Naphthalene aminoalkylene ethers and thioethers, and their pharmaceutical uses

A class of naphthalene aminoalkylene ether and thioether compounds exhibiting pharmacological activity including anti-secretory and anti-ulcerogenic activity, pharmaceutical compositions comprising these compounds, and methods for the treatment of gastrointestinal hyperacidity and ulcerogenic disorders in mammals using said compositions are disclosed.

FIELD OF THE INVENTION 
This invention relates to a class of naphthalene compounds characterized by 
an ether or thioether substituent on one ring and an exocyclic nitrogen 
substituent on the other ring of the bicyclic naphthalene ring system and 
methods for the treatment of physiological disorders, including 
gastrointestinal disorders in humans and other mammals. 
REPORTED DEVELOPMENTS 
Gastrointestinal hyperacid secretion, stomach and intestinal ulceration, 
and gastritis are major gastrointestinal 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 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.sub.1 - 
and H.sub.2 -receptors, was proposed by Ash and Schild (Brit. J. 
Pharmacol. Chemother, 1966, 27, 427) and Black et al (Nature 1972, 236, 
385). The H.sub.1 -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.sub.1 -receptor as the H.sub.2 
-receptors. Blocking the action of histamine at the H.sub.2 -receptors 
will selectively block histamine's stimulative action on gastric acid 
secretion and heart rate. Burimamide was the first clinically effective 
H.sub.2 -receptor antagonist inhibiting gastric secretion in man; but 
Burimamide'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 H.sub.2 
-receptor antagonists, for example, those disclosed in U.S. Pat. Nos. 
4,104,381, 4,279,819, 4,323,566, and British published patent application 
GB No. 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 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 active of strong 
gastric acid. Prostaglandins have been implicated in 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 Prostaglandin and Thromboxane Research, Vol. 8 (Raven Press, 
N.Y. 1980), and Robert et al, "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 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. 
Compounds of the present invention comprise naphthalene ethers and 
thioethers which exhibit anti-secretory activity, H.sub.2 -receptor 
antagonist activity, anti-ulcer activity and cytoprotective activity. 
SUMMARY OF THE INVENTION 
This invention comprises a class of compounds according to Formula I 
##STR1## 
wherein: 
a is 0, 1 or 2; 
d is 0 or 1; 
e is 2, 3 or 4; 
X is oxygen, sulfur, 
##STR2## 
or CH.sub.2 ; 
Z is --NHR.sub.4, 
##STR3## 
or --CN; R.sub.1 is --NR.sub.2 R.sub.3, 
##STR4## 
R.sub.2 and R.sub.3 are each independently H or alkyl, or both together 
with the nitrogen to which they are attached form a 5, 6 or 7-membered 
ring which may include one to three additional hetero atoms of N, O or S; 
R.sub.4 is selected from the group consisting of H, 
##STR5## 
R.sub.5 is H or lower alkyl; 
R.sub.6 is H or lower alkyl or R.sub.6 together with R.sub.2 are ethylene 
or propylene and form a 5 or 6 membered ring with the nitrogen atoms to 
which they are attached; 
or a pharmaceutically acceptable salt thereof. 
Compounds within the scope of Formula I exhibit physiological activity in 
mammals including anti-secretory activity, histamine H.sub.2 -receptor 
antagonist activity, 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 within the description of Formula I. 
DETAILED DESCRIPTION OF THE INVENTION 
Preferred classes of compounds according to this invention are described by 
Formulae II, III, and IV: 
##STR6## 
wherein: 
a is 0, 1 or 2; 
d is 0 or 1; 
e is 2, 3 or 4; 
X is oxygen or sulfur; 
Z is --NHR.sub.4 or 
##STR7## 
R.sub.1 is --NR.sub.2 R.sub.3 ; 
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as described above. 
##STR8## 
wherein: 
d is 0 or 1; 
e is 2, 3 or 4; 
X is oxygen or sulfur; 
Z is --NHR.sub.4 or 
##STR9## 
R.sub.1 is --NR.sub.2 R.sub.3 ; 
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as described above. 
