Carbostyril compounds connected via an oxyalkyl group with a piperidine ring and having pharmaceutical utility

Carbostyril derivatives of Formula I: ##STR1## wherein: m is 0, 1, or 2; PA0 n is 0, 1, or 2; PA0 R.sup.1 is hydrogen or lower alkyl; PA0 R.sup.2 is hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, aralkoxy, or acyloxy; PA0 R.sup.3 is hydrogen, halogen, lower alkyl, or lower alkoxy; PA0 R.sup.4 is hydrogen, hydroxy, lower alkyl, acyloxy, provided that when R.sup.4 is hydroxy or acyloxy, m and n are both 1; PA0 R.sup.5 is hydrogen or lower alkyl; and PA0 R.sup.6 is alkyl, hydroxyalkyl, alkoxyalkyl, or (dialkylamino)alkyl; and the pharmaceutically acceptable acid addition salts and N-oxides (at the carbostyril nitrogen) thereof, and compositions containing them, are useful in treating cardiovascular diseases, particularly arrhythmias. Methods of preparing intermediates, the compounds, their formulations and methods of treatment therewith are also disclosed.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention is concerned with carbostyril derivatives useful in treating 
cardiovascular diseases, particularly in treating arrhythmias. 
2. Background to the Invention 
Carbostyril derivatives are disclosed in the patent literature as having 
cardiotonic, anti-arrhythmic, .alpha.- and .beta.-adrenoceptor blocking 
activities, and as being calcium antagonist, antihistaminic and local 
anesthetic agents. See, for example, U.S. Pat. Nos. 4,210,753 and 
4,482,560, and Japanese Kokai Tokyo Koho Sho 57-018,674 (Derwent Abstract 
18695E/10). 
SUMMARY OF THE INVENTION 
A first aspect of this invention comprises carbostyril derivatives of 
Formula I: 
##STR2## 
wherein: m is 0, 1, or 2; 
n is 0, 1, or 2; 
R.sup.1 is hydrogen or lower alkyl; 
R.sup.2 is hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, aralkoxy, 
or acyloxy; 
R.sup.3 is hydrogen, halogen, lower alkyl, or lower alkoxy; 
R.sup.4 is hydrogen, hydroxy, lower alkyl, or acyloxy, provided that when 
R.sup.4 is hydroxy or acyloxy, m and n are both 1; 
R.sup.5 is hydrogen or lower alkyl; and 
R.sup.6 is alkyl, hydroxyalkyl, alkoxyalkyl, or (dialkylamino)alkyl; 
and the pharmaceutically acceptable acid addition salts and N-oxides 
thereof. 
A second aspect of this invention comprises pharmaceutical compositions 
containing at least one compound of Formula I and a pharmaceutically 
acceptable excipient. 
A third aspect of this invention comprises methods for treating 
cardiovascular disease in a mammal by administering an effective amount of 
a compound of Formula I, or a composition containing it, to the mammal. In 
a preferred embodiment, the cardiovascular disease treated is a cardiac 
arrhythmia. 
Further aspects of this invention are methods for preparing compounds of 
Formula I, including the single stereoisomers or mixtures of stereoisomers 
of the compounds of Formula I having a chiral center, as follows: 
(a) contacting a compound, that is a single stereoisomer or a mixture of 
stereoisomers, of the formula: 
##STR3## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, 
with a compound of the formula: 
##STR4## 
wherein R.sup.5 and R.sup.6 are as defined above, in a solvent that will 
dissolve both reactants; or 
(b) contacting a compound, or a single stereoisomer or a mixture of 
stereoisomers, of the formula: 
##STR5## 
wherein R.sup.1, R.sup.2, R.sup.3, m and n are as defined above, 
R.sup.4 is hydrogen or lower alkyl and Y is halo, with a compound of the 
formula: 
##STR6## 
wherein R.sup.5 and R.sup.6 are as defined above, in the presence of a 
hydrogen halide acceptor; or 
(c) acylating a compound of Formula I wherein either R.sup.2 or R.sup.4 is 
OH, or R.sup.2 and R.sup.4 are both OH; or 
(d) saponifying a compound of Formula I wherein either R.sup.2 or R.sup.4 
is --O--CO--alkyl, or R.sup.2 and R.sup.4 are both --O--CO--alkyl; or 
(e) deprotecting a compound of Formula I wherein R.sup.2 is aralkoxy; or 
(f) resolving a racemic mixture of stereoisomers of Formula I into pure 
enantiomers using an appropriate optically active acid; or 
(g) converting a compound of Formula I in free base form to an acid 
addition salt by treatment with the appropriate organic or inorganic acid; 
or 
(h) decomposing an acid addition salt of a compound of Formula I to the 
corresponding free base by treatment with a suitable base or by treatment 
with a suitably loaded ion exchange resin; or 
(i) interchanging an acid addition salt of a compound of Formula I with 
another acid addition salt. 
Still another aspect of the invention entails a process for preparing a 
5-hydroxy-3,4-dihydrocarbostyril compound of Formula 5a: 
##STR7## 
wherein: R.sup.1 is hydrogen or lower alkyl; and 
R.sup.3 is hydrogen, lower alkyl, or lower alkoxy; 
by hydrogenating a compound of the formula: 
##STR8## 
wherein R is lower alkyl. 
Another aspect of the invention entails a process for preparing a 
5-hydroxy-3,4-dihydrocarbostyril compound of Formula 5b: 
##STR9## 
wherein: R.sup.1 is hydrogen or lower alkyl; and 
R.sup.2 is hydrogen, lower alkyl, or lower alkoxy; 
by hydrogenating a compound of the formula: 
##STR10## 
wherein W is alkyl, aryl or cycloalkyl. 
A still further aspect of the invention entails a process for preparing a 
5-hydroxy-8-substituted-3,4-dihydrocarbostyril compound of Formula 5c: 
##STR11## 
by cyclizing a compound of the formula: 
##STR12## 
wherein: R is acetyl or phenylmethyl; 
by contacting it with a strong acid at room temperature, to give a cyclized 
compound of the formula 
##STR13## 
and hydrogenating the cyclized compound. 
Other and further aspects of the invention will become apparant to those of 
ordinary skill in the art from the detailed description, preparations and 
examples that follow. 
DETAILED DESCRIPTION OF THE INVENTION 
Definitions 
The following definitions are set forth to illustrate and define the 
meaning and scope of various terms used to describe the invention herein, 
unless otherwise stated or the context requires otherwise. 
The term "alkyl" means a straight, branched, or cyclic saturated 
hydrocarbon radical having from 1 to 12 carbon atoms. Examples include 
methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1,1-dimethylethyl 
(t-butyl), 2-methylpropyl (or "isobutyl"), pentyl, hexyl and heptyl, 
cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, 
cyclopentylmethyl, cyclohexyl, decyl, adamantoyl, dodecyl and the like. If 
more than one alkyl radical is present in a given molecule, each may be 
independently selected from "alkyl" unless otherwise stated. 
The term "alkoxy" means the group R--O-- wherein R is "alkyl" as defined 
above. Examples include methoxy, ethoxy, propoxy, 1,1-dimethylethoxy 
(tert-butoxy), pentyloxy, hexyloxy and the like. 
The term "aryl" or "Ar--" refers to a substituted or unsubstituted 
monovalent unsaturated radical, for example, phenyl, which, if 
substituted, can have one or more lower alkyl, lower alkoxy, or halo 
groups in any available position on the ring. 
The term "aralkoxy" means the group Ar--R--O-- wherein R is alkyl as 
defined above. 
The term "acyloxy" means the group R--C(O)--O-- wherein R is alkyl as 
defined above. 
The term "lower" modifies "alkyl" and "alkoxy" and refers to those radicals 
having four carbon atoms or less. 
The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo. 
The term "hydroxyalkyl" means the group HO--R-- wherein R is alkyl as 
defined above. 
The term "alkoxyalkyl" means the group R--O--R-- wherein each R is 
independently alkyl as defined above. 
The term "(dialkylamino)alkyl" means the group R.sub.2 N--R-- wherein each 
R is independently alkyl as defined above. 
The term "N-oxide" refers to the stable radical 
EQU &gt;N--O 
at the carbostyril nitrogen. 
The term "optional" or "optionally" means that the subsequently described 
event or circumstance may or may not occur, and that the description 
includes instances where the event or circumstance occurs and instances in 
which it does not. For example, "optionally substituted phenyl" means that 
the phenyl may or may not be substituted and that the description includes 
both unsubstituted phenyl and substituted phenyl; "optionally followed by 
converting the free base to the acid addition salt" means that the 
conversion may or may not be carried out in order for the process 
described to fall within the invention, and the invention includes those 
processes in which the free base is converted to the acid addition salt 
and those processes in which it is not. 
The terms "inert organic solvent" or "inert solvent" means a solvent inert 
under the conditions of the reaction being described in conjunction 
therewith [including, for example, benzene, toluene, acetonitrile, 
tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene 
chloride (or dichloromethane), diethyl ether, pyridine and the like]. 
Unless specified to the contrary, the solvents used in the reactions of 
the present invention are inert organic solvents. 
The term "arrhythmia" means any variation from the normal rhythm of the 
heartbeat, including supraventricular premature beat, heart block (first 
and second degree and complete), atrial fibrillation, atrial flutter, 
atrial tachyarrhythmia of other etiology, atrioventricular nodal or 
atrioventricular junctional arrhythmias, ventricular premature beats 
(unifocal and multifocal), torsades de pointes, ventricular 
tachyarrhythmia, and ventricular fibrillation. 
The term "mammal" includes both humans and non-human mammals (e.g. domestic 
and farm animals, such as cats, dogs, sheep, cattle, horses, and the 
like), especially, humans. 
The term "treatment" or "treating" means any treatment of a disease in a 
mammal, and includes: 
(i) preventing the disease, i.e., causing the clinical symptoms of the 
disease not to develop; 
(ii) inhibiting the disease, i.e., arresting the development of clinical 
symptoms; and/or 
(iii) relieving the disease, i.e., causing the regression of clinical 
symptoms. 
The term "therapeutically effective amount" is that amount which, when 
administered, is sufficient to effect treatment, as defined above. 
"Pharmaceutically acceptable acid addition salts" means those salts that 
retain the biological effectiveness and properties of the parent compounds 
and are not biologically or otherwise undesirable. Pharmaceutically 
acceptable acid addition salts may be formed with inorganic acids, such as 
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, 
phosphoric acid, and the like, and with organic acids such as acetic acid, 
propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, 
malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, 
citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic 
acid, ethanesulfonic acid, para-toluenesulfonic acid, salicylic acid, and 
the like. The salts may be single or multiple salts of one or more anions, 
e.g., from the above-described acids. 
Compounds that have identical molecular formulae but differ in the nature 
or sequence of bonding of their atoms or in the arrangement of their atoms 
in space are termed "isomers". Isomers are termed "stereoisomers" when 
they differ only in the arrangement of their atoms in space, and 
"constitutional isomers" when they differ in the nature and sequence of 
bonding of their atoms. Because constitutional isomers are considered in 
normal chemical usage to be different compounds (such as, for example, 
dimethyl ether and ethanol, which are constitutional isomers of molecular 
formula C.sub.2 H.sub.6 O), the term "isomer" is frequently used instead 
of "stereoisomer". Stereoisomers may be "achiral" (when a molecule is 
superimposable on its mirror image) or "chiral" (when it is not); and 
chiral stereoisomers are sometimes referred to as "optical isomers". 
Stereoisomers that are mirror images of one another are termed 
"enantiomers"; stereoisomers that are not mirror images are termed 
"diastereomers". A compound of Formula I in which R.sup.4 is not hydrogen 
is chiral, having the carbon atom to which R.sup.4 is attached as its 
center of chirality (that atom being sometimes referred to as an 
"asymmetric" carbon atom). When a compound has only one chiral center, a 
pair of enantiomers of opposite chirality is possible; and these 
enantiomers may be characterized and described in various ways, such as by 
the absolute configuration of the chiral center (using the R- and S- 
sequencing rules of Cahn and Prelog, and describing the compounds as (R)- 
and (S)-isomers), or by the rotation of polarized light by the molecule 
(and describing the compounds as (+)- and (-)-isomers). Such a compound 
may exist as individual enantiomers or as a mixture, especially a racemic 
mixture (i.e. a mixture containing equal proportions of the enantiomers, 
described as an (RS)- or (.+-.)-mixture), thereof. Conventions for 
stereochemical nomenclature, and methods for the determination of 
stereochemistry and the separation of stereoisomers, are well-known in the 
art (as exemplified by the discussion in, for example, Chapter 4 of 
"Advanced Organic Chemistry", 3rd edition, March, Jerry, John Wiley and 
Sons, New York, 1985). Unless indicated otherwise, the description or 
naming of a particular compound of Formula I in the specification and 
claims is intended to include both enantiomers and mixtures, racemic or 
otherwise, thereof. 
The compounds of Formula I are named and numbered as illustrated below. For 
example, the compound where m=n=1, R.sup.1, R.sup.2, R.sup.3 and R.sup.5 
are H, R.sup.4 is OH, and R.sup.6 is 2-methylpropyl (or isobutyl), i.e., 
the compound of Formula II, 
##STR14## 
is named 
3,4-dihydro-5-[2-hydroxy-3-(4-((2-methylpropoxy)carbonylamino)-1-piperidyl 
)propoxy]carbostyril. 
The compound where m=n=1, R.sup.1, R.sup.3 and R.sup.5 are H, R.sup.2 is 
Cl, R.sup.4 is OH, and R.sup.6 is cyclopropylmethyl is named 
8-chloro-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino) 
-1-piperidyl)propoxy]carbostyril. 
