Substituted isoquinoline derivatives and anti-ulcer agents

A compound of the formula: ##STR1## (wherein R is hydrogen, hydroxy, methoxy, acetoxy, acetoxymethyl or trifluoromethyl; PA0 R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each is hydrogen, hydroxy, optionally substituted C.sub.1 -C.sub.5 alkoxy, acetoxy, propynyloxy, allyloxy or benzyloxy; or R.sup.2 and R.sup.3 taken together form methylenedioxy; PA0 R.sup.5 is hydrogen, hydroxymethyl, C.sub.2 -C.sub.4 alkoxycarbonyl, C.sub.2 -C.sub.5 acyloxymethyl or phthalidyl; and n is 0 or 1 except for the case in which R is methoxy and R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each is hydrogen) or its pharmaceutically acceptable acid addition salt, being useful as anti-ulcer agents is provided through several routes.

The present invention relates to substituted isoquinoline derivatives. More 
particularly, this invention is directed to substituted isoquinoline 
derivatives which have been found to be particularly effective in the 
treatment of an ulcer, to their production, to their use and to 
pharmaceutical formulations containing the compounds. 
2-[(1-Isoquinolylmethyl)sulfinyl]-5-methoxybenzimidazole is hitherto known 
as this kind of compound, but this compound is defectively somewhat low in 
the acid secretion-suppressing action (Brit. Pat. No. 2134523-A). 
The inventors of the present inventions have been studying anti-ulcer 
agents of benzimidazole family. 
According to the present invention there is provided a substituted 
isoquinoline derivative of the formula: 
##STR2## 
(wherein R is hydrogen, hydroxy, methoxy, acetoxy, acetoxymethyl or 
trifluoromethyl; 
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each is hydrogen, hydroxy, optionally 
substituted C.sub.1 -C.sub.5 alkoxy, propynyloxy, allyloxy or benzyloxy; 
or R.sup.2 and R.sup.3 taken together form methylenedioxy; 
R.sup.5 is hydrogen, hydroxymethyl, C.sub.2 -C.sub.4 alkoxycarbonyl, 
C.sub.2 -C.sub.5 acyloxymethyl or phthalidyl; 
and n is 0 or 1 except for the case in which R is methoxy and R.sup.1, 
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each is hydrogen) 
or its pharmaceutically acceptable acid addition salt. 
The compounds of the present invention have an excellent anti-ulcer 
activity. Accordingly the invention also provides a pharmaceutical 
composition as an active ingredient 0.1 to 95% by weight of at least a 
compound of the formula (I) associated with at least one carrier, diluent 
and/or excipient therefor. 
This invention also provides a method of treating a patient suffering from 
an ulcer which comprises administering to the patient a pharmacologically 
effective amount of a compound of the formula (I). 
This invention further provides a process for preparing a compound of the 
formula (I) which comprises: 
(a) reacting a compound of the formula: 
##STR3## 
(wherein R is as defined above) with a compound of the formula: 
##STR4## 
(wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each has the same meaning 
as defined above) 
to give a compound of the formula: 
##STR5## 
(wherein R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each has the same 
meaning as defined above), 
(b) subjecting the compound (Ia) to (i) hydroxymethylation followed by 
O-acylation of (ii) N-substitution with halomethyl alkanoate or 
3-halophthalide to give a compound of the formula: 
##STR6## 
(wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each has the 
same meaning as defined above), 
(c) oxidizing the compound (Ia) to give a compound of the formula: 
##STR7## 
(wherein R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each has the same 
meaning as defined above), 
(d) oxidizing the compound (Ib) to give a compound of the formula: 
##STR8## 
(wherein R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each has the same 
meaning as defined above and R.sup.5 is C.sub.2 -C.sub.4 alkoxycarbonyl, 
C.sub.2 -C.sub.5 acyloxymethyl or phthalidyl), or 
(e) subjecting the compound (Ic) to N-substitution with halomethyl 
alkanoate or 3-halophthalide to give a compound of the formula: 
##STR9## 
(wherein R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each has the same 
meaning as defined above and R.sup.5 is C.sub.2 -C.sub.5 acyloxymethyl or 
phthalidyl). 
