Field of the Invention

* This invention relates to a class of bicyclic heterocyclic compounds characterized by an ether or thioether 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.

Reυorte.d Developments

Gastrointestinal hyperacid secretion, stomach and intestinal ulceration, and gastritis 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

OMPI

administration of antisecretory 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 H* _j _- and ^-receptors, was proposed by Ash and Schild (Brit. J. Pharmacol. Chemσther, 1966, 27, 427) and Black et al (Nature 1972, 236, 385) . The H* _j _-receptor is involved in the bronchial and gastrointestinal smooth muscle stimulative action of histamine. Drugs which block this action are labelled "antihistamines" (e.g. mepyramine) .

Black et al., cited above, described the group of substances which act at histamine receptors other than the H _j -receptor as H2-receptor agonists/antagonists. Blocking the action of histamine at the H2~rece tors will selectively block histamine ^r s stimulative action on gastric acid secretion and heart rate. Burimamide was the first clinically effective ^-receptor antago¬ nist inhibiting gastric secretion in man; but Burimam¬ ide*s oral absorptivity is poor. Subsequent studies developed the orally active Metiamide, the side effects of which limited clinical use, and Cimetidine which has

been marketed as an anti-ulcer drug. A number of classes of heterocyclic chemical compounds have been reported as ^-receptor antagonists, for example, those disclosed in U.S. Pat. Nos. 4,104,381, 4,279,819, 5 4,323,566, and British published patent application GB . 2067987A, the disclosures of which are incorporated by reference.

Another method for the prevention or treatment of gastric ulcer comprises the use of drugs which _T _ _Q 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" τ_5 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 been implicated in 0 the mechanism of cytoprotection by a number of workers in the field. See, the discussion of cytoprotection in Robert, Andre, "Prostaglandins and Digestive Diseases", Advances in Prostaqlandin and Thromboxane Research, Vol. 8 (Raven Press, N.Y. 1980), and Robert et al, 5 "Cytoprotection by Prostaglandins in Rats", Gastroenterology, 77, 433-443 (1979), hereby incorporated by reference. Drugs, other than prostaglandins, which exhibit cytoprotective activity include carbenoxolone sodium, reported to exhibit 0 undesirable side effects, such as edema, diastolic hypertension or hypokalemia, and the thiazol-2-yl- carbamoylcarboxylic acids, esters and imides described in U.S. Pat. No. 4,321,372.

The compounds of the present invention are a class of novel bicyclic heterocyclics which exhibit cytoprotective, ^' a i-secretory, H2~receρtor antagonist and anti-ulcer activity.

Summary of the Invention

This invention comprises a class of compounds according to Formula I

wherein: j_ is CH, CH ₂ , CHR or CR; 2 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_. _f i;

Z iiss O0,, S S,, SS,, .S S , or CH2; •* // _ 0 o 0 and wherein:

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

NH 0

H 11 halo alkyl, -(CH ₂ ) _n -NS_8R9, -C-NR8R9, or -C-NR8R9;

R _] _ is H, alkyl, acyl, haloalkyl, alkoxy alkyl, hydroxyalkyl, aminoalkyl, mono- and di-alkylamino alkyl, or together with Wτ_ forms a carbon-nitrogen double bond;

R2 is selected from the group consisting of NH2/

N - CN N - CN It 11 -NH-C - NHR ₅ , -NH-C - S -alk l.

N ^" S(0) _e alkaryl

R3 is alkyl, halo, alkoxy, hydroxy, hydroxy alkyl, haloalkyl, aminoalkyl, mono- and di-alkylamino alkyl, ami no , alk lamino, or dialkylamino;

R4 is H, alkyl, or acyl;

R5 is H or alkyl;

Rg is H, alkyl or acyl;

Rg 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, 0 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;

-^t_Rl-X

OMPI

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~rece tc antagonist acti¬ vity, 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 other 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: (A) Wherein: ]_, and W3 are CH; b and c are 1; and l together with W ^* _j _ forms a double bond; or

(B) Wherein:

Wτ_ is CHR or CH2; and and W3 are CH2; or

(C) Wherein either A or B above apply, and

X is (CH) ₃ _ _d ;

Y is (CH) _d ;

Z is 0; and a is zero; or

OMPI

( D ) Wherein either A or B above apply , and X is N or CH; Y is 0 , S or NR4 ; Z is S ; and a is 1.

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

R3 (R when the 1-position is substituted)

In Formulae II and III, R, R and R3 are as defined above; R_ is H, alkyl, substituted alkyl, acyl or toge- ther with R7 forms a carbon-nitrogen double bond; and R7 is H or together with Ri forms a carbon-nitrogen double bond; provided that in Formula III when Rτ_ and R7 form a double bond then R is other than alkyl, halo, alkoxy, hydroxy, hydroxy alkyl or halo alkyl. In Formu- lae II and III, the R propoxy substituent may be sub¬ stituted at the 5, 6, 7 or 8 position.

OMPI

Another preferred embodiment of this invention comprises the bicyclic compounds including a heteroatom in both rings and including a thioether ring substitu- ent as defined herein. This embodiment includes the compounds of Formulae IV and V

R3 (R when the 1-position is substituted)

wherein W* _j _ is CRR7 when b is 1 or CH ₂ when b is 2, and R, R ^* j_, 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 inten- ded to encompass all hydrates and tautomers, as well as any diastereomers and optical enantiomers.

As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Alkyl" means a saturated aliphatic hydrocarbon which may be either straight- or branched-chained. Preferred alkyl groups have no more than about 6 carbon

atoms and may be methyl, ethyl and structural isomers of propyl, butyl, pentyl, and hexyl.

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

The term "halo" includes all four halogens; namely, fluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred. ■ The "acyl" radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group such as acetyl, propionyl, 3-carboxy propionyl, benzoyl, etc. Preferred acyl radicals are radicals of lower alkyl organic acids. "Substituted alkyl" means an alkyl group substituted by a halo, alkoxy, hydroxy, amino, mono- or di-alkylamino group.

"Haloalkyl" means an alkyl 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 oxy radical of an alkyl group, preferably a lower alkyl group, such as methoxy, ethoxy, n-propoxy, and i-propoxy. "Alkoxy alkyl" means an alkyl group substituted by an alkoxy group as defined above.

"Hydroxy alkyl" means an alkyl group substituted by a hydroxy group.

"Amino alkyl" means an alkyl group substituted by an amino group.

"Mono- or di-alkylamino alkyl" means an alkyl group substituted by an alkyl- or di-alkyl-substituted amino group.

"Alkylamino" means a primary or secondary alkyl- substituted amino group.

Representative examples of compounds of this invention are listed below in Tables A, B, C and D.

^• ^TTREA

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TABLE A

wherein substitution may be at the 5,6,7 or 8 position 2 R

CHNO

II -NH-C-NHCH3 H

CHN0 ₂

II

-NH-C-NH ₂ NH ₂

TABLE A

wherein substitution may be at the 5,6,7 or 8 position R ₂ R

N-CN

N-CN

II

-NH-C-S-CH3 CH3

N-CN

N-CN

- 3R£Λ OMPI

TABLE A

wherein substitution may be at the 5,6,7 or 8 position R ₂ R

-NH NH-

N N CH3

\ /

S i O

-NH

OMPI

TABLE A

wherein substitution may be at the 5,6,7 or 8 position R ₂ R

CH ₃

N ^■ N

TABLE A

wherein substitution may be at the 5,6,7 or 8 position R ₂ R

CH-

N "N

-NH „ \

N NH- ^■ O

CH-

⁽ OMPI

TABLE A

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

TABLE A

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

R- R

OMPI

TABLE A

wherein substitution may be at the 5,6,7 or 8 position R ₂ R

NS0 NH -C-NH ₂ -NH ₂

NS0 ₂ NH ₂ -C-NH ₂ -H

NS0 NH -C-NH ₂ -N

t • ~ p

TABLE A

wherein substitution may be at the 5,6,7 or 8 position R ₂ R

NS0 ₂ NH2 -C-NH ₂ -N

V

NS0 ₂ H NH -C-NH ₂ -'_ N NIH* ₂

NS0 ₂ NH ₂ 0

II -C-NH ₂ -C- ^■ NH ₂

NS0 ₂ NH -C-NH ₂ -CH ₂ NH

NS0 ₂ NH ₂ -C-NH ₂ -NHCΪI3

NS0 ₂ NH ₂ -C-NH ₂ "N(CH ₃ ) ₂

NS0 ₂ NH2 -C-NH ₂ -CH NHCH3

TABLE A

wherein substitution may be at the 5,6,7 or 8 position R ₂ R

NS0 ₂ NH ₂ -C-NH ₂ -CH ₂ N(CH ₃ ) ₂

NS0 H2 NH II

-C-NH. -C-N ⁽ CH ₃ ⁾ ₂

N _u SO _9_NH _9_ NH

II

-C-NH ₂ -C-NHCH.