The compound where m=n=1, R.sup.1, R.sup.3 and R.sup.4 are H, R.sup.2 is 
methoxy, R.sup.5 is methyl, and R.sup.6 is 2-methoxyethyl is named 
3,4-dihydro-8-methoxy-5-[3-(4-((2-methoxyethoxy) 
carbonyl-N-methylamino)-1-piperidyl)propoxy]carbostyril. 
The N-oxide of the compound where m=n=1, R.sup.1, R.sup.2, R.sup.3 and 
R.sup.5 are H, R.sup.4 is OH, and R.sup.6 is 2-(dimethylamino)ethyl is 
named 
3,4-dihydro-5-[2-hydroxy-3-(4-((2-dimethylaminoethoxy)carbonylamino)-1-pip 
eridyl)propoxy]carbostyril N-oxide. 
The compound where m=1, n=0, R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are H, 
R.sup.2 is methoxy, and R.sup.6 is cyclopropylmethyl is named 
3,4-dihydro-8-methoxy-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperi 
dyl)ethoxy]carbostyril. 
The compound where m=n=2, R.sup.1 and R.sup.4 are H, R.sup.2 and R.sup.3 
(at the 6-position) are methoxy, R.sup.5 is methyl, and R.sup.6 is 
2-methoxyethyl is named 
3,4-dihydro-6,8-dimethoxy-5-[5-(4-((2-methoxyethoxy)carbonyl-N-methylamino 
)-1-piperidyl)pentoxy]carbostyril. 
COMPOUNDS OF THE INVENTION 
The compounds of this invention comprise carbostyril derivatives of Formula 
I: 
##STR15## 
wherein: m is 0, 1, or 2; 
n is 0, 1, or 2; 
R.sup.1 is hydrogen or lower alkyl; 
R.sup.2 is hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, aralkoxy, 
or acyloxy; 
R.sup.3 is hydrogen, halogen, lower alkyl, or lower alkoxy; 
R.sup.4 is hydrogen, hydroxy, lower alkyl, or acyloxy, provided that when 
R.sup.4 is hydroxy or acyloxy, m and n are both 1; 
R.sup.5 is hydrogen or lower alkyl; and 
R.sup.6 is alkyl, hydroxyalkyl, alkoxyalkyl, or (dialkylamino)alkyl; 
and the pharmaceutically acceptable acid addition salts and N-oxides 
thereof. 
The compounds of Formula I where m is 1 are preferred, particularly those 
where n is 1 and R.sup.4 is hydroxy, or where n is 0 and R.sup.4 is 
hydrogen. For both preferred subgenuses it is preferred that R.sup.3 and 
R.sup.5 are hydrogen, and further preferred that R.sup.1 is hydrogen. 
Finally, further preferred are the compounds where R.sup.2 is hydrogen, 
lower alkyl or lower alkoxy, and most preferred are those compounds where 
R.sup.6 is lower alkyl. Also preferred are the pharmaceutically acceptable 
acid addition salts of the foregoing compounds, particularly the 
hydrochloride salts. 
For the subgenus of compounds where m and n are 1, and R.sup.4 is hydroxy, 
it is preferred that R.sup.1, R.sup.3 and R.sup.5 are hydrogen, further 
preferred that R.sup.2 is hydrogen, and most preferred that R.sup.6 is 
lower alkyl (particularly ethyl, butyl, 2-methylpropyl and 
cyclopropylmethyl, especially 2-methylpropyl). 
For the subgenus of compounds where m is 1, n is 0, and R.sup.4 is 
hydrogen, it is preferred that R.sup.1, R.sup.3 and R.sup.5 are hydrogen, 
further preferred that R.sup.2 is lower alkyl or lower alkoxy (especially 
methoxy), and most preferred that R.sup.6 is lower alkyl (particularly 
ethyl, butyl, 2-methylpropyl and cyclopropylmethyl, especially 
cyclopropylmethyl). 
The compounds of Formula I that are presently most preferred are: 
3,4-dihydro-5-[2-hydroxy-3-(4((2-methylpropoxy)carbonylamino)-1-piperidyl)p 
ropoxy]carbostyril hydrochloride, and 
8-methoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperid 
yl)ethoxy]carbostyril hydrochloride. 
UTILITY 
The compounds of this invention are useful for the treatment of 
cardiovascular diseases in mammals, particularly humans, including a wide 
variety of arrhythmias, including supraventricular premature beat, heart 
block (first and second degree and complete), atrial fibrillation, atrial 
flutter, atrial tachyarrhythmia of other etiology, atrioventricular nodal 
or atrioventricular junctional arrhythmias, ventricular premature beats 
(unifocal and multifocal), torsades de pointes, ventricular 
tachyarrhythmia, ventricular fibrillation, and to prevent sudden death, 
particularly after myocardial infarction or in congestive heart failure. 
In particular, the compounds of the present invention are useful for the 
treatment of supraventricular arrhythmia, ventricular tachycardia, and 
junctional re-entry arrhythmia. 
The utility of a compound for treating arrhythmia can be assessed in vitro 
by measuring the ability of the compound to prolong the effective 
refractory period in guinea-pig papillary muscle as described by Bruckner, 
Schmitz & Scholz (Naunyn-Schmiedeberg's Arch. Pharmacol. (1985) 329, 
86-93) using the preparation described by Dumez, Patmore, Ferrandon, 
Allely & Armstrong (J. Cardiovascular Pharmacol., 1989, 14, 184-193). The 
in vivo antiarrhythmic activity of a compound may be determined by 
measuring its ability to prolong the ventricular refractory period and the 
QTc-interval of the ECG in an anesthetized guinea-pig (see, e.g., Poizot, 
J. Pharmacol. (Paris) 17 (1986) 712-719). 
The compounds of this invention demonstrate anti-arrhythmic activity in the 
above-mentioned tests, the details of which are set out below in Examples 
8 and 9. 
FORMULATION AND ADMINISTRATION 
A second aspect of this invention comprises pharmaceutical compositions 
useful in the treatment of arrhythmia in mammals. Such compositions 
contain a therapeutically effective amount of a compound of Formula I or a 
pharmaceutically acceptable acid addition salt or N-oxide thereof, in 
admixture with pharmaceutically acceptable excipient(s). 
The level of the drug in the formulation can vary from about 0.1 percent 
weight (% w) to about 95% w of the drug based on the total formulation and 
about 99.9% w to 5% w excipient. Preferably the drug is present at a level 
of about 0.1% w to about 80% w. 
Useful pharmaceutical excipients for the preparation of the pharmaceutical 
compositions hereof can be solids or liquids. Thus, the compositions can 
take the form of tablets, capsules, powders, sustained release 
formulations, solutions, suspensions, aerosols, and the like. 
Liquid excipients can be selected from the various oils, including those of 
petroleum, animal, vegetable or synthetic origin, for example, peanut oil, 
soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous 
dextrose, and glycols are preferred liquid carriers, particularly for 
injectable solutions. 
Suitable solid excipients include starch, cellulose, microcrystalline 
cellulose, talc, glucose, lactose, sucrose, gelatin, povidone, 
crosscarmellose sodium, magnesium stearate, sodium stearate, glycerol 
monostearate, sodium chloride, and the like. 
Other suitable pharmaceutical excipients and their formulations are 
described in "Remington's Pharmaceutical Sciences" 16th Edit. 1980, by E. 
W. Martin. 
A third aspect of this invention comprises methods for treating arrhythmia 
in mammals (particularly humans) which comprise administering a 
therapeutically effective amount of a compound of Formula I or a 
pharmaceutically acceptable acid addition salt or N-oxide thereof, or a 
composition containing it, to the mammalian subject. 
In the practice of this method, a therapeutically effective amount of the 
compound of Formula I or a pharmaceutical composition containing it is 
administered in any of the usual and acceptable methods known in the art, 
either singly or in combination with another compound or compounds of the 
present invention or other pharmaceutical agents. These compounds or 
compositions can thus be administered orally, systemically (e.g., 
transdermally, intranasally or by suppository) or parenterally (e.g. 
intramuscularly, subcutaneously and intravenously), and can be 
administered either in the form of solid or liquid dosages including 
tablets, solutions, suspensions, aerosols, and the like, as discussed in 
more detail above. It is preferred to administer compounds of Formula I 
orally and parenterally. 
The formulation can be administered in a single unit dosage form for 
continuous treatment or in a single unit dosage form ad libitum when 
relief of symptoms is specifically required. 
In view of the foregoing as well as in consideration of the degree of 
severity of the condition being treated, age of subject and so forth, all 
of which factors are determinable by routine experimentation by one 
skilled in the art, the effective dosage in accordance herewith can vary 
over a wide range. Generally a therapeutically effective amount ranges 
from about 0.01 to about 25 mg/kg body weight per day and preferably about 
0.05 to about 20 mg/kg body weight per day. In alternative terms, for an 
average 70 kg adult human subject, a therapeutically effective amount in 
accordance herewith would be, in preferred embodiments from about 0.7 mg 
to about 1750 mg per day per subject, and preferably from about 3.5 mg to 
1400 mg per day per subject. 
PREATION OF COMPOUNDS OF THE INVENTION 
The compounds of Formula I are prepared as shown below in Reaction Schemes 
I-V, where Reaction Scheme I shows the preparation of 4-piperidylcarbamate 
intermediates of Formula 4 and Reaction Scheme II shows the preparation of 
the compounds of Formula I from those intermediates. Reaction Schemes III, 
IV and V show the preparation of 3,4-dihydrocarbostyril intermediates of 
Formula 5. 
In the Reaction Schemes, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and 
R.sup.6, are as described in the broadest scope of the invention, except 
as noted. For those compounds in which R.sup.6 is lower alkyl, it is 
convenient to prepare intermediates of Formula 2 directly, following 
Alternate A of Step 1 of Reaction Scheme I. Intermediates of Formula 2 may 
also be prepared indirectly, following Alternate B of Step 1 of Reaction 
Scheme I and passing through intermediates of Formula 3, as described in 
Preparations 2 and 3 below. 
##STR16## 
STARTING MATERIALS 
The starting materials used in preparation of the compounds of the present 
invention, including the dihydrocarbostyrils, alkyl chloroformates, 
carbonyldiimidazole, 4-amino-1-phenylmethylpiperidine, epoxides (glycidyl 
halides and glycidyl sulfonates), dihalo compounds, and the other 
reagents, solvents, catalysts and equipment described are typically 
commercially available or can be prepared by methods known to those 
skilled in the art. 
5-Hydroxy-3,4-dihydrocarbostyrils of Formula 5 may be made as described 
with reference to Reaction Schemes III to V, or according to methods 
described in the literature: e.g., 5-hydroxy-3,4-dihydrocarbostyril may be 
easily prepared according to the method described in J. Org. Chem. 1981, 
46, 3719; 5,8-dihydroxy-3,4-dihydrocarbostyril may advantageously be 
obtained from methods described by Uchida, et al., in Yakugaku Zasshi, 96, 
571, 1976; and 5-hydroxy-8-phenyl-methoxy-3,4-dihydrocarbostyril may be 
prepared according to the method described by Tominaga, et al., in Chem. 
Pharm. Bull, 29(8) 2161-65, 1981; and 5-hydroxy-8-bromo and 
5-hydroxy-6,8-dichloro-3,4-dihydrocarbostyrils may be synthesized as per 
methods described in U.S. Pat. No. 4,482,560. 
Alkyl chloroformates (e.g., methyl chloroformate, ethyl chloroformate, 
propyl chloroformate, butyl chloroformate, isobutylchloroformate) are 
readily available from inter alia Aldrich Chemical Co. (Wisconsin). 
Carbonyldiimidazole is commercially available from e.g., Aldrich Chemical 
Co. (Wisconsin). 
4-Amino-1-phenylmethylpiperidine is readily available from e.g., Aldrich 
Chemical Co. (Wisconsin). 
Epihalohydrins (e.g., epibromohydrin, epichlorohydrin) and glycidyl 
sulfonates (e.g. (2R) or (2S)-glycidyl tosylate) are commercially 
available from inter alia Aldrich Chemical Co. (Wisconsin). 
.omega.-Dihaloalkanes (e.g., 1,2-dibromoethane, 1,2-dichloroethane, 
1,3-dibromo-2-propanol, 1,3-dichloro-2-propanol) are commercially 
available from e.g., Adrich Chemical Co. (Wisconsin). 
PREATION OF FORMULA 2 
As shown in Reaction Scheme 1, Alternate A, Step 1, a 4-(optionally 
substituted)amino-1-phenylmethylpiperidine (Formula 1) and a chloroformate 
(Formula a) are reacted in a suitable inert solvent to give the 
corresponding substituted carbamic acid ester of Formula 2. The reaction 
conditions can be generalized as follows: addition temperature: from 
-10.degree. to +40.degree. C., preferably -5.degree. to +10.degree. C.; 
reaction time: from 4 to 48 hours, preferably 8 to 24 hours; reaction 
temperature: from 10.degree. to 100.degree. C., preferably 20.degree. to 
40.degree. C. 
Similar reactions (the action of a chloroformate on a primary or secondary 
amine) are well known to persons of ordinary skill in the art, for example 
as described in Patent Fr. Demande 2,321,890 from SYNTHELABO S.A. 
ALTERNATIVE PREATION OF FORMULA 2 
Preparation of Formula 3 
As shown in Reaction Scheme I, Alternate B, Step 1a, a 4-(optionally 
substituted)amino-1-phenylmethylpiperidine (Formula 1) and 
carbonyldiimidazole (CDI) are mixed in a polar aprotic solvent, e.g. 
tetrahydrofuran (THF), dioxane, dimethylformamide or the like, and heated 
between 20.degree. and 100.degree. C. for approximately 4 to 24 hours. 
When the reaction is substantially complete, a precipitate forms giving 
the corresponding 4-imidazolylcarbonylamino-1-phenylmethylpiperidine 
compound of Formula 3, which is isolated by conventional means. 
