAN
-NH-C-NHCH3 H

SHEEHAN
-NH-C-NH2 NH2

NUN
-NH-C-S-CH3 H

HO SHEA O

-NH N O> NHCH3

32 12;3~
TABLE C

CE~2SCH2C~2R2
N Y

Y may be oxygen or sulfur
R2 R


> -N 3

NHCN
-NH-C-NHCH3 -N

NHCN
-N~-C-NHCH3 -SHEA-

O SHEA

-NH N N SHEA

-NH NH2

S SUE




.~.

33 23~375
TABLE C

R I- CH2SCH2C~2R2


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

I

SHEA
N No

I NH2
-NH N NEW 2

SHEA
NUN O
-C -NHC H 3
-NH N NH2

SHEA
N - N
-Chinese 3
--NH N NH 2

~30~
34
TABLE C

CH2SCH2CH2R2
N I/ y
R




Y may be oxygen or sulfur
R2 R
SHEA
N N.
SHEEHAN S C~3 2
--NH N NH 2

Et
No
Jo H
-NH N /J~NHC H 3

HO ON
I\ H
-NH Jo No NHCH 3

SHEA
NUN

-NH N NH 2

SHEA
N N

-NH N NH2 -N


TABLE C

OH 2 SUCH 2C~ OR 2


Y may be oxygen or sulfur
R2 R

SHEA
N N \

--NH N NH 2 NO

OH 3

-NH N No /--\

SHEA
NUN ,/--~
~<~ -N I
-NH N NH2

SHEA
N N NH

C--NH2
-NH N NH 2

36
TABLE C

CH2SC~2CH2R2


Y may be oxygen or sulfur
R2 R
_ .
SHEA
N NH
CON
--NH N Ho

SHEA
N - N NH
<\ -C -NHCH 3
--NH N NH 2

Ions 2NH 2
-C -NH 2 H

NO 2NH 2 /--\\
--C--NH2 -N Jo

NS2NH2
-C -NH 2 -N

INSANE
--C--NH 2 -No)

I [)~375
37
TABLE C

CH2SCH2CH2R2
No Y
R




Y may be oxygen or sulfur
R2 R
NS02NH2
--C--NH 2 -NO

NS2~H2
--C--NH 2 --N

NS2NH2 NH
CUE 2 -C--NH 2

NISSAN NH
-C -NH 2 -C -N

NO 2NH 2 NH
-C--NH 2 -C--NHC H 3

NISSAN
--C--NH2 -SHEEHAN

INSANE
-C -NH 2 -OH 2 -NHC H 3

NS02NH2 /--\
-C-NH2 -SHEEHAN

38 5
Taste D

f CH~SCH2CH2R2
/ N O
Al R R7

R1 I R R7
.. . . . _

NICK
CH3-NH-C-NHCH3 H H

SHEEHAN
CH3-NH-C-NHCH3 SHEA H

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

-NH NH2
double ~NH2 double
bond N ON bond
with R7 S with R
2

~23~S
39
TAB LYE

CH2SCH2CH2R2
N O
Pal R R7

Al R2 R R7
.

-NH NH 2
SHEA H H
/
2

--Nil NHC H 3
SHEA H H
S

o

O SHEA

I H H
-NH N N OH 3

p SHEA

an I owe H

SHEA
N N
Et I H H
-NH N NHCH3

I I
TABLE D

I- CH2SCH2CH2R2
/ 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
-NH N NH2

SHEA\
N N NH
SHEA -C-NHCH3
-MY N NH2

SHEA\
N - N NH
-C-N H
-NH N NH2

SHEA\
N -N NH
-C-N 3 H
-NH N No 2

41 lo
TABLE D

/ CUD CH2SCH2CH2R2

Al R R7

Al R2 R R7

OH I
N N o
SHEA I Ho H
-NH N NH 2

OH 3\
N- N
SHEA SHEEHAN H
-NH N NH 2

SHEA\

SHEEHAN No NH2 -SHEEHAN H

SHEA
N N
SHEA Jo -CHINCH H
-NH N NH 2

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




_,

42 1'~3C)~75
TALE D

CH2SCH2CH2R2
. / 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
44
TABLE D

CH2SCH2CH2R2
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

46 5
TABLE D

C~2SCH2CH2R2

I R R7

R 1 R 2 R R 7
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~
47

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

48 I 5

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


0 SO 2 ON
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
1 2
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
N 2 I LAY

COO I \ N R8
R


OUCH OH O
N SCHICK N O Brush
SHEA ITCH




N N
/ \ / \
R8 Rug R8 Rug


53

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

54 I I 375

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

I --H20 1 1
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
58

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

R R7 R R7

ashy. SHEA/
Hal

2Nh2
~)( SHEA ) SHEA

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

R R7 SHEA R R7
Scheme XIII

The analogous mercaptan compounds may be prepared
by reacting a cyan mercaptan with the appropriate halo-


59 1230875

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

R R7 R R7
HS-CH2CH2CN
N-S02N~2 base
~2ScH2cH2-c-NH2

1. anhv. HCl/MeOH CH2S-CH2CH2CN
ON 2. Sue /
l /\ SHEA Al /\
R R7 R R7
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.

EXAMPLE 1
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
61
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
62
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.

EXAMPLE 2
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
63

EXAMPLE 3
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.


64
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.

EXAMPLE 4
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.

EXAMPLE 5
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

EXAMPLE 6
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.

EXAMPLE 7
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


- EXAMPLE 8
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

EXAMPLE 9
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

EXAMPLE 10
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.

76
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,

0875
78
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.

EXAMPLE 11
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~
79
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.

EXPEL 12
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.

EXAMPLE 13
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.

EXAMPLE 14
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~

EXPEL 15
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
83
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.

EXAMPLE 16
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~;
84
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.

EXAMPLE 17
THE PREPARATION OF 3-AMINO-4-
[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.

EXAMPLE 18
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
86
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
87
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.

EXAM LYE 19
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
89
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
91


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

92 I


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.

0875
93


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
96

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.

99
~'~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.