A New Series of CNS Stimulants’
Rcsearch Laboratories, A . H . R o b m C‘oinpcmy, Inc., Itichmond, Vwginau
Receiced October 11. 1 N J The conversion of CY-( 1-substituted 3-pyrrolidinyl)-a,a-diphenylacetic acids jIVb) to the corresponding acid chlorides (IVc) is followed by the facile “rearrangement” of the latter to 1-substituted 4-(2-chloroet,hyl)-3,3diphenyl-2-pyrrolidinones (111,X = Cl). Several such compounds have been prepared and this series has been extended by replacement of the halogen with a variety of bases. Proof that t’he materials have the 2pyrrolidinone structure and evidence that their formation from the acid chlorides (IVc) proceeds through a transitory quaternary amide (VI) are presented. The starting acids are prepared by hydrolysis of the corresponding nitriles (IVa) which, in turn, are obtained b y alkylation of diphenylacetonitrile n i t h an appropriate l-substit,ut,ed3-chloropyrrolidine. AIembers of this series of pyrrolidinones fall into two pharmacological activity classes-those which exhibit pronounced central nervous system ( C S Sj and respirat’ory stimulation in the dog, usually accompanied by varying degrees of pressor activity, and those which exhibit. depressor activity with little or no CNS stimulation. One compound, 3,3-dipheriyl-l-ethyl-4-(2-niorpliolinoetliyl)-2-pyrrolidinoiie hydrochloride hydrate ( X I I ) , selected for extensive evaluation, produces prolonged respiratory stimulation and marked analeptic signs in the phenobarbital anesthetized dog at doses significantly below the convulsive dose.
The coiiversioii of y-dinietliylamiiio-~,a-diphenyl-p- in summary form the salient features of their biological methylbutyryl chloride to 1,4-dimethyl-3,3-diphenyl-2activity. The detailed pharmacology of selected pyrrolidinone mas reported by Gardner, et aZ.,2 in 1945, members of the series will be presented elsewhere. and this type of reaction was subsequently studied by Chemistry.-The reaction sequence leading to the others.3 A typical example, observed by Clark,3h 1-substituted 4-(2-haloethyl)-3,3-diphenyl-2-pyrrolidiis the formation of 3-(2-diethylamiiioethyl)-l-ethyl-3- nones (111, X = C1 or Br) is illustrated by the route phenyl-2-pyrrolidiiioiie (11)from (Y,a-bis(diethy1aminoused for the preparation of 4-(2-chloroethyl)-3,3-dict1iyl)pheiiylacetic acid (I) through the corresponding phenyl-1-isopropyl-2-pyrrolidinone (IIIa) . acid chloride.
1
C&j
R
111 X = C1, Br (subsequently replaced by various basic residues) =
alkyl, cycloalkyl, benzyl
IIaiiy members of this iiem series of compounds are centrally acting respiratory stimulants and selected ones appear to be among the most potent compounds ever described for antagonizing phenobarbital anesthesia in the dog. It is the purpose of this report to describe the chemistry of the compounds and to present (1) Presented in p a r t before the Division of JIedicinal Chemistry a t the 14lst National Meeting of the American Cliernical Society, Kashington, (2) .T. 11. Gardntxr, S . It. Enstiln, and .T. R . Stevens, J . Am. Chern. Soc.. 70, 21400 [1!4-l8). (3) (a) 11. J. l h l i r e , ,J. Elks, 13. A. Hems, 1;. N. Speyer, and It. R I . Evan% J . P h r m . SOC., 500 (1949); (h) R. I,. Clark, A . XIooradian, P. Lucas, ancl T. .T. Slauson, .I. Am. Chem. Soc., 71,2821 (1010); i c ) 1’. Luras, It. I,. Clark, xiid A , loor radian. TT, R. Patents 2,,555,3,5.‘%, ?..i.i.i.?.ii (19.jI).
CH
CH(CHJ2
I1
The utility of this reaction has been increased to allow the formation of a 1-substituted 3,3-dipheiiy1-2-pyrrolidinone having a p-substituted ethyl group in the 4position (111).