The condensation between an amine and the carbonyl diimidazole to produce 
compounds such as Formula 3 is described in H. A. Staab and W. Benz, Ann. 
der Chem. 648, 72 (1961). 
Conversion to Formula 2 
As shown in Reaction Scheme I, Alternate B, Step 1b, the imidazolyl 
derivative of Formula 3 is contacted with an alcohol of Formula b. When 
R.sup.6 of Formula b represents C.sub.1 to C.sub.4 lower alkyl or lower 
alkoxyalky, the alcohol can be used in large excess and also serve as the 
solvent. In the other cases, a polar aprotic solvent (e.g., THF, dioxane), 
can be used. The recommended temperature range is 10.degree. to 60.degree. 
C. and the reaction is usually complete after 6 to 24 hours. The 
corresponding substituted carbamic acid ester of Formula 2 is isolated by 
conventional means. 
PREATION OF FORMULA 4 
As shown in Reaction Scheme I, Step 2, the protecting group 
(N-phenylmethyl) of Formula 2 is removed by hydrogenolysis. A compound of 
Formula 2 is dissolved in an inert solvent (such as methanol, ethanol, 
propanol, ethylacetate, tetrahydrofuran or acetic acid), and a catalyst (5 
to 40% by weight of 5 to 10% palladium or palladium hydroxide on carbon) 
is added. The hydrogenolysis takes place at 10.degree. to 50.degree. C. 
under 1 to 3 atmospheres of hydrogen. The reaction is ordinarily complete 
after 4 to 24 hours. The catalyst is removed by filtration and the desired 
4-piperidylcarbamate of Formula 4 is recovered by conventional means, 
typically giving a yield of about 60 to 100%. 
Classical methods for hydrogenolysis are described in "Catalytic 
Hydrogenation in Organic Synthesis: Procedures and Commentary" by Morris 
Freifelder; John Wiley and Sons, 1978, p. 112, and, "Protective Groups in 
Organic Synthesis" by Theodora W. Greene; John Wiley and Sons, 1981, p. 
272. 
PREATION OF FORMULA 6 
As shown in Reaction Scheme II, Alternate A, Step 1, a 
5-hydroxy-3,4-dihydro-carbostyril of Formula 5 (obtained as discussed 
above in the starting materials section, or as described below in 
conjunction with Reaction Schemes III to V) and an epihalohydrin of 
Formula c are contacted in the presence of a suitable basic compound, 
preferably an alkali hydroxide (such as sodium hydroxide), in an 
appropriate inert solvent (e.g., lower alkanol or water). The reactants 
are used in an equimolar ratio or the epihalohydrin can be up to 10 times 
the molar quantity of the compound of Formula 5. Reaction temperature 
ranges from 20.degree. to 100.degree. C., preferably at the reflux 
temperature of the solvent and reaction is generally complete after 4 to 
24 hours. The reaction product, a 
5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril compound of Formula 6, is 
purified by conventional means, e.g., extractions by an organic solvent, 
fractional recrystallizations, column chromatography methods, or the like. 
The preparation of Formula 6 may be conducted according to the procedure 
described in U.S. Pat. No. 4,482,560. 
PREATION OF FORMULA 7 
As shown in Reaction Scheme II, Alternate B, Step 1, a 
5-hydroxy-3,4-dihydro-carbostyril of Formula 5 (obtained as discussed 
above, or as described in conjunction with Reaction Schemes III, IV and V 
below) and 1 to 2 molar equivalents of an .omega.-dihaloalkane of Formula 
d are contacted together in the presence of a dehalogenating agent, 
preferably an alkali hydroxide (such as sodium hydroxide), in an inert 
solvent at room temperature to 100.degree. C. for 4 to 12 hours. A small 
quantity of a metal iodide can optionally be added to increase the yield. 
Isolation and purification of the resulting 
5-(haloalkoxy)-3,4-dihydrocarbostyril compound of Formula 7, if required, 
are achieved by common methods, like extraction, crystallization or column 
chromatography. 
The compounds of Formula 7 can be obtained using known procedures, e.g., as 
described in JP 5,1133.274 and in U.S. Pat. No. 4,482,560. 
PREATION OF FORMULA I WHEREIN R.sup.4 IS OH 
As shown in Reaction Scheme II, Alternate A, Step 2, a 
5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril of Formula 6 is contacted with 
a secondary amine of Formula 4 in an inert solvent that will dissolve both 
reactants, for example, a lower alkanol polar solvent (such as methanol or 
butanol, preferably ethanol or isopropanol). The reaction is generally 
complete after heating the medium in the range of 40.degree. to 
100.degree. C. (preferably at the reflux temperature of the selected 
solvent) while stirring for about 6 to 24 hours, preferably for 12 to 16 
hours. The desired corresponding compound of Formula I (where R.sup.4 is 
hydroxy) is recovered as a free base using conventional means or as an 
acid addition salt. The compound of Formula I is preferably recovered as a 
hydrochloride salt by addition of an excess of hydrochloric acid to the 
cooled reaction medium. 
The reaction of a 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and a 
secondary amine which is analogous to that shown in Formula 4 is described 
particularly in U.S. Pat. No. 4,482,560 and by K. Nakagawa et al., J. Med. 
Chem. 1974, vol. 17, No. 5, p. 529-533. 
PREATION OF FORMULA I WHEREIN R.sup.4 IS H OR LOWER ALKYL 
As shown in Reaction Scheme II, Alternate B, Step 2, a 
5-(haloalkoxy)-3,4-dihydrocarbostyril compound of Formula 7 is contacted 
with a secondary amine of Formula 4 on an equimolar basis; the medium is 
kept basic by addition of one molar equivalent of an agent able to capture 
hydrochloric acid (or "hydrogen halide receptor", e.g., triethylamine, 
potassium or sodium carbonate, and the like). The reaction takes place in 
a variety of polar or nonpolar solvents (e.g. tetrahydrofuran, dioxane, 
toluene, methanol, ethanol, isopropanol). The reaction medium is heated 
while stirring at 15.degree.-130.degree. C. (preferably at the reflux 
temperature of the selected solvent) for 6 to 72 hours (preferably 24 to 
48 hours). The desired corresponding compound of Formula I (where R.sup.4 
is hydrogen or lower alkyl) is recovered as a free base using conventional 
means, and can then be converted into an addition salt by methods known to 
those of ordinary skill in the art. 
The 5-(haloalkoxy)-3,4-dihydrocarbostyrils and secondary amines can be 
condensed using conventional methods. Such methods are described in: GER. 
OFFEN. 3.034.237 and U.S. Pat. No. 4,482,560. 
ALTERNATE PREATION OF FORMULA 5 Where R.sup.2 and/or R.sup.3 are Methyl 
The compounds of Formula 5 where R.sup.2 and/or R.sup.3 are methyl can be 
advantageously prepared as described below with reference to Reaction 
Schemes III and IV. 
Adding Methyl at R.sup.2 
As illustrated in Reaction Scheme III, Step 1, a 
5-hydroxy-3,4-dihydrocarbostyril of Formula 5, where R.sup.1 is hydrogen 
or lower alkyl, R.sup.2 is hydrogen, and R.sup.3 is hydrogen, halo, lower 
alkyl or lower alkoxy at the 6-position (obtained as described above in 
the Starting Materials section, or described below with reference to 
Reaction Scheme IV) is contacted with a large excess of formaldehyde and 
one to two molar equivalents of a dialkyl amine (Formula 8 where R is 
lower alkyl) in an aqueous solvent, preferably water. After stirring at 
room temperature for about 2 to 10 hours, preferably 5 hours, a 
precipitate forms and is isolated by conventional means, e.g., filtration 
and washing with cold water) to give the 5-hydroxy-6-(optionally lower 
alkyl)-8-(dialkylaminomethyl)-3,4-dihydrocarbostyril of Formula 9, which 
can serve as a Mannich base in subsequent reactions. 
As illustrated in Reaction Scheme III, Step 2, a Mannich base of Formula 9 
is dissolved in an inert solvent (such as a polar solvent, e.g., a lower 
alcohol, preferably ethanol) and hydrogenated at elevated temperature 
(such as about 50.degree. to 75.degree. C., preferably 60.degree. C.) over 
a palladium hydroxide on carbon catalyst for 12 to 24 hours, preferably 
about 16 hours. The catalyst is removed (e.g., by filtration) and the 
compound of Formula 5(a) is isolated by conventional means (e.g., 
evaporation of the solvent and recrystallization from ethanol). 
Adding Methyl at R.sup.3 
As illustrated in Reaction Scheme IV, Step 1, a 
5-hydroxy-3,4-dihydrocarbostyril of Formula 5, where R.sup.1 is hydrogen 
or lower alkyl, R.sup.2 is hydrogen, halo, lower alkyl or lower alkoxy, 
and R.sup.3 is hydrogen (obtained as described above in the Starting 
Materials section or with reference to Reaction Scheme III) is contacted 
with two to three molar equivalents of formaldehyde and one molar 
equivalents of a primary amine (Formula 10 where W is alkyl, aryl or 
cycloalkyl) in an aqueous solvent, preferably water. After stirring at 
room temperature for about 8 to 16 hours, preferably about 12 hours, a 
precipitate forms and is isolated by conventional means (e.g., filtration 
and recrystallization from methanol) to give the oxazine of Formula 11. 
As illustrated in Reaction Scheme IV, Step 2, an oxazine of Formula 11 is 
dissolved in an inert solvent (such as a polar solvent, e.g., a lower 
alcohol, preferably methanol) and hydrogenated at room temperature or 
optionally at elevated temperature (such as about 50.degree. to 75.degree. 
C., preferably at room temperature) over a palladium hydroxide on carbon 
catalyst for 12 to 24 hours, preferably about 16 hours. The catalyst is 
removed (e.g., by filtration) and the compound of Formula 5(b) is isolated 
by conventional means (e.g., evaporation of the solvent and 
recrystallization from ethanol). 
Conversion to Formula I 
The compounds of Formulae 5a and 5b can be employed as the compound of 
Formula 5 in the reactions described with reference to Reaction Scheme II, 
and thereby be converted to compounds of Formula I wherein R.sup.2 and/or 
R.sup.3 are methyl. 
SECOND ALTERNATE PREATION OF FORMULA 5 
The compounds of Formula 5 where R.sup.1 and R.sup.3 are hydrogen, and 
R.sup.2 is lower alkoxy (particularly methoxy), can be advantageously 
prepared as described below with reference to Reaction Scheme V. 
Preparation of Formula 12 
Compounds of Formula 12, where R is phenylmethyl or acetyl are obtained as 
follows. 
Where R is phenylmethyl 
4-Phenylmethoxy-phenol in acetic acid is nitrated by contact with a slight 
molar excess of nitric acid at room temperature, giving 
2-nitro-4-phenylmethoxy-phenol. 
2-Nitro-4-phenylmethoxy-phenol is methylated by contacting it with a slight 
molar excess of potassium carbonate and a large molar excess of methyl 
iodide and tetrabutylammonium bromide (TBAB) in an inert solvent (such as 
acetone) and refluxed for 8 to 15 hours, preferably 12 hours. After 
cooling, filtration and evaporation of the solvent, the residue is 
purified by conventional means to give 2-nitro-4-phenylmethoxyanisole, 
which in turn is hydrogenated to give the corresponding aniline of Formula 
12. 
Where R is acetyl 
4-methoxy-phenol is acetylated by reflux in a mixture of acetic anhydride 
and acetic acid for a period of about 10 to 15 hours, preferably about 12 
hours. The acetylated derivative is nitrated by contact with a slight 
molar excess of nitric acid at room temperature, with stirring for about 1 
to 4 hours, preferably about 2 hours giving 2-nitro-4-acetyloxy-anisole. 
The 2-nitro-4-acetyloxy-anisole is hydrogenated to give the corresponding 
aniline of Formula 12. 
Preparation of Formula 13 
To a cooled solution of an aniline of Formula 12 and a slight molar excess 
of 3,3-dimethoxy-propanoic acid (prepared, e.g., by refluxing methyl 
3,3-dimethoxy-propanoate and 2N NaOH in water, followed by acidification 
with hydrochloric acid and isolation by conventional means) in an inert 
solvent (e.g., methylene chloride), is added 1,3-dicyclohexylcarbodiimide 
(DCC), followed by stirring at a temperature of about 20.degree. C. to 
reflux for about 1 to 15 hours, preferably at room temperature for about 4 
to 6 hours. The dimethoxy derivative of Formula 13 is isolated by 
evaporation of the solvent and working up in an alkyl ether, preferably 
diisopropyl ether. 
Preparation of Formula 14 
A dimethoxy derivative of Formula 13 is cyclized upon addition to a cooled 
solution of a strong organic or inorganic acid, such as methanesulfonic 
acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like, 
preferably concentrated hydrochloric acid (about 37%) and stirring at a 
temperature of about 20.degree. to 80.degree. C., preferably at room 
temperature for about 30 minutes to about 3 hours, preferably about 1.5 
hour. The crude 5-hydroxy-carbostyril of Formula 14 is isolated by 
filtration of the cooled reaction medium, and purified by trituration in 
cold water. 
Preparation of Formula 5c 
A carbostyril of Formula 14 is hydrogenated, e.g., in a mixture of 
methanol/acetic acid, or preferably in N-methylpyrrolidinone, with a 
palladium hydroxide catalyst at elevated temperature (e.g., 40.degree. to 
80.degree. C.) and under a source of hydrogen for 24 to 48 hours, 
preferably about 36 hours. The catalyst is removed to give the 
3,4-dihydrocarbostyril compound of Formula 5c. 
Similarly, by starting with a 4-(lower alkoxy)phenol the corresponding 
2-(lower alkoxy)aniline compounds can be prepared and converted to the 
corresponding 8-(lower alkoxy)-5-hydroxy-3,4-dihydrocarbostyrils. 
