Table Of ContentPURDUE UNIVERSITY
THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION
by________Myron William McKinney________________________________
ENTrmm SPASMOLYTICS : BASIC ESTERS OF SUBSTITUTED ACETIC
__________ACIDS AND OF THE CORRESPONDING MA.LOMC ACIDS_______
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
Head of School or Department
August 14. 19 51
TO THE LIBRARIAN t—
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THIS THESIS IS NâT TO BE REGARDED AS CONFIDENTIAL.
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GRAD. SCHOOL FORM 9
SPASMOLYTICS: BASIC ESTERS OF SUBSTITUTED ACETIC ACIDS
AND OF THE CORRESPONDING- MA.LOÎÎIC ACIDS
A Thesis
Submitted to the Faculty
of
Purdue University
ty
Myron William McKinney
In Partial Fulfillment of the
Requirements for the Degree
of
Doctor of Philosophy
August, 1951
ProQuest Number: 27716047
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ACKNOWLEDGEMENT
The author wishes to express sincere appreciation to
Dr. John B. Data, under whose supervision this work was carried out,
for his advice and criticism s, to Dr. Henry M. Lee, Department of
Pharmacology, Research Division, Eli Lilly and Company, for the
preliminary pharmacological studies reported herein, to Mr. Roger Smith,
Analytical Department, Eli Lilly and Company for assistance in some of
the analytical data reported herein, and to the American Foundation for
Pharmaceutical Education whose fellowship made this work possible.
table of contents
Page
INTRODUCTION........................................................... 1
HISTORICAL ........................................................................................................................... 8
METHODS OF PREPARATION .............................................................. 30
EXPERIMENTAL................................. 38
Attempt to Prepare ft-Diethylaminoethyl Ethyl Diphenylmalonate • 38
Method A . ................................................... 38
Preparation of Ethyl Hydrogen Oxalate .......... 38
Preparation of Ethoxalyl Chloride ........................ 38
Preparation of Benzoin .......... 39
Preparation of Benzil ......... 39
Preparation of Benzil Monohydrazone ....................«••• 40
Preparation of Azibenzil ......... 40
Attempt to Prepare Diphenylketene .......................... 41
Method B 41
Preparation of Diphenylacetyl Chloride ................... 41
Preparation of -Diethylaminoethy1 Diphenylacetate ...... 42
Attempt to Prepare -Diethyleminoethyl Ethyl Di phenylmalonate • 42
Method C ................. 44
Preparation of Benzilic Acid .......... 44
Preparation of -Diethyleminoethyl Benzilate ................. 44
Preparation of ft -Diethylaminoethyl ^-Chiorodiphenyl-
acetate ................. 45
Attempt to Prepare ft-Diethylaminoethyl o( -Cyanodiphenyl-
acetate 45
TABLE OF CONTENTS (Cont'd.)
Page
Attempt to Prepare -Diethylaminoethyl Ethyl Phenylmal onate ... 46
Preparation of ft-Diethylaminoethyl Chloride Hydrochloride ...... 47
Preparation of ft-Diethylaminoethyl Chloride .................... 47
Preparation of Benzhydryl Bromide ............................... 48
Preparation of 9-Fluorenyl Bromide ................ 48
Preparation of Diethyl Substituted Maionates . . . . . . . . . . . . . . . . . . . 49
Diethyl Alkylmal on ate s, Method A .................... 49
Diethyl Benzhydrylmalonates, Method B ................. 50
Diethyl 9-Fluorenylmalonates, Method C . . . . . . . . . . . . . . . . . . . . 50
Preparation of Substituted Acetic Acids ......................... 55
Preparation of ft-Diethylaminoethyl Substituted Acetates ............... 55
Preparation of ft-Diethylaminoethyl Ethyl Monosubstituted
Malonates .,••• 58
Preparation of ft-Diethylaminoethyl Ethyl Disubstituted
Malonates ...................... 61
Preparation of Bis-( /^-Diethylaminoethyl) Monosubstituted
Malonates .......................... 63
Preparation of Bis-( /3-Diethylaminoethyl) Disubstituted
Malonates ............. 65
PHARMACOLOGICAL ACTIVITY ............................................................................. 67
SUMMARY ...................................................................................... 73
REFERENCES . 74
LISTS OP TABLES ANT) BLOW CHARTS
List of Flow Charts
Preparation of -Diethylaminoethyl Substituted
Acetates .................. 33
Preparation of /^-Diethylaminoethyl Ethyl
Substituted Malonates ......... 35
