Antihistaminics: Basic Derivatives of Ethyl Diphenylacetate

78 Pages·03.652 MB·English

by  Comer, Jack Payne

PURDUE UNIVERSITY
THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION
BY -Jack- Payne Comer
ANTIHLSTAMINICS* BASIC DERIVATIVES OF____________
en titled
___________ETHYL DIPHKNYLACETATE_______________________________
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 Phil osophy-------------------------------------------------
Professor in Charoe of Thesis
Head of School, or Department
-April 7__ ig 50-
TO THE LIBRARIAN:----
IS 'fYO
THIS THESIS IP nüOTTO BE REGARDED AS CONFIDENTIAL.
A& y
PROFESS <
GRAD, SCHOOL FORM 9—3-49—IM

ANTIHISTAHINICS:
BASIC DERIVATIVES OF ETHÏL DIPHENÏLACETATE
A Thesis
Submitted to the Faculty
of
Purdue University
by
Jack Payne Comer
In P artial Fulfillm ent of the
Requirements for the Degree
of
Doctor of Philosophy
June, 1950
ProQuest Number: 27712242
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ACKNOWLEDGMENT
The author is grateful for the guidance and personal
assistance given to him by Professor John B. Data and Dean
Glenn L* Jenkins and also for the financial aid received from
the Purdue Research Foundation#
TABLE OF CONTENTS
Page
INTRODUCTION............................................................................................................... 1
A SURVEY OF THE LITERATURE.......................................................................... 3
RELATIONSHIP OF CHEMICAL STRUCTURE TO PHYSIOLOGICAL ACTIVITY*.## 12
NATURE OF THE PROBLEM.......................................................................................... 18
METHODS OF SYNTHESES................. 23
EXPERIMENTAL PART.................................................................................................... 29
Preparation of Benzilic Acid ........... 29
Preparation of a-Chlorodiphenylacetic Acid .* ... ......* * * # 29
Preparation of a-Chlorodiphenylacetyl Chloride ..* .* . ..**.* 30
Preparation of Ethyl Benzilate 30
Preparation of Ethyl a-Chlorodiphenylacetate 31
Preparation of Ethyl o»Anilinodiphenylacetate . . . . . . . . . . . . . . 32
Preparation of a-Anilinodiphenylacetic Acid . . . . . . . . . . . . . . . 32
Preparation of o-Benzylaminodiphenylac et ic Acid .•*•*•••••♦. 33
Preparation of a—(P-Dimethylaminoethoxy)diphenylacetic
Acid Hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Preparation of Dimethylami,noacetonitrile . . . . . . . . . . . . . . . . . . 34
Preparation of N,N*-Dimethylethylenediamine . . . . . . . . . . . . .... 34
Preparation of a -(0-Dimethylaminoethylamino)diphenyl-
acetic Acid Dihydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
The Reaction of a-Chlorodiphenylacetic Acid With
N,N-Dimethyl-N1-phenylethylenediamine . . . . . . . . . . . . . . . . . . . . 35
Preparation of Diethylaminoethyl a-Benzylamino-
diphenylacetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Preparation of P-Diethylaminoethyl a- (P-Dimethylamino-
ethojcy)diphenylacetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
TABLE OF CONTENTS (Cont'd.)
Page
Preparation of Ethyl a -(P-Dimethylaminoethoxy)diphenyl-
acetate 37
Preparation of Ethyl a -(p-Diethylaminoethoxy)-
diphenylacetate 38
Preparation of Ethyl 0^-(^-Dimethylaminoethylamino)-
diphenylacetate 39
Preparation of Diethylaminoacetonitrile . . . . . . . . . . . . . . . . . . 39
Preparation of N,N-Diethylethylenediamine . . . . . . . . . . . . . 39
Preparation of Ethyl a-(P-Diethylaminoethylamino)~
diphenylacetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Preparation of 1-Chloro—3-iodopropane . . . . . . . . . . . . . . . . . . . . 40
Preparation of y-Dimethylaminopropyl Chloride . . . . . . . . . . . . . 40
Preparation of Diphenylaceto nitrile . . . . . . . . . . . . . . . . . . . . . 41
Preparation of 5—Dimethylamino-2,2-diphenyl-
pentanenitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Preparation of 5—Dimethylajnino-2 , 2-diphenyl-
pentanoic Acid B isulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Preparation of Ethyl 5-Dimethylajnino—2,2~diphenyl-