A most preferred class of compounds within the scope of Formula I comprises 
the compounds of Formula I wherein: 
a is 0; 
d is 0; 
e is 3; 
X is oxygen; and 
Z is --NHR.sub.4 or 
##STR10## 
A preferred subclass of compounds is described by Formula IV, wherein: 
e is 3; and 
X is oxygen. 
Another preferred subclass of compounds is described by Formula IV, 
wherein: 
d is 1; 
e is 2; and 
X is sulfur. 
A most preferred class of compounds is described by Formula V. 
##STR11## 
wherein: 
d is 0 or 1; 
e is 2, 3 or 4; 
X is oxygen or sulfur; 
R.sub.1 is --NR.sub.2 R.sub.3 ; 
R.sub.2 and R.sub.3 together with the nitrogen to which they are attached 
form a 5, 6 or 7 membered heterocyclic ring which may include one to three 
additional hetero atoms of N, O or S; 
or a pharmaceutically acceptable salt thereof. 
A particularly interesting class of compounds according to Formula V 
comprises those compounds wherein R.sub.1 is N-piperidyl, N-pyrrolidinyl, 
N-morpholinyl or N-azepinyl. 
The compounds of Formulae I to V may also form hydrates and exhibit 
tautomerism. Formulae I to V are intended 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: 
"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. 
"5, 6 or 7 membered heterocyclic ring" means a nitrogen-containing ring of 
the formula --NY where Y is alkylene or alkylidinyl having from one to six 
carbon atoms, and may include one to three atoms of N, O or S. Exemplary 
heterocyclic groups include piperidyl, pyrrolidinyl, morpholinyl, 
azepinyl, pyrrolyl, imidazolyl, pyrazolyl, and thiamorpholinyl. 
Representative examples of compounds of this invention are listed below in 
Tables A, B and C. 
TABLE A 
______________________________________ 
##STR12## 
wherein substitution may by at the 5,6,7 or 8 position 
R.sub.1 Z 
______________________________________ 
N(CH.sub.3).sub.2 
##STR13## 
##STR14## 
##STR15## 
##STR16## 
##STR17## 
NH.sub.2 
##STR18## 
##STR19## 
##STR20## 
##STR21## 
##STR22## 
##STR23## 
##STR24## 
N(CH.sub.3).sub.2 
##STR25## 
NHCH.sub.3 
##STR26## 
##STR27## 
##STR28## 
##STR29## 
##STR30## 
N(CH.sub.3).sub.2 
##STR31## 
N(CH.sub.3).sub.2 
##STR32## 
##STR33## 
##STR34## 
##STR35## 
##STR36## 
##STR37## CN 
##STR38## 
##STR39## 
##STR40## NH.sub.2 
##STR41## CN 
##STR42## 
##STR43## 
##STR44## NH.sub.2 
##STR45## 
##STR46## 
##STR47## 
##STR48## 
##STR49## 
##STR50## 
##STR51## 
##STR52## 
##STR53## 
##STR54## 
##STR55## 
##STR56## 
______________________________________ 
TABLE B 
______________________________________ 
##STR57## 
R.sub.1 Z 
______________________________________ 
N(CH.sub.3).sub.2 
##STR58## 
N(CH.sub.3).sub.2 
##STR59## 
##STR60## 
##STR61## 
##STR62## 
##STR63## 
##STR64## 
##STR65## 
NH.sub.2 
##STR66## 
NHCH.sub.3 
##STR67## 
N(CH.sub.3).sub.2 
##STR68## 
N(CH.sub.3).sub.2 
##STR69## 
N(CH.sub.3).sub.2 
##STR70## 
N(Et).sub.2 
##STR71## 
N(Et).sub.2 
##STR72## 
NHEt 
##STR73## 
NHCH.sub.3 
##STR74## 
##STR75## 
##STR76## 
______________________________________ 
TABLE C 
______________________________________ 
##STR77## 
R.sub.1 Z 
______________________________________ 
##STR78## CN 
##STR79## 
##STR80## 
##STR81## NH.sub.2 
##STR82## CN 
##STR83## 
##STR84## 
##STR85## NH.sub.2 
______________________________________ 
The compounds of this invention may be prepared by one of the following 
general synthetic schemes. 
