Acetylene amines and their use as vasodilators and antihypertensives

Acetylenes of the following formula (I): ##STR1## wherein Y, m, R.sup.1, R.sup.2, R.sup.3, n and R.sup.4 are defined herein and R.sup.5 is hydrogen, alkyl, cycloalkyl or substituted alkyl are useful vasodilators and antihypertensives.

The present invention comprises various aromatic derivatives of amino 
acetylenes which are useful as vasodilators and in the treatment of 
hypertension, e.g. in humans. 
Various phenylethynyl benzylamines are claimed in U.S. Pat. No. 3,719,712 
and are taught as antiarrhythmic agents. 
SUMMARY OF THE INVENTION 
Aromatic acetylenes of the following formula (I): 
##STR2## 
wherein Y, m, R.sup.1, R.sup.2, R.sup.3, n and R.sup.4 are as defined 
herein and R.sup.5 is hydrogen, alkyl, cycloalkyl or substituted alkyl 
possess vasodilating and anti-hypertensive properties when administered to 
a mammal in need thereof. Also part of the invention are pharmaceutical 
compositions containing compounds of the formula (I) and methods of 
treatment using such compositions. 
DETAILED DESCRIPTION OF THE INVENTION 
Compounds of the invention are of the following formula 
##STR3## 
wherein Y is independently alkyl, alkoxy, alkylthio, alkylsulfinyl, 
alkylsulfonyl, alkanoyloxy, alkanoylamino, amino, monoalkylamino, 
dialkylamino, hydroxy, halogen or cyano or methylenedioxy or ethylenedioxy 
at adjacent ring carbons; 
m is 0, 1, 2 or 3; 
R.sup.1 and R.sup.2 are independently hydrogen, alkyl 
##STR4## 
R.sup.3 is hydrogen, alkyl or alkoxyalkyl n is 0, 1 or 2; 
R.sup.4 is hydrogen or alkyl; 
R.sup.5 is hydrogen, alkyl, cycloalkyl or alkyl substituted by amino, 
monoalkylamino, dialkylamino, hydroxy, cycloalkyl, alkoxy, phenyl or 
phenyl substituted by 1 to 3 Y groups; 
Alk is a straight chain alkylene of about 1 to 4 carbons; Ar is a phenyl, 
phenoxy, thiophenoxy or a 5- or 6-membered heterocyclic aromatic ring 
which rings may be substituted independently by one or more of alkyl, 
alkoxy, alkylthio, hydroxy, halogen, fluoroalkyl, amino or dialkylamino or 
by methylenedioxy at adjacent ring carbons; 
R.sup.6 is alkyl; and 
q is 0, 1 or 2 or 3 if Alk is alkylene of about 2 to 4 carbons, 
and the pharmaceutically acceptable acid addition salts and quarternary 
ammonium compounds thereof. 
In particular, Y is alkyl of about 1 to 6 carbons such as methyl or ethyl; 
alkoxy of about 1 to 6 carbon atoms such as methoxy or ethoxy; alkylthio 
of about 1 to 6 carbons such as methylthio; alkylsulfinyl of about 1 to 6 
carbons such as methylsulfinyl; alkylsulfonyl of about 1 to 6 carbons such 
as methylsulfonyl; alkanoyloxy of about 2 to 6 carbons such as acetoxy; 
alkanoylamino of about 2 to 6 carbons such as acetylamino; amino; 
monoalkylamino of about 1 to 6 carbons such as ethylamino; dialkylamino of 
about 2 to 12 carbons such as dimethylamino; hydroxy; halogen such as 
fluoro, chloro or bromo; cyano; or methylenedioxy or ethylenedioxy wherein 
the two oxygen atoms are attached to two adjacent carbons of the benzene 
ring. Although the Y groups may be attached at any of the 4 open positions 
of the benzene ring, particularly preferred are compounds wherein the Y 
groups are attached at the 4- and/or 5-positions of the ring relative to 
the amino side chain with the acetylene moiety being at the 2-position. 
R.sup.1 and R.sup.2 are independently hydrogen; alkyl of about 1 to 8 
carbons, e.g., 1 to 4 carbons such as methyl, ethyl, n-Propyl, iso-propyl, 
tert-butyl or n-hexyl; or 
##STR5## 
R.sup.3 is hydrogen; alkyl of about 1 to 6 carbons such as methyl, ethyl, 
iso-propyl and n-pentyl; or alkoxyalkyl of about 1 to 6 carbons in each 
alkyl portion such as methoxymethyl, n-butoxymethyl and ethoxyethyl. 
R.sup.4 is in particular, hydrogen; or alkyl of about 1 to 6 carbons with 
examples being methyl, ethyl and n-butyl. 
R.sup.5 is in particular hydrogen; alkyl of about 1 to 12 carbons, e.g., 
about 1 to 8 carbons, such as methyl, ethyl, n-butyl, iso-butyl, 
sec-butyl, tert-butyl, n-hexyl or n-octyl; cycloalkyl of about 5 to 7 
carbons such as cyclopentyl, cyclohexyl and cycloheptyl; or an alkyl of 
about 1 to 6 carbons, such as methyl, ethyl, n-propyl, or iso-propyl, 
substituted by an amino, monoalkylamino of about 1 to 6 carbons, 
dialkylamino of about 2 to 12 carbons, hydroxy, cycloalkyl of about 5 to 7 
carbons, e.g., cyclopentyl, cyclohexyl or cycloheptyl, alkoxy of about 1 
to 6 carbons such as methoxy or ethoxy, phenyl or phenyl substituted by 1, 
2 or 3 Y groups such as methyl, methoxy, fluoro, chloro or cyano. Alkyl 
groups for the mono- and di-alkylamino include methyl, ethyl and n-propyl, 
particular examples being the dialkylamino groups wherein the alkyl groups 
are the same. 
Alk is methylene, ethylene, trimethylene or tetramethylene. 
Ar in particular is phenyl; phenoxy; thiophenoxy; or a 5- or 6-membered 
heterocyclic aromatic ring, preferably one having 1 heteroatom such as 
nitrogen, sulfur or oxygen, e.g. furan or thiophene attached at the 2 or 3 
position, pyrrole attached at the 1, 2 or 3 position and pyridine attached 
at the 2, 3 or 4 position. The open positions of the ring of Ar may be 
substituted by one or more, e.g. one or two, same or different, of alkyl 
of about 1 to 6 carbons such as methyl or ethyl; alkoxy of about 1 to 6 
carbons such as methoxy and ethoxy; alkylthio of about 1 to 6 carbons such 
as methylthio; hydroxy; halogen such as fluoro, chloro and bromo; 
fluoroalkyl of about 1 to 6 carbons and one or more fluorine atoms with 
examples being 2,2,2-trifluoroethyl and trifluoromethyl; amino; or 
dialkylamino of about 2 to 12 carbons such as dimethylamino; or 
methylenedioxy at adjacent ring carbons particularly if Ar is phenyl, 
phenoxy or thiophenoxy, e.g., 3,4-methylenedioxyphenyl. 
R.sup.6 is alkyl of about 1 to 4 carbons such as methyl, ethyl or 
iso-propyl. 
q is 0, 1 or 2 or 3 if Alk is alkylene of about 2 to 4 carbons, and in 
particular is 0, 1 or 2. 
"Alkyl" in the present specification, e.g., as part of an alkoxy group, is 
meant to include straight and branched chain alkyl. 
The pharmaceutically acceptable acid-addition salts of the compounds of 
formula (I) include those of a mineral or organic acid such as 
hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, fumaric, 
maleic, cyclohexylsulfamic, citric, lactic, methanesulfonic and similar 
acids. 
The quaternary ammonium compounds of the compounds of formula (I) include 
those formed with an alkylhalide or sulfate of about 1 to 6 carbons, e.g., 
an alkyl bromide or iodide such as methyl iodide. The salts and ammonium 
compounds may be prepared by conventional techniques. 
Compounds of Formula (I) and other compounds of the invention may exist in 
various isomeric forms, e.g., in view of the presence of an asymmetric 
carbon. It is understood that the present invention includes all such 
individual isomers and their racemates. Also within the scope of the 
invention are compounds of the invention in the form of hydrates and other 
solvate forms. 