TABLE B

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

Rl R- R-

NCN II

CH3 -NH-C-NHCH- H H

double UN' CH- double bond CH* bond with R ₇ -NH N 0 with R_

TABLE B

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

Ri R-

-NH NH- double NH- double bond N N bond with R- S with R _j _ •V °2

double e bond with R7 R* _j _

-NH NH-

CH- H H

N N \ /

S

0 ₂

-NH NHCH.

CH. K H

N N \ /

S

-V

0

OMP

TABLE B

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

Rl R

CHNOo

II ^l

Et -NH-C-NH ₂ H H

NCN II

CH- -NH-C-SCH. CH H

N-CN II n-propyl -NH-C-NHCH3 H H

TABLE B

Rτ_ R R ₇ wherein substitution may be at the 5,6,7 or 8 position Rl R ₂ ^" R R ₇

OMPI

TABLE B

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

Ri R- R R-

CH*

\ double ^■ N double

CH-

\ double N N double

w R*L

TABLE B

2

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

Rl 2 ^R 7

double double

double . double bond NS0 ₂ NH ₂ bond with R7 -C-NH- NHCH3 with R* _j _

double double bond NSO2NH2 bond with R7 -C-NH ₂ NH ⁽ CH3 ⁾ 2 with Ri

MPI

TABLE B

R R R7 wherein substitution may be at the 5,6,7 or 8 position

Rl R- R R-

double double bond NSOoNH -N bond II ^Δ with R7 -C-NH ₂ with R _j _

double double

/ \ bond NSO _nNH -o N 0 bond with R7 -C-NH ₂ \ / with R* _j _

double double bond NSOoNHo -N bond

11 ^Δ with R7 -C-NH ₂ \-__J with R*-_

double double bond NS0 NH ₂ bond with R7 -C-NH ₂ -CH-.NH* with R* _j _

OMPI

TABLE B

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

*1 R- R-

double double bond NS0 ₂ NH ₂ bond with R7 -C-NH ₂ -CH ₂ NHCH ₃ with Rτ_

double double bond NS0 ₂ NH ₂ bond

11 with R7 -C-NH ₂ -CH ₂ N(CH ₃ ) ₂ with R- _j _

double double bond NSOoNHo bond II ^ ^Δ with R ₇ -C-NH ₂ -CH ₂ N with R* _j _

double double bond N _{j (} SO_.NH__ NH bond II with R7 -C-NH ₂ -C-NHCH3 with R-*_

double double bond NSOo H NH bond

11 ^{Δ Δ} II with R7 -C-NH ₂ -C-NH ₂ with R- _] _

t ^~~ _*? _l

TABLE B

v _/ herein substitution may be at the 5,6,7 or 8 position l R7

double double bond NSO ₉ NH 0 bond |1 ^Δ II with R7 -C-NH ₂ -C-NHCH3 with R

double double bond N ^SO _ ₉ NH _ 0 bond with R ₇ -C-NH ₂ - -N ⁽ CH ₃ ⁾ ₂ with Ri

NSO ₉ NH9

II ^{Δ Δ}

CH ₃ -C-NH -CH NH- H

N,!SO__NH_9.

CH* -C-NH ₂ -CK ₂ ⁽ CH ₃ ⁾ 2 H

TABLE B

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

Rl ^R 2 ^{R R} 7

NSO. >N_.H__.' NH

II II

CH- -C-NH ₂ -C-NH- H

NSO9NH 0 π - - II

CH-. -C-NHo -C-NHCH- H

NSO9NH-. 0

II

CH- -C- H-7 -C-N ⁽ CH ₃ ⁾ ₂ H

TABLE C

Y may be oxygen or sulfur

R- R

NCN II

-NH-C-NH ₂ CH-

CHNO

II -NH-C-NH ₂ NH ₂

N-CN II -NH-C-S-CH3 H

TABLE C

Y may be oxygen or sulfur

R-

NHCN II

-NH-C-NHCH3 -N

TABLE C

Y may be oxygen or sulfur

R- R

CH-

\

N N

OMPI

Y may be oxygen or sulfur R ₂ R

OMPI

Y may be oxygen or sulfur

R« R

PI

TABLE C

Y may be oxygen or sulfur

R<

NS0 ₂ NH2 -C-NHo H

TABLE__C

R

Y may be oxygen or sulfur

R

NS0 ₂ NH2 II -C-NH ₂ -N 0

NS0 ₂ NH2 NH 11 -C-NH ₂ -C-NH ₂

NS0 ₂ NH ₂ NH II -C-NH -C-NHCH3

NS0 ₂ NH ₂ -C-NH ₂ -CH ₂ -NH

NS0 ₂ NH ₂ -C-NH ₂ -CH ₂ -NHCH3

OMPI

Rl R- R

CHNOo II CH3 * -NH-C-NHCH3 CH- H

-NH NH- double NH ₂ double bond N N bond

\ / with R7 S with R* _j _ Ψ

°2

• TABLE D

Rl R2 R 7

^■ 0

TABLE D

Rl R2 R R7

CHNO2 1 1

Et -NH-C-NH ₂ H H

NCN

I I

CH ₃ -NH-C-SCH3 CH- H

N-CN n-propyl -NH-C -NHCH 3 H H

TABLE D

Ri *2 R *7

fϊ-E___ OMPI

t

TABLE D

Rl R2 R R7

' OMPI

R- R R-

e

R*j_

Rl R *7

double ouble

double double bond NSOoNH- bond with R7 . -NH [-- with R* _j _

double double bond NSO NH -N bond with R ₇ -C-NHo \ / with Rτ_

Rl R- R R- double double

/ \ bond NS02NH2 ^■ N S bond with R7 -C-NH \ / with Rτ_

double double

double double bond _u NSO ₉ _NH _ NH bond

|l with R7 -C-NH ₂ -C-NHCH3 with Ri

double double bond NS0 ₂ NH ₂ NH bond with R7 -C-NHo -C-N with Ri

double double with N _{ SO _NH _ 0 bond II v/ith R7 -C-NH ₂ -C-NH ₂ with R* _j _

double double bond NSO _NH _ :H NH- bond with R7 -C-NH ₂ with Ri

Rl R ₇ double double bond NSG ₂ NH ₂ -CH -N r bond with R- -C-NH ₂ with R _] _

double double bond NSOoNH -CH2 KCH3 bond II with R ₇ -C-NH ₂ with R ^* L

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 aro¬ matic hydroxy (or thiol) precursor either obtained from a commercially available source or prepared according to procedures known in the art. If the tetrahydrobicy- clic compound is desired, the quaternary or acid addi¬ tion salt of the aromatic precursor is partially hydro- genated. (Scheme I)

R ^ R

Scheme I

When R is other than hydrogen, for example when an amino group is present in the 1-position, the dihy- drocompound may be prepared by an electrophilic cycli- zation of a 2-(N-formyl)ethyl aromatic compound. (Scheme II)

The protecting group, P _R , may be methyl, benzyl or the N-phthalimido propyl as described below. If the

^O ^R E

OMPI

protecting group is chosen to be other than the N- phthali ido propyl, the protecting group is removed according to methods known in the art, and the formation of the ether linkage is accomplished by treat¬ ing the hydroxy compound with a protected N-propylbro- mide 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)

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 a ine compound is obtained by the removal of the protecting group, for example, the phthalimido group is removed with hydrazine hydrate. (Scheme IV)

Scheme IV

A preferred route to the 3,4-dihydroisoquino- lines within the scope of Formula I comprises the pre- paration of the 3-aminopropoxy derivative of a 1-amino-

JυRE

OMPI

3,4-dihydroisoquinoline ⁱⁱ intermediate by means of the partial hydrogenation of an isoquinolone followed by the transformation of the 1-carbonyl to the desired' substituent. Scheme V, below, details an exemplary preparation of the 5-(3-aminopropoxy) intermediate.

Compounds within the scope of Formula I where R

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NH 0

11 II is -(CH ₂ ) _n -NR ₈ R _g , -C-NR3R9, or -C-NR ₈ Rg and n is greater than zero, may be prepared by the addition of one or more carbon units at the 1-position of the star¬ ting bicyclic heterocyclic compound. An exemplary reac- tion sequence involving the isoquinoline ring system is shown in Scheme VI, below. The isoquinoline 1-position may be functionalized by treatment with an arylsulfonyl halide in the presence of cyanide. Preferred reagents for this reaction are benzenesulfonylchloride and potas- sium cyanide in methylene chloride. The resulting sul- fonamide adduct is aromatized and the cyano intermedi¬ ate may then be hydrolyzed to the carbo liσ acid or amide or transformed into an amidine by treatment with alcoholic HC1 followed by a desired amine.