When the naphthalene ring is directly attached to the X component of 
Formula I, these compounds may be prepared from the naphthol (or 
naphthmercaptan) intermediate shown by Formula VI below. The appropriately 
substituted naphtholic (or mercaptyl) intermediate of Formula VI may be 
prepared by the reaction sequences illustrated in Scheme I. 
The starting material may be a 1, 2, or 3-cyano or a 1, 2, or 
3-nitronaphthol or naphthmercaptan, having the oxy or mercaptan 
substituent in the 5, 6, 7 or 8 position. These compounds can either be 
obtained from a commercially available source or prepared according to 
standard procedures known in the art. 
The nitro compound may be converted in excellent yield to the amine by 
reduction using hydrazine in the presence of a catalyst such as palladium 
or charcoal. 
The cyano compound may be converted to the amide by acid hydrolysis, 
treatment with a Lewis acid such as BF.sub.3 in acetic acid, hydrogen 
peroxide in aqueous ethanolic sodium hydroxide solution, or by sodium 
hydroxide in DMSO. The resulting amide is either further reduced resulting 
in the methylene amine or subjected to a Hoffman or Curtius rearrangement 
to the corresponding amino compound. The rearrangement may be conducted by 
treatment of the amide with bromine and sodium methoxide in methanol 
followed by workup with calcium oxide and water. 
The protecting group, P.sub.R, may be methyl, benzyl or the N-phthalimido 
alkyl. If the protecting group is chosen to be other than the 
N-phthalimido alkyl, the protecting group is removed according to methods 
known in the art. If the protecting group is N-phthalimido alkyl, then it 
can remain on the synthetic intermediate preceding VI and used as in the 
subsequent reaction step. 
The phenolic protecting group is then cleaved to obtain the intermediate of 
Formula VI. 
##STR86## 
The starting material may also be the 1, 2, 3, or 4-carboxylic acid or 
ester thereof which may be converted to the amide by the condensation of 
the desired amine followed by reduction as shown in Scheme II. 
##STR87## 
The formation of the ether linkage from VI is accomplished by treating the 
phenolic compound with a protected N-propylbromide in the presence of a 
base such as sodium methoxide, potassium t-butoxide or potassium 
carbonate. Ether coupling reagents other than a base and a bromide may 
also be used. (Scheme III) 
##STR88## 
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) 
##STR89## 
The addition of the terminal R.sub.4 group comprises treating the amine 
with an R.sub.4 end group precursor unit including those groups listed in 
Scheme V below. The preparation of the precursors of the R.sub.4 groups 
and the reaction conditions under which they are coupled to the primary 
amine are fully described in U.S. Pat. Nos. 4,104,381, 4,279,819, 
4,323,566 and GB No. 2067987A, hereby incorporated by reference. 
##STR90## 
Treatment of the S-alkyl compound with a primary amine results in the 
N-cyano, N-alkyl guanidine analog. 
Compounds within the scope of Formula I and having a methyleneoxy or 
methylenethioxy substituent (d=1) on the phenyl 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-bromoethylene phthalimide in the presence of base or 
2-thioethylamine, respectively, with the methylene hydroxy compound. 
Scheme VI illustrates the formation of the methylenethio ether. 
##STR91## 
Addition of the R.sub.4 group may proceed as described above in Scheme V. 
The methyleneoxy compound may be obtained by the reduction of a phenyl 
carboxylic acid or ester precursor such as Formula VII. The reduction may 
be accomplished by hydrogenation over a rhenium catalyst, by a hydride in 
the presence of a Lewis acid or by acidic electrolysis and depending on 
choice of conditions may take place before or after the formation of the 
amine. 
##STR92## 
If the reduction to the methylene hydroxy compound occurs after the 
formation of the amine, the carboxylic acid intermediate is prepared 
analogously to the phenolic intermediate VI, with the acid being protected 
by its ester where appropriate. 