PREATION OF PRODUCTS OF FORMULA I WHEREIN R.sup.2 IS OH 
Formulae 6 and 7 Wherein R.sup.2 is Phenylmethoxy 
A compound of Formula 5 (wherein R.sup.2 is hydroxy) is contacted with a 
phenylmethyl halide in the presence of a base to give the corresponding 
compound of Formula 5 wherein R.sup.2 is phenylmethoxy. The resulting 
5-hydroxy-8-phenylmethoxy-3,4-dihydrocarbostyril is contacted either with 
an epihalohydrin or with an .omega.-dihaloalkane in the presence of a base 
as described above with reference to Reaction Scheme II, Alternatives A 
and B, Steps 1, or e.g., following the method described in U.S. Pat. No. 
4,210,753. 
Formula I Wherein R.sup.2 is Phenylmethoxy 
A compound of Formula 6 or 7 wherein R.sup.2 is phenylmethoxy is condensed 
with a secondary amine of Formula 4 using the methodology described with 
respect to Reaction Scheme II, Alternatives A and B, Steps 2, 
respectively, or e.g., following the method described in Chem. Pharm. 
Bull, 29(8), 2161-65, 1981. 
Formula I Wherein R.sup.2 is Hydroxy 
Compounds of Formula I wherein R.sup.2 is OH are prepared from compounds of 
Formula I wherein R.sup.2 is phenylmethoxy by removing the phenylmethyl 
protecting group using the methodology described with respect to Reaction 
Scheme I, Step 2, or according to Chem. Pharm. Bull, 29(8), 2161-65, 1981. 
PREATION OF COMPOUNDS OF FORMULA I WHERE R.sup.2 AND/OR R.sup.4 ARE AN 
ACYLOXY GROUP. 
Esterification of one or both of the hydroxy groups (R.sup.2 and R.sup.4) 
of compounds of Formula I can be done according to known methods, using 
selective reactions when monoacylation is desirable. See "Protecting 
Groups in Organic Synthesis," Theodora W. Greene, John Wiley and Sons, 
1981. 
Esterification is generally accomplished by heating the compound of Formula 
I (R.sup.2 and/or R.sup.4 are OH) with an equivalent or an excess of the 
appropriate carboxylic acid anhydride, chloride or bromide in a suitable 
solvent in the presence of a tertiary amine. Temperature is kept at 
10.degree.-90.degree. C. for 4-24 hours, preferably at 
15.degree.-30.degree. C. for 6-8 hours. The desired ester is then 
recovered by conventional extraction and purification methods. Examples 
can be found in U.S. Pat. No. 4,374,835 and the appropriate sections of 
Morrison and Boyd, supra and Fieser and Fieser, Reagents for Organic 
Synthesis, John Wiley and Sons, Inc., New York, published in 1967. 
Suitable esters which are prepared include acetates, propionates, 
butanoates, hexanoates, octanoates, dodecanoates and the like. 
PREATION OF COMPOUNDS OF FORMULA I AS PURE ENANTIOMERS 
From a Racemic Mixture of Formula I 
Products of Formula I wherein R.sup.4 is not a hydrogen atom exist in two 
different enantiomeric forms which can be resolved using conventional 
methods. 
One such method consists of contacting a racemic compound of Formula I with 
a suitable optically active acid e.g. preferably L-pyroglutamic acid in a 
ratio which may vary from 0.8:1 to 1.4:1, preferably 1:1, in a lower 
alkanol solvent, at a temperature within approximately 10.degree. C. of 
the reflux temperature of the solvent, and then allowing the resulting 
insoluble optically active acid salt of Product I to crystallize from the 
solution. 
The crystalline insoluble optically active acid salt of Product I is then 
cleaved with a suitable base, preferably with sodium or potassium 
hydroxide, to produce the (R)(+) enantiomer of Product I. 
The (S)(-) enantiomer of Product I can be prepared starting from the 
remaining mother liquors of the crystallized optically active acid salt of 
Product I obtained above. 
The mother liquors are concentrated under reduced pressure and the residue 
is treated with aqueous potassium or sodium hydroxide. The aqueous phase 
is extracted with a suitable organic solvent (preferably methylene 
chloride or chloroform) which is then worked up by conventional means to 
recover the crude (S)(-) enantiomer of Product I. Purification is achieved 
by contacting the crude (S)(-) enantiomer of Product I with D-pyroglutamic 
acid following the method described above. 
From Optically Active Intermediates 
Enantiomers of compounds of Formula I wherein R.sup.4 is OH can also be 
prepared by reacting first a compound of Formula 5 with a chiral 
epihalohydrin according to general conditions described under Reaction 
Scheme II, Alternate A, then condensing the resulting chiral compound of 
Formula 6 with a piperidylcarbamate of Formula 4 following the reaction 
conditions given under Reaction Scheme II, Alternate A, Step 2. 
Chiral epihalohydrins are commercially available, e.g. (2R) and 
(2S)-epichlorohydrins may be obtained from DAISO Co. Ltd. (Japan). 
Alternatively, in Reaction Scheme II, Alternate A, epihalohydrins can be 
replaced by chiral glycidyltosylates which are readily available, e.g. 
(2R)-and (2S)-glycidyltosylates can be obtained from Aldrich Chemical Co. 
(Wisconsin). 
The reaction between a glycidyltosylate and a 5-hydroxycarbostyril (Formula 
5) is carried out in the presence of a suitable base, preferably an 
alkaline hydride or hydroxide, in an appropriate solvent (e.g. a solvent 
in which the alkaline salt of Formula 5 is soluble at low temperature). 
Reaction temperature ranges from 20.degree. to 100.degree. C., preferably 
50.degree.-80.degree. C., and reaction is generally complete within 2 to 8 
hours. The reaction product is purified by conventional means, e.g. 
extraction by an organic solvent, fractional recrystallization, column 
chromatography, or the like. 
PREATION OF PRODUCTS OF FORMULA I AS ACID ADDITION SALTS 
The compounds of Formula I in free base form may be converted to the acid 
addition salts by treatment with the appropriate organic or inorganic 
acid, such as, for example, phosphoric, pyruvic, hydrochloric or sulfuric 
acid and the like. Typically, the free base is dissolved in a polar 
organic solvent such as ethanol or methanol, and the acid added thereto. 
The temperature is maintained between about 0.degree. C. and about 
100.degree. C. The resulting acid addition salt precipitates spontaneously 
or may be brought out of solution with a less polar solvent. 
The acid addition salts of the compounds of Formula I may be decomposed to 
the corresponding free base by treatment with a suitable base, such as 
potassium carbonate or sodium hydroxide, typically in the presence of an 
aqueous solvent, and at a temperature of between about 0.degree. C. and 
100.degree. C. The free base form is isolated by conventional means, such 
as extraction with an organic solvent. 
Salts of the compounds of Formula I may be interchanged by taking advantage 
of differential solubilities and volatilities, or by treatment with a 
suitably loaded ion exchange resin. This conversion is carried out at a 
temperature between about 0.degree. C. and the boiling point of the 
solvent being used as the medium for the procedure. 
In summary, compounds of Formula I are prepared according to the following 
last steps: 
a. contacting a racemic or chiral 
5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril with a 4-piperidylcarbamate to 
give a compound according to Formula I where R.sup.4 is OH; or 
b. contacting a 5-(haloalkoxy)-3,4-dihydrocarbostyril with a 
4-piperidylcarbamate to give a compound according to Formula I where 
R.sup.4 is H or lower alkyl; or 
c. acylating a compound of Formula I wherein either R.sup.2 or R.sup.4 is 
OH, or R.sup.2 and R.sup.4 are both OH; or 
d. saponifying a compound of Formula I wherein either R.sup.2 or R.sup.4 is 
--O--CO--alkyl, or R.sup.2 and R.sup.4 are both --O--CO--alkyl; or 
e. deprotecting a compound of Formula I wherein R.sup.2 is aralkoxy; or 
f. resolving a racemic mixture of stereoisomers of Formula I into pure 
enantiomers using an appropriate optically active acid; or 
g. converting a compound of Formula I in free base form to the acid 
addition salt by treatment with the appropriate organic or inorganic acid; 
or 
h. decomposing an acid addition salt of a compound of Formula I to the 
corresponding free base by treatment with a suitable base or by treatment 
with a suitably loaded ion exchange resin; or 
i. interchanging an acid addition salt of a compound of Formula I with 
another acid addition salt by taking advantage of differential 
dissociation constants, solubilities or by treatment with a suitably 
loaded ion exchange resin.

The following preparations and examples are given to enable those skilled 
in the art to more clearly understand and practice the present invention. 
They should not be considered as a limitation on the scope of the 
invention, but merely as being illustrative and representative thereof. 
PREATIONS 
PREATION 1 
Lower Alkyl (1-Phenylmethyl-4-piperidyl)carbamates 
Intermediates of Formula 2 
(A) Ethyl (1-phenylmethyl-4-piperidyl)carbamate 
Ethyl chloroformate (30 g, 0.276 mol) was added at 0.degree. C. to 
4-amino-1-phenylmethylpiperidine (50 g, 0.262 mol) in pyridine (600 mL). 
After the addition, the mixture was kept at room temperature overnight, 
and the pyridine was then evaporated. The residue was extracted with 
methylene chloride; and the resulting solution washed with water, dried 
over sodium sulfate, and the methylene chloride evaporated to dryness. The 
residue was dissolved in diisopropyl ether. A white product precipitated, 
which was isolated by filtration to yield 42.71 g (62%) of ethyl 
(1-phenylmethyl-4-piperidyl)-carbamate, m.p. 100.degree. C. 
(B) Similarly, proceeding as in part A above, but replacing ethyl 
chloroformate by: 
methyl chloroformate, 
propyl chloroformate, 
isopropyl chloroformate, 
butyl chloroformate, and 
isobutyl chloroformate, respectively, 
the following compounds were prepared: 
methyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 88.degree. C., 
propyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 92.degree. C., 
isopropyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 95.degree. C., 
butyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 94.degree. C., and 
isobutyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 110.degree. C. 
(C) Similarly, proceeding as in part A above, but replacing 
4-amino-1-phenylmethylpiperidine with a compound of Formula 1 where 
R.sup.5 is lower alkyl, and optionally replacing ethyl chloroformate with 
a different lower alkyl chloroformate, the following intermediates of 
Formula 2 are prepared: 
methyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, 
methyl N-ethyl-(1-phenylmethyl-4-piperidyl)carbamate, 
methyl N-isobutyl-(1-phenylmethyl-4-piperidyl)carbamate, 
ethyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, 
ethyl N-ethyl-(1-phenylmethyl-4-piperidyl)carbamate, 
ethyl N-isobutyl-(1-phenylmethyl-4-piperidyl)carbamate, 
propyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, 
propyl N-ethyl-(1-phenylmethyl-4-piperidyl)carbamate, 
propyl N-isobutyl-(1-phenylmethyl-4-piperidyl)carbamate, 
isopropyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, 
isopropyl N-ethyl-(1-phenylmethyl-4-piperidyl)carbamate, 
isopropyl N-isobutyl-(1-phenylmethyl-4-piperidyl)carbamate, 
butyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, 
butyl N-ethyl-(1-phenylmethyl-4-piperidyl)carbamate, 
butyl N-isobutyl-(1-phenylmethyl-4-piperidyl)carbamate, 
isobutyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, m.p. 125.degree. 
C., 
isobutyl N-ethyl-(1-phenylmethyl-4-piperidyl)carbamate, and 
isobutyl N-isobutyl-(1-phenylmethyl-4-piperidyl)carbamate, m.p. 133.degree. 
C. 
(D) Other lower alkyl N-(R.sup.5)-(1-phenylmethyl-4-piperidyl)carbamate 
intermediates of Formula 2 may be prepared in similar fashion, starting 
with the appropriate lower alkyl chloroformate and 
4-(R.sup.5)amino-1-phenylmethylpiperidine of Formula 1. 
PREATION 2 
4-Imidazolylcarbonylamino-1-phenylmethylpiperidines 
Intermediates of Formula 3 
(A) 4-imidazolylcarbonylamino-1-phenylmethylpiperidine 
4-Amino-1-phenylmethylpiperidine (57.5 g) was dissolved in tetrahydrofuran 
(150 mL), and the solution added dropwise over a 30 minute period to a 
cold solution (0.degree. to 5.degree. C.) of carbonyldiimidazole (50 g) in 
tetrahydrofuran (500 mL). When the addition was complete, the reaction 
medium was allowed to return to room temperature (20.degree. C.) and 
stirred continuously for another 20 hours. The solid which precipitated 
was filtered and washed with ethyl acetate, giving 50 g of 
4-imidazolylcarbonylamino-1-phenylmethylpiperidine, m.p. 156.degree. C. 
The mother liquors were concentrated by evaporating two-thirds of the 
solvent, producing an additional 14 g yield of the desired compound. The 
overall yield of 4-imidazolylcarbonylamino-1-phenylmethylpiperidine was 
73%. 
(B) Similarly, proceeding as in part A above, but replacing 
4-amino-1-phenylmethylpiperidine with a compound of Formula 1 wherein 
R.sup.5 is lower alkyl, the following compounds are prepared: 
4-(N-methylimidazolycarbonylamino)-1-phenylmethylpiperidine; 
4-(N-ethylimidazolycarbonylamino)-1-phenylmethylpiperidine; 
4-(N-isopropylimidazolycarbonylamino)-1-phenylmethylpiperidine; and 
4-(N-butylimidazolycarbonylamino)-1-phenylmethylpiperidine. 
(C) Other 4-(N-lower 
alkylimidazolylcarbonylamino)-1-phenylmethylpiperidines may be prepared in 
similar fashion, starting with the appropriate 
N-(R.sup.5)-4-amino-1-phenylmethylpiperidine of Formula 1. 