VI

N gRg

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 followed by the use of the N-phthalimido propyl protected group.

Scheme VII

It should be noted that the phthalimido propyl• 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 nitrile group to an acid group do not remove the phthalimido group.

Compounds within the scope of Formula I and having a msthyleneoxy or ethylenethio substituent (a=l) 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-thiosthylamine with the methylene hydroxy ring system according to Scheme VIII.

eme VI II

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

Scheme IX

Scheme IX starts with a preformed nitrogen- containing ring ketone which is either commercially available or prepared by procedures known in the literature. The ketone is reacted with an acetylenic

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 furan moiety. The alcohol is then deprotected. Compounds having symmetrical substituents in the 5- and 7- positions of the bicyclic ring (counting the furano oxygen as the

1-position and the pyridinyl nitrogen as the δ-position) may be prepared by this route.

Aromatic bicyclics may be prepared by cyclizing an appropriately substituted 3-hydroxy-4-( 3' -hydroxy-1- propynyD-pyridine prepared according to Scheme X.

Scheme X

Treatment of a 5-alkoxy oxazole with a vinyl hydroxymethyl acetylene (the hydroxy group may or may not be protected) at elevated temperature and/or pressure results in the oxy bridged ring Diels-Alder product. Treatment of the bridged ring system with mild acid forms the 3-hydroxy, 4-oxym thylacetylenic

-£T__.E

OMPI

pyridine which upon treatment with base forms the 2-oxymethyl-furano[2,3-c3pyridine.

Another route to this ring system proceeds by way of the 2-methyl furan as the starting point, as shown in Scheme XI.

Scheme XI

Exemplary reaction conditions for the synthetic sequence of Scheme XI are described by Mertes, J. Org. Chem, 33, 133 (1968). The keto 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 2 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 U.S. Patent Nos.

4,104,381, 4,279,819, 4,323,566 and GB 2067987A, hereby incorporated by reference.

Scheme XII

Treatment of the S-alkyl 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 R ₂ is CN, or sulfonyl amidine, the reaction sequence may be slightly modified as shown below in Scheme XIII. Reaction of the phenolic intermediate with

f OMPI

a cyano-substituted alkylating agent such as 3-cyanoprop- ylchloride in the presence of a base produces the cyano ether compound. Reduction of the cyano group with a hydride such as lithium aluminum hydride results in the amino compound. Treatment of the cyano compound with anhydrous ethanolic HC1 yields an imidate intermediate which is converted to the sulfonyl amidine by treatment with sulfamide in methanol. For a complete discussion of this preparatory sequence, see U.S. Patent No. 4,283,408, incorporated herein by reference.

Scheme XIII

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

MPI

ethylene intermediate as shown in Scheme XIV below. The amino sulfonyl amidine compound is prepared by reaction sequences similar to those described above.

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 non-toxic salts of this invention are those salts the acid component of which is pharmacologically acceptable in the intended dosages, including those prepared from inorganic acids such as hydrochloric acid, hydrobroraic acid, sulfuric acid, nitric acid and phosphoric acid, and from organic acids such as methane sulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, malic acid, oxalic acid, succinic acid, glycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, abietic acid, etc.

The following are selected examples of the pre¬ paration of the compounds according to this invention.

EXAMPLE 1 THE PREPARATION OF 1-CYAN0-3-C3-(5-IS0- QUINOLYLOX )PROPYL]-2-METHYL-PSEUD0THI0UREA

Step 1. 5-(3-Phthalimido)propoxy isoquinoline

5-hydroxyisoquinoline (39.3 g) is dissolved in dimethylformamide (350 ml). The solution is purged with nitrogen for several minutes. Anhydrous potassium carbonate (41.2 g) and N-( -bromopropyl) phthalimide (72.7 g) are added to the solution and the reaction mixture is stirred for four days at RT under N ₂ . The mixture is poured into 1 liter of H ₂ 0, stirred for 1-1/2 hours and filtered. The resulting solid is washed with H 0 and partially dried in air. The wet solid is added to CHCI3 (1-1/2 liters) and the mixture is slowly filtered and rinsed with CHCI3 (500 ml). The layers are separated, the chloroform layer dried over Na ₂ S0 , filtered and the filtrate evaporated .i vacuo to yield the phthalimido isoquinoline as a solid.

Step 2. 5-(3-Aminopropoxy)isoquinoline

The dark purple solid of Step 1 is added to 750 ml of absolute ethanol. 17 ml of an 85% solution of hydrazine hydrate are added to the solution. The reac- tion mixture is stirred under reflux for 3 hours, fil¬ tered and the dark red filtrate evaporated n vacuo. The residue is dissolved in 750 ml of concentrated HCl, stirred for 1 hour and filtered, and the filtered solid rinsed with a 5% HCl solution. The dark filtrate is alkalinized with a 50% aqueous NaOH solution and stirred with 500 ml methylene chloride. The layers are separated and the aqueous layer extracted with methy-

lene chloride. The methylene chloride extract is washed with saturated NaCl solution and dried over Na ₂ S0 « The dried extract is filtered and the filtrate evaporated vacuo yielding a dark red oil. The oil is distilled under vacuum and the distillate fraction¬ ating up to a temperature of approximately 205°C at 1 mm Hg 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_ v cuo. The residue is dissolved in absolute ethanol causing the precipitation of crystals. The precipitate is fil- tered, and the solid washed with ethanol, diethyl ether and dried under house vacuum at approximately 70°C for 2 hrs, yielding the methanesulfonic acid salt of the aminopropoxyisoquinoline as a powder, M.P. 180-182°C.

Step 3. l-Cyano-3-[ 3-(S-isoquinolyloxy) propyl]-2- meth l-pseudothiourea

8 g of the a inopropoxy 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 RT under nitrogen. The mixture is slowly filtered and the solid washed with isopropanol and diethyl ether and then dried in air yielding the pseudothiourea as a solid, M.P. 164-165°C.

The Methanesulfonic Salt of l-Cyano-3-C3-(5-isoσuino- lyloxy)propyl3 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- thiourea dissolved in 100 ml of methanol. The resul¬ ting solution is evaporated ir vacuo. The solid resi¬ due is triturated in 40 ml absolute ethanol, the resul¬ ting solution filtered, the solid washed with ethanol and diethyl ether, dried in air, stored in a vacuum dessicator overnight, and dried under house vacuum for 2 hrs, yielding the methanesulfonic acid salt as a powder, M.P. 190-191°C.

EXAMPLE 2 THE PREPARATION OF 2-CYAN0-1-[3-(5-IS0QUIN0- LYL0XY)PR0PYL]-3-METHYL GUASIDI-.Ξ HYDROCHLORIDΞ

A solution of 14.3 g anhydrous methylamine 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 methylamine is bubbled into the reaction mixuture. The reaction mixture is allowed to warm to RT while stirring is continued and then heated to reflux for 1 hr. After cooling, the solution is filtered and the resulting solid washed v/ith ethanol, diethyl ether and dried in air, yielding the desired guanidina as a white solid. The solid is suspended in methanol and the pH adjusted to 3-4 with methanolic HCl. This solution is filtered and the filtrate evaporated n vacuo. The residue is triturated in ethyl acetate, filtered and the solid washed with ethyl acetate and diethyl ether. The solid is dried and stored in a vacuum dessicator, yielding the hydrochloride salt of the desired guanidine as a powder, M.P. 177-179°C

EXAMPLE 3

THE PREPARATION OF N-METHYL-N'-[3-[5-(2-METHYL-

1,2,3,4-TETRAHYDROISOQUINOLYLOXY) ] PROPYL]-

2-NITRO-l,1-DIAMINOETHENE

Step 1. 5-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 reflux for 2-1/2 hours. The mixture is cooled, filtered and the precipitate washed with absolute ethanol, anhydrous diethyl ether, and dried in air, yielding the isoquinolenium iodide as a solid, M.P. 23β-237°C.

Step 2. 5-Hy.drσι-_y-2-methyl-l,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 borohydride (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 refluxed for ten minutes. Acetone (250 ml) is added and the resulting mixture allowed to cool and evaporated In vacuo. The residue is shaken with 375 ml of a 3.5% 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, M.P. 183.5°C.