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, hydrobromic 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 preparation of the compounds 
according to this invention.

EXAMPLE 1 
The Preparation of 
3-Amino-5-[3-[5-(1-Pyrrolidinylnaphthyloxy)]Propylamino]-1-Methyl-1H-1,2,4 
-Triazole 
Step 1. 1-Amino-5-methoxy naphthalene 
Hydrazine hydrate (150 ml) is added slowly to a stirred mixture of 
5-methoxy-1-nitro-naphthalene (320 g), and palladized charcoal (0.1 g) in 
95% ethanol (2 liters) previously warmed to 50.degree. C. When the 
hydrazine addition is complete, additional palladized charcoal (0.1 g) is 
added and the mixture heated to reflux for about one hour. The reaction 
mixture is filtered through Celite and the filtrate evaporated in vacuo 
resulting in a white solid which is recrystallized from H.sub.2 O and 
ethanol. 
Step 2. 5-Methoxy-1-pyrrolidinyl-naphthalene 
1,4-Dibromobutane (220 g) is added dropwise to a stirred suspension of 
1-amino-5-methoxynaphthalene (170 g) and sodium carbonate (200 g) in THF 
(300 ml), while maintaining the reaction temperature at less than 
10.degree. C. When the addition is complete, the stirred mixture is 
allowed to reach RT and refluxed overnight. 
The reaction mixture is evaporated in vacuo, and the residue partitioned 
between ether and aqueous hydrochloric acid. The aqueous layer is made 
acidic (pH 5-6) by the addition of conc. HCl. The layers are separated and 
the ether layer washed with aqueous HCl. The aqueous extracts are combined 
and made basic with saturated sodium bicarbonate resulting in the 
formation of an immiscible oil. The oil is extracted with methylene 
chloride and the organic extract washed with saturated NaCl, dried over 
Na.sub.2 SO.sub.4, filtered and evaporated in vacuo. The residual oil is 
used in the next step without further purification. 
Step 3. 5-Hydroxy-1-pyrrolidinyl-naphthalene 
5-Methoxy-1-pyrrolidinyl-naphthalene (90 g) is dissolved in glacial acetic 
acid (1 liter). 48% hydrobromic acid is added to the solution and the 
resulting reaction mixture heated to reflux for 3 hours. The reaction 
mixture is poured into water and crushed ice and the solution made 
alkaline to pH 8 to 9. The aqueous mixture is extracted with methylene 
chloride. The methylene chloride extract is back-extracted with 2% KOH 
solution and the combined basic layers made acidic by the addition of 
aqueous HCl. The addition is continued until a white precipitate appears. 
The aqueous solution is extracted with methylene chloride and the organic 
layer washed with H.sub.2 O, dried, filtered and evaporated in vacuo, 
yielding the desired product. 
Step 4. 1-7-[3-(N-Phthalimido)propoxy]-1-pyrrolidinylnaphthalene 
Potassium t-butoxide (6 g) is added to a stirred solution of 
7-hydroxy-1-pyrrolidinyl-naphthalene (10 g) in dimethylformamide (100 ml). 
26 g of N-(3-bromopropyl)phthalimide is added to the stirred reaction 
mixture and stirring is continued for about 24 hours. The reaction is 
partitioned between slightly basic H.sub.2 O and diethyl ether. The layers 
are separated and the aqueous layer extracted with ether. The combined 
ether extracts are washed with 5% sodium hydroxide solution and H.sub.2 O. 
The ether extract is stirred with 5% aqueous hydrochloric acid solution, 
the layers separated and the ether extracted with additional aqueous 5% 
hydrochloric acid. The combined acidic aqueous layers are washed with 
ether and made strongly alkaline, resulting in an oily precipitate. The 
precipitate is extracted with diethyl ether which is washed with H.sub.2 O 
and saturated sodium chloride solution dried and evaporated in vacuo, 
yielding the desired ether as a solid. 