PREATION 3 
Lower alkyl(1-phenylmethyl-4-piperidyl)carbamates 
Intermediates of Formula 2 
(A) Cyclopropylmethyl (1-phenylmethyl-4-piperidyl)carbamate 
A solution of 4-imidazolylcarbonylamino-1-phenylmethylpiperidine (10 g, 
0.035 mol), from Preparation 2, in dioxane (100 mL) was added to 
cyclopropanemethanol (2.42 g, 0.035 mol), then heated overnight at 
80.degree.-100.degree. C. with stirring. The reaction mixture was allowed 
to return to room temperature and the dioxane evaporated under reduced 
pressure, and the residue was flash-chromatographed using ethyl 
acetate/heptane (50:50) as eluent. 9.5 g of cyclopropylmethyl 
(1-phenylmethyl-4-piperidyl)carbamate, m.p. 70.degree.-72.degree. C., was 
recovered and used in the next step without further purification. 
(B) Similarly, proceeding as in part A above, but replacing the 
cyclopropylmethanol with other alcohols, the following 
(1-phenylmethyl-4-piperidyl)carbamates were prepared: 
methyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 88.degree. C., 
ethyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 100.degree. C., 
propyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 92.degree. C., 
isopropyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 95.degree. C., 
butyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 94.degree. C., 
isobutyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 100.degree. C., 
tert-butyl (1-phenylmethyl-4-piperidyl)carbamate, oil, 
isopentyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 125.degree. C., 
2,2-dimethylpropyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 137.degree. 
C., 
2-methoxyethyl (1-phenylmethyl-4-piperidyl)carbamate, oil, 
4-hydroxybutyl (1-phenylmethyl-4-piperidyl)carbamate, oil, and 
2-dimethylaminoethyl (1-phenylmethyl-4-piperidyl)carbamate, oil. 
(C) Similarly, proceeding as in part A above, but replacing 
4-imidazolylcarbonylamino-1-phenylmethylpiperidine with 
4-(N-methylimidazolylcarbonylamino)-1-phenylmethylpiperidine or 
4-(N-isobutylimidazolylcarbonylamino-1-phenylmethylpiperidine, 
respectively, there were prepared: 
isobutyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, m.p. 125.degree. 
C., and 
isobutyl N-isobutyl-(1-phenylmethyl-4-piperidyl)carbamate, m.p. 133.degree. 
C. 
(D) Similarly, proceeding as in part A above, but optionally replacing 
4-imidazolylcarbonylamino-1-phenylmethylpiperidine with a compound of 
Formula 3 where R.sup.5 is lower alkyl, and optionally replacing 
cyclopropanemethanol with another alcohol, the following intermediates of 
Formula 2 are prepared: 
cyclopropylmethyl N-methyl-(1-phenylmethyl-4-piperidyl)carbamate, 
cyclopropylmethyl N-butyl-(1-phenylmethyl-4-piperidyl)carbamate, 
isobutyl N-ethyl-(1-phenylmethyl-4-piperidyl)carbamate, 
ethyl N-propyl-(1-phenylmethyl-4-piperidyl)carbamate, and 
methyl N-isopropyl-(1-phenylmethyl-4-piperidyl)carbamate. 
(E) Other N-(R.sup.5)-(1-phenylmethyl-4-piperidyl)carbamate intermediates 
of Formula 2 may be prepared in similar fashion, starting with the 
appropriate alcohol and compound of Formula 3. 
PREATION 4 
4-Piperidylcarbamates 
Intermediates of Formula 4 
(A) 2-methoxyethyl 4-piperidylcarbamate 
2-Methoxyethyl (1-phenylmethyl-4-piperidyl)carbamate (9.6 g), prepared 
according to Preparation 3, was dissolved in ethyl acetate (100 mL). 
Palladium hydroxide (10% on carbon, 1 g) was added, and the mixture was 
stirred under hydrogen (1 bar) for 6 hours. The catalyst was removed by 
filtration, and the solvent evaporated to give 6.5 g of 
2-methoxyethyl-4-piperidylcarbamate as an oil, which was used without 
further purification. 
(B) Similarly, proceeding as in part A above, but replacing 2-methoxyethyl 
(1-phenylmethyl-4-piperidyl)carbamate with other intermediates of Formula 
2, the following 4-piperidylcarbamates were prepared: 
methyl 4-piperidylcarbamate, m.p. 72.degree. C., 
ethyl 4-piperidylcarbamate, m.p. 84.degree. C., 
propyl 4-piperidylcarbamate, m.p. 76.degree. C., 
isopropyl 4-piperidylcarbamate, m.p. 90.degree. C., 
butyl 4-piperidylcarbamate, m.p. 80.degree. C., 
isobutyl 4-piperidylcarbamate, m.p. 106.degree. C., 
tert-butyl 4-piperidylcarbamate, m.p. 145.degree. C., 
isopentyl 4-piperidylcarbamate, m.p. 112.degree. C.; 
2,2-dimethylpropyl 4-piperidylcarbamate, m.p. 145.degree. C., 
cyclopropylmethyl 4-piperidylcarbamate, m.p. 125.degree. C., 
cyclopentylmethyl 4-piperidylcarbamate, m.p. 120.degree. C., 
(4-hydroxybutyl) 4-piperidylcarbamate, oil, 
diethylaminoethyl 4-piperidylcarbamate, oil, 
(2-hydroxy-2-methylpropyl) 4-piperidylcarbamate, m.p. 142.degree. C., 
isobutyl N-methyl-4-piperidylcarbamate, m.p. 118.degree. C., and 
isobutyl N-isobutyl-4-piperidylcarbamate, m.p. 129.degree. C. 
(C) Other 4-piperidylcarbamates of Formula 4 may be prepared in similar 
fashion, starting with the appropriate 1-phenylmethyl intermediate of 
Formula 2. 
PREATION 5 
5-(2,3-Epoxypropoxy)-3,4-dihydrocarbostyrils 
Intermediates of Formula 6 
(A) 8-Phenylmethoxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril 
8-Phenylmethoxy-3,4-dihydro-5-hydroxycarbostyril (32.5 g) was dissolved in 
ethanol (300 mL). Potassium carbonate (25 g) and epichlorohydrin (45 g) 
were added to the solution, and the mixture heated under reflux for four 
hours. After cooling, the ethanol was evaporated and water added. The 
aqueous solution was then extracted with methylene chloride, the resulting 
solution was washed with water, dried over sodium sulfate and the 
methylene chloride was evaporated under reduced pressure. The residue was 
worked up with diisopropyl ether (10 mL), yielding 35 g of 
8-phenylmethoxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril, m.p. 
106.degree.-108.degree. C. 
(B) Similarly, proceeding as in part A above, but replacing the 
8-phenylmethoxy-3,4-dihydro-5-hydroxycarbostyril with: 
3,4-dihydro-5-hydroxycarbostyril, 
3,4-dihydro-5-hydroxy-1-methylcarbostyril, 
8-bromo-3,4-dihydro-5-hydroxycarbostyril, 
8-chloro-3,4-dihydro-5-hydroxycarbostyril, 
8-fluoro-3,4-dihydro-5-hydroxycarbostyril, 
3,4-dihydro-5-hydroxy-8-methylcarbostyril, 
3,4-dihydro-5-hydroxy-8-methoxycarbostyril, and 
3,4-dihydro-5-hydroxycarbostyril N-oxide, 
respectively, the following intermediates of Formula 6 were prepared: 
5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril, m.p. 172.degree.-173.degree. 
C., 
5-(2,3-epoxypropoxy)-3,4-dihydro-1-methylcarbostyril, m.p. 76.degree. C., 
8-bromo-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril, m.p. 
220.degree.-222.degree. C., 
8-chloro-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril, m.p. 
258.degree.-260.degree. C., 
5-(2,3-epoxypropoxy)-8-fluoro-3,4-dihydrocarbostyril, 
5-(2,3-epoxypropoxy)-3,4-dihydro-8-methylcarbostyril, m.p. 180.degree. C., 
5-(2,3-epoxypropoxy)-3,4-dihydro-8-methoxycarbostyril, m.p. 
196.degree.-198.degree. C., and 
5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril N-oxide. 
(C) Other 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyrils of Formula 6 may be 
prepared in similar fashion, starting with the appropriate 
3,4-dihydro-5-hydroxycarbostyril and either epichlorohydrin or another 
epihalohydrin. 
PREATION 6 
5-(.omega.-Haloalkoxy)-3,4-dihydrocarbostyrils 
Intermediates of Formula 7 
(A) 5-(2-chloroethoxy)-3,4-dihydrocarbostyril 
Potassium hydroxide (20 g) was added to a solution of 
3,4-dihydro-5-hydroxycarbostyril (32.5 g) in propanol (250 mL), and 
stirred at 50.degree.-60.degree. C. until complete dissolution. 
1-bromo-2-chloroethane (30 g) was then added, and the mixture heated at 
reflux temperature for 15 hours. After cooling, the reaction mixture was 
poured into aqueous sodium hydroxide (2N, 500 mL). The crude product thus 
formed was isolated by filtration, then recrystallized from diisopropyl 
ether to yield 31 g of pure 5-(2-chloroethoxy)-3,4-dihydrocarbostyril. 
(B) Similarly, proceeding as in part A above, but replacing 
3,4-dihydro-5-hydroxycarbostyril with another compound of Formula 5, the 
following compounds of Formula 7 are prepared: 
8-chloro-5-(2-chloroethoxy)-3,4-dihydrocarbostyril, 
5-(2-chloroethoxy)-3,4-dihydro-8-methylcarbostyril, and 
5-(2-chloroethoxy)-3,4-dihydro-8-methoxycarbostyril. 
(C) Similarly, proceeding as in part A above, but replacing 
1-bromo-2-chloroethane by: 
1-bromo-2-chloropropane, 
1-bromo-3-chloropropane, 
1-bromo-4-chlorobutane, 
1-bromo-5-chloropentane, 
1-bromo-3-chloro-2-methylpropane, and 
2-bromo-1-chloropropane, respectively, 
and replacing 3,4-dihydro-5-hydroxycarbostyril with an appropriate compound 
of Formula 5, there are obtained: 
5-(2-chloropropoxy)-3,4-dihydrocarbostyril, 
5-(3-chloropropoxy)-3,4-dihydrocarbostyril, 
5-(4-chlorobutoxy)-3,4-dihydrocarbostyril, 
5-(5-chloropentoxy)-3,4-dihydrocarbostyril, 
5-(3-chloro-2-methylpropoxy)-3,4-dihydrocarbostyril, and 
5-(2-chloro-1-methylethoxy)-3,4-dihydrocarbostyril. 
(D) Similarly, proceeding as in part A above, but replacing 
3,4-dihydro-5-hydroxycarbostyril with another compound of formula 5 and 
1-bromo-2-chloroethane with another bromochloroalkane, the following 
compounds of Formula 7 are prepared: 
5-(2-chloroethoxy)-3,4-dihydro-1-methylcarbostyril, 
8-phenylmethoxy-5-(2-chloroethoxy)-3,4-dihydrocarbostyril, 
8-chloro-5-(3-chloropropoxy)-3,4-dihydrocarbostyril, 
5-(2-chloro-1-methylethoxy)-3,4-dihydro-8-methylcarbostyril, and 
5-(2-chloroethoxy)-3,4-dihydrocarbostyril N-oxide. 
PREATION 7 
8-(dialkylaminomethyl)-3,4-dihydro-5-hydroxycarbostyrils 
Intermediates of Formula 9 
(A) 8-diethylaminomethyl-3,4-dihydro-5-hydroxycarbostyril 
To a stirred suspension of 3,4-dihydro-5-hydroxycarbostyril (30 g, 184 mM) 
in water (300 mL) was added diethylamine (14 g, 191 mM) followed by a 36% 
solution of formaldehyde in water (300 mL). The mixture was stirred for 5 
hours and the resulting precipitate was filtered and washed with ice-water 
(50 mL) to give 8-diethylaminomethyl-3,4-dihydro-5-hydroxycarbostyril. 
(B) Similarly, proceeding as in part A above, but replacing 
3,4-dihydro-5-hydroxycarbostyril with 
3,4-dihydro-5-hydroxy-6-methylcarbostyril, there was obtained 
8-diethylaminomethyl-3,4-dihydro-5-hydroxy-6-methylcarbostyril. 
PREATION 8 
Intermediates of Formula 5a 
(A) 3,4-dihydro-5-hydroxy-8-methylcarbostyril 
8-Diethylaminomethyl-3,4-dihydro-5-hydroxycarbostyril from Preparation 7, 
as the crude wet product without further purification was dissolved in 
ethanol (500 mL) and hydrogenated at 60.degree. C. over 10%-Pd(OH).sub.2 
/C (1 g) for 16 hours. The catalyst was removed by filtration, the solvent 
was evaporated and the crude product recrystallized from ethanol to yield 
15.2 g (47%) of 3,4-dihydro-5-hydroxy-8-methylcarbostyril as a white 
solid, m.p. 186.degree.-187.degree. C. 
(B) Similarly, proceeding as in part A above, but replacing 
8-diethylaminomethyl-3,4-dihydro-5-hydroxycarbostyril with 
8-diethylaminomethyl-3,4-dihydro-5-hydroxy-6-methylcarbostyril, there was 
obtained 3,4-dihydro-5-hydroxy-6,8-dimethylcarbostyril, m.p. 212.degree. 
C. 