The term "C.sub.1 -C.sub.5 alkoxy" represent methoxy, ethoxy, n-propoxy, 
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 
iso-pentyloxy, sec-pentyloxy, neo-pentyloxy, or tert-pentyloxy. The 
optical substitutent on the C.sub.1 -C.sub.5 alkoxy includes C.sub.3 
-C.sub.6 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl and one 
or more halogens such as fluorine, chlorine or bromine. 
The term "C.sub.2 -C.sub.4 alkoxycarbonyl" includes ethoxycarbonyl, 
propoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl. 
The term "C.sub.2 -C.sub.5 acyloxymethyl" includes alkanoyloxymethyl (e.g. 
acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 
valeryloxymethyl) and alkoxycarbonyloxymethyl (e.g. 
ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, 
butoxycarbonyloxymethyl). 
The process for preparing the compound (I) is shown by the scheme as 
follows: 
##STR10## 
(wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each has the 
same meaning as defined above). 
STEP I 
Method A 
In this step, the compound (II) is allowed to react with the compound (III) 
in the presence of a base in an appropriate solvent, whereby the objective 
compound (Ia) is obtained. 
As the base used in this reaction, an inorganic base (e.g. K.sub.2 
CO.sub.3, Na.sub.2 CO.sub.3, NaOH, NaHCO.sub.3, etc.) and an organic base 
(e.g. Et.sub.3 N, pyridine, etc.) are exemplified. 
As the solvent MeOH, EtOH, benzene, CHCl.sub.3, carbon tetrachloride, 
dimethyl sulfoxide, tetrahydrofuran, dimethylformamide and water are 
exemplified. 
The reaction was performed at 0.degree.-120.degree. C., preferably 
15.degree.-50.degree. C. 
Method B 
In this step, the compound (II) is allowed to react with the compound (IV) 
to give the objective compound (Ia) as in Method A. 
This reaction is peformed by using the said base and solvent at 
15.degree.-120.degree. C., but it is preferable to use the KOH-EtOH system 
with heating up to a reflux temperature of the solvent. 
In this reaction the aromatization of the dihydroquinoline ring by 
dehydrogenation brings about at the same time, whereby the objective 
compound (Ia) is obtained in a good yield. 
STEP II 
Method A 
The compound (Ia) obtained in the former step is allowed to react with 
formaldehyde in a solvent such as acetonitrile or dimethylformamide to 
give the compound (Ib) (R.sup.5 =CH.sub.2 OH). This hydroxymethylation is 
performed at 15.degree.-100.degree. C., preferably at 
50.degree.-80.degree. C. 
Then, the compound (Ib) (R.sup.5 =CH.sub.2 OH) is subjected to acylation to 
produce the O-acylate (Ib) containing the R.sup.5 moiety. 
This reaction is performed by using an acid anhydride (e.g. acetic 
anhydride, butyric anhydride, etc.) or lower alkyl haloformate (e.g. ethyl 
chloroformate, n-propyl chloroformate, etc.). If necessary, it can be 
carried out in a conventional manner for acylation in the presence of a 
solvent and/or a base as illustrated above. The reaction is performed at 
15.degree. to 120.degree. C., preferably 50.degree. to 100.degree. C. 
In the case of using lower alkyl haloformate as an acylating agent, 
eventually the N-alkoxycarbonyl compound (Ib) (R.sup.5 =alkoxycarbonyl) is 
produced together with the N-acyloxymethyl compound (Ib) (R.sup.5 
=alkoxycarbonyloxymethyl). 
Method B 
Alternatively, the compound (Ia) is subjected to N-substitution to give the 
N-substituted compound (Ib) (R.sup.5 =alkanoyloxymethyl or phthalidyl). 