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 vacuo. The residue is dissolved in dimethylformamide, 68.1 g of N-(3-bromopropyl)phthalimide added and the mixture stirred at RT for 20 hours. The reaction mix¬ ture is partitioned between water and ethyl acetate. The layers are separated and the aqueous layer extrac¬ ted v/ith ethyl acetate. The combined organic extract is washed with water, saturated sodium chloride, dried over sodium sulf te, filtered, and the filtrate evapo¬ rated n vacuo yielding a light brown solid. The solid is dissolved in hot absolute ethanol, the solution fil¬ tered, the solid rinsed with hot ethanol and the fil¬ trate cooled at RT 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, M.P. 111-112°C.

Step . 2-Methyl-5-(3-aminopropoχy) -1,2,3,4-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 is added and the mixture heated to reflux for three hours. The mixture is cooled, filtered and the filtrate evaporated i_n vacuo. The residue is triturated with a 5% HCl solution and the slurry is slowly filtered. The clear filtrate is alkalinized by adding a 50% NaOH solution. The resulting oily precipi¬ tate is extracted with diethyl ether, washed with satu¬ rated NaCl, dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo yielding the aminopropoxy compound as a light yel¬ low oil, which crystallizes on standing.

Step 5. N-Methyl-N'-[ 3-[5-(2-methy1-1,2,3,4-tetra- hydroisoquinolyloxy) Ipropyl]-2-nitro-l,1-diaminoethene

5.47 g of the aminopropoxy compound of Step 4 and 3.68 g of l-nitro-2-methylamino-2-methylthioethene are mixed in 50 ml of absolute ethanol and heated to reflux with stirring for an hour and 15 minutes. The reaction mixture is cooled and evaporated _i_n vacuo. 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 dia ino ethene as a white powder, M.P. 133-135°C, which is recrystallized from acetone, M.P. 136.8°C.

EXAMPLE 4 THE PREPARATION OF 2-CYANO-1- ETHYL-3-[3- [5-(2-METHYL-l,2,3,4-TETRΛHYDRO- ISOQUINOLYLOXY) ]PROPY ] GUANIDINE

Step 1. l-Cyar.o-2-methyl-3-.3-.5-( 2-raethyl-l, 2, 3,4- tetrahydrolsocruinolyloxy) Ipropyl]oseudothiourea

60 g of S,S-dimethyl-N-cyanoiminodithiocarbonimi- date is dissolved in 75 ml isopropanol and the mixture stirred at RT while purging with N ₂ . 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 t 2 thick slurry fil- tered, washed with isopropanol, diethyl ether ana air- dried, yielding the pseudothiourea as a white solid, M.P. 135.6°C.

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, diethyl ether, dried in air and under house vacuum, yielding the hydrochloride salt as a white solid, M.P. 170-172°C.

Step 2. 2-Cyano-l-methyl-3-[3-[5-( _. 2-methyl-l,2,3,4- tetrahydroiso uinolyloxy) Iprooyll guanidine

6.0 g of the S-methyl compound is dissolved in 120 ml of warm absolute ethanol. 12.2 g of anhydrous 5 methylamine in 50 ml absolute ethanol are added to the cooled ethanolic solution and stirred at RT overnight. The reaction mixture is filtered and the solid washed with ethanol, diethyl ether and dried in air, yielding the desired guanidine as a white powder, M.P. 90-96°C.

-,« This powder is suspended in 50 ml methanol and slightly acidified with ethanol/HCl. The solution is filtered and the filtrate evaporated _irι vacuo resulting in a clear oil and foam which is dissolved in absolute ethanol and recrystallized twice yielding the hydro-

15 chloride guanidine salt, M.P. 170-172°C.

EXAMPLE 5 THE PREPARATION OF 3-AMINO-5-.3-[5-(2- METHYL-1,2,3,4-TETRAHYDROISOQUINOLYLOXY) 3 PROPYLAMINO3-1-METH L-1H-1,2,4-TRI ZOLE

20 Methyl hydrazine (2.9 g) is added to a stirred solution of l-cyano-2-methyl-3-C3-[5-( 2-methyl-l,2,3,4- tetrahydroisoquinolyloxy) 3 propyl] seudothiourea (4.0 g) dissolved in 40 ml of dimethyl formamide and stirring is continued at 40°C for 20 hrs. The reaction mixture is

25 evaporated resulting in an oil which crystallizes on standing. The crystalline product is dissolved in hot acetonitrile, filtered, washed with acetonitrile and diethyl ether, dried in a vacuum dessicator, recrystal¬ lized from ethanol and dried at elevated temperature,

30 affording the desired triazole product, M.P. 150-152°C, with shrinkage beginning at 140°C. Elemental analysis indicates the presence of a 1/10 mole percent quantity of ethanol.

- ^R -*- OMPI

EXAMPLE 6 THE PREPARATION OF 2-CYANO-l-[3-(7-ISOQUINO- LYLOXY.PROPYL.-3-METHYL GUANIDINE

Step 1. 7-[3-(N-phthalimido)propoxy1isoquinoline

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 i_n vacuo and the residue dissolved in dimathylformamide. N-(3-bromo- propyDphthalimide (57.6 g) is added to the solution and stirred overnight at RT. The reaction mixture is poured into H ₂ 0, creating a yellow precipitate. The suspension is stirred for 1 hour, filtered, the solid washed with H ₂ 0. The moist solid is stirred in abso¬ lute ethanol for 1 hour, filtered and washed with ethanol/H2θ (1:1) and dried in air. The phthalimido compound is obtained by recrystailizing 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 com¬ pound of Step 1 (37.4 g) in absolute ethanol and the reaction mixture is heated to reflux for 3 hours, cooled and filtered. The resulting solid is washed with ethanol and the filtrate evaporated in_ vacuo. The evaporated residue is triturated in 250 ml of a 5% HCl solution, slowly filtered and the filtrate stored in the refrigerator overnight. The next day the solution is washed with methylene chloride and alkalinized with a 50% aqueous sodium hydroxide solution, giving an oily. precipitate. The aqueous layer is extracted with methy¬ lene chloride and the combined organic extracts washed with saturated sodium chloride solution and dried over sodium sulfate. After filtering the resulting mixture,

the filtrate is evaporated i i vacuo to give the aminopro- poxy compound as an amber oil. The dihydrochloride acid salt of the aminopropoxy compound is prepared by the addition of a methanolic HCl solution to a methanol solu- tion of the amber oil, and after drying the salt under vacuum, yields a light yellow powder, M.P. 212-215°C; the methanesulfonic acid salt is a white powder, M.P. 182-183°C.

Step 3. l-Cyano-3-[3-(7-isoquinolyloxy)propyl3-2-methyl- pseudothiourea

11.0 g of 7-(3-aminopropoxy)isoquinoline in 20 ml isopropanol is added to a solution of S,Ξ-dimethyl- N-cyanoiminodithiocarbonimidate (7.2 g) in 90 ml isopro¬ panol. The reaction mixture is stirred at RT for 2 hours. The mixture is filtered, the resulting solid washed with isopropanol, diethyl ether, and dried in air, yielding the desired pseudothiourea as a white powder, M.P. 112-114°C. The methanesulfonic acid salt of the pseudothiourea crystallizes from methanol as a solid, M.P. 202-204°C.

Step 4. 2-Cyano-l-[3-(7-isoquinolyloxy)f.rooyl3-3- ethyl guanidine

A solution of anhydrous methylamine (18.2 g) in 90 ml of absolute ethanol is added to a stirred suspen- sion of the psuedothiourea (8.4 g) obtained in Step 3 in 175 ml methanol. The reaction mixture is stirred at RT overnight, filtered, the resulting solid washed with ethanol and diethyl ether, and dried in air, yielding the desired isoquinolyloxy guanidine as a white fluffy powder, M.P. 175-177°C. The methanesulfonic acid salt

OMPI

of the guanidine is recrystallize twice from ethanol and methanol to give a powder, M.P. 162.5-164°C.

EXAMPLE 7 THE PREPARATION OF 2-CYANO-l-METHYL- 3-[3-E7-(2-METHYL-l,2,3,4-TETRAHYDRO-

ISOQUINOLYLOXY) 3PR0PYL 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 liter absolute ethanol. The mixture is stirred at reflux for two hours, cooled, and filtered. The solid is washed with ethanol and diethyl ether and dried in air, yielding the methyliodide salt of the isoquinoline as a crystal¬ line material, M.P. 233-235°C.

Step 2. 7-Hydroxy-2-methyl-l,2; 3,4-tetrahydro- isoquinoline

41.6 g of aBH^ are slowly added over a period of 30 minutes to a stirred solution of the methiodide of Step 1 (75.0 g) in 1550 ml of 10% H ₂ 0 in methanol under a stream of nitrogen. After the addition is complete, the mixture is kept at reflux for 20 minutes, after which 700 ml acetone are added, and the mixture is cooled and evaporated i_n vacuo. The residue is shaken with a 3.5% sodium carbonate solution, filtered and the solid washed with H2O and dried in air over¬ night, giving the desired tetrahydroisoquinoline as a powder, M.P. 167-169°C.