Preparation of Bis-(/^-Diethylaminoethyl)
Substituted Malonates .......................................... 37
List of Tables
-ge
Diethyl Substituted Malonates ......................... 52
Substituted Acetic Acids ..................................................... 54
ft -Diethylaminoethyl Substituted Acetates ......... 57
/^-Diethylaminoethyl Ethyl Monosubstituted
Malonates ..................................... 60
/3-Diethylaminoethyl Ethyl Disubstituted
Malonates ............................. . . . 62
Bis-( -Diethylaminoethyl) Monosubstituted
Malonates ................................................................................ 64
Bis-( /^-Diethylaminoethyl) Disubstituted
Malonates ............. 66
Spasmolytic Activity of the Acetic Ester Series ... 70
Spasmolytic Activity of the Monobasic
Malonic Ester Series .............................. 71
Spasmolytic Activity of the Dibasic Malonic
Ester Series ................................................. 72
1
SPASMOLYTICS: BASIC ESTERS OF SUBSTITUTED ACETIC ACIDS
AMD OF THE COHRESPOMDIMU MALONIC ACIDS
INTRODUCTION
According to Randall (1) spasmolytics are substances, both natural
and synthetic, which relieve spasm of smooth muscle» The word spasmolytic
is used synonymously with anti spasmodic; the latter term, however, is a
more general one used to describe the action of any materials which
relieve smooth muscle spasm.
The innervation of the body consists of the involuntary nervous
system, usually referred to as the autonomic nervous system, and the
voluntary nervous system usually called the somatic nervous system. The
latter exercises control over the skeletal muscle. The autonomic nervous
system is further divided into the parasympathetic and the sympathetic
nervous system. Agents which stimulate the parasympathetic system are
termed cholinergic drugs, since acetylcholine which occurs normally in the
body accomplishes this parasympatho stimulation. Compounds that depress
the parasympathetic system, such as atropine-like compounds, are called
parasympatholytics. These parasympatholytic agents may act by blocking
the response of parasympathetic nerve fibers to the stimulating effect of
acetylcholine which naturally occurs in the tissues (2). Those drugs which
abolish spasm, which is a sudden involuntary contraction of smooth muscle
(3), primarily through neural action are called neurotropic spasmolytics.
Papaverine-like substances act to abolish spasm by direct muscular action
which appears to be independent of the innervation to the effector cells.
Compounds which relieve spasm in this manner are termed musculotropic
spasmolytics.
2
Smooth muscles are referred to also as unstriated muscles or
involuntary muscles, These muscles are found in the walls of abdominal
tissue and in the blood vessels (4). This type of muscle tissue is
particularly prone to spasm. When such a spasm is persistent it is
referred to as tonic and when characterized hy alternate contraction and
relaxation it is called clonic. The relief of both tonic and clonic
spasms is generally accomplished by musculotropic or neurotropic spasmolytic
medication.
The number of spasmolytic agents used today by the physician is far
greater than the number of agents used a decade ago. Even though some
of these drugs have proven very useful, certain characteristic pharma
cological properties which are inherent in these drugs makes further
research in this area desirable. These properties w ill be reviewed
briefly.
Among the spasmolytic agents which occur naturally the most useful is
atropine. Atropine is a potent spasmolytic but is relatively toxic.
Undesirable side-effects at therapeutic dose levels are observed. These
are (a) slowing of the heart rate (b) a slight arrest of secretion of
those glands governed by central innervation and (c) a mild dilation of the
pupil of the eye and a slight paralysis of accommodation (5,6).
Papaverine, also a naturally occurring drug, relaxes many smooth
muscles of the body, especially those of the blood vessels. The toxicity
is very low. The ingestion of more than ten times the therapeutic dose
does not produce side effects. However, it is not useful clinically in
all instances for it is claimed to be ineffective in spastic colic of
various organs and is not of too great importance for intestinal spasm.
It is not as effective as epinephrine in bronchial spasm (7,8,9).