Particularly preferred aspects of the present invention are compounds of 
formula (I) wherein: 
A. Y is alkoxy and m is 1 or 2. 
B. Y is alkoxy and m is 1 at the position para to acetylene moiety or Y is 
alkoxy and m is 2 at positions para to the acetylene moiety and to the 
--CHR.sup.4 (CH.sub.2).sub.n --CHR.sup.3 NR.sup.1 R.sup.2 moiety. 
C. one of R.sup.1 and R.sup.2 is hydrogen or alkyl. 
D. R.sup.1 and R.sup.2 are both alkyl or R.sup.1 is alkyl and R.sup.2 is 
2-(3,4-dimethoxyphenyl)ethyl. 
E. R.sup.5 is hydrogen, alkyl, cycloalkyl or alkyl substituted by 
dialkylamino, hydroxy or phenyl. 
F. R.sup.1 is alkyl and R.sup.2 is 
##STR6## 
wherein Alk is ethylene and q is 0. G. Y is alkoxy, alkylthio, amino, 
halogen or methylenedioxy at adjacent ring carbons; m is 0, 1 or 2; 
R.sup.1 and R.sup.2 are independently alkyl or 
##STR7## 
R.sup.3 is hydrogen or alkyl; n is 0 or 1; R.sup.4 is hydrogen; R.sup.5 is 
hydrogen, alkyl, cycloalkyl or alkyl substituted by dialkylamino, hydroxy 
or phenyl; and Ar is phenyl substituted by one or more alkoxy groups. 
Particular compounds of the invention of the formula (I) are the following: 
2-(1-Hexynyl)-5-methoxy-N,N-dimethylbenzeneethanamine 
2-(Cyclohexylethynyl)-3,4-dimethoxy-N,N-dimethylbenzeneethanamine 
2-(1-Hexynyl)-5-methoxy-N,N-dimethylbenzenepropanamine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-6-(1-hexynyl)-N-methyl-1,3-benzodioxole-5- 
propanamine 
2-(1-Decynyl)-5-methoxy-N,N-dimethylbenzenepropanamine 
2-(3,3-Dimethylbutynyl)-5-methoxy-N,N-dimethylbenzenepropanamine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(1-hexynyl)-5-methoxy-N-methylbenzenepro 
panamine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(3,3-dimethylbutynyl)-5-methoxy-N-methyl 
benzenepropanamine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-5-methoxy-N-methyl-2-(4-phenyl-1-butynyl)b 
enzenepropanamine 
2-[3-(Diethylamine)-1-propynyl]-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy- 
N-methylbenzenepropanamine 
2-(Butynyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-N-methylbenzenepropa 
namine 
2-(Cyclohexylethynyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-N-methylbe 
nzenepropanamine 
2-(1-Hexynyl)-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine 
2-(Cyclohexylethynyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-N,alphadim 
ethylbenzeneethanamine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(1-hexynyl)-5-methoxy-N,alphadimethylben 
zeneethanamine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(3-hydroxy-3-methylbutynyl)-5-methoxy-N- 
methylbenzenepropanamine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-ethynyl-5-methoxy-N-methylbenzene-propan 
amine 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(1-hexynyl)-5-methoxy-N-methyl-.alpha.-p 
entyl-benzenepropanamine. 
Compounds of formula (I) may be prepared according to the following 
Reaction Scheme I: 
##STR8## 
Three primary stages are used in the preparation of compounds of the 
formula (I) by starting with arylalkanoic acids or arylalkanones of the 
formula (II) wherein Z is OH, O-alkyl or R.sup.3, e.g., hydrogen, alkyl or 
alkoxyalkyl. The stages are halogenation, construction of an amine 
functionality and condensation with an R.sup.5 -acetylene. In the 
halogenation stage A, wherein X is a halogen such as Br or I, the aryl 
ring of (II) is halogenated in the position ortho to the eventual 
aminoalkyl side chain. Brominations may be carried out with bromine in 
halocarbon solvents or acetic acid at temperatures from about -20.degree. 
to 80.degree. C. and may be conducted in the presence of a Lewis acid 
catalyst such as ferric chloride. Iodinations may be carried out using 
iodine monochloride in halocarbon solvents or acetic acid over a range of 
room temperature to about 100.degree. C. Iodinations may be carried out 
using iodine in the presence of an iodine scavenger such as silver 
acetate, silver sulfate, mercuric oxide or nitric acid. For reactive 
substrates, iodine may be used alone or in conjunction with a mild base 
such as sodium bicarbonate. Alternatively, the halogenation may be 
accomplished by mercuration, e.g., with HgCl.sub.2 or thallation, e.g., 
with T1(O.sub.2 CCF.sub.3).sub.3, followed by treatment with iodide or 
bromide as described by A. McKillop, et al. in J. Am. Chem. Soc., 93, 4841 
(1971). 
In stage B or B' the desired amine function is constructed. In a first 
embodiment for Stage B and if R.sup.3 is to be hydrogen, a compound of 
formula (III) wherein Z is OH may be converted to the corresponding acid 
chloride by reagents such as oxalyl chloride, thionyl chloride or 
phosphoryl chloride. The reaction may be carried out at room temperature 
to about 100.degree. C. in an aprotic, nonpolar solvent such as toluene, 
chloroform or methylene chloride or the reaction may be carried out neat. 
The preferred method employs oxalyl chloride in toluene in the presence of 
DMF. The acid chloride is converted to the corresponding amide of formula 
(III) wherein Z is NR.sup.1 R.sup.2. This conversion may be carried out by 
treatment of the acid chloride with an excess of amine of the formula 
R.sup.1 R.sup.2 NH, for instance in toluene or a halocarbon solvent at 
temperatures from -30.degree. C. to 45.degree. C. Alternatively, slightly 
more than one equivalent of amine may be used in the presence of an 
auxillary base such as triethylamine, pyridine, sodium hydroxide or 
potassium carbonate. The amide is then reduced to the corresponding amine 
of the formula (IV) wherein R.sup.3 is hydrogen to complete elaboration of 
the amine function. The reduction of the amide is preferably carried out 
with an excess of borane in THF at the reflux temperature of the solvent. 
The excess borane is decomposed by addition of water and the amine borane 
complex is decomposed by heating in the presence of an alkanoic acid, 
preferably propionic acid, a mineral acid or an alkali metal hydroxide to 
give the amine of formula (IV) wherein R.sup.3 is hydrogen. Alternatively, 
the amide may be reduced with lithium aluminum hydride, sodium borohydride 
plus aluminum chloride or sodium borohydride in acetic or trifluoroacetic 
acid. A second embodiment for the construction of the amine function 
consists of reductive alkylation by aldehydes or ketones of the formulae 
(III) or (V) wherein Z is R.sup.3, i.e., hydrogen, alkyl or alkoxyalkyl, 
of amines of the formula NHR.sup.1 R.sup.2. The reductive alkylation may 
be carried out in one step from the carbonyl compound and the amine using 
sodium cyanoborohydride as the reducing agent in a lower alkanol or 
acetonitrile as the solvent at neutral to mildly acidic pH at temperatures 
from 0.degree. to 40.degree. C. Hydrogenation over a noble metal catalyst 
may also be used to bring about the reduction. Reductive alkylation may 
also be carried out in two steps. The carbonyl compound and amine are 
first converted to an imine or iminium salt by treatment with molecular 
sieves or azeotropic removal of water. Reduction is then effected by 
sodium cyanoborohydride or catalytic reduction. Using the two step 
reductive alkylation, the alkyl groups R.sup.1 and R.sup.2 may be attached 
sequentially. In stage B', the reductive alkylation cannot be carried out 
by catalytic hydrogenation in view of the possibility of hydrogenation of 
the acetylene moiety. 
If R.sup.1 is to be methyl, the Eschweiler-Clark procedure using 
formaldehyde as the carbonyl compound and formic acid or sodium 
cyanoborohydride as the reducing agent is used. 