Step 5. 7-(3-Aminopropoxy)-1-pyrrolidinyl-naphthalene 
85% hydrazine hydrate (9.6 ml) is added to a stirred solution of the 
phthalimido naphthalene prepared as described in the previous step (about 
50 g) in absolute ethanol (about 500 ml). The reaction mixture is heated 
at reflux for about 3 hours and allowed to cool. The resulting precipitate 
is removed by filtration and washed with absolute ethanol. The filtrate is 
evaporated in vacuo and the residue triturated with 5% aqueous 
hydrochloric acid. The aqueous suspension is filtered and the solid washed 
with 5% hydrochloric acid. The filtrate is made strongly alkaline with 50% 
sodium hydroxide solution, resulting in an oily precipitate which is 
extracted into diethyl ether. The ether extract is washed with saturated 
sodium chloride solution, dried, filtered and the filtrate evaporated in 
vacuo, yielding the desired amine as an oil. 
Step 6. 1-Cyano-3-[3-[7-(1-pyrrolidinyl 
naphthyloxy)]propyl]-2-methylpseudothiourea 
The amine from the preceding step (10 g) is dissolved in isopropanol (35 
ml) and is added over a period of one minute to a stirred solution of 
S,S-dimethyl-N-cyanoiminodithiocarbonimidate (7 g) dissolved in 100 ml of 
isopropanol. The reaction mixture is stirred at RT overnight and 
evaporated in vacuo, yielding the desired cyano product as a viscous amber 
oil. 
Step 7. 3-Amino-5-[3-[7-(1-pyrrolidinyl 
naphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole 
Methyl hydrazine (11 ml) is added to a stirred solution of the 
cyanonaphthalene from the previous step (about 10 g) dissolved in 
dimethylformamide (110 ml). The reaction mixture is stirred at about 
40.degree. C. for 24 hours, and evaporated under vacuum resulting in a 
residue of amber oil. The oil is separated on a silica gel column (290 g; 
70-230 mesh) using as eluent methanol in methylene chloride ranging from 
10% methanol to 30% methanol. The major fractions are pooled and 
evaporated in vacuo, resulting in a viscous amber oil. The oil is 
triturated in anhydrous ether, resulting in the formation of the desired 
product as a solid which is filtered, washed with ether and dried. This 
solid is recrystallized from hot acetonitrile and dried under vacuum, 
resulting in a near-white powder. 
EXAMPLE 2 
The Preparation of N-[3-[5-(1-Diethylaminomethylene 
Naphthyloxy)]Propyl]-N'-Methyl-2-Nitro-1,1-Diaminoethane 
Step 1. 1-Carbamoyl-5-methoxy-naphthalene 
1-Cyano-5-Methoxy-naphthalene (36 g) is stirred with concentrated sulfuric 
acid (250 ml) and H.sub.2 O (20 ml) on a steam bath for two hours and is 
allowed to cool. The reaction mixture is poured into a slurry of crushed 
ice and concentrated ammonium hydroxide (250 ml). The mixture is extracted 
with methylene chloride and the organic extract dried, filtered and 
evaporated, yielding the desired amide as a solid. 
Step 2. 1-(N,N-Diethylcarbamoyl)-5-methoxy-naphthalene 
1-Carbamoyl-5-methoxy-naphthalene (20 g) is suspended in 100 ml of 40% 
diethylamine hydrochloride in water and stirred under reflux overnight. 
The reaction mixture is evaporated in vacuo and the residue partitioned 
between 5% aqueous HCl and methylene chloride. The organic layer is 
separated, dried over Na.sub.2 SO.sub.4, filtered and evaporated yielding 
the desired product as a white crystalline solid. 