The compound (Ia) is allowed to react with halomethyl alkanoate (e.g. 
chloromethyl pivalate, bromomethyl butyrate, chloromethyl acetate, etc.) 
or 3-halophthalide (e.g. 3-chlorophthalide, 3-bromophthalide). 
The reaction with halomethyl alkanoate is performed in the presence of a 
base such as alkali metal hydride (e.g. sodium hydride) or potassium 
hydride in a solvent such as dimethylformamide, hexamethylphosphoramide or 
the like at 15.degree. to 100.degree. C., preferably at room temperature. 
Further, the reaction with 3-halophthalide is performed in the presence of 
a base such as sodium hydride or triethylamine in a solvent such as 
dimethylformamide, hexamethylphosphoramide or the like at 15.degree. to 
120.degree. C., preferably at 50.degree. to 80.degree. C. 
STEP III 
The compound of (Ia) is oxidized with a peracid to give the sulfinyl 
compound (Ic). The oxidation is performed with appropriate oxidizing 
agents (e.g. hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid 
or the like) in a solvent such as chloroform, 1,2-dichloroethane, carbon 
tetrachloride, dimethylformamide, acetic acid or the like at a temperature 
from -100.degree. to 0.degree. C., preferably -30.degree. to -5.degree. 
C., or at room temperature (e.g. 15.degree. to 25.degree. C.). After 
finishing the reaction, the mixture is treated with aqueous sodium 
bisulfite for decomposing a certain amount of the peracid remaining there 
in a conventional manner. 
STEP IV 
The compound (Ib) is oxidized with a peracid to give the sulfinyl compound 
(Id). This oxidation is performed under the same conditions as in Step 
III. 
STEP V 
The compound (Ic) is subjected to N-substitution with halomethyl alkanoate 
or 3-halophthalide to give the N-substitution compound (Id). The 
N-substitution is performed under the same conditions as in Method B of 
Step II. 
The starting material (III) and (IV), for example, can be manufactured by 
the following process. 
##STR11## 
The compound (I) can be converted into its pharmaceutically acceptable acid 
addition salts. Such acids illustratively include an inorganic acid such 
as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid and an 
organic acid such as acetic acid, maleic acid, malic acid, citric acid, 
lactic acid, succinic or methanesulfonic acid. 
The compounds (I) can be administered enterally or parenterally to human 
being. They can be formulated as tablets, capsules, pills, granules, 
injections, suppositories and syrups according to customary pharmaceutical 
practice. As pharmaceutically acceptable carriers, diluents or excipients, 
there are examplified lactose, sucrose, wheat starch, potato starch, 
magnesium steareate, gelatin, methyl cellulose, agar, water and the like. 
A necessary, appropriate stabilizers, emulsifiers, spreaders, buffers and 
other pharmaceutical adjuvants can be added. Appropriate daily dosage of 
the compound (I) is 0.1 to 500 mg in oral route and 0.1 to 3000 mg in 
injection. 
The present invention will be explained in more detail by the following 
Examples, Reference Examples and Formulations. 
The abbreviations used in the Examples, Reference Examples and Tables are 
as follows. 
Me: methyl 
Ph: phenyl 
EtOH: ethanol 
AcOH: acetic acid 
CH.sub.3 CN: acetonitrile 
Et.sub.2 O: ethylether 
CH.sub.2 Cl.sub.2 : dichloromethane 
CHCl.sub.3 : chloroform 
THF: tetrahydrofuran 
DMF: dimethylformamide 
POCl.sub.3 : phosphorus oxychloride 
LiAlH.sub.4 : lithium alminium hydride 
MeO: methoxy 
EtO: ethoxy 
O-Al: allyloxy 
O-Bz: benzyloxy 
O-i-Pro: isopropyloxy 
(d): decomposition 
Et: ethyl 
MeOH: methanol 
KOH: potassium hydroxide 
NaOH: sodium hydroxide 
KCN: potassium cyanide 
AcOEt: ethyl acetate 
HCHO: formaldehyde 
Et.sub.3 N: triethylamine 
NaH: sodium hydride.