Depressors: α,ω-Dicarbocyclic Derivatives of Amino Alkanes and Hydroxy Amino Alkanes

93 Pages·4.701 MB·English

by  Charnicki, Walter F

PURDUE UNIVERSITY
THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION
by____________W alter F- C h arn ickl____________________________________________
DEPRESS OHS : 01 .(J-DICARBOGYCLI0 DEHIVATIVES
ENTITLED
_________OF AMINO ALKANES AND HYDROXY AMINO ALKANES
COMPLIES WITH THE UNIVERSITY REGULATIONS ON GRADUATION THESES
AND IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS
FOR THE DEGREE OF
■Doctor, of Philosophy
PROFESSOR IN Charge of Thesis
H eap of School or Department
June______ 51
19
TO THE LIBRARIAN:-----
IS Vvo'f'
THIS THESIS IS-NOT TO BE REGARDED AS CONFIDENTIAL.
G2?AX>. SCHOOl FOHM D

DEPRESSORS :
Ol,<a>-DICARBOCYCLIC DERIVATIVES OF AMINO
ALKANES AND HYDROXY AMINO ALKANES
A Thesis
Submitted to the Faculty
of
Purdue University
by
Walter F* Charnicki
In Partial Fulfillment of the
Requirements for the Degree
of
Doctor of Philosophy
June, 1951
ProQuest Number: 27714209
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ACKNOWLEDGSMSNT
The author wishes to express his sincere
appreciation to Dr. John B. Data for his valu­
able guidance and criticisms, Mr. Albert L.
Picchioni and Dr. Leroy D. Edwards for invalu­
able assistance in performing the pharmacolog­
ical testing, and to the American Foundation for
Pharmaceutical Education whose fellowship grant
made this work possible.
TABLE OF CONTENTS
Page
INTRODUCTION................................ 1
HISTORICAL....................................... 6
EXPERIMENTAL.................... 25
Preparation of De s oxybe nz o i n ........... 25
Preparation of ci ,W-Dicarbocyclic Amino Alkanes ...... 25
Preparation of 2-Amino-l,2-diphenyl-
1-ethanol Hydro chloride ............. 28
Preparation of Benzalacetophenone ..... 28
Preparation of Benzylacetophenone .............. ••• 29
Preparation of Isonitrosobenzylacetophenone ........ 29
Preparation of 2-Amino-1,3-diphenyl-l-
propanol Hydro chloride ...................... 30
Preparation of 2-Amino-1,3-diphenyl-1-
propanone Hydrochloride .......... 31
Preparation of 3-Cyclohexyl-2-isonitroso-
l-phenyl-l-propanone .. ............. 31
(a) 3-Cyclohexyl-l-phenyl-l-propanone ••••• 31
(b) 3-Cyclohexyl-2-isonitroso-1-
phenyl-l-propanone ......................... 32
Preparation of 2-Amino-3-cyclohexyl-l-
phenyl-1-propanol Hydrochloride ........... 33
Preparation of p-Pheny 1 ethyl Bromide .......... 33
Preparation of Cyclohexanecarboxylic Acid ........... 34
Preparation of Cyclohexanecarbonyl Chloride ....... 35
Preparation of l-Cyclohexyl-3-phenyl-l-
propanone .................. 35
Preparation of 4-Pheny1butanoy1 Chloride ......... 36
Preparation of 1,4-Diphenyl-l-butanone ............. 36
Preparation of 2-1sonitroso-1,4-
diphenyl-l-butanone ............... 38
TABLE OF CONTENTS (Cont'd.)
Page
Preparation of 2-Amino-l,4-diphenyl-
1-butanol Hydrochloride ......... 38
Preparation of Diethyl Substituted Malonates ....... 39
Preparation of Dibenzylacetic Acid .... 41
Preparation of 2-Amino-l,3-
diphenylpropane Hydrochloride ....... 41
Preparation of 2-Benzyl-4-phenylbutanoic Acid ...... 42
Preparation of 2-Amino-1,4-
dlphenyl butane Hydrochloride ••••................•••• 42
Preparation of 3-Phenylpropanenitrile ..... 43
Preparation of 1,5-Diphenyl-3-pentanone ......43
PHARMACOLOGICAL ACTIVITY.................................. 45
SUMMARY.............................. 49
REFERENCES ............................................. 50
LIST OF TABLES
Table Page
1 oc,io-Bicarbocyclic Derivatives
of Amino Alkanes ...............* 27
2 Diethyl Substituted Malonates .... 40
3 Effects of ol ,u-Dicarbocyclic
Amino Alkanes and Hydroxy
Amino Alkanes on Blood
Pressure of Rats 46
X
DEPRESSORS ! et #<O-DICARB0CYCLIC DERIVATIVES OE
AMINO ALKANES AND HYDROXY AMINO ALKANES
INTRODUCTION
Certain chemical compounds will produce a fall in blood
pressure when administered to an experimental animal. Phar­
macologically, such compounds are often referred to as "de­
pressors" . The pharmacological action of such drugs is dia­
metrically opposite to "pressors" which are substances that
produce a rise in blood pressure. With reference to blood
pressure the term depressor is a general one since it is not
restrictive in meaning to the manner in which the lowering
of blood pressure is brought about# There are, however,
other terms used in conjunction with lowering of blood press­
ure which are quite specific in their meaning# For example,
antihypertensive is one of such terms. An antihypertensive
agent is a substance which lowers the blood pressure to nor­
mal levels by dilating the arteriolar system in hypertensive
subjects (1). This is done with no effect upon the function
of the heart, or the volume or viscosity of the blood. The
ideal drug would affect the blood pressure in normal states
to little or no extent#
It has only been since about the early 1900 * s that hy­
pertension, a state of abnormal high blood pressure,has been
recognized as a disease and treated as such (2). Today hy­
pertension is said to afflict approximately half of the
people over fifty years of age (5)# For obvious reasons the
2
need for a depressor agent with antihypertensive properties
exists even though there has been some question of the value
of the medicinal treatment of the disease (4). Such a drug
would not necessarily be one which would lower blood pressure
and maintain it at a low level for there are such substances *
A drug is needed which would meet the criteria of a true
antihypertensive agent but which would have none of the dis­
advantages of the medicinals that are employed for such pur­
pose at the present time.
A great number of substances have been used in the past
for the treatment of hypertension. For the most part, how­
ever, such drugs can be divided into three groups : bromides
and barbiturates, nitrites and nitrates, and thiocyanates
(5). These drugs have certain disadvantages. The seda­
tives, bromides and barbiturates, must be administered in
relatively large doses in order to obtain the proper results.
This is very undesirable. The nitrites and nitrates are
either too brief in their duration of action, the absorption
is too variable, or side-effects such as headache, weakness
and depression are produced. The thiocyanates are toxic as
evident by weakness, muscular aching, nausea and vomiting,
dizziness and confusion.
A review of the literature reveals that information on
the relationship of depressor activity and chemical struct­
ure is nil. Depressor activity has been observed with va­
rious chemical substances during their pharmacological in­
vestigation; however, it seems that many such compounds