The third stage in Reaction Scheme I is the replacement of halide X by an 
R.sup.5 -acetylene and is labeled C and C'. The coupling of the 
arylhalides (III) or (IV) with an R.sup.5 -acetylene may be accomplished 
by treating the arylhalide with chlorozinc R.sup.5 -acetylide in the 
presence of a palladium or nickel catalyst, preferably 
Pd[(Ph.sub.3)P].sub.4 in an ethereal solvent such as THF at -30.degree. C. 
to ambient temperature, as described by A. O. King et al. in J. Org. 
Chem., 43, 358 (1978). The coupling may also be accomplished by treating 
the arylhalide (III) or (IV) with the R.sup.5 -acetylene and catalytic 
quantities, e.g., 0.5 to 10 mole percent, of Pd(OAc).sub.2 [P(Ph).sub.3 
].sub.2 or PdCl.sub.2 [P(Ph).sub.3 ].sub.2 in an amine solvent such as 
diethylamine, piperidine, pyrrolidine or triethylamine at ambient 
temperature to the reflux temperature of the solvent in the presence or 
absence of cuprous iodide as described by K. Sonogashira et al. in 
Tetrahedron Letters, 4467 (1975) or H. A. Dieck et al. in J. Organometal. 
Chem. 93, 253 (1975). 
For the preparation of the compounds of formula (I) wherein R.sup.5 is 
hydrogen, the corresponding compound wherein R.sup.5 is 
1-hydroxy-1-methylethyl may be treated with base. For example, the 
compound of formula (I) wherein R.sup.5 is 1-hydroxy-1-methylethyl may be 
heated at 50.degree.-140.degree. C. in an inert solvent such as toluene, 
xylene or chloroform in the presence of concentrated aqueous sodium 
hydroxide in the presence of a quaternary ammonium phase transfer catalyst 
such as, for example, tetrabutylammonium chloride. 
The stages of reaction Scheme I may be carried out in the sequence A, B and 
C or the sequence A, C' and B'. When R.sup.1 is to be alkyl, such may be 
attached by reductive alkylation after carrying out stage C or B'. If 
desired, the order in which the stages are carried out may be varied so 
tht amine elaboration may preceed halogenation. 
A second general method for preparation of compounds of formula (I) where n 
is 0 R.sup.4 is H and R.sup.3 is alkyl is shown in Reaction Scheme II: 
##STR9## 
An aromatic aldehyde (VI) is condensed with a nitroalkane of the formula 
R.sup.3 CH.sub.2 NO.sub.2 to afford a nitroolefin (VII). Condensation of 
the nitroalkane with the aromatic aldehyde is carried out using ammonium 
acetate or a primary alkylamine as catalyst in, for example, glacial 
acetic acid, ethanol or toluene as the solvent at ambient to elevated 
temperatures preferably at the reflux temperature of the solvent. The 
nitroolefin (VII) is then reduced to an amine (VIII) where R.sup.7 is 
hydrogen with lithium aluminum hydride in an ether solvent, or by 
catalytic reduction over Raney nickel or a noble metal catalyst. The amine 
(VIII) is halogenated on the aromatic ring using the methods described for 
Stage A to afford a halogenated amine of the formula (VIII) where R.sup.7 
is halo. The haloamine is coupled with an R.sup.5 -acetylene using the 
procedure of King et al. or Sonogashiri et al. as described for Stage C to 
give an acetylene of formula (VIII) where R.sup.7 is --C.tbd.C--R.sup.5. 
Attachment of the groups R.sup.1 and/or R.sup.2 by reductive alkylation 
starting with the appropriate carbonyl compounds, e.g., CH.sub.3 CHO to 
have ethyl as the R.sup.1 moiety or benzaldehyde to give benzyl as the 
-Alk-Ar moiety, affords the product of the formula (I) wherein n is 0 
R.sup.4 is hydrogen and R.sup.3 is hydrogen or alkyl. 
Starting materials for Reaction Schemes I and II are widely known. However, 
starting materials with particular substituents may be synthesized by the 
following methods: 
First, alkanones of the formula (II) wherein Z is R.sup.3, n is 0 and 
R.sup.4 is hydrogen may be prepared by condensation of an aromatic 
aldehyde (VI) with an alpha-haloester, e.g. of the formula R.sup.3 
CHBrCOOAlkyl in the presence of an alkali metal alkoxide to give a 
glycidic ester of the formula (IX). Hydrolysis with an alkali metal 
hydroxide followed by thermal decarboxylation affords the arylalkanone 
(II) wherein Z is R.sup.3, n is O and R.sup.4 is hydrogen. Conversion of 
such a (II) compound to one wherein R.sup.4 is alkyl may be carried out by 
alkylation of an alkali metal enolate of the carbonyl compound (II) with a 
reagent such as ethyl iodide. 
Second, arylalkanones of the formula (II) where Z is R.sup.3, n is 1 and 
R.sup.4 is hydrogen may be prepared by a Claisen-Schmidt condensation of a 
methyl ketone, CH.sub.3 COR.sup.3 with an aromatic aldehyde (VI) in the 
presence of an alkali metal hydroxide followed by hydrogenation of the 
alpha,beta-unsaturated ketone (X) over a noble metal catalyst. Third, 
arylalkanoic acids of the formula (II) wherein Z is OH, R.sup.4 is 
hydrogen and n is 1 may be prepared by Knoevenagel condensation of an 
aromatic aldehyde (VI) with malonic acid followed by hydrogenation of the 
resulting cinnamic acid (XI) over a noble metal catalyst: 
##STR10## 
In each of the above three sequences, the aromatic aldehyde may be one with 
an X group ortho to the CHO and such a starting material will result in 
final products of the formula (III) after the steps described above. 
For the preparation of intermediates (II) and (III) where Y is halo, 
alkylthio, hydroxy, cyano or dialkylamino, the corresponding compounds 
(XII) where p is 0 or 1, respectively, may be utilized as starting 
materials. The arylamine (XII) may be diazotized to give (XIII) and the 
diazonium group may be treated with CuCl, CuBr or CuCN to yield (II) or 
(III) wherein Y is Cl, Br or CN, respectively. Pyrolysis of the diazonium 
fluoroborate or hexafluoro phosphate gives the corresponding aryl 
fluoride. Hydrolysis of the diazonium salt would lead to the corresponding 
phenol. Treatment of the diazonium salt successively with potassium ethyl 
xanthate, base and an alkyl halide leads to the alkylthio product. 
Reductive alkylation of the amino compound (XII) with formaldehyde or an 
alkanal and sodium cyanoborohydride gives rise to intermediates (II) or 
(III) bearing the dialkylamino group. 
##STR11## 
The various Y groups in compounds such as those of formulae (II), (III), 
(IV) and (XII) may be transformed among each other by techniques known in 
the art. For example, when Y is amino, the corresponding compound wherein 
Y is monoalkylamino may be prepared by acylation with an acyl halide or 
anhydride to yield the corresponding compound where Y is alkanoylamino 
followed by hydride reduction with borane or lithium aluminum hydride. 
When Y is alkylthio the corresponding compound where Y is alkylsulfinyl or 
alkylsulfonyl may be produced by oxidation with hydrogen peroxide or a 
peracid such as trifluoroperacetic acid known in the art. Variation in the 
reaction temperature, reaction time and reactivity of the substrate and 
the particular reagent will all be factors influencing whether the product 
is the sulfinyl or sulfonyl and manipulation of such variables is well 
known in the art. When Y is alkoxy, the corresponding compound wherein Y 
is hydroxy may be produced by conventional dealkylating reagents such as 
boron tribromide, boron trichloride, trimethylsilyliodide and hydrogen 
iodide. The thus-produced amino compound may be iodinated at the 
2-position to yield a compound of formula (III) and then the Y group may 
be transformed into an alkylthio group by reaction with sodium nitrate, 
potassium ethyl xanthate and an alkyliodide or into a fluoro group by 
reaction with hexafluorophosphoric acid in hydrochloric acid. In addition, 
compounds wherein Y is alkoxy may be produced from the phenol by 
alkylation with a reagent such as alkyl halide, e.g., methyl iodide, in 
the presence of a base. 