PREATION 9 
(1,3)oxazino(6,5f)-3,4,7,8,9,10-hexahydrocarbostyrils 
Intermediates of Formula 10 
(A) To a solution of 3,4-dihydro-5-hydroxycarbostyril (15 g, 92 mM) in 
methanol (500 mL) was added cyclohexylamine (10.5 g, 92 mM) and a 36% 
solution of formaldehyde in water (50 mL). The mixture was stirred for at 
room temperature overnight, and the resulting precipitate was filtered and 
recrystallized from methanol to give 
(1,3)oxazino(6,5f)-3,4,7,8,9,10-hexahydrocarbostyril as a white solid, 
m.p. 214.degree.-215.degree. C. 
(B) Similarly, proceeding as in part A above, but replacing 
3,4-dihydro-5-hydroxycarbostyril with 
3,4-dihydro-5-hydroxy-8-methylcarbostyril, there was obtained 
(1,3)oxazino(6,5f)-3,4,7,8,9,10-hexahydro-8-methylcarbostyril, m.p. 
138.degree.-140.degree. C. 
PREATION 10 
Intermediates of Formula 5b 
(A) 3,4-dihydro-5-hydroxy-6-methylcarbostyril 
(1,3)Oxazino(6,5f)-3,4,7,8,9,10-hexahydrocarbostyril from Preparation 9 (10 
g, 35 mM) was dissolved in methanol (150 mL) and hydrogenated at 
60.degree. C. over 10%-Pd(OH).sub.2 /C (0.5 g) overnight. The catalyst was 
removed by filtration, the solvent was evaporated and the crude product 
recrystallized from ethanol to yield 5.2 g (84%) of 
3,4-dihydro-5-hydroxy-6-methylcarbostyril as a white solid, m.p. 
181.degree.-182.degree. C. 
(B) Similarly, proceeding as in part A above, but replacing 
(1,3)oxazino(6,5f)-3,4,7,8,9,10-hexahydrocarbostyril with 
(1,3)oxazino(6,5f)-3,4,7,8,9,10-hexahydro-8-methylcarbostyril, there was 
obtained 3,4-dihydro-5-hydroxy-6,8-dimethylcarbostyril, m.p. 212.degree. 
C. 
PREATION 11 
Intermediates of Formula 12 where R is Acetyl 
A. One mole of 4-methoxy-phenol in a mixture of 300 ml acetic anhydride and 
300 ml acetic acid was refluxed for 12 hours. After cooling, 54 ml of 
nitric acid (1.3 equivalents, fuming nitric acid, d=1.52) was added 
dropwise at room temperature. The temperature rose to about 70.degree. C. 
and nitrous vapors appeared. After completion of the addition the mixture 
was left under stirring for 2 hours to give 4-methoxy-3-nitrophenyl 
acetate as a precipitate. Isopropyl ether (300 ml) was added and the 
mixture was cooled to 0.degree. C. The precipitated material was collected 
and dried, giving 190 g (yield=90%), m.p. 116.degree. C. 
B. 4-Methoxy-3-nitrophenyl acetate (56 g) was added to 400 ml of ethyl 
acetate with 2.5 g of palladium hydroxide at 20% and stirred under 
hydrogen for 4 hours. After filtration through Celite the solvent was 
evaporated under reduced pressure and the residue triturated with a small 
amount of heptane affording 46.7 g (Yield=97.4%, m.p. 81.degree. C.) of 
5-acetoxy-2-methoxyaniline. 
PREATION 12 
Intermediates of Formula 12 where R is Phenylmethyl 
A. To 20 g (0.1 mole) of 4-phenylmethoxy-phenol in 200 ml acetic acid were 
added, dropwise at room temperature, 7.26 ml of nitric acid (d=1.4, 0.105 
mole). 2 Hours after completion of the addition the reaction medium was 
poured onto cold water and extracted twice with 250 ml of methylene 
chloride. The organic phase was washed twice with 200 ml of water and 
dried over sodium sulfate. Then the solvent was evaporated and the residue 
flash chromatographed using ethyl acetate/heptane 30/70 as eluting solvent 
to give 17.3 g (Yield=70.6%) of 2-nitro-4-phenylmethoxy-phenol. 
B. With 82 g (0.335 mole) of 2-nitro-4-phenylmethoxy-phenol, 46 g (0.035 
mole) of K.sub.2 CO.sub.3, 83 ml (1.34 moles) of methyl iodide and 2 g of 
TBAB in 400 ml of acetone were refluxed for 12 hours. The cooled solution 
was filtered and evaporated. The residue was taken up with methylene 
chloride, washed with water then dried on sodium sulfate. Evaporation of 
the solvent gave 73 g (Yield=85%) of 2-nitro-4-phenylmethoxy-anisole. 
C. 2-Nitro-4-phenylmethoxy-anisole (73 g) and 1.3 g of platinium oxide in 
600 ml of methanol were hydrogenated at room temperature. The catalyst was 
filtered on Celite and the methanol evaporated. The residue was dissolved 
in methylene chloride and washed with dilute sodium hydroxide then water. 
Evaporation of the solvent gave 49.35 g (Yield=76%) of 
2-methoxy-5-phenylmethoxy-aniline. 
PREATION 13 
50 g (0.33 mol.) of Methyl 3,3-dimethoxy-propanoate in 200 ml of 2N NaOH 
solution in water were refluxed 2 hours. After cooling the solution was 
acidified with hydrochloric acid then extracted two times with 200 ml of 
CH.sub.2 Cl.sub.2. The extracts were dried on sodium sulfate and 
evaporated to leave 35 g (Yield=78%) of 3,3-dimethoxy-propanoic acid as an 
oil. 
PREATION 14 
A. To a cooled solution (0.degree. C.) of 2-methoxy-5-acetyloxy-aniline (5 
g, 0.0276 mole), 3,3-dimethoxy-propanoic acid (5 g, 0.0373 mole) in 75 ml 
of methylene chloride was added DCC (5.7 g, 0.0276 mole) in 20 ml of 
methylene chloride. After completion of the addition, the solution was 
stirred for a further 4 hours. The reaction medium was concentrated to 25 
ml, diluted with 200 ml of isopropyl ether, cooled to 5.degree. C. and the 
resulting precipitate was isolated by filtration, giving 
N-(3,3-dimethoxypropanoyl)-2-methoxy-5-acetoxy-aniline 7.7 g (Yield=95%). 
B. To a cooled solution of hydrochloric acid (37%, 40 ml) were added 4 g of 
the dimethoxy derivative obtained in part A above. After completion of the 
addition the solution was stirred at room temperature for a further 1.5 
hours, at which time a precipitate formed and was filtered and taken up in 
15 ml of water, to give 5-hydroxy-8-methoxycarbostyril, 2.2 g 
(Yield=85.5%, m.p. 236.degree. C.). 
C. 5-Hydroxy-8-methoxycarbostyril (12.5 g) in 200 ml of 
N-methylpyrrolidinone with 500 mg of palladium hydroxide (20%) were 
hydrogenated at 50.degree. C. under 1,2 bar hydrogen. The catalyst was 
removed by filtration through Celite and the solvent evaporated to give 
12.4 g of 5-hydroxy-8-methoxy-3,4-dihydrocarbostyril (mp=190.degree. C.). 
D. By starting with the 4-phenylmethyl derivative obtained in Preparation 
12, and following steps A, B and C above, 
5-hydroxy-8-methoxy-3,4-dihydrocarbostyril is likewise obtained. 
EXAMPLES 
EXAMPLE 1 
3,4-Dihydro-5-[2-hydroxy-3-(4-R.sup.6 
O-carbonylamino)-1-piperidyl)propoxy]carbostyrils 
Compounds of Formula I where m=n=1 and R.sup.4 =OH 
(A) 
3,4-dihydro-5-[2-hydroxy-3-(4-(ethoxycarbonylamino)-1-piperidyl)propoxy]ca 
rbostyril (A compound of Formula I where m=n=1, R.sup.1 =R.sup.2 =R.sup.3 
=R.sup.5 =H, R.sup.4 =OH, and R.sup.6 =C.sub.2 H.sub.5 
Ethyl 4-piperidylcarbamate (2 g), from Preparation 4, and 
5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (2.54 g), from Preparation 5, 
were dissolved in ethanol (50 mL) and the resulting solution was heated 
under reflux for 6 hours and then cooled to room temperature. Concentrated 
hydrochloric acid (1 mL) was added. A white product precipitated, which 
was collected by filtration. The crude product was recrystallized from 
ethanol to yield 2.8 g (56.5%) of 
3,4-dihydro-5-[2-hydroxy-3-(4-(ethoxycarbonylamino)-1-piperidyl)propoxy]ca 
rbostyril hydrochloride, m.p. 232.degree.-234.degree. C. (dec.). 
(B) Proceeding as in part A above, but replacing ethyl 
4-piperidylycarbamate with isopropyl 4-piperidylcarbamate, there was 
obtained 
3,4-dihydro-5-[2-hydroxy-3-(4-((2-methylpropoxy)carbonylamino)-1-piperidyl 
)propoxy]carbostyril hydrochloride, m.p. 150.degree. C. 
(C) Similarly, proceeding as in part A above, but replacing ethyl 
4-piperidylycarbamate with a corresponding compound of Formula 4 and 
replacing 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril with a corresponding 
compound of Formula 6, the following compounds of Formula I were prepared: 
3,4-dihydro-5-[2-hydroxy-3-(4-(methoxycarbonylamino)-1-piperidyl)propoxy]ca 
rbostyril hydrochloride, m.p. 250.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-(propoxycarbonylamino)-1-piperidyl)propoxy]ca 
rbostyril hydrochloride, m.p. 236.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-butoxycarbonylamino)-1-piperidyl)propoxy]carb 
ostyril hydrochloride, m.p. 252.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-isobutoxycarbonylamino)-1-piperidyl)propoxy]c 
arbostyril hydrochloride, m.p. 240.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-(tert-butoxycarbonylamino)-1-piperidyl)propox 
y]carbostyril hydrochloride, m.p. 138.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-(isopentoxycarbonylamino)-1-piperidyl)propoxy 
]carbostyril hydrochloride, m.p. 220.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-((2,2-dimethylpropoxy)carbonylamino)-1-piperi 
dyl)propoxy]carbostyril hydrochloride, m.p. 170.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1-piperid 
yl)propoxy]carbostyril hydrochloride, m.p. 250.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopentylmethoxy)carbonylamino)-1-piperid 
yl)propoxy]carbostyril hydrochloride, m.p. 240.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-((4-hydroxy-n-butoxy)carbonylamino)-1-piperid 
yl)propoxy]carbostyril hydrochloride, m.p. 206.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-((diethylaminoethoxy)carbonylamino)-1-piperid 
yl)propoxy]carbostyril hydrochloride, m.p. 160.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-((2-hydroxy-2-methylpropoxy)carbonylamino)-1- 
piperidyl)propoxy]carbostyril hydrochloride, m.p. 210.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonyl-N-methylamino)-1-piperidyl 
)propoxy]carbostyril hydrochloride, m.p. 206.degree. C.; 
1-methyl-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl 
)propoxy]carbostyril hydrochloride, m.p. 208.degree. C.; 
8-benzyloxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperi 
dyl)propoxy]carbostyril hydrochloride, m.p. 196.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-((2-methoxyethoxy)carbonylamino)-1-piperidyl) 
propoxy]carbostyril hydrochloride, m.p. 230.degree. C.; 
3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonyl-N-isobutylamino)-1-piperid 
yl)propoxy]carbostyril hydrochloride, m.p. 128.degree.-130.degree. C.; 
8-methoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidy 
l)propoxy]carbostyril hydrochloride, m.p. 218.degree. C.; 
8-methoxy-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino) 
-1-piperidyl)propoxy]carbostyril hydrochloride, m.p. 220.degree. C.; 
8-methyl-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl 
)propoxy]carbostyril hydrochloride, m.p. 202.degree. C.; and 
8-methyl-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)- 
1-piperidyl]carbostyril hydrochloride, m.p. 205.degree. C. 
(D) Similarly, proceeding as in part A above, but optionally replacing 
ethyl 4-piperidylcarbamate with a compound of Formula 4 wherein R.sup.5 
and R.sup.6 are as defined above, and optionally replacing 
5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril with a compound of Formula 6 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, the following 
compounds of Formula I are prepared: 
3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy] 
carbostyril N-oxide; 
3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1-piperid 
yl)propoxy]carbostyril N-oxide; 
6-methyl-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl 
)propoxy]carbostyril; 
6,8-dimethyl-3,4-dihydro-5-[2-hydroxy-3-(4-isobutoxycarbonylamino)-1-piperi 
dyl)propoxy]carbostyril; 
6,8-dibromo-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperi 
dyl)propoxy]carbostyril; 
8-chloro-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl 
)propoxy]carbostyril; and 
8-fluoro-3,4-dihydro-5-[2-hydroxy-3-(4-isobutoxycarbonylamino)-1-piperidyl) 
propoxy]carbostyril. 
EXAMPLE 2 
3,4-Dihydro-5-[.omega.-(1-piperidyl)alkoxy]carbostyrils 
Compounds of Formula I where R4 is H or lower alkyl 
(A) 
3,4-Dihydro-5-[3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyr 
il (A compound of formula 1 where m=n=1, R.sup.1 =R.sup.2 =R.sup.3 =R.sup.4 
=R.sup.5 =H, and R.sup.6 =isobutyl 
5-(3-chloropropoxy)-3,4-dihydrocarbostyril (2.5 g), from Preparation 6, and 
isobutyl 4-piperidylcarbamate (2 g), from Preparation 4, were dissolved in 
tetrahydrofuran (50 mL) containing triethylamine (1.5 mL). The reaction 
medium was heated for 48 hours under reflux, and the solvent was then 
removed by evaporation. The residue was dissolved in chloroform (100 mL), 
and the solution washed with water (2.times.50 mL), dried over sodium 
sulfate, and the solvent evaporated. Flash chromatography of the residue, 
using ethyl acetate/methanol (95:5) as eluent, afforded 0.64 g (15% yield) 
of the title compound, m.p. 195.degree. C. 