Step 3. 2-Methyl-7-[3-(N-phthalimido)propoxy3- 1,2,3,4-tetrahydroisoquinσline

10.1 g of sodium methoxide is added to a solu¬ tion of the tetrahydroisoquinoline of Step 2 (30.7 g) in methanol and the resulting mixture evaporated in vacuo. The oily residue is dissolved in dimethylform- amide and 50.4 g of N-(3-bromopropyl) phthalimide added to the solution. The reaction mixture is stirred at RT for 21 hours and partitioned between H2O and ethyl ace- tate. The layers are separated and the aqueous layer extracted with ethyl acetate. The combined organic extract is washed with H2O and saturated NaCl solution, dried over sodium sulfate, filtered, and the filtrate evaporated n vacuo to give the desired product as a solid.

Step 4. 7-(,3-Aminopropoxy)-2-methyl-l,2,3,4-tetra- hydroisoquinoline

6.6 ml of an 85% hydrazine hydrate solution are added to a stirred suspension of the phthalimido iso- quinoline of Step 3 (34.4 g) in 350 ml absolute ethanol, The reaction mixture is heated to reflux for 3 hours, allowed to cool and evaporated i_n vacuo. The residue is triturated with 250 ml 5% HCl and filtered. The clear filtrate is stored in the refrigerator overnight, extracted with methylene chloride, alkalinized with 50% sodium hydroxide solution, and extracted again with methylene chloride. The combined organic extract is washed with saturated NaCl solution, dried over sodium sulfate, filtered, and the filtrate evaporated Let vacuo, giving the desired aminopropoxy compound as a light amber oil.

"^ϊj_.___■_ ^" OMPI

The monohydrate of the dihydrochloride acid salt of the tetrahydroisoquinoline compound is a white solid, M.P. 120-123°C.

Step 5. l-Cyano-2-methyl-3-[3-C7-(2-methyl-1,2,3,4- tetrah.ydroisoquinolyloxy) 3ρropyl3pseudothiourea

A suspension of the aminopropoxytetrahydroiso- quinoline of Step 4 (7.1 g) in isopropanol is added to a solution of S,S-dimethyl-N-cyanoiminodithiocarbon- imidate (4.7 g) in 60 ml isopropanol. The reaction mixture is stirred at RT for 1-1/2 hours, filtered, the resulting solid washed with isopropanol and diethyl ether and.dried in air, giving the desired pseudothio¬ urea as a white powder, M.P. 147-149°C.

Step 6. 2-Cyano-l-methyl-3-[ 3-[7-(2-methyl-l,2,3,4- tetrahydroiso uinolyloxy) 3propyl3 guanidine

A solution of anhydrous methylamine (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 RT and the resul- ting clear solution is evaporated -ι vacuo. The resi¬ 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 diethyl ether and dried in air, giving the desired isoquinolyloxy guanidine as a white powder, M.P. 142-144°C.

EXAMPLE 8 THE PREPARATION OF 3-AMINO-4-.3-[5-(2- METHYL-1,2,3,4-TETRAHYDROISOQUINOLYLOXY)3 PROPYLAMINO3-1,2,5-THIADIAZOLE-l-OXIDE

A solution of 5.0 g of 5-(3-aminopropoxy)-2- methyl-1,2,3,4-tetrahydroisoquinoline in 50 ml of methan¬ ol is added, over a one-hour period, to a stirred solu¬ tion of 3.68 g of 3,4-dimethoxy-l,2,5-thiadiazole-l- oxide in 200 ml methanol while maintaining the tempera- ture at approximately 0°C. After stirring the mixture in an ice bath for 1-1/2 hours, anhydrous ammonia (18.3 g) is bubbled in over a period of 10 minutes and stirring is continued at RT for 1-1/2 hours. The reaction mixture is evaporated iα vacuo and the residue (light foam/glass) is triturated in anhydrous ether. The resulting solid material is filtered, the solid washed with ether and dried in air, giving a white powder, melting with decompo¬ sition at 166-171°C. The powder is dissolved in 10% methanol in methylene chloride, filtered and the impuri- ties separated on a silica gel column. The purified frac¬ tions are evaporated _in vacuo and the resulting foam tri¬ turated in ether, filtered, the solid washed with ether and dried in air, giving the desired thiadiazole-1-oxide as a white solid, M.P. 172-174°C.

^3REΛ OMPI

EXAMPLE 9

THE PREPARATION OF 3-AMINO-4-.3-[7-(2-METHYL-

1,2,3,4-TETRAHYDROISOQUINOLYLOXY) 3PROPYLAMIN03-

1,2,5-THIADIAZOLE-l-OXIDE

A solution of 7-(3-aminopropoxy)-2-methyl-l,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-dimethoxy-l,2,5-thiadiazole-l-oxide (3.68 g) in 375 ml of methanol at a temperature of 3°C. The reaction mixture is stirred for an additional one hour and 25.0 g anhydrous ammonia is bubbled in over a period of 10 minutes. The resulting mixture is warmed to RT with stirring and the solution is evaporated in_ vacuo. 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 diethyl ether and dried in air, giving the desired tetrahydroisoquinoline thiadia- zole-1-oxide as a white powder, M.P. 193-194°C.

"gt3RE_ OMPI

WIPO

EXAMPLE 10

THE PREPARATION OF 3-AMINO-1-METHYL-5-

E3-(l-PIPERIDINO-5-ISOQUINOLYLOXY)

PROPYLAMINO3-1H-1,2,4-TRIAZOLE

Step 1. 5-Hydroxy-l,2-dihydro-l-(2H)-iso uinolone

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 250-268°C for

30 minutes, after which the mixture is cooled to 135°C, followed by the addition of 2 liters of H2O. The aqueous mixture is poured into a second liter of H2O and the reaction vessel washed with a third liter of H2O. The combined aqueous mixtures are filtered and the filtrate added to an ice bath adjusted to pH of about 7. The chilled mixture is filtered and resultant solid stirred with 2 liters of 2N aqueous HCl. The acidic mixture is filtered, the solid washed with H2O and dried, yielding 212 g of the desired product as a solid, M.P. 170-172°C.

Step 2. 5-(3-Phthalimido-propoxy)-l-hydroxy-isoquinoline

N-(3-Bromopropyl) phthalimide (164 g) is added to a stirred solution of 5-hydroxy-l,2-dihydro-l-(2H)- isoquinolone (96.7 σ) and anhydrous K ₂ C0 ₃ (91.2 g) in

750 ml of DMF. The reaction mixture is stirred at room temperature for one week, diluted with 3 liters of H ₂ 0 and stirring continued at RT for an additional 30 minutes. The reaction mixture is filtered and the solid resuspended in 2 liters of H ₂ 0 and stirred at RT

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 RT 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 aqid. The resulting dark solution is concentrated and cooled. The crystalline precipitate is collected and dried, washed with diethyl ether, resuspended in diethyl ether, stirred at RT for 30 minutes, filtered and dried _irι vacuo overnight, yielding 59.3 g of the desired product, M.P. >300°C.

Step 3. l-Chloro-5-(3-N-phthalimido-propoxy) isoquinoline

A mixture of 5-(3-N-phthalimido-propoxy)-l-hydroxy isoquinoline (59.2 g) and P0C1 ₃ (340 ml) is stirred under reflux for 4 days. The reaction mixture is cooled to RT and the volatile material removed under reduced pressure. The residue is suspended in H2O (850 ml) and the aqueous mixture poured into 1.7 liters of methylene chloride. The aqueous layer is made alkaline with solid sodium bicarbonate and the organic phase separated. The aqueous layer is extracted with methy¬ lene chloride and the organic extracts combined and dried over sodium sulfate. The extract is filtered and evaporated, yielding 61.7 g of crude product, which is dissolved is boiling ethyl acetate and filtered through Celite, the filtrate concentrated, cooled. The crystal¬ line precipitate is collected, washed with ethyl ace¬ tate and dried, affording 51.6 g of the- desired com- pound as a crystalline product, M.P. 173-175°C.

Step A . 5-(3-Phthalimidopropoxy)-1-piperidino-isoquinoline

" Piperidine (12.4 ml) is added to a stirred suspen¬ sion of l-chloro-5-(3-N-phthalimido-propoxy)-isoquinoline (18.3 g) in 100 ml of pyridine. The reaction mixture is ' heated to reflux for 3 days, cooled and evaporated under reduced pressure. The resulting dark residue is suspen¬ ded in methylene chloride and washed with 5% aqueous HCl, saturated aqueous sodium bicarbonate, and H2O. The organ¬ ic phase is dried over sodium sulfate, filtered and evapo- rated iri vacuo. The resulting solid is stirred in abso¬ lute ethanol at RT for 30 minutes and cooled in an ice bath. The solid is collected, washed with absolute ethanol and dried _in vacuo overnight, yielding 16.5 g of the desired product as a powder, M.P. 146-147°C.