R.sup.5 -acetylenes used in Stage C or C' may be obtained from Farchan 
Laboratories of 4702 East 355th Street, Willoughby, Ohio 44094. 
Alternatively, the terminal R.sup.5 -acetylenes may be prepared by 
alkylation of metalloacetylenes as described by G. H. Viehe in "Chemistry 
of the Acetylenes", Marcel Dekker, New York (1969) page 170. 
Compounds of the formula (I), including the acid-addition salts and 
quaternary compounds thereof, are calcium blockers and as such, are 
effective against angina, hypertension and cardiac arrhythmias in mammals, 
particularly as described by S. F. Flaim et al. in "Calcium 
Blockers--Mechanisms of Action and Clinical Applications", Urban and 
Schwarzenberg, Baltimore, Md. (1982). Techniques used to determine 
efficacy as a calcium blocker are described by S. F. Flaim et al. in 
Pharmacology, Vol. 22, p. 286 to 293 (1981). Compounds of the invention 
have the advantage of a significant separation between the desirable 
coronary vasodilator effects and the less desirable side effect of 
decreased myocardial contractile force. 
The activity of compounds of formula (I) for the treatment of hypertension 
was determined using the Spontaneously Hypertensive Rat (SHR) test as 
described below. 
In this test, the arterial pressure of adult spontaneously hypertensive 
rats (Charles River) is monitored directly via an aortic cannula. The SH 
rats are anesthetized with an inhalation anesthetic (ether). The left 
carotid artery is isolated and cannulated. The tip of the cannula is 
advanced to the aorta and the cannula is exteriorized behind the neck at 
the level of the scapula. Animals are placed in individual cages and 
allowed to recover from the anesthetic and are kept unrestrained. The 
arterial cannula is connected to the pressure transducer which is attached 
to the recorder. The test compounds are administered to at least 3 rats at 
doses selected in the range of 0.1 to 100 mg/kg of body weight by 
intraperitoneal (i.p.) or oral (p.o.) routes of administration. The 
arterial pressure and heart rate are monitored for a minimum of 24 hours. 
A test compound is considered to be active as an antihypertensive agent if 
the mean arterial pressure (MAP) indicates a fall of &gt;15 mm of Hg. Each 
animal serves as its own control. 
In addition to their utility in the treatment of hypertension, the 
compounds of formula (I) are useful in the treatment of the symptoms of 
angina pectoris by virtue of their ability to dilate coronary arteries. 
Their activity was measured using the "Langendorff's isolated heart" 
preparation. This test has been described in "Pharmacological Experiments 
on Isolated Preparations", Staff of the Department of Pharmacology, 
University of Edinbourgh, 2nd Ed., Churchill Livingstone, N.Y., 1970, pp. 
112-119. The test compounds were adminsistered at concentrations of 30.0, 
10.0, 3.0, 1.0, 0.3, 0.1, 0.03, and 0.01 micromolar (10.sup.-6 molar). 
The utility of compounds of the invention is demonstrated by results 
obtained in the above tests for compounds of formula (I) wherein R.sup.1 
=CH.sub.3 ; R.sup.2 =Alk(R.sup.6)q Ar; Alk=--CH.sub.2 CH.sub.2 ; q=O; 
Ar=3,4-dimethoxyphenyl; and R.sup.4 =H in the following Table I: 
__________________________________________________________________________ 
SHR Langendorff 
Compound Max fall bp.sup.d 
EC.sub.30 
Example 
Y n R.sup.3 
R.sup.5 
(dose).sup.e 
(10.sup.-6 M) 
__________________________________________________________________________ 
20 5-OCH.sub.3.sup.a 
1 H n-C.sub.4 H.sub.9 
-35(30) 
0.1 
29 5-OCH.sub.3.sup.b 
1 n-C.sub.5 H.sub.11 
n-C.sub.4 H.sub.9 
-36(30) 
0.03 
20 4,5-(OCH.sub.2 O).sup.c 
1 H n-C.sub.4 H.sub.9 
-30(100) 
0.3 
22 5-OCH.sub.3 
0 CH.sub.3 
cyclo- 
-65(10) 
0.03 
hexyl 
__________________________________________________________________________ 
.sup.a administered as the cyclohexylsulfamate 
.sup.b administered as the oxalate 
.sup.c administered as the free base 
.sup.d in mm of Hg 
.sup.e in mg/kg of body weight per os 
For the treatment of hypertension or angina, compounds of the present 
invention of the formula (I) may be administered orally or parenterally in 
a pharmaceutical composition comprising about 1 to 2,000 mg, preferably 
about 30 to 400 mg of one or more of the acetylene compounds per day for 
an average adult human depending on the activity of the particular 
compound chosen. The dosage may be divided into 1 to 4 unit dosage forms 
per day. While the therapeutic methods of the invention are most useful 
for human subjects in need of alleviation of hypertension or angina, the 
compounds may be administered to other mammals at comparable dosages per 
weight of the subject. 
Pharmaceutical compositions containing the acetylene compounds of the 
present invention of formula (I), an acid addition salt thereof or a 
quaternary ammonium compound thereof as the active ingredient may be 
prepared by intimately mixing the acetylene compound with a pharmaceutical 
carrier according to conventional pharmaceutical compounding techniques, 
which carrier may take a wide variety of forms depending on the form of 
preparation desired for administration, e.g., oral or parenteral. In 
preparing the compositions in oral dosage form, any of the usual 
pharmaceutical media may be employed, including liquid carriers such as 
water, glycols, oils, alcohols and the like for oral liquid preparations 
such as suspensions, elixers and solutions; and solid carriers such as 
starches, sugars, kaolin, calcium stearate, ethyl cellulose, etc., 
including materials which function as lubricants, binders, disintegrating 
agents and the like for powders, capsules and tablets. Because of their 
ease in administration, tablets and capsules represent the most 
advantageous oral dosage form. These compositions employ solid 
pharmaceutical carriers such as the aforementioned starches, sugars, 
kaolin and the like, generally with a lubricant such as calcium stearate. 
It is especially advantageous to formulate the aforementioned 
pharmaceutical compositions in dosage unit form for ease of administration 
and uniformity of dosage. The term "dosage unit form" as used in the 
specification and claims herein refers to physically discrete units 
suitable as unitary dosages, each unit containing a predetermined quantity 
of active ingredient calculated to produce the desired therapeutic effect 
in association with the required pharmaceutical carrier. Examples of such 
dosage unit forms are tablets, capsules, pills, powder packets, wafers, 
teaspoonful, tablespoonful and the like, and segregated multiples thereof. 
In the following Examples, the following abbreviations are used: E (trans); 
Z (cis); bp (boiling point); mp (melting point); g (grams); ml 
(milliliters); glc (gas liquid chromatography); NMR (nuclear magnetic 
resonance); J (coupling constant); d (doublet); dd (doublet of doublets); 
s (singlet); m (multiplet); t (triplet); N (normal); M (molar); THF 
(tetrahydrofuran); MeOH (methanol); DMF (dimethylforamide); mmoles 
(millimoles); mg (milligrams); mm (millimeters); and C,H,N, etc. (the 
chemical symbols for the elements). Unless otherwise indicated, all 
temperatures are reported in degrees centigrade (.degree.C.) and all 
pressures in mm of mercury.

EXAMPLE 1 
2-Iodo-5-methoxybenzeneacetic Acid 
A solution of 45 g (0.27 mole) of 3-methoxybenzeneacetic acid, 52.6 g (0.32 
mole) of iodine monochloride and 1 g of iodine was allowed to stand in 500 
ml of glacial acetic acid for six days at room temperature. The reaction 
was poured into water and the solid collected. It was recrystallized from 
toluene to give 51 g of crystalline 2-iodo-5-methoxybenzeneacetic acid, mp 
133.5.degree.-134.5.degree. C. (65% yield). 
EXAMPLE 2 
Using the procedure of Example 1 and employing equivalent quantities of the 
following benzenealkanoic acids in place of 3-methoxybenzeneacetic acid, 
the following o-iodobenzenealkanoic acids were obtained respectively as 
products: 
______________________________________ 
Starting Acid Product % Yield mp (.degree.C.) 