Step 3. 5-Methoxy-1-N,N-diethylaminomethylenenaphthalene 
5-Methoxy-1-N,N-diethylcarbamoyl-naphthalene (25 g) dissolved in THF (100 
ml) is added dropwise to a stirred mixture of lithium aluminum hydride 
(3.5 g) in THF (50 ml) while maintaining a gentle boiling under a nitrogen 
atmosphere. When the addition is complete, the reaction mixture is gently 
refluxed for two hours. The reaction mixture is allowed to cool and 3.5 ml 
of H.sub.2 O added to the reaction mixture dropwise, followed by 3.5 ml of 
15% sodium hydroxide solution and 10.5 ml of H.sub.2 O. The reaction 
mixture is filtered and the solid washed with methylene chloride. The 
filtrate is evaporated and the solid residue partitioned between methylene 
chloride and H.sub.2 O. The organic layer is separated, washed with 
saturated sodium chloride, dried over NaSO.sub.4, filtered and evaporated, 
resulting in the desired product as a crystalline solid. 
Step 4. 1-Diethylaminomethylene-5-hydroxy-naphthalene 
15 g of 1-diethylaminomethylene-5-methoxy naphthalene obtained in the 
previous step are dissolved in glacial acetic acid (150 ml). 48% 
hydrobromic acid (150 ml) is added to the solution and the resulting 
reaction mixture heated to reflux for 3 hours. The reaction mixture is 
poured into H.sub.2 O and crushed ice and the solution made alkaline to pH 
8 to 9. The aqueous mixture is extracted with methylene chloride. The 
methylene chloride extract is back-extracted with 2% KOH solution and the 
combined basic layers made acidic by the addition of aqueous HCl. The 
addition is continued until a white precipitate appears. The aqueous 
solution is extracted with methylene chloride and the organic layer washed 
with H.sub.2 O, dried, filtered and evaporated in vacuo, yielding the 
desired product as an oil. 
Step 5. 1-Diethylaminomethylene-5-[3-(N-phthalimido)propoxy]-naphthalene 
Potassium t-butoxide (6 g) is added to a stirred solution of 
1-diethylaminomethylene-5-hydroxynaphthalene (10 g) in dimethylformamide 
(100 ml). 26 g of N-(3-bromopropyl) phthalimide is added to the stirred 
reaction mixture and stirred continued for about 24 hours. The reaction is 
partitioned between slightly basic H.sub.2 O and diethyl ether. The layers 
are separated and the aqueous layer extracted with ether. The combined 
ether extracts are washed with 5% sodium hydroxide solution and H.sub.2 O. 
The ether extract is stirred with 5% aqueous hydrochloric acid solution, 
the layers separated and the ether extracted with additional aqueous 5% 
hydrochloric acid. The combined acidic aqueous layers are washed with 
ether and made strongly alkaline. The resulting oily precipitate is 
extracted with diethyl ether which is washed with H.sub.2 O and saturated 
sodium chloride solution dried and evaporated in vacuo, yielding the 
desired ether as a solid. 
Step 6. 5-(3-Aminopropoxy)-1-diethylaminomethylenenaphthalene 
85% hydrazine hydrate (1 ml) is added to a stirred solution of the 
phthalimido naphthalene prepared as described in the previous step (about 
5 g) in absolute ethanol (about 50 ml). The reaction mixture is heated at 
reflux for about 3 hours and allowed to cool. The precipitate is removed 
by filtration and washed with absolute ethanol. The filtrate is evaporated 
in vacuo and the residue triturated with 5% aqueous hydrochloric acid. The 
aqueous suspension is filtered and the solid washed with 5% hydrochloric 
acid. The filtrate is made strongly alkaline with 50% sodium hydroxide 
solution. The resulting oily precipitate is is extracted into diethyl 
ether. The ether extract is washed with saturated sodium chloride 
solution, dried, filtered and the filtrate evaporated in vacuo, yielding 
the desired amine as an oil. 
Step 7. 
N-[3-[5-(1-diethylaminomethylene-naphthyloxy)]propyl]-N'-methyl-2-nitro-1, 
1-diaminoethene 
1-Methylamino-1-methylthio-2-nitroethene (2 g) is added to a solution of 
the 1-diethylaminomethylenenaphthyloxy propylamine prepared in the 
preceding step (3 g) in absolute ethanol (30 ml). The reaction mixture is 
heated to reflux for about 2 hours while purging the reaction mixture with 
N.sub.2. The mixture is allowed to cool and the resultant solid filtered, 
washed with diethyl ether and dried. The filtrate is evaporated in vacuo 
and the residue dissolved in hot absolute ethanol. Diethyl ether is added, 
resulting in the formation of a solid which is filtered and dried. The two 
solids are combined and dissolved in boiling isopropyl alcohol, allowed to 
cool, filtered, washed with isopropyl alcohol and ether, and dried under 
vacuum, resulting in the desired product as a white powder. 