Step 5. 5-(3-Aminopropoxy)-1-piperidino-isoquinσline succinate

85% hydrazine hydrate (23.5 ml) is added to a stirred suspension of 5-(3-N-phthalimidoproρoxy)-1-piper¬ idino-isoquinoline (33.2 g) in 800 ml of absolute ethanol. The reaction mixture is heated under reflux for 72 hours, after which the solvent is removed under vacuo and the residue triturated with methylene chloride. The methylene chloride mixture is stirred at RT for 30 minutes and filtered. The solid is washed with methylene chloride and the filtrate is evaporated under reduced pressure. The residue is dried _in vacuo 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 reflux 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 n vacuo overnight, yielding the desired product as a powder, M.P. 167-168°C.

Step 6. l-Cyano-3-_ 3-(l-piperidino-5-isoquinoIyloxy)- propyl3-2-methylpseudothiourea

50% aqueous sodium hydroxide is added to a stirred solution of 5-(aminopropoxy)-l-ρiperidino-isoquinoline succinate (18.2 g) in 400 ml of H ₂ 0 until the reaction mixture is strongly alkaline. The reaction mixture is extracted with methylene chloride, the extract dried over sodium sulfate, filtered and evaporated under vacuo, yiel¬ ding 12.25 g of a brown oil. The oil is dissolved in isopropanol and the alcoholic solution added dropwise to a vigorously stirred solution of S,S-dimethyl-N-cyano- iminodithiocarbonimidate (6.58 g) in isopropanol (90 ml). The reaction mixture is stirred at RT 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 Celite. 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, M.P. 186-187°C.

Step 7. 3-Amino-l-methyl-5-[ 3-(l-oiperidino-5-isoquino- lyloxy) propylamino3-lH-l,2,4-t iazole

Methyl hydrazine (5.7 ml) is added to a stirred suspension of l-cyano-3-[3-(l-piperidino-5-isoquinolyl- oxy)propyl3-2-methylpseudothiourea (7.77 g) in 62 ml of DMF under nitrogen. The reaction mixture is stirred at 40°C under nitrogen for 24 hours, cooled to RT, evaporated under vacuo 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 i_n vacuo and the residue crystallized from acetonitrile and dried overnight,

yielding 5.3 g of the crude product as an off-white solid, M.P. 173-175°C. The crude product is placed on a silica gel column and eluted with methylene chloride/meth- anol. The combined pure fractions are evaporated and recrystallized from acetonitrile, yielding the desired product, M.P. 181-182°C.

EXAMPLE 11 THE PREPARATION OF 3-AMINO-4-[3-(l-PIPERIDINO- 5-ISOQUINOLYLOXY) PROPYLAMINO3-1,2,5- THIADIAZOLΞ-1-OXIDE HEMIHYDRATE

Sodium methoxide (2.70 g) is added slowly to a stirred solution of 5-(3-aminopropoxy)-l-piperidino-iso- quinoline succinate (10.09 g) in 200 ml of methanol. The reaction mixture is stirred at RT for 30 minutes and the solvent evaporated under reduced pressure. The residual solid is broken up and stirred with methylene chloride overnight. The reaction mixture is filtered and the solid washed with methylene 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 methylene chloride and reacted with a 50% aqueous sodium hydroxide solution. The aqueous phase is separated and extracted with methylene chloride and diethyl 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 dropwise to a stirred ice cold solution of 3,4-dimethoxy-l,2,5-tria- diazole-1-oxide (4.05 g) in methanol (425 ml) under nitrogen over a period of 2-1/2 hrs and stirring continued at RT for 2 hrs. The reaction mixture is cooled to ice bath temperature, saturated with ammonia, stirred at RT overnight and evaporated ij vacuo. The

residue is reprecipitated with methanol and methylene 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 eluted with ethanol/ethylacetate,

95% ethanol. The purest fractions containing the desired material are combined and concentrated, affording a powder, M.P. 209-211°C with decomposition. Elemental analysis indicates the product exists as a hemihydrate.

EXAMPLE 12

THE PREPARATION OF l-CYANO-2- METHYL-3-[3-(l-MORPHOLINO-5-ISO- QUINOLYLOXY)PROPYL3 PSEUDOTHIOUREA

Step 1. 5-(3-Aminopropoxy)-1-morpholinoisoquinoline succinate-1-1/2 hydrate

Hydrazine hydrate (85%) (85.5 ml) is added to a stirred solution of l-morpholino-5-( 3-phthalimido propoxy)-isoquinoline (121.1 g) in absolute ethanol (2.9 1) . The stirred reaction mixture is heated to boiling and refluxed for 72 hrs. After cooling to RT, the reaction mixture is evaporated and the residue stirred in methylene chloride. The mixture is filtered and the solids washed with methylene chloride. The filtrate is evaporated under i_n vacuo 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 Darco G-60. The boiling mixture is filtered through Celite, cooled and the solid collected, washed with isopropanol and dried i_n vacuo. The solid is stirred in 5% aqueous HCl and the mixture, filtered. The insoluble material is washed with H2O and dried, resul¬ ting in the desired succinate as a powder, M.P. 159-161°C.

Step 2. 1-Cyano-2-methy1-3-[3-(l-morpholino-5-isoquino- lyloxy)propyl3 pseudothiourea

A solution of 5-(3-aminopropoxy)-l-morpholino- isoquinoline (24.3 g) in 600 ml of H2O is made strongly alkaline with 50% aqueous sodium hydroxide. The reaction mixture is extracted with methylene chloride and the extracts are dried, filtered and evaporated n vacuo, affording 13.1 g of a dark oil which is dissolved in 60 ml of isopropanol. The isopropanol solution is added dropwise 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 RT for 2 days. The reaction precipitate is collected, washed with isopro¬ panol and dried in air, resulting in crude product which is dissolved in boiling acetonitrile. The acetonitrile solution is treated with Darco G-60, filtered through Celite, partially evaporated and cooled affording the desired pseudothiourea as a solid, M.P. 160-161°C.

EXAMPLE 13 THE PREPARATION OF 3-AMINO-l-METHYL-

5-[3-(l-MORPHOLINO-5-ISOQUINOLYLOXY) PR0PYLAMIN03-1H-1,2,4-TRIAZOLE

Methyl hydrazine (7.3 g) is added to a stirred suspension of l-cyano-2-methyl-3-[3-(l-morpholino-5-iso- quinolyloxy) propyl3 pseudothiourea (11.56 g) in DMF

(91.5 ml). The reaction mixture is stirred at 40°C under nitrogen for 24 hrs and evaporated _in. vacuo 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 Darco G-60, filtered through Celite, concentrated and cooled. The precipitate is collected, washed with acetonitrile and dried in vacuo

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at elevated temperature. The dried precipitate is recrystallized from absolute ethanol, dried in_ vacuo at 75°C affording the desired product as a powder, M.P. 178-180°C. Elemental analysis indicates the product as a 1/4 hydrate.

EXAMPLE 14

THE PREPARATION OF 3-AMINO-4-.3-

(1-MORPHOLIN0-5-IS0QUIN0LYL OXY)

PROPYLAMINO3-1,2,5-THIADIAZOLE-l-OXIDE

A solution of 5-(3-aminopropoxy)-l-morpholinoiso- quinoline (19.46 g) in H ₂ 0 (480 ml) is made strongly alkaline with 50% aqueous sodium hydroxide and extracted with methylene chloride. The organic extract is dried over sodium sulfate, filtered and evaporated _i_n vacuo. The residue is dissolved in 150 ml of methanol and the methanolic solution added dropwise to a stirred solution of 3,4-dimethoxy-l, 2,5-thiadiazole-l-oxide (7.78 g) in methanol (825 ml) maintained at -10 to 0°C. The addition takes about 5 hrs, after which the reaction mixture is stirred overnight and allowed to warm slowly to RT. The reaction mixture is cooled again to -10 to 0°C and the cooled solution saturated with anhydrous ammonia. The solution is allowed to reach RT over a period of 2 hrs and then stirred at RT under nitrogen for a period of 3 days. The reaction mixture is filtered and the resultant solid dried _ir vacuo, affording the desired product as a powder, M.P. 222-224°C, with /dec.