The hydrochloride addition salt was formed by treating the free base (0.5 
g) with ethanolic hydrochloric acid (6N, 5 mL), then diluting the solution 
to 100 mL by addition of diethyl ether. 
3,4-Dihydro-5-[3-(4-(2-methylpropoxy)carbonylamino-1-piperidyl)propoxy]car 
bostyril hydrochloride (0.52 g), m.p. 220.degree. C. (dec.), was obtained 
by filtration. 
(B) Proceeding as in part A above, but replacing isobutyl 
4-piperidylcarbamate with cyclopropylmethyl 4-piperidylcarbamate, and 
replacing 5-(3-chloropropoxy)-3,4-dihydrocarbostyril with 
5-(2-chloroethoxy)-3,4-dihydro-8-methoxycarbostyril there was obtained 
8-methoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperi 
dyl)ethoxy]carbostyril hydrochloride, m.p. 218.degree.-220.degree. C. 
(C) Similarly, proceeding as in part A above, but replacing 
5-(3-chloropropoxy)-3,4-dihydrocarbostyril with another compound of 
Formula 7 and replacing isobutyl 4-piperidylcarbamate with another 
compound of Formula 4, the following compounds were prepared: 
3,4-dihydro-5-[2-(4-(isobutoxycarbonylamino)-1-piperidyl)ethoxy]carbostyril 
hydrochloride, m.p. 230.degree. C.; 
3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidyl)ethoxy] 
carbostyril hydrochloride, m.p. 169.degree.-171.degree. C.; 
3,4-dihydro-5-[3-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidyl)propoxy 
]carbostyril hydrochloride, m.p. 223.degree.-225.degree. C.; 
3,4-dihydro-5-[2-methyl-2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidy 
l)ethoxy]carbostyril hydrochloride, m.p. 225.degree.-227.degree. C.; 
8-chloro-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidy 
l)ethoxy]carbostyril hydrochloride, m.p. 215.degree.-217.degree. C.; 
8-methyl-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidy 
l)ethoxy]carbostyril hydrochloride, m.p. 185.degree.-187.degree. C.; and 
6-methyl-3,4-dihydro-5-[2-(4-((cyclopropymethoxy)carbonylamino)-1-piperidyl 
)ethoxy]carbostyril hydrochloride, m.p. 168.degree.-170.degree. C.; 
8-methoxy-6-methyl-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)- 
1-piperidyl)ethoxy]carbostyril hydrochloride, m.p. 137.degree.-140.degree. 
C.; 
6,8-dimethyl-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-pipe 
ridyl)ethoxy]carbostyril hydrochloride, m.p. 163.degree.-165.degree. C.; 
and 
8-methoxy-3,4-dihydro-5-[2-(4-((isobutoxycarbonylamino)-1-piperidyl)ethoxy] 
carbostyril hydrochloride, m.p. 224.degree.-226.degree. C. 
(D) Similarly, proceeding as in part A above, but optionally replacing 
5-(3-chloropropoxy)-3,4-dihydrocarbostyril with another compound of 
Formula 7, and optionally replacing isobutyl 4-piperidylcarbamate with 
another compound of Formula 4, the following compounds are prepared: 
3,4-dihydro-5-[4-(4-(isobutoxycarbonylamino)-1-piperidyl)butoxy]carbostyril 
; 
3,4-dihydro-5-[5-(4-(isobutoxycarbonylamino)-1-piperidyl)pentoxy]carbostyri 
l; 
3,4-dihydro-5-[1-methyl-2-(4-isobutoxycarbonylamino)-1-piperidyl)ethoxy]car 
bostyril; 
3,4-dihydro-5-[3-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidyl)propoxy 
]carbostyril; 
8-chloro-3,4-dihydro-5-[5-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidy 
l)pentoxy]carbostyril; 
1-methyl-3,4-dihydro-5-[3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]c 
arbostyril; and 
8-phenylmethoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-p 
iperidyl)ethoxy]carbostyril. 
EXAMPLE 3 
Compounds of Formula I wherein R.sup.2 is Hydroxy 
(A) 
8-Phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-p 
iperidyl)propoxy]carbostyril 
5-(2,3-epoxypropoxy)-8-phenylmethoxy-3,4-dihydrocarbostyril (130 mg) was 
dissolved in isopropanol (10 mL) and isobutyl 4-piperidylcarbamate (80 mg) 
was added. The mixture was then heated under reflux for 20 hours with 
stirring. After completion of the reaction, the isopropanol was evaporated 
under reduced pressure. The residue was then purified by flash 
chromatography (AcOEt/MeOH-99:1) to yield 160 mg of the title compound, 
8-phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-p 
iperidyl)propoxy]carbostyril. 
(B) 
8-Hydroxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperid 
yl)propoxy]carbostyril 
8-Phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-pi 
peridyl)propoxy]carbostyril, the compound from Step A above (160 mg), was 
dissolved in ethanol (15 mL). Palladium (10% on carbon) was added, and the 
mixture was stirred under hydrogen at room temperature for 48 hours. The 
catalyst was removed by filtration, and the solvent evaporated to give 100 
mg of crude product which was recrystallized from aqueous ethanol, 
yielding the title compound, 
8-hydroxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperid 
yl)propoxy]carbostyril, m.p. 199.degree.-200.degree. C. 
(C) Similarly, proceeding as in part A above, but optionally replacing 
5-(2,3-epoxypropoxy)-8-phenylmethoxy-3,4-dihydrocarbostyril with an 
appropriate compound of Formula 6 wherein R.sup.2 is phenylmethoxy, and 
optionally replacing isobutyl 4-piperidylcarbamate with an appropriate 
compound of Formula 4, the following compounds of Formula I are prepared: 
8-phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonyl 
amino)-1-piperidyl)propoxy]carbostyril; 
1-methyl-8-phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(ethoxycarbonylamino 
)-1-piperidyl)propoxy]carbostyril; and 
8-phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonyl-N-methylam 
ino)-1-piperidyl)propoxy]carbostyril. 
(D) Similarly, proceeding as in part B above, but optionally replacing 
8-phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-p 
iperidyl)propoxy]carbostyril with a compound of Formula I from part C 
above, wherein R.sup.2 is OH, the following compounds of Formula I are 
prepared: 
8-hydroxy-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino) 
-1-piperidyl)propoxy]carbostyril; 
8-hydroxy-3,4-dihydro-5-[2-hydroxy-3-(4-(ethoxycarbonylamino)-1-piperidyl)p 
ropoxy]carbostyril; and 
8-hydroxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonyl-N-methylamino)-1 
-piperidyl)propoxy]carbostyril. 
(E) 
8-Phenylmethoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1- 
piperidyl)ethoxy]carbostyril 
5-(2-chloroethoxy)-8-phenylmethoxy-3,4-dihydrocarbostyril (0.7 g), from 
Preparation 6, and cyclopropylmethyl 4-piperidylcarbamate (0.5 g) were 
dissolved in dimethylformamide (35 mL) containing potassium carbonate (0.3 
g) and lithium bromide (0.3 g). The reaction medium was heated for 34 
hours at 110.degree. C., and the solvent was then removed by evaporation 
under reduced pressure. The residue was dissolved in chloroform (70 mL), 
and the solution was washed with water (2.times.40 mL), dried over sodium 
sulfate, and the solvent was evaporated under reduced pressure. Flash 
chromatography of the residue, using dichloromethane/methanol (90:10) as 
eluent, afforded 1 g of the title compound 
8-phenylmethoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1- 
piperidyl)ethoxy]carbostyril as a yellow oil (ca. 95%). 
(F) 
8-Hydroxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbamylamino)-1-piperi 
dyl)ethoxy]carbostyril 
The phenylmethoxy compound (1 g), from Step E above, was dissolved in 
ethanol (350 mL). Palladium hydroxide was added, and the mixture was 
stirred under hydrogen at room temperature for 3 hours. The catalyst was 
removed by filtration, and the solvent was evaporated to give 0.7 g (87%) 
of crude product which was purified via its hydrochloric acid addition 
salt, to give 
8-hydroxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbamylamino)-1-piperi 
dyl)ethoxy]carbostyril, m.p. 168.degree.-170.degree. C. 
(G) Similarly, proceeding as in part E above, but optionally replacing 
8-phenylmethoxy-5-(2-chloroethoxy)-3,4-dihydrocarbostyril with an 
appropriate compound of Formula (7) wherein R.sup.2 is phenylmethoxy, and 
optionally replacing cyclopropylmethyl (4-piperidyl)carbamate with an 
appropriate compound of Formula (4), the following compounds of Formula I 
are prepared: 
8-phenylmethoxy-3,4-dihydro-5-[3-(4-(isobutoxycarbonylamino)-1-piperidyl)pr 
opoxy]-carbostyril; 
8-phenylmethoxy-1-methyl-3,4-dihydro-5-[2-(4-(cyclopropylmethoxy)carbonylam 
ino)-1-piperidyl)ethoxy]carbostyril; and 
8-phenylmethoxy-3,4-dihydro-5-[3-(4-(isopropoxycarbonyl-N-methylcarbonylami 
no)-1-piperidyl)propoxy]carbostyril. 
(H) Similarly, proceeding as in part F above, but replacing 
8-phenylmethoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethyl)carbonylamino)-1-p 
iperidyl)ethoxy]carbostyril with 
8-phenylmethoxy-3,4-dihydro-5-[3-(4-isobutoxycarbonylamino)-1-piperidyl)pr 
opoxy]carbostyril, the following compound of Formula I was prepared: 
8-hydroxy-3,4-dihydro-5-(3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy] 
carbostyril. 
EXAMPLE 4 
Compounds of Formula I wherein R.sup.4 is acyloxy 
(A) 
3,4-Dihydro-5-[2-acetyloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propo 
xy]carbostyril 
3,4-Dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy] 
carbostyril (3 g) was dissolved in pyridine (30 mL) and acetic anhydride 
(0.9 mL) was added dropwise with stirring. After the addition, the mixture 
was stirred at room temperature for 12 hours, and the pyridine was then 
evaporated under reduced pressure. The residue was dissolved in chloroform 
(100 mL) and the organic solution was washed twice with water (50 mL each) 
and dried over sodium sulfate. The solvent was then evaporated and the 
residue recrystallized from isopropyl ether to yield 1.5 g of the title 
compound, 
3,4-dihydro-5-[2-acetyloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propo 
xy]carbostyril, m.p. 120.degree. C. 
(B) 
3,4-Dihydro-5-[2-pivaloyloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)pro 
poxy]carbostyril 
A cold solution (0.degree.-5.degree. C.) of 
3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy 
]carbostyril (3 g) in pyridine (50 mL) was slowly added to pivaloyl 
chloride (2 mL). The reaction medium was allowed to return to room 
temperature and then stirred for 20 hours. The resulting dark brown 
solution was treated as described in part A above, yielding 3.8 g of the 
title compound, 
3,4-dihydro-5-[2-pivaloyloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)pro 
poxy]carbostyril, m.p. 110.degree. C. 
(C) Similarly, proceeding as in part A above, but optionally replacing 
3,4-dihydro-5-[2-hydroxy-3-(4-isobutoxycarbonylamino)-1-piperidyl)propoxy] 
carbostyril with an appropriate compound of Formula I wherein R.sup.4 is 
OH, and optionally replacing acetic anhydride with the appropriate acid 
anhydride of formula (R--CO).sub.2 O wherein R corresponds to the desired 
acyl group, the following compounds of Formula I are prepared: 
3,4-dihydro-5-[2-butyryloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propo 
xy]carbostyril; 
3,4-dihydro-5-[2-propionyloxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1-pi 
peridyl)propoxy]carbostyril; and 
3,4-dihydro-5-[2-acetyloxy-3-(4-(propoxycarbonylamino)-1-piperidyl)propoxy] 
carbostyril. 
(D) Similarly, proceeding as in part B above, but optionally replacing 
3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy 
]carbostyril with an appropriate compound of Formula I wherein R.sup.4 is 
OH, and optionally replacing pivaloyl chloride with an appropriate acyl 
chloride of formula R--COCl wherein R corresponds to the desired acyl 
group, the following compounds of Formula I are prepared: 
3,4-dihydro-5-[2-pivaloyloxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1-pip 
eridyl)propoxy]carbostyril; 
3,4-dihydro-5-[2-adamantoyloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)pr 
opoxy]carbostyril; 
3,4-dihydro-5-[2-hexanoyloxy-3-(4-(ethoxycarbonylamino)-1-piperidyl)propoxy 
]carbostyril. 
EXAMPLE 5 
Compounds of Formula I as Pure Enantiomers Prepared from Racemic Mixtures 
of Same 
(A) L-pyroglutamic acid (38 g, 0.29 mol) in hot (70.degree.-75.degree. C.) 
isopropanol (300 mL) was added to a solution of a racemic mixture of 
3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy 
]carbostyril (123 g, 0.29 mol) in hot isopropanol (1400 mL). The resulting 
mixture was stirred and heated at 70.degree.-75.degree. C. for 30 minutes, 
and then allowed to return to room temperature. After 24 hours 63 g of 
crude L-pyroglutamate salt m.p. 166.degree.-169.degree. C. was recovered 
and recrystallized twice from isopropanol to give 40 g of the 
L-pyroglutamate salt, m.p. 173.5.degree.-174.5.degree. C. 
(B) The L-pyroglutamate salt (40 g) from part A above was dissolved in 
water (200 mL); 1N sodium hydroxide was added. The crude (R)(+) free base 
precipitated and was recovered by filtration (34 g) and then directly 
converted into 
(R)(+)-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl) 
propoxy]carbostyril hydrochloride, m.p. 232.degree.-234.degree. C., 
[.alpha.].sub.D : +10.7.degree.. 