______________________________________ 
3,4-Dimethoxybenzene- 
4,5-Dimethoxy-2- 
82 165-7 
acetic Acid iodobenzeneacetic 
Acid 
3-Methoxybenzene- 
2-Iodo-5-methoxy- 
69 98-101 
propanoic Acid 
benzenepropanoic 
Acid 
3,4-Dimethoxybenzene- 
4,5-Dimethoxy-2- 
88 149-151 
propanoic Acid 
iodobenzene- 
propanoic Acid 
3,5-Dimethoxybenzene- 
3,5-Dimethoxy-2- 
propanoic Acid 
iodobenzene- 
propanoic Acid 
1,3-benzodioxole-5- 
6-Iodo-1,3 benzo- 
66 143-5 
propanoic acid 
dioxole-5- 
propanoic Acid 
______________________________________ 
EXAMPLE 3 
2-Iodo-5-methoxybenzenepropanoic Acid 
Samples of iodine (138.6 g, 0.759 mole) and silver acetate (126.7 g, 0.759 
mole) were added in portions over 20 min to a solution of 138.6 g (0.759 
mole) of 3-methoxybenzenepropanoic acid in 750 ml glacial acetic acid. An 
additional 250 ml of glacial acetic acid was added. The mixture became 
warm and was stirred for one hour. The precipitated silver iodide was 
filtered and washed with acetic acid and the iltrate was poured into ice 
water and the solid collected. The solid was taken up in eiother, washed 
with sodium thiosulfate solution and brine, dried with MgSO.sub.4 and the 
solvent evaporated in vacuo. The residue was recrystallized from 
CHCl.sub.3 /ligroin to give 148.7 (64% yield) of 
2-iodo-5-methoxybenzenepropanoic acid, mp 105.degree.-106.degree. C. 
EXAMPLE 4 
1-(2-Iodo-5-methoxyphenyl)butane-3-one 
Samples of iodine (42.4 g, 0.167 mole) and silver acetate (27.87 g, 0.167 
mole) were added in portions to a solution of 29.8 g (0.167 mole) of 
1-(3-methoxyphenyl)butane-3-one in 167 ml of glacial acetic acid. The 
mixture was stirred one hour. The silver iodide was removed by filtration 
and washed with acetic acid. The filtrate was partitioned between ether 
and water. The ether layer was washed with water, sodium bicarbonate 
solution and sodium thiosulfate solution. The ether solution was dried 
with MgSO.sub.4 and evaporated to dryness in vacuo. There was obtained 
41.8 g (82% yield) of oily 1-(2-iodo-5-methoxyphenyl)butane-3-one. 
.sup.1 HNMR (CDCl.sub.3): 7.5-7.8 (d, J=9, 1H); 6.75-6.9 (d, J=3, 1H); 
6.3-6.65 (dd, J=3, 10, 1 H); 3.7-4.0 (s, 3H); 2.5-3.1 (m, 4H); 2.2 (s, 
3H). 
EXAMPLE 5 
Using the procedure of Example 4 and substituting the appropriate ketone 
for 1-(3-methoxyphenyl)butane-3-one the following products were obtained 
respectively: 
(2-iodo-5-methoxyphenyl)-2-propanone, mp 57.degree.-58.degree. 
1-(2-iodo-5-methoxy-phenyl)octan-3-one 
EXAMPLE 6 
N,N-Dimethyl-2-iodo-5-methoxybenzeneacetamide 
A 16.7 g (0.19 mole) sample of oxalyl chloride was added dropwise at 
0.degree. C. to a solution of 50.0 g (0.17 mole) of 
2-iodo-5-methoxybenzeneacetic acid in 310 ml dry toluene and 31.7 ml of 
DMF. The mixture was allowed to warm to room temperature and stir for 16 
hours. The solution was cooled to 0.degree. C. and dimethylamine gas was 
admitted until the mixture was strongly basic. The mixture was allowed to 
warm to room temperature and stir for three hours and methylene chloride 
was added. The organic layer was washed with water, dilute hydrochloric 
acid, and sodium hydroxide. The organic layer was dried with MgSO.sub.4 
and evaporated in vacuo to give 54.2 g of 
N,N-dimethyl-2-iodo-5-methoxybenzeneacetamide, mp 86.degree.-89.degree. C. 
Elemental Analysis: Calculated for C.sub.11 H.sub.14 INO.sub.2 : C, 41.39; 
H, 4.42; Found: C, 41.43; H, 4.45. 
EXAMPLE 7 
2-Iodo-5-methoxybenzenepropanoyl chloride 
To a solution of 13.0 g (0.042 mole) of 2-iodo-5-methoxybenzenepropanoic 
acid and 4 ml of DMF in 80 ml of dry toluene at 0.degree. C. was added 
4.00 ml (0.046 mole) of oxalyl chloride over 15 min. The reaction was 
stirred overnight to give a solution 2-iodo-5-methoxybenzenepropanoyl 
chloride in toluene. 
EXAMPLE 8 
Following the procedure of Example 7 and employing equivalent quantities of 
the appropriate iodoarylalkanoic acid in place of 
3-methoxybenzenepropanoic acid there were obtained as products, 
respectively: 
3,4-Dimethoxy-2-iodobenzenacetyl chloride 
1,3-Benzodioxole-2-iodo-5-propanoyl chloride 
2-Iodo-5-methylthiobenzenepropanoyl chloride 
2-Iodo-5-fluorobenzenepropanoyl choride 
EXAMPLE 9 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-iodo-5-methoxy-N-methylbenzenepropanamid 
A solution of 13.8 g (0.042 mole) of 2-iodo-5-methoxybenzenepropanoyl 
chloride in 80 ml of toluene was cooled to 0.degree. C. and 24.6 g (0.126 
mole) of N-methylhomoveratrylamine was added over a 15-minute period. An 
additional 50 ml of toluene was added. The temperature was allowed to warm 
to room temperature and stirring continued for 31/2 hours. The mixture was 
partitioned between 500 ml of methylene chloride and 400 ml of water. The 
methylene chloride layer was separated and washed with 400 ml of 5% 
hydrochloric acid followed by a washing with 400 ml of 5% sodium hydroxide 
solution. The organic phase was dried over anhydrous magnesium sulfate and 
evaporated in vacuo to yield 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-iodo-5-methoxy-N-methylbenzenepropanami 
de, a pale yellow oil that partially crystallized on standing. 
EXAMPLE 10 
Following the procedure of Example 9 and employing an equivalent quantity 
of the appropriate arylalkanoyl halide in place of 
2-iodo-5-methoxybenzenepropanoyl chloride and an equivalent quantity of 
the appropriate amine for N-methylhomoveratrylamine the following amides 
were added obtained as products, respectively: 
______________________________________ 
Product mp .degree.C. 
______________________________________ 
2-Iodo-4,5-dimethoxy-N,N--dimethylbenzene- 
101-103 
acetamide 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-2-iodo- 
oil 
N--methyl-5-methylthiobenzenepropanamide 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-6-iodo- 
oil 
N--methyl-1,3-benzodioxole-5-propanamide 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-2-iodo- 
105-106 
5-methoxy-N--methylbenzenepropanamide 
2-Iodo-5-methoxy-N,N--dimethylbenzene- 
oil 
propanamide 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-5-fluoro- 
oil 
2-iodo-N--methylbenzenepropanamide 
______________________________________ 
EXAMPLE 11 
2-Iodo-5-methoxy-N,N-dimethylbenzeneethanamine hydrochloride 
A solution of 80.8 g (0.253 mole) of 
2-iodo-5-methoxy-N,N-dimethylbenzeneacetamide in 800 ml of THF was added 
over ten minutes of 760 ml of 1M borane in THF. The mixture was heated 
under reflux for two hours. A 50 ml portion of water was added and the 
mixture stirred. The solvent was evaporated in vacuo and replaced with 200 
ml of propionic acid. The mixture was heated for two hours and poured into 
ice/sodium hydroxide solution and extracted with ether. The ether solution 
was washed with sodium hydroxide and water and dried with K.sub.2 
CO.sub.3. The ether was evaporated in vacuo to give 67.3 g of a clear oil 
which was distilled in a Kugelrohr at 125.degree.-150.degree. C. (0.17 
Torr). The distillate was taken up in dilute hydrochloric acid and washed 
with ether. The aqueous layer was made basic with sodium hydroxide and 
extracted with ether. The ether solution was dried with K.sub.2 CO.sub.3 
and evaporated in vacuo to give 38.6 g (76% yield) of clear oily 
2-iodo-5-methoxy-N,N-dimethylbenzeneethanamine. The hydrochloride was 
prepared from ether-hydrogen chloride, mp 167.5.degree.-169.degree. C. 