I1
CbH
C’H,CH,N(CZH~)L
CH~CHZN(CZH 5 )z
The starting nitrile (IT-a) was obtained by alkylating dipheiiylacetonitrile with 3-chloro-1-isopropylpyrrolidine using sodaniide, and toluene as a solvent. The preparation of the I-alkyl-3-chloropyrrolidinm has h e n described4 aiid the properties of those not picyiously reported are given in Table I. Hydrolysis of the iiitrile (IVa) iii 70yo sulfuric acid a t 130-140” yielded CY- (l-isoprop~-1-3-pyrrolidinyl)-a, a-diplien ylacetic acid (IVb). This acid, usually without isolation in a purified form, was converted to its hydrochloride salt and treated with thionyl chloride, eflectiiig formation of 4-(2-chloroethyl)-3,3-diphenyl-l-isopropyl2-pyrrolidinone (IIIa) through the acid chloride (IVc). In no case was IVc isolated since rearrangement to the pyrrolidinone occurred readily when solutions of it were heated or isolation was attempted. Howem-, appearance of the carbonyl chloride absorption in the infrared spectrum at 5.62 p5 and the formation of dtrivatis-es indicate clearly the existence of this interinediatr. Tlie cntii-c coursc of tlic reaction, froni . I‘ranlo ?nd C’ 1) T.unsf(rr~l,J l l c d I ’ h n r m C l i i In , 2, 52 I (1’360) i l l spectra reported %ere obtained i n cliloroform o n a I3e~hrnan I1 r at position 2 of tlic origiiial (ahloride ioii rail o ( ~ u (1) pyrrolidiiie ring foriuiiig 2-piperidiuone (VIII) ; or ( 2 ) at the S-alkyl hirlistitueiit, rcsultiiig i i i its f.limiiiatioii as ail equivalwil of alkyl halidr and tlic formatioir of R I I aznl~ic.yc.lolicptnllc.;01' ( 3 ) a t posit i o i i :f o m -
May, 1964
4-(/%SUBSTITUTED T.4BLE
Iv:
305
ETHYL)-~,~-DIPHENYL-2-PYRROLIDINONES
1-SUBSTITUTED 4-(~-AMINOETHYL)-3,3-Dll"ENYL-2-PYRROLIDl?JONES
C6Hs C ~ +-,--cH~cH~N, H ~
/R' 'R'
NR'R'
Salt
N-(CHdz
HC1. Hz0
NH-CHzCHzOH
HC1
N-(CHzCHzOH)z
HC1
M.p., OC
Recryst. solvent
161-164
Empirical formula CzrH31ClNzOz
209.5-211.5
h
196-198
b
h.p. 206-210(0.06)
N- (n-CaHd 2
169-1 72
c
Piperidino
89
d
NHz
102-1 0 3 . 5
e
237-239
a
m i .H ~ O
Pyrrolidino
HCI
NHCHa N(CHzCHz0H)z
HC1
197-200
b
N'-methylpiperazino
2HC1.2HzO
185-189
a
N'-phenylpiperazino
Hexamethyleneimino
67.94 67.87 66.57 66.63 79.95 79.82 69.13 69.23 79.74 79.89 78.22 78.38 70.85 70.93 67.17 66.95
7.20 7.36
59.02
7.51 7.56 7.68 7.74 9.59 9,45 7.97 8.75 8.57 8.60 8.13 8.05 7.84 7.99 7.89 7.89 8.03 7.64
6.66 6.41 6.72 6.73 7.44 7.70 8.69 8.57 7.51 7.56 6.27 7.56 8.17 8.26
68.92 68.95
7.84 7.31
7.78 7.77
HCI
154-155
I
CzaHssClNzO
218-219
c
CzsHs~BrNzo
HC1. Hz0
181-183
0
CziHsaCINzOz
71.88 72.08 65.35 65.49 71.58 71.90
8.29 8.42 7.68 7.87 7.34 7.65
6.99 7.25 17.39 17.30 6.19 6.29
Fumarate
156-159
c
CzoHasNzOs
163-165
h
C~iHcaNzOs
70.42 70.66 71.51 71.51 76.15 76.01 76.97 76.74 75. 40 75.41 75.79 75.89 66.57 66.60 74,37 74.55 63.42 63,31 66.87 67.08
7.74 7.76 7.74 7.50 7.99 7.97 6.24 6.29 7.48 7.18 7.74 7.79 7.68 7.53 7.25 7.16 7.03 7.03 8.31 7.79
79.05 78.81 64.84 65.94
7.32 7.33 7.62 7.57
5.65 5.65 5.38 5.38 7.40 7.51 6.19 6.11 7.99 8.23 7.69 7.58 6.47 6.52 5.60 5.59 5.92 6.05 6.24 6.10 5.42 5.61 6.36 6.34 6.05 6.05
69.39 69.29
7.51 7.62
5.22 5.22
69.39 69.40
7.51 7.46
5.22 5.24
Fumarate
CriHaaNzO
120-121
CzeHzsNzOa
200-202.5
k
CzzHzaNzOz
SIorpholino
130-131
i
CzaHzsNzOz
Morpholino
HC1. Hz0
217-219
c
CzaHaaClNzOa
blorpholino
Benzoate
123-124
blorpholino
CHsBr
247-250
llorpholino
HC1. HzO
182-185
Slorpholino
HCI , Hz0
150.5-152.5
m
CaoHaaCINzOa
97-98
n
CzoHszNzOn
HCI- HzO
225-230
b
CzsHssClNzOzS
Maleate
177-178
h
Maleate
149-150
h
Slorpholino
blorpholino
R
7.17 7.27
CaiHczCINsOa
164-166
Po
8.00 8.05
I
Phthalimido
N
67.58 67.75
60.69
i
N S U
%N Calcd. Found
145-151
CHaNCOCHa
A
%H Calcd. Found
HC1'2HzO
CHaBr
N (CzHs)z
%C Calcd. Found
CaiHasN?Oa b
CzsHaaBrNz02 CzsHasClNzOa
Csi Hca Nz0 e