Various tests in animals may be carried out to show the ability of the 
compounds of this invention to exhibit pharmacological responses that can 
be correlated with activity in humans. These tests involve such factors as 
the effect of the compounds of Formula I on gastric secretion and their 
H.sub.2 antagonist and cytoprotective activity. 
One such test is the gastric secretion test. This test is carried out as 
follows: Shay rats are fasted for 4-8 hours, and water is given ad lib. 
The rats are selected at random and separated into groups of 10. The 
animals are treated intraduodenally (I.D.) with the test compounds of the 
vehicle immediately subsequent to the ligation of the stomach at the 
pyloric sphincter. The animals are sacrificed with chloroform at 4 hours 
post-drug administration, the stomach removed and its contents assayed for 
volume, pH and total acids. 
A second gastric secretion test is carried out on the dog. This is outlined 
in the Handbook of Physiology, Section 6: Alimentary Canal, Volume II: 
Secretion. American Physiology Society, Washington, D.C., 1967. 
These tests are known to correlate well with gastric activity in humans and 
are standard tests used to determine anti-secretory properties. 
The following tests determine the histamine H.sub.2 -receptor antagonist 
activity of the compound according to the present invention. 
A. Isolated Guinea Pig Atria 
The H.sub.2 -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.degree. C. The bath 
consists of a Krebs-Henseleit buffer aerated with 95% O.sub.2 -5% 
CO.sub.2, (pH 7.4). The buffer is prepared by mixing: 4 ml of an aqueous 
(distilled deionized) solution of CaCl.sub.2.2H.sub.2 O (0.37 g/ml); 4 ml 
of an aqueous (distilled deionized) solution of MgSO.sub.4.7H.sub.2 O 
(0.29 g/ml); 7.2 g of glucose; and, 2 liters of aqueous (distitlled 
deionized) solution containing NaCl (28 g), NaHCO.sub.2 (8.4 g), KCl (1.4 
g) and KH.sub.2 PO.sub.4 (0.6 g). 
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 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 30.0M 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 
agaonist 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 100M 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 exophagus 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.degree. 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-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 5 or 10, with 
one group serving as controls and receiving vehicle (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 administered (10 ml/kg) aspirin or 
indomethacin suspended in 0.1% Tween 80 at a dose of 150.0 or 20.0 mg/kg, 
respectively. Four hours following indomethacin administration (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 10.times. 
magnifying glass; the following scale is employed: 
______________________________________ 
Grade Description 
______________________________________ 
0 No lesions 
1 5 lesions, all &lt;2 mm 
2 5 lesions, at least 1 &gt; 2 mm 
3 5-10 lesions, all &lt;2 mm 
4 5-10 lesions, at least 1 &gt; 2 mm 
5 10 lesions, all &lt;2 mm 
6 10 lesions, at least 1 &gt; 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: 
##EQU1## 
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 solution). 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 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 
2.times.-10.times. magnifying glass. 
The reduction of lesion count, lesion severity score and ulcer index as 
compared to similar measurements made in the controls was expressed as a 
percentage. 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: 
##EQU2## 
The compounds of the present invention that exhibit anti-secretory, 
anti-ulcer, H.sub.2 -antagonist and cytoprotective activity are useful in 
the treatment of gastrointestinal ulcerogenic disorders in mammals, 
including humans. These compounds both aid in the healing of such ulcers 
and also prevent their formation. 
In particular, the compounds according to Formulae I to VI 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 parenterally. 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.sub.1 -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, 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 stearate, sodium lauryl sulphate and talc, can be used in 
producing tablets. For a capsule form, lactose and high molecular weight 
polyethylene glycols are among the preferred pharmacetically 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 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. 
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.