EXAMPLE 12 
Using the procedure of Example 11 and employing an equivalent quantity of 
the appropriate amide from Example 10 in place of 
2-iodo-5-methoxy-N,N-dimethylbenzeneacetamide the following amines were 
obtained as products, respectively: 
______________________________________ 
Product mp (.degree.C.) 
______________________________________ 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-2-iodo-5- 
105-106 
methoxy-N--methylbenzenepropanamine p-toluen- 
sulfonate 
2-Iodo-4,5-dimethoxy-N,N--dimethylbenzene- 
201-203 
ethanamine hydrochloride 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-2-iodo-N-- 
132-135 
methyl-5-methylthiobenzenepropanamine oxalate 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-5-fluoro-2- 
129-131 
iodo-N--methylbenzenepropanamine oxalate 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-6-iodo-N-- 
oil 
methyl-1,3-benzodioxole-5-propanamine 
2-Iodo-5-methoxy-N,N--dimethylbenzenepropan- 
168-170 
amine hydrochloride 
______________________________________ 
EXAMPLE 13 
4-(3-Methoxyphenyl)-3-buten-2-one 
A solution of 19.08 ml of 10% sodium hydroxide solution was added dropwise 
to a mixture of 103.6 g (0.761 mole) of 3-methoxybenzaldehyde, 117.2 g 
(2.02 mole) of acetone and 75 ml of water. The temperature was kept 
between 24.degree. and 28.degree. by intermittent application of cooling. 
After 2.75 hours the mixture was acidified with dilute hydrochloric acid 
and partitioned between CH.sub.2 Cl.sub.2 and water. The organic layer was 
washed with water, dried with MgSO.sub.4 and concentrated in vacuo to give 
132.6 g of a yellow oil. The oil was distilled in a Kugelrohr at 0.5 Torr. 
A forerun bp 90.degree.-110.degree. C. was taken and discarded. The main 
fraction was taken between 110.degree. and 120.degree. C. There was 
obtained 91.68 g (68% yield) of 4-(3-methoxyphenyl)-3-buten-2-one as a 
yellowish oil. 
EXAMPLE 14 
1-(3-methoxyphenyl)-1-octen-3-one 
Following the procedure of Example 13 and substituting an equivalent 
quantity of 2-heptanone for acetone there was obtained 
1-(3-methoxyphenyl)-1-octen-3-one, bp 110.degree.-134.degree. C., 0.3 
mm/Hg. 
EXAMPLE 15 
4-(3-Methoxyphenyl)-2-butanone 
A solution of 30.1 g of 4-(3-methoxyphenyl)-3-buten-2-one in 200 ml of MeOH 
was hydrogenated over 200 mg of 10% palladium on carbon for two hours. The 
catalyst was filtered and the solvent evaporated in vacuo to give 30.2 g 
of yellow oily 4-(3-methoxyphenyl)-2-butanone. 
EXAMPLE 16 
1-(3-Methoxyphenyl)octan-3-one 
Following the procedure of Example 15 and substituting an equivalent 
quantity of 1-(3-methoxyphenyl)-1-octen-3-one for 
4-(3-methoxyphenyl)-3-buten-2-one there was obtained as the product 
1-(3-methoxyphenyl)octan-3-one as a colorless oil. 
EXAMPLE 17 
2-Iodo-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine hydrochloride 
A mixture of 13.0 g (0.036 mole) of 1-(2-iodo-5-methoxyphenyl)heptan-2-one, 
46.6 ml (0.18 mole) of a solution of 3.86 M dimethylamine in methanol, 
8.24 g (0.101 mole) of dimethylamine hydrochloride, 100 ml of methanol and 
1.82 g (0.029 mole) of sodium cyanoborohydride was stirred overnight under 
an atmosphere of nitrogen. Stirring was continued an additional two hours 
and the reaction mixture acidified to pH 1 by addition of concentrated 
hyirochloric acid. The solvent was evaporated in vacuo, the residue 
partitioned between methylene chloride and water, and the methylene 
chloride layer separated, washed with Na.sub.2 S.sub.2 O.sub.5 solution 
followed by a washing with 3 M sodium hydroxide solution. The organic 
phase was dried over anhydrous potassium carbonate and evaporated in vacuo 
to yield a yellow oil. The oil was dissolved in methanol and the solution 
treated with ethereal hydrogen chloride to pH 5. The solvent was removed 
in vacuo and the residue dissolved in 45 ml of refluxing ethyl acetate. 
Some slight turbidity was removed by filtration through filter aid. The 
filtrate was cooled to room temperature and diluted with 20 ml of diethyl 
ether. The solution was cooled overnight in a refrigerator and the 
resulting solid, 3.34 g, removed by filtration. The filtrate was 
evaporated in vacuo, the residue triturated with ether and seeded to yield 
a second crop of off-white solid, 1.66 g. One recrystallization from ethyl 
acetate yielded pure 
2-iodo-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine hydrochloride, 
mp 100.degree.-103.degree. C. 
EXAMPLE 18 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-iodo-N,alphadimethylbenzeneethanamine 
Oxalate 
A solution of 14.5 ml (86.2 mmoles) of homoveratrylamine, 19.0 g (65.5 
mmoles) of (2-iodo-5-methoxyphenyl)-2-propanone and 0.162 g (0.86 mmole) 
of p-toluene sulfonic acid in 250 ml of toluene was heated under reflux 
with azeotropic removal of water for three hours. The solvent was 
evaporated in vacuo to give 34.7 g of the corresponding imine as an oil. 
The imine was dissolved in 250 ml of MeOH and 3.5 g (55.2 mmoles) of sodium 
cyanoborohydride was added. The mixture was stirred for 18 hours. Hydrogen 
chloride gas was admitted slowly to lower the pH to below one. The residue 
was partitioned between ether and aqueous NaOH solution. The ether layer 
was washed with brine and dried (K.sub.2 CO.sub.3). Carbon dioxide was 
passed through the solution over one hour. The precipitated 
homoveratrylamine carbonate was removed by filtration. The filtrate was 
evaporated to dryness in vacuo. 
The residue, 29.9 g (65.7 mmoles) of crude 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-iodo-5-methoxyalphamethylbenzeneethanam 
ine, was taken up in 300 ml of MeOH and 10 ml (0.131 mole) of formalin and 
5.0 g (78.8 mmoles) of sodium cyanoborohydride were added. The mixture was 
stirred for 22 hours. 
Methanolic hydrogen chloride was added to bring the pH to one. The solvent 
was evaporated in vacuo. The residue was partitioned between ether and 
aqueous NaOH solution. The ether was dried (K.sub.2 CO.sub.3) and the 
solvent evaporated in vacuo to give 30.2 g of a colorless oil. 
An oxalate salt was prepared in 95% ethanol to give 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-iodo-5-methoxy-N,alphadimethylbenzeneet 
hanamine oxalate as a white crystalline solid, mp 178.degree.-179.degree. 
C. 