pent ano ate Hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Preparation of y-Diethylaminopropyl Chloride . . . . . . . . . . . . . . 44
Preparation of 5-Diethylamino-2,2-diphenyl-
pentanenitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Preparation of 5-Diethylamino-2,2-diphenyl-
pentanoic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Preparation of Ethyl 5-Diethylamino-2,2-diphenyl-
pentanoate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
SUMMARY........................................... 48
REFERENCES................. 49
LIST OF TABLES
Table Page
1 A List of a Few of the Recently Prepared Compounds
Possessing Antihistazninic A ctiv ity 10
2 Tabulation of Compounds To Be Prepared ••*••••••••• 21
1
INTRODUCTION
In the last decade there has come into use a new type of medicinal
agents known as antihistam inics • The term 1 antihistam inics1 connotes
a pharmacological activity which excludes some drugs which antagonize
the action of histamine* The sympathomimetic amines, such as epineph­
rine, w ill increase the blood pressure, decrease the m otility of the
intestine, and relax bronchial spasms* Mus culot ro pic spasmolytics,
such as papaverine, relax the spasm of smooth muscles produced by cer­
tain agents* Histamine acts diam etrically opposite to epinephrine and
papaverine in its physiological effects. These la tte r drugs oppose the
physiological responses produced by histamine. Loew (l) defines the
antihistam inics as 11 those drugs which are capable of diminishing or
preventing several of the pharmacological effects of histamine and which
do so by a mechanism other than the production of pharmacological
responses diam etrically opposed to those produced by histamine". In
other words, the true antihistam inic drug would be one which would
prevent the physiological action of histamine, but in the absence of
such as effect it would produce no physiological response.
Although the present day antihistam inics are useful in relieving
some of the toxic manifestations of histamine, such as allergic
responses, the perfect antihistam inic compound has yet to be discov­
ered. Several cases of acute toxicity caused by the use of the anti­
histaminics have been reported by various authors (2,3,4*5,6)•
Undesirable side reactions of therapeutic doses of the various
antihistam inic drugs are drowsiness, dizziness, palpitations, and
headache • In the treatment of allergic disorders in children 'with
certain antihistam inic agents, Logan (7) found that these side re­
actions occurred in about twenty—four percent of the cases studied*
The same reactions were observed by Kierland and Porter (d) in about
twenty-seven percent of the cases studied*
In a study of six widely used antihistam inics in seven hundred and
eighty-one allergic patients, Schwartz (9) found that a ll six produced
side effects when studied at dosages which gave equal therapeutic re­
sults. Benadryl, Byribenzamine, Neoantergan, A ntistine, Histadyl, and
Neoheteramine produced side effects in sixty-one, th irty -six , twenty-
five, twenty-three, twenty, and seven percent, respectively, of the
cases investigated. Thus, the report of these undesirable reactions
indicate that there is a need for the continuous search for antihis­
taminic agents with fewer side effects.
The object of this research project was to prepare a series of
compounds introducing certain changes in the general structure of the
several classes of therapeutically useful antihistam inic agents. It
was hoped that such compounds when tested might show better antihis­
taminic properties than the effective antihistam inics now in use, and
also, that the compounds selected for preparation would permit a study
of the relationship of certain chemical structures to physiological
activ ities.
The general formula of the compounds chosen for study is repre­
sented by the graphic formula I in vhich X is nitrogen, oxygen, or
methylene radical and
for each of these
compounds Y is
C
amino or the Z N diethylandno group*
x-ch2ch2- i