Journal of Medicinal Chemzktry, 19Y1, Vol. 14, No. 2 161
POTENTIAL ANTIDEPRESSANTS
Substituted l,l-Diphenyl-3-aminoprop-l-enesand l,l-Diphenyl-3-aminopropanesas Potential Antidepressant Agents G. JONES, R. F. MAISEY,*A. R. SOMERVILLE, AND B. A. WHITTLE Imperial Chemical Industries Limited, Pharmaceuticals Division, Alderleg Park, Maccle-sjield, Cheshire, England Received April I S , 1970
A series of substituted l,l-diphenyl-3-aminoprop-l-enesand l,l-diphenyl-3-aminopropaneshas been prepared. These compounds display interesting properties as potential antidepressant agents.
The observation of antireserpine activity of a low order in compounds of the general structure I' and the structural relationship of these compounds to known antidepressant drugs, such as amitryptyline (11) and imipramine (111),led us to investigate the pharmacological properties of compounds of the general structures IV and V. l,l-Diphenyl-3-aminoprop-l-enes (IV) and 1,1-diphenyl-3-aminopropanes(V) have previously been examined as potential analgetics, antihistamine^,^ antis p a s m o d i c ~ , ~and - ~ analeptic^.^ This paper is concerned with the synthesis of new compounds of the generic structures I V and V and their evaluation as potential antidepressants.
route A
C,H5O2C(CH,),NR3R4
R
1
I@
OH a C
\
II
(CH2)2NR3R4
/
route B
COCH2CH2NR3R4 VI11
v[
I
I
(CH2)2NR3R'
I
CHCH2NR3R4
lv
II,X = =CH(CH,),NMe, 111,X = N(CH2)3NMez
V
I
(CH2)2NR3R4 V
Chemistry.-The l,l-diphenyl-3-aminoprop-l-enes IV were prepared in most cases by the methods illustrated below. The amino alcohols VI1 in which R 1 = R 2were prepared best by reaction of a Grignard reagent with the appropriate ethyl @-aminopropionate derivative VI (route A). The alternative reaction of a Grignard reagent with a Mannich base VI11 (route B) generally gave inferior yields, probably on account of enolization of the Mannich base.6 Dehydration of amino alcohols VI1 in which the aromatic rings have different substituents (R' Z R2) gave rise to mixtures of the geometrical isomers of the corresponding l,l-diphenyl-3-aminoprop-l-enes. It was evident from the nmr spectra of these products that the geometrical isomers were generally formed in about equal proportions. Isomeric mixtures were tested as such in the form of either the HC1 or oxalate salt. (*) To whom inquiries should be addressed. (1) Unpublished observation from this laboratory. (2) P . A . J. Janssen, "Synthetic Analgesics," Part 1 , Pergamon Press, London, 1960. (3) A . C . White, A . F. Green, and A. Hudson, &it. J. Pharmacol, 6, 560 (1951). (4) P . V. Petersen, Acta Pharmacol. Tozicol., 7, 51 (1951). (5) K. Zipf, Arzneimik-Forsch., 18, 166 (1963). (6) R . Baltzly and J. W. Billinghurst, J . 078. Chem., SO, 4330 (1965).
Primary l,l-diphenyl-3-aminoprop-l-enes(IV, R3 =
R4 = H) were prepared by LAH reduction of the corresponding unsaturated nitriles (route C). When this reaction was carried out in Et,O a t room temp reduction of the conjugated double bond was significant, but a t -20" reduction of the nitrile was not accompanied by reduction of the double bond. l,l-Dipheny1-3-aminopropanes(V) were prepared by catalytic hydrogenation of the corresponding 1,l-diphenyl-3-aminoprop-l-enes (IV) or, in the case of secondary amines (V, R 3 = H), by hydrogenolysis of the corresponding 1,l-diphenyl-3-bensylaminoprop-l-enes (IV, R3 = CH2CsHs). Structure-Activity Relationships.-The more active members of this series, e.g., 6,16, and 17, have activities comparable with those of known clinically effective antidepressants such as amitryptyline or imipramine, and some, particularly the monomethylamino compounds, e.g., 5, 15, and 18, are more active in the pharmacological and biochemical tests reported. I n the olefinic series substitution in the P h rings with halogen, especially F, marginally improves the
162 Journal of Medicinal Chemistry, 1971, Vol. 14, 1Vo. 2
T-ABLE I
570
Yield,a
RZ
R'
R'
R'
Method
%
C
70 70 50 48 43
M p of HCl or oxalate, OC 214-216 186-188 180-182 189-190 147-148 168-170 155-157 (OX) 144-146 146-147 146-147
Reversal of reserpine induced hypothermia EDio, mg/ke 100 100 100 100
>
1 2 3 4 5 6 7 8 9 10
H 2-CHa 2-F 4-F H H H H H H
H H H H H €1 H €1 H H
11
H
H
J -h
h
165-167
100
12
H
H
J-h
A
209-210
100
A
2 18-2 19
100
195-200
100
H H H H CHI CHI CHa (CHdzCH CzHs CHnCH=CHz
H H H H H CHI CZH5 H CnHa H
-
C C C
B A or B C
d .\ or h
u
84 21 60
1
1 5 1-3 > 100 30-100 100
inhibition of Oral 5-HT acute LDsa uptake at 10 (mice) a / m l mdkg
96 88
20 1 27 1
96 81 78 98 64
177 225 352 110 -400 180 118 28 1 609 284
r--l
H
H
14
H
H
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
4-F H 4-F H 3-F H 4-Cl H 4-C1 H H 4-Br H 3-CF3 H 2-CH3 H 2-CH3 H 2-CHaO 4-F 4-F 4-F 4-F 4-F 4-F 3-F 3-F 3-F 3-F 3-CFa 3-CFa 4-CI 4-C1 4-c1 4-Cl 4-0 4-C1 4-Cl 4-F 4-C1 3-F 4-CI 2-CH30 H (.e,) Amitriptyline Imipramine Desimipramine Nortriptyline
13
C H3 CH3 CHI CHa CHI CHI CH3 CH3 CH3 CHs CHs CH3 CHa CHI CH3 CHa CHa CH3 CH3 CH3 CH3 CHa CHI
B
O
~
~
C
H CH3 CHs H CHI CH? CH3 H CH3 CHI H CH3 CHzCaHs H CH3 CH3
H.-i B 13 B
u
I3 B
u I3
u
I3 A A
.I .I
.I
.\
H
.I
CHI CHzCsHs CHI CHI CH3 CH3
I3 A
B ll
n
I3
J
75 22 10 31 12 12 35 45 20 18 41 13
37 33 31 32 47 10 40 38 18 20 25 22
136-140 188-190 144-148 140-142 210-212 170-171 175-179 156-160 192-194 172-175 215-216 (ox) 211-213 130-132 177-179 156-1 59 158-160 216-219 (ox) 230-232 185-187 194-196 145-147 156- 159 147-150
0 6 0 6 0 5 O i
3 0 6 3 15 15 8 3
3 10-30 2 2 100 2 3 60 100 4
97 74
287
99 66