EXAMPLE 19 
2-(1-Hexynyl)-5-methoxy-N,N-dimethylbenzeneethanamine hydrochloride (1:1) 
A solution of 2.7 ml (0.027 mole) 1-hexyne in 10 ml dry (4 A sieves) 
tetrahydrofuran was cooled to 0.degree. C. in an ice bath. Argon was 
passed over the solution 10.4 ml (0.027 mole) 2.69 M n-BuLi was added 
slowly via syringe through a serum cap. The resulting solution was stirred 
20 minutes under argon. During this time, a second flask containing 3.2 g 
(0.027 mole) anhydrous zinc chloride was attached to the first flask via 
cannula. After the 20 minutes the contents of the first flask was 
transferred to the second flask via cannula. The second flask was cooled 
to 0.degree. C. This solution was stirred for 20 minutes, then 5 g (0.016 
mole) 2-iodo-5-methoxy-N,N-dimethylbenzeneethanamine in 20 ml dry 
tetrahydrofuran was added via syringe. 0.32 g (mole 1%) 
tetrakis(triphenylphosphine) palladium was added to the reaction mixture 
which was stirred overnight at room temperature under nitrogen. Water was 
added to the reaction mixture and the organics were evaporated in vacuo. 
The residue was taken up in methanol, the solid catalyst was filtered off 
and the methanol was evaporated in vacuo. Methylene chloride was added to 
the aqueous residue, the organic layer was washed with sodium bicarbonate 
solution, water, brine solution and dried over potassium carbonate. The 
organics were evaporated in vacuo to give a red oil. Addition of ethereal 
hydrogen chloride gave white crystals which upon recrystallization from 
acetonitrile gave 1.27 g (27% yield) of 
2-(1-hexynyl)-5-methoxy-N,N-dimethylbenzeneethanamine hydrochloride, mp 
145.5.degree.-147.5.degree. C. 
EXAMPLE 20 
Following the procedure of Example 19 and employing an equivalent quantity 
of the appropriate iodoarylalkaneamine in place of 
2-iodo-5-methoxy-N,N-dimethylbenzeneethanamine and the appropriate 
1-alkyne in place of 1-hexyne there were obtained as products, 
respectively: 
______________________________________ 
Product mp (.degree.C.) 
______________________________________ 
2-(Cyclohexylethynyl)-3,4-dimethoxy-N,N--dimethyl- 
162-163 
benzeneethanamine (E)-2-Butenedioate (1:1) 
2-(1-Hexynyl)-5-methoxy-N,N--dimethylbenzene- 
139-140 
propanamine Cyclohexylsulfamate (1:2) 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-6-(1-hexynyl)- 
oil 
N--methyl-1,3-benzodioxole-5-propanamine 
2-(1-Decynyl)-5-methoxy-N,N--dimethylbenzene- 
68-70 
propanamine 2-Naphthalenesulfonate hydrate 
(10:10:11) 
2-(3,3-Dimethylbutynyl)-5-methoxy-N,N--dimethyl- 
146-148 
benzenepropanamine Cyclohexylsulfamate (1:2) 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-2-(1-hexynyl)-5- 
107-110 
methoxy-N--methylbenzenepropanamine Cyclohexyl- 
sulfamate Hydrate (2:4:1) 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-2-(3,3-dimethyl- 
117-119 
butynyl)-5-methoxy-N--methylbenzenepropanamine 
Cyclohexylsulfamate (1:2) 
N--[2-(3,4-Dimethoxyphenyl)ethyl]-5-methoxy-N-- 
109-111 
methyl-2-(4-phenyl-1-butynyl)benzenepropanamine 
Cyclohexylsulfamate (1:2) 
2-[3-(Diethylamino)-1-propynyl]-N--[2-(3,4- 
171-173 
dimethoxyphenyl)ethyl]-5-methoxy-N--methyl- 
benzenepropanamine Hydrochloride (1:2) 
2-(Butynyl)-N--[2-(3,4-dimethoxyphenyl)ethyl]-5- 
114-117 
methoxy-N--methylbenzenepropanamine Cyclohexyl- 
sulfamate (1:2) 
2-(Cyclohexylethynyl)-N--[2-(3,4-dimethoxyphenyl)- 
115-117 
ethyl]-5-methoxy-N--methylbenzenepropanamine 
Cyclohexylsulfamate (1:2) 
______________________________________ 
EXAMPLE 21 
2-(1-Hexynyl)-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine 
(E)-2-butendioate 
A solution of 4.59 g (11.8 mmoles) of 
2-iodo-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine in 22 ml of 
triethylamine was treated with 1.76 ml (15.3 mmoles) of 1-hexyne. 0.022 g 
(0.12 mmole) of copper (I) iodide and 0.041 g (0.06 mmole) of (Ph.sub.3 
P).sub.2 Pd(II)Cl.sub.2. The mixture was stirred for three days at room 
temperature. The reaction mixture was treated with 150 ml of water and 
extracted with ether. The ether phase was washed four times with water and 
once with brine, dried (K.sub.2 CO.sub.3) and evaporated in vacuo to give 
3.72 g of an oil. A fumarate salt was prepared in MeOH solvent. There was 
obtained 3.35 g of cyrstalline product in three crops. Recrystallization 
from acetonitrile-ether afforded 3.07 g (57% yield) of crystalline 
2-(1-hexynyl)-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine 
(E)-2-butenedioate (2:3), mp 125.degree.-126.degree. C. 
Elemental Analysis: Calculated for C.sub.23 H.sub.37 NO.1.5 C.sub.4 H.sub.4 
O.sub.4 : C, 67.29; H, 8.37; N, 2.70 Found: C, 67.21; H, 8.41; N, 2.70. 
EXAMPLE 22 
Following the procedure of Example 21 and substituting an equivalent 
quantity of 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-iodo-5-methoxy-N,alpha-dimethylbenzenee 
thanamine for 2-iodo-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine 
and an equivalent quantity of the appropriate acetylene for 1-hexyne there 
were obtained as products (oils), respectively: 
2-(Cyclohexylethynyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-N,alphadim 
ethylbenzeneethanamine 
.sup.1 H NMR (CDCl.sub.3): 7.24-7.20 (m, 1H); 6.78-6.62 (m, 5H); 3.85 (s, 
3H); 3.83 (s, 3H); 3.75 (s, 3H); 2.71-2.65 (m, 5H); 2.50 (m, 1H); 2.39 (s, 
3H); 1.82-1.68 (m, 4H); 1.46-1.27 (m, 6H) 0.94 (d, J=7.2 Hz, 3H). 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(1-hexynyl)-5-methoxy-N,alphadimethylben 
zeneethanamine 
.sup.1 H NMR (CDCl.sub.3) 7.30-7.25 (m, 1H); 6.76-6.66 (m, 5H); 3.86 (s, 
3H); 3.84 (s, 3H); 3.76 (s, 3H); 3.18-3.02 (m, 3H); 2.75 (s, 4H); 
2.62-2.55 (m, 1H); 2.39 (s, 3H); 2.31 (t, J=7 Hz, 2H); 1.58-1.37 (m, 4H); 
0.95 (d, J=7 Hz, 3H); 0.87 (t, J=7 Hz, 3H). 
EXAMPLE 23 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(3-hydroxy-3-methylbutynyl)-5-methoxy-N- 
methylbenzenepropanamine (E)-2-butenedioate (2:1) 
A solution of 5.0 g (10.7 mmoles) of 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-iodo-5-methoxy-N-methylbenzenepropanami 
ne in 100 ml of triethylamine was treated with 1.3 ml of 
2-methyl-3-butyn-2-ol, 214 mg of Pd (.phi..sub.3 P).sub.2 Cl.sub.2 and 107 
mg Copper (I) iodide. The mixture was stirred overnight and the 
triethylamine removed in vacuo. The residue was dissolved in diethyl ether 
and the insoluble solids removed by filtration. The filtrate was washed 
sequentially with water, sodium bicarbonate solution, water, and brine. 
The ether layer was dried over anhydrous potassium carbonate and the 
solvent removed in vacuo to yield 9.5 g of a brown liquid. The brown 
liquid was treated under additional vacuum to remove all triethylamine and 
the residue treated with one-half equivalent of fumaric acid in methanol 
and isopropanol to yield a crude fumarate salt. The crude salt was 
recrystallized from methanol/isopropanol to yield 6.69 g of pure 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(3-hydroxy-3-methylbutynyl)-5-methoxybe 
nzenepropanamine (E)-2-butenedioate (2:1), mp 160.degree.-161.degree. C. 