EXAMPLE 15 THE PREPARATION OF 1-CYANO- 3-[3-(1-OXO-l,2-DIHYDRO-5-ISOQUINOLYLOXY)- PROPYL3-2-METHYL PSEUDOTHIOURE

Step 1. 5-(3-Aminopropoxy)-l,2-dihydro-l-(2H) isoquino¬ lone hydrochloride

Hydrazine hydrate (85%: 17.2 g) is added to a stirred suspension of 5-(3-phthalimidoρropoxy)-l,2- dihydro-l-(2H) isoquinolone (34.84 g) in absolute ethanol (550 ml). The reaction mixture is heated to boiling and stirred under reflux for 60 hrs, after which the reaction mixture is cooled to RT and evaporated ij vacuo. The residue is suspended in H2O and the suspension evaporated in vacuo. The residue is resuspended in methanol and acidified with methanolic HCl. The suspension is again evaporated n vacuo and the residue suspended in H ₂ 0 and stirring is continued at RT overnight, after which the slurry is filtered and the filtered solid washed with H ₂ 0 and dried. The filtrate is evaporated iτ\ vacuo, until a precipitate begins to form. The aqueous mixture is heated to boiling, treated with Darco G-60 and filtered while hot. The filtrate is partially evaporated and cooled in an ice bath. The resulting crystalline precipitate is collected, washed v/ith cold H ₂ 0, absolute ethanol and dried iri vacuo at 100°C overnight, affording the desired product as a crystalline solid, M.P. >300°C.

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Step 2. l-Cyano-3-[ 3-(1-oxo-l, 2-dihydro-5-isoquino- lyloxy) propy13.-2-methyl pseudothiourea *>

5-( 3-aminopropoxy)-1, 2-dihydro-l-( 2H)isoquinolone hydrochloride (15.28 g) is added to a stirred solution under nitrogen of S,S-dimethyl-N-cyanoiminodithiocarbon- imidate (8.77 g) in 150 ml of isopropanol. Triethylamine (16.7 ml) is added to the reaction mixture which is stirred at RT while a flow of nitrogen flushes evolved methyl mercaptan into a chlorox trap. The reaction mixture is stirred at RT for 18 hrs followed by slowly heating the reaction mixture to boiling and refluxing for an additional hour. The reaction mixture is cooled to RT, 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 diethyl ether. The suspension is stirred at RT for an hour, filtered and the solid dried _irt vacuo at 100°C for 4 hrs, resulting in the desired pseudothiourea product as a white powder, M.P. 244-245°C.

EXAMPLE 16 THE PREPARATION OF 3-AMINO-1-METHYL-5-L3- (1-0X0-1, 2-DIHYDRO-5-ISOQUINOLYLOXY)PROPYLAMINO3 - 1H-1,2,4-TRIAZ0LE HYDROCHLORIDE SΞSQUIHYDRATE

Methyl hydrazine (5.7 ml) is added to a stirred suspension of l-cyano-3-C 3-( 1-oxo-l , 2-dihydro-5-isoquino- lyloxy) propyl3-2-methylthiopseudourea (6.3 g ⁾ in DMF (61 ml). The reaction mixture is stirred at 40°C for 24 hrs, cooled to RT and evaporated _irι vacuo. The residue is triturated in absolute ethanol and the mixture stirred at RT overnight. The reaction mixture is filtered, and the filtered solid washed with absolute ethanol and dried in

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air, affording the desired triazole as a white solid, M.P. 276-278°C. The triazole is suspended in 150 ml of methanol and methanolic HCl added. After stirring the suspension at RT for 15 minutes, the solution is filtered through Celite and the filtrate evaporated _in vacuo. 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, M.P. 252-254°C, identified as the hydrochloride sesquihydrate of the triazole.

EXAMPLE 17 THE PREPARATION OF 3-AMINO-4- [3-(1-0X0-1,2-DIHYDRO-5-ISOQUINOLYLOXY)- PROPYLAMINO3-1,2,5-THIADIAZ0LE-1-0XIDE

Over a period of 5 hrs, 5.65 g of 5-(3-aminopro- poxy)-l,2-dihydro-l-(2H) isoquinolone are added portion- wise to a stirred solution of 3,4-dimethoxy-l,2,5-thia¬ diazole-l-oxide (4.22 g) in absolute methanol (520 ml) under nitrogen at 0°C. The reaction mixture is allowed to warm to RT and is stirred at RT under nitrogen overnight. The reaction mixture is again cooled to ice bath temperature and is saturated with anhydrous ammonia over a period of 1 hr. The reaction mixture is allowed to warm slowly to RT and stirred at RT for 2 hrs. The stirred reaction mixture is again cooled to ice bath temperature and saturated with ammonia over a period of 2 hrs and stirred overnight, concentrated ij vacuo and the solid filtered, washed with, methanol and dried. The filtered solid is dissolved in hot DMF and the hot solution filtered using Darco G-60. The filtrate is cooled and diluted with H ₂ 0. The resultant precipitate is collected, washed with H2O, absolute ethanol and dried in vacuo at 75°C overnight. The resulting tan solid is suspended in methanol and the mixture heated to boiling

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and refluxed for 2 hrs. The mixture is filtered while hot and the resulting tan solid washed with methanol and dried iji vacuo overnight, yielding the desired product as a powder, M.P. 235°C w/dec.

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

EXAMPLE 18 THE PREPARATION OF 3,4-DIHYDROISO- QUINOLINES ACCORDING TO FORMULA I

Step 1. 5-Hydroxy-l,2,3,4-tetrahydro-l-(2H) isoquinolone

A mixture of 5-hydroxy-l,2-dihydro-l-(2H) 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 psi of hydrogen is consumed. The reaction mixture is cooled, evacuated, filtered and evaporated _irι vacuo. The residue is triturated in aceto¬ nitrile which affords, after drying, the desired isoquino¬ lone as a white solid, M.P. 187-190°C.

Step 2. 5-(3-Phthalimidopropoxy)-1,2,3,4-tetrahydro-l- (2H) isoquinolone

Anhydrous K2CO3 (47.13 g) , N-(3-bromopropyl) phthalimide (87.27 g) and H ₂ 0 (39 ml) are added to a stirred solution of 5-hydroxy-l,2, 3,4-tetrahydro-l-(2H)- isoquinolone (50.59 g) in DMF (388 ml) and stirred at RT for 5 days. 2.5 1 of H2O are added to the reaction . mixture which is stirred for an additional 1-1/2 hrs and then filtered. The filtered white solid is washed with H ₂ 0, dried and suspended in THF. The suspension is stirred at RT for 1-1/2 hrs, filtered, and the filtered solid washed with THF and dried, affording the desired

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product as a white powder, M.P. 219-221°C. The powder is is recrystallized from boiling glacial acetic acid and dried iτι vacuo at 100°C, resulting in white crystals of the desired product having a melting point of 221-222°C.

Step 3. l-Chloro-3,4-dihydro-5-(3-phthalimidopropoxy)- ^* isoquinoline hydrochloride

5-(3-Phthalimidopropoxy)-1,2,3,4-tetrahydro-l-(2H)- isoquinolone (7 g) is added to a stirred solution of phosgene (25 g) in methylene chloride (200 ml) while maintaining a reaction temperature of -10°C. The stirred reaction mixture is allowed to warm slowly to RT and stirring is continued at RT overnight. The reaction mixture is heated to reflux, stirred at reflux for 2 hrs. Excess phosgene is removed by adding toluene to the residue twice and evaporating the supension. The resulting residue is the desired 1-chloro product. NMR spectrum (100 MHz) (CF3-COOD) 2.32 (m,2H), 3.28 (t,2H), 4.06cT (t,2H), 4.15 (m,4H), 7.4-7.9 S (m,7H) .

Step 4. l-Ethoxy-3,4-dihydro-5-(3-phthalimidopropoxy)- isoquinoline

5-(3-Phthalimidopropoxy)-1,2,3,4-tetrahydro-l-(2H)- isoquinolone (7 g) is added to a stirred solution of phosgene (25 g) in methylene chloride (200 ml) while maintaining a reaction temperature of -10°C. The reaction mixture is stirred and allowed to warm slowly to RT and stirring is continued at RT for an hour. The reaction mixture is evaporated i^ri vacuo and the residue suspended in methylene chloride, cooled to -10°C and treated with absolute ethanol (25 ml). The reaction mixture is stirred for 30 minutes, allowed to reach RT and stirred overnight. The reaction mixture is evapo¬ rated _in vacuo affording the desired 1-ethoxy product as

a solid. NMR spectrum (100 MHz) (CDCI3/CD3OD) 1.3 (t,3H), 2.2 (m,2H), 2.6, (t,2H), 3.48 (t,2H), 3.8-4.3^ (m7H).