(C) The mother liquors remaining after crystallization of the (R)(+) 
enantiomer from part A above were concentrated under reduced pressure, the 
residue was treated with 0.5N sodium hydroxide (500 mL) and the aqueous 
phase was extracted twice with dichloromethane (250 mL each). Organic 
extracts were combined, dried over sodium sulfate, and the solvent was 
then evaporated under reduced pressure. The residue (66.6 g) was dissolved 
in hot (70.degree. C.) propanol (750 mL). D-pyroglutamic acid (21.5 g) in 
hot propanol (200 mL) was added. The resulting mixture was heated at 
70.degree. C. for 30 minutes then allowed to crystallize for 24 hours. 60 
g of crude D-pyroglutamate salt was isolated by filtration and 
crystallized from isopropanol to give 43 g of D-pyroglutamate salt, m.p. 
173.degree.-175.degree. C. 
(D) Using the method described in part B above, but starting from the 
D-pyroglutamate (43 g), isolated in part C above, the (S)(-) compound was 
prepared and converted into the hydrochloride salt, yielding 28 g of 
(S)(-)-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl) 
propoxy]carbostyril hydrochloride, m.p. 231.degree.-233.degree. C.; 
[.alpha.].sub.D : -10.8.degree. C. 
(E) Similarly, but replacing 
3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy 
]carbostyril with a compound of Formula I wherein R.sup.4 is OH or lower 
alkyl, and following the procedures described in parts A and B above, the 
following pure enantiomers of compounds of Formula I were prepared: 
(R)(+)-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1- 
piperidyl)propoxy]carbostyril hydrochloride, m.p. 250.degree.-252.degree. 
C.; [.alpha.].sub.D : +11.07.degree.; 
(S)(-)-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1- 
piperidyl)propoxy]carbostyril hydrochloride, m.p. 255.degree.-257.degree. 
C.; [.alpha.].sub.D : -10.93.degree.; and 
(S)(-)-3,4-dihydro-5-[2-hydroxy-3-(4-((2-hydroxy-2-methylpropoxy)carbonylam 
ino)-1-piperidyl)propoxy]carbostyril hydrochloride, m.p. 220.degree. C.). 
EXAMPLE 6 
Preparation of Products of Formula I as Pure Enantiomers from Optically 
Active Intermediates of Formula 1 
(A) (2S)-(+)-(2,3-epoxy)-propoxy-3,4-dihydrocarbostyril 
NaH (5 g, 0.124 mol) (50-60% in oil) was added to DMF (100 mL). The mixture 
was stirred, cooled to 0.degree. and 5-hydroxy-dihydrocarbostyril (20 g, 
0.123 mol) in DMF (150 mL) was added dropwise. After the addition, the 
mixture was stirred at room temperature for 1 hour, and then (2S)-(+) 
glycidyl tosylate (26.5 g, 0.116 mol) in DMF (120 mL) was added. The 
mixture was heated at 60.degree. C. for 3 hours, then allowed to cool to 
room temperature. The solution was poured onto a mixture of ice water and 
extracted twice with CHCl.sub.3 (500 mL each). The organic layer was 
washed with water and dried over sodium sulfate. Evaporation of the 
solvent under reduced pressure gave a residue which was chromatographed on 
silica gel using CH.sub.2 Cl.sub.2 /CH.sub.3 OH 9/1 as eluent to afford 
10.1 g (40%) of the title compound, 
(2S)-(+)-(2,3-epoxy)propoxy-3,4-dihydrocarbostril, m.p. 182.degree.); 
[.alpha.].sub.D : +27.85 (c=1, CH.sub.3 OH). 
(B) Similarly, proceeding as in part A above, but using 
(2R)-(-) glycidyl tosylate the following compound was prepared: 
(2R)-(-)-5-(2,3-epoxy)propoxy-3,4-dihydrocarbostyril, m.p. 182.degree. C.; 
[.alpha.].sub.D : -26.06.degree. (c=1, CH.sub.3 OH). 
(C) (2S)-(+)-5-(2,3-epoxy)-propoxy-3,4-dihydrocarbostyril (2.5 g, 0.0124 
mol) of part A above, and isobutyl 4-piperidylcarbamate (2.8 g, 0.0114 
mol) of Preparation 4 in isopropanol (75 mL) were heated under reflux for 
24 hours. The reaction medium was allowed to return to room temperature. 
The white solid which precipitated was filtered, dissolved in ethanol and 
a solution of hydrochloric acid in ethanol was added. The resulting 
precipitate was collected, washed with ether and dried to give 3.2 g (60%) 
of 
(S)(-)3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)p 
ropoxy]carbostyril hydrochloride, m.p. 232.degree. C., [.alpha.].sub.D : 
-10, (c=1, CH.sub.3 OH). 
(D) Similarly, proceeding as in part C above, but replacing 
(2S)-(+)-5-(2,3-epoxy)propoxy-3,4-dihydrocarbostyril with 
(2R)-(-)-5-(2,3-epoxy)-propoxy-3,4-dihydrocarbostyril, the following 
compound was prepared: 
(R)-(+)-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl) 
propoxy]carbostyril hydrochloride m.p. 228.degree. C., [.alpha.].sub.D : 
+10.55 (c=1, CH.sub.3 OH). 
(E) Similarly, proceeding as in part C above but replacing isobutyl 
4-piperidylcarbamate with cyclopropylmethyl 4-piperidylcarbamate the 
following compound was prepared: 
(S)-(-)-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1 
-piperidyl)propoxy]carbostyril hydrochloride, m.p. 255.degree. C., 
[.alpha.].sub.D : -10.93 (c=1, CH.sub.3 OH). 
(F) Similarly, proceeding as in part D above, but replacing isobutyl 
4-piperidylcarbamate with cyclopropylmethyl 4-piperidylcarbamate the 
following compound was prepared: 
(R)-(+)-3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1 
-piperidyl)propoxy]carbostyril hydrochloride, m.p. 250.degree. C., 
[.alpha.].sub.D : +11.07 (c=1, CH.sub.3 OH). 
EXAMPLE 7 
Conversion of Free Base to Salt 
(A) 3,4-Dihydro 
5-[2-hydroxy-3-(4-(tert-butoxycarbonylamino)-1-piperidyl)propoxy]carbostyr 
il (1 g, m.p. 138.degree. C.) was dissolved in ethanol (10 mL) and 
acidified with hydrochloric acid-saturated ethanol. The resulting mixture 
was diluted with 2 volumes of diisopropylether and kept at room 
temperature for 24 hours. A white precipitate was collected by filtration 
and washed with ether to give 1,1 g of 
3,4-dihydro-5-[2-hydroxy-3-(4-(tert-butoxycarbonylamino)-1-piperidyl)propo 
xy]carbostyril hydrochloride, m.p. 195.degree.-197.degree. C. (dec.). 
(B) Similarly, proceeding as in part A above, but replacing 
3,4-dihydro-5-[2-hydroxy-3-(4-(tert-butoxycarbonylamino)-1-piperidyl)propo 
xy]carbostyril with an appropriate free base of a compound of Formula I, 
the corresponding hydrochloride salts are prepared. 
(C) 
3,4-Dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1-piperi 
dyl)propoxy]carbostyril (1.5 g, m.p. 185.degree. C.) was dissolved in hot 
ethanol and added to a solution of fumaric acid (1 g) in ethanol (10 mL). 
The reaction medium was kept at reflux for 5 minutes then left at room 
temperature overnight. 1.6 g of the desired fumaric acid addition salt was 
recovered by filtration then further purified by crystallization from a 
mixture of isopropylether:ethanol (m.p.: 188.degree.-190.degree. C.). 
(D) Similarly, proceeding as in part C above, but optionally replacing 
3,4-dihydro-5-[2-hydroxy-3-(4-((cyclopropylmethoxy)carbonylamino)-1-piperi 
dyl)propoxy]carbostyril with a compound of Formula I and optionally 
replacing fumaric acid by another pharmaceutically acceptable organic acid 
(e.g., acetic acid, propionic acid, glycolic acid, malonic acid, maleic 
acid, oxalic acid, citric acid, ascorbic acid, lactic acid, benzoic acid, 
glutamic acid, tartaric acid, cinnamic acid, mandelic acid, 
methanesulfonic acid, paratoluenesulfonic acid, pamoic acid, salicylic 
acid, and the like) the corresponding pharmaceutically acceptable organic 
acid addition salts are obtained. 
EXAMPLE 8 
In vitro Determination of Effects on the Effective Refractory Period 
Right ventricular papillary muscles from guinea-pigs were stimulated at 1 
Hz and continuously superfused with physiological salt solution. 
Ventricular Effective Refractory Period (VERP) was determined after 20 
minutes incubation with each concentration of drug, compared with control 
values and expressed as % increase in VERP. Concentrations of the drug 
which increased VERP by 15% were calculated from concentration-effect 
curves and mean values with standard error (s.e.) range computed. 
The compounds of Formula I demonstrated activity in this assay. For 
example, 3,4-dihydro-5-[2-hydroxy-3-(4-((2-methylpropoxy)carbonylamino)-1- 
piperidyl)propoxy]carbostyril provoked at 15% prolongation of the 
ventricular effective refractory period (VERP) at concentrations less than 
10.sup.-5 mol/liter. 
EXAMPLE 9 
In vivo Determination of Anti-arrhythmic Effects 
The techniques followed to measure in vivo the effects of compounds of 
Formula I on cardiac electrical activity are an exact replication of those 
described by POIZOT (ref. cited above). They are adaptations to the 
guinea-pig of methods previously developed by Lhoste et al. (Eur. Journal 
of Pharmacology, 39, 171-177, 1976) and by Harper et al. (Cardiovascular 
Research, 13, 303-310, 1979), in dog and man, respectively, and in vitro 
by Ellis (Annal. N.Y. Acad. Sci., 64, 552-63, 1956). 
In anesthetized, artificially ventilated guinea-pig, surface electrodes are 
installed for right ventricular stimulation and Electro Cardiogram (ECG) 
recording (lead II). Afterwards, the heart is paced to determine the 
ventricular effective refractory period calculated from the maximum 
driving frequency. After a control period of 15 minutes the antiarrhythmic 
agent to be studied is injected intravenously at increasing doses and at 
30 minute intervals. The ECG parameters, QTc (indicative of action 
potential duration) and RR (indicative of cardiac frequency) intervals are 
measured at the end of each 30 minute period and the maximum driving 
frequency is determined. 
Compounds of Formula I induced a prolongation of the QTc and RR intervals 
of the ECG as well as a decrease in the maximum driving frequency and are 
therefore effective anti-arrhythmic agents. 
EXAMPLE 10 
The following example illustrates the preparation of representative 
pharmaceutical formulations containing an active compound of formula I, 
e.g., 
3,4-dihydro-5-(2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy 
]carbostyril hydrochloride. 
CAPSULE FORMULATION 
The composition contains: 
______________________________________ 
% wt./wt. 
______________________________________ 
Active Ingredient 20.0% 
Pregelatinised Starch 
79.5% 
Magnesium Stearate 0.5% 
______________________________________ 
A weight of formulation sufficient to give a suitable dose of active 
ingredients are mixed and dispensed into capsules. 
TABLET FORMULATION 
The composition contains: 
______________________________________ 
% wt./wt. 
______________________________________ 
Active Ingredient 20.0% 
Magnesium Stearate 0.5% 
Crosscarmellose Sodium 
4.0% 
Lactose 74.5% 
PVP (polyvinylpyrrolidone) 
1.0% 
______________________________________ 
The above ingredients with the exception of the magnesium stearate and half 
of the crosscarmellose sodium are combined and granulated using water as a 
granulating liquid. The formulation is then dried, mixed with the 
magnesium stearate and the remaining crosscarmellose sodium and formed 
into tablets with an appropriate tableting machine. 
ORAL SOLUTION FORMULATION 
The composition contains: 
______________________________________ 
Active Ingredient 250-1500 mg 
Citric Acid Monohydrate 
105 mg 
Sodium Hydroxide 18 mg 
Flavouring q.s. 
Water to 100 ml 
______________________________________ 
The citric acid monohydrate and sodium hydroxide are dissolved in a 
sufficient quantity of water. The active ingredient is dissolved in this 
solution. Sufficient flavouring is added. A sufficient quantity of water 
is then added with stirring to provide 100 ml of the solution which is 
filtered and bottled. 
SUPPOSITORY FORMULATION 
The composition contains: 
______________________________________ 
% wt./wt. 
______________________________________ 
Active Ingredient 1.0% 
Polyethylene Glycol 1000 
74.5% 
Polyethylene Glycol 4000 
24.5% 
______________________________________ 
The ingredients are melted together and mixed on a steam bath and poured 
into molds containing 2.5 g total weight. 
ENTERAL FORMULATION (IV) 
______________________________________ 
Active Ingredient 2.5-15.0 mg 
Dextrose Monohydrate 
q.s. to make isotonic 
Citric Acid Monohydrate 
1.05 mg 
Sodium Hydroxide 0.18 mg 
Water for Injection to 1.0 ml 
______________________________________ 
The citric acid monohydrate and sodium hydroxide are dissolved in a 
sufficient quantity of the water for injection. The active ingredient is 
dissolved in the resulting solution followed by the dextrose monohydrate. 
The remainder of the water for injection is added with stirring. The 
solution is filtered, filled into 1.0 ml ampoules which are sealed. The 
content of the ampoules is then sterilized by autoclaving. 
While the present invention has been described with reference to the 
specific embodiments thereof, it should be understood by those skilled in 
the art that various changes may be made and equivalents may be 
substituted without departing from the true spirit and scope of the 
invention. In addition, many modifications may be made to adapt a 
particular situation, material, composition of matter, process, process 
step or steps, to the objective, spirit and scope of the present 
invention. All such modifications are intended to be within the scope of 
the claims appended hereto.