Elemental Analysis: Calculated for C.sub.26 H.sub.35 NO.sub.4.1/2 C.sub.4 
H.sub.4 O.sub.4 : C, 69.54; H, 7.71; N, 2.90 Found: C, 69.51; H, 7.75; N, 
2.87. 
EXAMPLE 24 
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-ethynyl-5-methoxy-N-methylbenzenepropana 
mine Cyclohexylsulfamate (1:2) 
A solution of 4.6 g (0.01 mole) of 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(3-hydroxy-3-methylbutynyl)-5-methoxy-N 
-methylbenzenepropanamine in 150 ml of toluene when treated with 1 ml of 
50% aqueous NaOH solution and 0.3 g of tetra-n-butylammonium choloride. 
The mixture was heated under reflux for 16 hours. An additional 0.6 g of 
tetra-n-butylammonium chloride was added and refluxing was continued for 
four hours. An additional 0.6 g of tetra-n-butylammonium chloride was 
added and refluxing was continued for 20 hours. The solvent was evaporated 
in vacuo and the residue partitioned between ether and water. The organic 
phase was washed with water and brine, dried (K.sub.2 CO.sub.3) and the 
solvent evaporated in vacuo to give 5.2 g of a brown oil. The oxalate salt 
was prepared and recrystallized from 95% ethanol. The oxalate was 
reconverted to the base by partitioning between ether and NaOH solution. 
The resulting ether solution was evaporated and the residue flash 
chromatographed on silica gel using a mixture of one part MeOH to 20 parts 
CHCl.sub.3 as the eluant. The fraction containing the desired amine was 
evaporated in vacuo. The residue was dissolved in 2-propanol and treated 
with two equivalents of cyclohexylsulfamic acid. There was obtained 0.61 g 
of 
N-[2-(3,4-dimethoxyphenyl)ethyl]-2-ethynyl-5-methoxy-N-methylbenzenepropan 
amine cyclohexylsulfamate (1:2) as a crystalline solid, mp 
120.degree.-122.degree. C. 
Elemental Analysis: Calculated for C.sub.23 H.sub.29 NO.sub.3.2 C.sub.6 
H.sub.13 NO.sub.3 S: C, 57.91; H, 7.64; N, 5.79 Found: C, 57.55; N, 7.72; 
N, 5.74. 
EXAMPLE 25 
Ethyl 3-aminobenzenepropanoate hydrochloride 
A suspension of 100 g (0.52 moles) of 3-nitrocinnamic acid in 800 ml 
glacial acetic acid and 100 ml of methanol was hydrogenated at 50 pounds 
per square inch over 2.5 g 10% palladium on carbon until four equivalents 
of hydrogen were absorbed. The catalyst was filtered off, the filtrates 
combined and the solvent was concentrated in vacuo leaving a brown glass 
of 3-aminobenzenepropanoic acid. To this was added 1 liter of ethanolic 
hydrochloric acid which was brought to reflux for five hours. The solvent 
was evaporated off in vacuo leaving a purple solid. Recrystallization from 
ethyl acetate yielded 88.0 g of ethyl 3-aminobenzenepropanoate 
hydrochloride, mp 132.degree.-135.degree. C., (74% yield). 
EXAMPLE 26 
Ethyl 5-amino-2-iodobenzenepropanoate hydrochloride 
To a solution of 88.0 g (0.38 moles) ethyl 3-aminobenzenepropanoate in 380 
ml glacial acetic acid was added 97.3 g (0.38 moles) iodine and 96.0 g 
(0.57 moles) silver acetate portionwise, alternating the additions 
beginning with the iodine. After two hours of stirring 10 g of iodine was 
added and stirring was continued for an additional hour. The reaction 
mixture was filtered and the solid washed well with acetic acid. The 
filtrate was extracted with chloroform. The chloroform layer was washed 
with sodium bisulfite solution then evaporated in vacuo. The resulting red 
oil was converted to the hydrochloric acid salt giving 118.3 g of ethyl 
5-amino-2-iodobenzenepropanoate hydrochloride, mp 124.degree.-127.degree. 
C. (72% yield). 
EXAMPLE 27 
Sodium 2-iodo-5-methylthiobenzenepropanoate 
A mixture of 30 g (0.089 moles) of ethyl 5-amino-2-iodobenzenepropanoate, 
30 ml water, 20 g ice and 45 ml of hydrochloric acid was stirred for one 
hour. The solution was cooled to 0.degree. C. and 5.8 g (0.084 moles) of 
sodium nitrite in 15 ml of water were added dropwise keeping the 
temperature below 5.degree. C. After stirring for one hour the reaction 
mixture was added to a solution of 13.5 g (0.084 moles) of potassium ethyl 
xanthate in 20 ml of water. This was stirred for three hours. The reaction 
mixture was extracted several times with diethyl ether which was 
evaporated in vacuo. The resulting brown oil was taken up in 95% ethanol 
and 18.9 g (0.336 moles) of potassium hydroxide was added. After refluxing 
overnight under nitrogen the reaction was cooled. Methyl iodide (10.5 ml; 
0.168 moles) was added and the reaction was stirred three more hours. The 
ethanol was evaporated in vacuo. The residue was partitioned between 3 N 
hydrochloric acid and diethyl ether. The ether was washed with water, 
brine solution and dried over MgSO.sub.4. The ether was evaporated off. 
Conversion to the sodium salt gave 14.3 g of sodium 
2-iodo-5-methylthiobenzenepropanoate, mp 118.degree.-122.degree. C. (49% 
yield). 
EXAMPLE 28 
3-(5-Fluoro-2-iodophenyl)propionic acid 
A mixture of 30 g (0.084 mole) of ethyl 3-(5-amino-2-iodophenyl) propanoate 
45 ml of concentrated hydrochloric acid, 25 ml of water, and 40 g of ice 
was stirred for 40 minutes then cooled to -10.degree. C. A solution of 5.8 
g of sodium nitrite in 20 ml of water was added dropwise with stirring 
while maintaining a temperature of -10.degree. C. Stirring was continued 
for 11/2 hours then 13 ml of 65% hexafluorophosphoric acid was added 
slowly and the mixture allowed to warm to room temperature and stirring 
for a period of one hour. The resulting solid was removed by filtration 
and washed with water, 1:4::ethanol:water, and finally water. The solid 
was dried in vacuo, placed in 500 ml of xylene and heated at 130.degree. 
for 2.5 hours, until gas evolution ceased. The solvent was removed in 
vacuo and the residue partially dissolved in ether. The insolubles were 
removed by filtration and the filtrate washed with sodium bicarbonate 
solution, 3 N hydrochloric acid, water, and brine. The solvent was removed 
in vacuo to yield a brown oil which was purified by flash chromatography 
on silica using mixtures of ethyl acetate and hexane as the eluting 
solvent. The eluate was stripped in vacuo, the residue dissolved in ether, 
insolubles removed by filtration, and finally the solvent removed in vacuo 
to yield 9.3 g of nearly pure fluoro-iodo ester, a yellow oil. 
The ester was dissolved in 100 ml of methanol and treated with 15.5 ml of 3 
N sodium hydroxide solution. The mixture was refluxed for three hours and 
the solvent removed in vacuo. The resulting residue was poured into 3 N 
hydrochloric acid while cooling by addition of ice. The aqueous mixture 
was extracted with ether, the ether washed with brine and dried over 
anhydrous magnesium sulfate. The solvent was removed in vacuo to yield 8.9 
g of 3-(5-fluoro-2-iodophenyl)propionic acid, a yellow oil. 
EXAMPLE 29 
Starting with 1-(3-methoxyphenyl)octanone from Example 16 and employing the 
procedures of Examples 18 and 21 there was obtained as the product 
N-[2-(3,4-dimethoxyphenyl)-ethyl]-2-(1-hexynyl)-5-methoxy-N-methyl-.alpha. 
-pentyl-benzenepropanamine ethanedioate (1:1), mp 102.degree.-104.degree. 
C.