Treatment of the 1-chloro dihydroisoquinolinium salt with an amine such as piperidine instead of ethanol results in the desired 1-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. '

EXAMPLE 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 15-20°C under nitrogen. The reaction temperature is dropped to 10°C and iodomethane (67 ml) in DMF (500 ml) is added to the reaction mixture over a period of 20 minutes, while maintaining the reaction temperature at less than 20°C. The reaction mixture is stirred at RT overnight, after which a mixture of H ₂ 0 and ethyl acetate is added. The organic phase is separated and washed with 5% sodium hydroxide solution and ice cold 5% 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 H 0 and saturated chloride solution and dried over sodium sulfate. The' dried extract is filtered and the filtrate evaporated in vacuo, affording a dark red oil. Vacuum distillation .

results in the desired methoxy compound as a clear colorless oil, B.P. 98-103°C (0.5 mm Hg).

Step 2. l-Cyano-2-benzenesulfonyl-5-methoxy-l,2-dihydro- isoquinoline

Benzylsulfonyl chloride (125 ml) is added over a period of 2 hrs to a stirred reaction mixture of 5-methoxy isoquinoline (78 g) and potassium cyanide (98 g) in methylene chloride (650 ml) under nitrogen while maintaining the temperature below 23°C. After the addition is complete, stirring at RT is continued for 4 hrs. The reaction mixture is partitioned between H ₂ 0 and methylene chloride. The organic extract is separated, washed with H2O and stirred with 10% hydrochloric acid. The layers are separated and the organic layers washed with H2O, 5% sodium hydroxide solution and dried over sodium sulfate. The dried extract is filtered and the filtrate evaporated ^_n vacuo, 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- fonyl compound as a white crystalline solid, M.P. 152.5-154°C.

Step 3. l-Cyano-5-methoxyisoquinoline

Sodium hydride (1.2 g of 60% in mineral oil) is added to a stirred suspension of l-cyano-2-benzenesul- fonyl-l,2-dihydro-5-methoxyisoquinoline (10 g)in xylene (100 ml). The reaction mixture is refluxed under nitrogen for 3 hrs, cooled to RT, stirred for an additional hour, and filtered. The filtered solid is washed with xylenes. The filtrate is evaporated iji vacuo.

The filtered solid is stirred with methylene chloride and aqueous 5% sodium hydroxide solution. The methylene chloride phase is combined with the residue from the evaporated filtrate and the combined extracts are washed with 5% sodium hydroxide solution, H2O and dried over sodium sulfate. The dried extract is filtered and the filtrate evaporated n vacuo, affording a moist solid which is triturated in hexanes. The triturated solid is filtered, washed with hexanes, and dried, affording a fluffy orange solid, M.P. 166-175°C. 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, M.P. 180-182°C. Hydrolysis of the cyano group followed by amidation and hydride reduction affords the chain extended amines. Deprotection of the 5-oxy group followed by the addition of the R2~propyle e chain according to the reacton sequences described above results in the chain extended compounds of Formula I.

The compounds of Formula I have been found to be histamine H ₂ -receptor antagonists by the results obtained in the following ^-antagonist tests.

A. Isolated Guinea Pig Atria

The H2-receptor antagonist activity of the compounds of Formula I is measured by observing the beat rate response versus compound concentration in isolated guinea pig atria. A discussion of criteria to evaluate these dose-response curves may be found in, E.J. Ariens, G.A.J. vanOs, A.M. Simonis, and T.M. van

Rossum, "A Molecular Approach to General Pharmacology", Sections 11A, 11B, 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 30°C. The bath consists of a Krebs-Henseleit buffer aerated with 95% 0 ₂ - 5% C0 ₂ , (pH 7.4). The buffer is prepared by mixing: 4 ml of an aqueous (distilled deionized) solution of CaCl ₂ • 2H2O (0.37 g/ml); 4 ml of an aqueous (distilled deionized) solution of MgS0 • 7H2O (0.29 g/ml); 7.2 g of glucose; and, 2 liters of aqueous (distilled deionized) solution containing NaCl (28 g) , NaHC0 ₂ (8.4 g) , KCl (1.4 g) and KH ₂ P0 (0.6 g) .

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2. Preparation of Atria .

Male albino guinea pigs (400-700 g, preferably 500-600 g) are killed by a blow to the back of the head and exsanguinated 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 petri dish of the same buffer. Since the pericardium is removed, it is possible to slip iris scissors between the atria and ventricles while holding the aorta and vessels with tweezers and cut off the atria. The atria 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 rack and pinion clamp. The upper hook of the strain gauge is placed in the edge of the left atrium and the lower hook in the tip of the right atrium. The lower support is clamped in a femur clamp and the upper hook is suspended from the strain gauge lug. The strain gauge is raised until the resting tension on the tissue is 1 gram. The tissue is allowed to stabilize for about one hour with several buffer washings and tension adjustments before the addition of the test compounds.

3. Test Procedure

A control dose-response curve using cumulative, approximately tripling doses is obtained in all three running from 0.1 to 30.0_ M histamine (0.1, 0.3, 1.0, 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 mM 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 1 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 1.0 mM. 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 (._+ SEM) is plotted as a function of agonist concentration (either histamine or test compound) to evaluate the type of response.

B. Lumen Perfused Rat Stomach - Effect on the Gastric Secretion

Male Sprague-Dawley rats weighing between 350 and 500 gm 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 PE 100 tubing. The jugular vein is exposed and cannulated with PE 50 tubing bevelled at the tip. The abdomen is opened through a midline incision,' and the esophagus is isolated excluding the vagus nerve. PE 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 PE 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 pylorus. Using a 50 ml syringe, the stomach is flushed out with 0.4 mM NaOH 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 mN NaOH (pH 10.0) is perfused and collected in 30 ml beakers. The beakers are changed every 10 or 15 minutes and the pH of these samples are recorded. Once

the pH 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 pH initiated by a gastric stimulant, such as histamine. See, Ghosh, M.N. and Schild, H.O., Brit. 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 rat according to the following test procedure.

See, Corell, 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", Acta. Pharmacology et. Toxicology, 45, 225-231 (1979).

Male Sprague-Da ley 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 5 or 10, with one group serving as controls and receiving vehi¬ cle (for example, distilled water or a 0.1% Tween 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 adminis¬ tered (10 ml/kg) aspirin or indomethacin suspended in 0.1% Tween 80 at a dose of 150.0 or 20.0 mg/kg, respec- tively. Four hours following indomethacin administra¬ tion (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 mm

2 5 lesions, at least 1 > 2 mm 3 5-10 lesions, all < 2 mm

4 5-10 lesions, at least 1 > 2 mm

5 10 lesions, all < 2 mm

6 10 lesions, at least 1 > 2 mm 7 Perforation

The average ulcer severity (+ S.E.) 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

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% Methocel solu¬ tion). 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

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administered 1 ml of absolute alcohol, 0.2N NaOH (1 ml) or 0.6N HCl (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- ments made in the controls was expressed as a percen¬ tage. Measurement of statistical significance of the results was done by standard methods.

The average ulcer severity (_+ S.E.) 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

The results of the anti-secretory, anti-ulcer and cytoprotective assays, detailed above., establish the anti-secretory activity, the ^-receptor antagonist activity, the anti-ulcer activity, the cytoprotective activity, and the utility of the compounds of the pre¬ 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 for¬ mation.

A preferred cytoprotective compound is l-cyano-3- [3-(5-isoquinolyloxy)propyl3-2-methyl-pseudothiourea which is 100% effective in the above described cytopro¬ tective tests at doses. of less than 25 mg/kg.

Other preferred cytoprotective compounds include 2-cyano-l-[3-(5-isoquinolyloxy)propyl3-3-methylguanidine and 5-(3-aminopropoxy) isoquinoline.

A preferred H ₂ -antagonist compound is 3-amino-l- methyl-5-[3-(l-piperidino-5-isoquinolyloxy) propyl- amino3-1H-1,2,4-triazole.

In particular, the compounds according to Formu¬ lae 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 paren- terally. 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, H* _j _-antagonists, or known antacids such as aluminum hydroxide, magnesium hydroxide, magnesium trisilicate, aluminum glycinate, or calcium carbonate. Suitable carriers include diluents or fillers, sterile aqueous media and various non-toxic organic solvents. The compositions may be formulated in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspensions, or solutions, injectable solutions, elixirs, syrups and the like and may contain

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 solubility and chemical properties of the compounds, tho 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 stearate, sodium lauryl sulphate and talc, can be used in producing tablets. For a capsule form, lactose and high molecular v/eight 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. Diluents 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 pH is properly adjusted, suitably buffered, and made isotonic with sufficient saline or glucose.

P

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 day.