Mise. Calcd. Found 9.07 9.04 4.60 4 80
8.50 8.58
9.51 9.79
13.78 13.89 Hz0, 7 . 0 0 7.60 C1, 6.57 6.78 Hz0. 6 67 6.66 8.84 8 53 6 10 6.28 7.83 8.05 3.98 3.80
8.19 8.22
7.90 8.18
7.67 7.76 3.89 3.3
Isobutyl methyl ketone-methanol. c Ethyl methyl ketone. Methanol-water. e Isopropyl a 1sobut)vl methvl ketone. - - . ether. Ethanol-hydroccloric acid. Tolue%isobutyl methyl ketone. Ethanol-ether. ' Isopropyl ether-ethyl acetate. EthanolEthyl acetate. 2,V Hydrochloric acid. Ethyl alcohol-Ligroin. water. f
'
'
voi. 7
306
t,,L
h1.p.. o c
01-945 104-107h 123-135b
€I
C'aicd. Found
7.43 7.32 7.42 7.54 7 .70 i.91
so-87"
s ,:E
103-10W
8.07 7 ,!)O 7 .:E 7 , -10 7 .i!)
h.21
104-1 06"
1 80-1 8'2" 135-137' a
Recrystallized from methanol-water.
>:
N Calcd. Found
3.83 3.90 4.13 4 .?3
3.96 4.15
hliac. Calcti. Found
d, 0.44 I).73 P, ! ! . O i S.65
3 .no 4.04
4.15
i.90
3.17 3.51 :3 .5:3 4 .3:3 4.32
7.28 7.50
3.26 3.42
Recrystallized from ethanol-water.
length 6.08 p. This infrared evidence, which corresponds to published work,6 is taken as proof that the rearrangement in the present series, ie., the acid chloride (IT'c) to the 2-pyrrolidinone (IIIa), occurs in the manlier indicated. By analogy and the fact that they all show carbonyl absorption a t 5.89-5.92 p it is coiiVI11 cluded that all members of the series of lactams reing a 2-pyrrolidinone (IIIa) as has proven to be the case. ported have this 2-pyrrolidinone structure. The second possibility can be eliminated since the The &-@-halogen)of the 2-pyrrolidinones (111, X = actual product is isomeric with the starting acid chloC1 or Br) has been replaced by a variety of amines ride. To establish that the 2-pyrrolidinone (IIIa) and other bases resulting in the compounds presented and not the 2-piperidinone (T'III) was, in fact, the in Tables IT' and V, respectively. product of the reaction, the following sequence of reacPharmacology.-Some of the 2-pyrrolidinones of tions was completed. Tables 111, IT', and V were found to be unusually effective in stimulating respiration in the phenobarbital C H ~ C H ~ G I CI H ~ )anesthetized dog. The frequency and amplitude of C1 (CsHi),Cj (CeHB)&~ C H i C H I d breathing was increased markedly and the duratioii OAK C1O = h of t,hese effects was often in excess of 60 min. even after CHJ CH3 relatively small intravenous doses. The strong respiraIIIb IX tory stimulants were also found (a) to be powerful 1 1 antagonists to the barbiturate anesthetic and (b) to (Ct7;)33= CHCH? produce prolonged pressor effects (Table VI). 111 ( C &0AN ,)&jc2H' tc N general, respiratory stimulation and pressor activity CHI CH? were the first effects observed and were quite apparent XI X a t doses which did not cause pronounced antianesthetic activity. IIIb was converted to the 4-(@-trimethylammonium) Other compounds of this series produced only decompound (IX) which was then degraded under the pressor effects (Table VI). In general, the depressor Hofmaiin conditions. The infrared spectrum indicated agents (a) had little or 110 direct effect 011 respiration that the resulting double bond shifted from the terand (b) caused little or 110 antagonism to the anesminal position giving the 4-ethylidene-2-pyrrolidinone thetic. Only two compounds (10 and 27) caused con(X). This was catalytically reduced to 3,3-diphenyl-4vulsions. Although it may be coincidental, it is inethyl-1-methyl-2-pyrrolidinone(XI) which was also obteresting to note that in each case the @-substituentof tained by zinc-acetic acid reduction of IIIb. The the 4-ethyl group is methoxyl. infrared spectrum of XI corresponded closely to those of It is difficult to differentiate the degree of activity of 3,3-diphenyl-l-methyl-2-pyrrolidinone3a and 1,4-dimany of the 2-pyrrolidinones where the @-substituent methyl-3,3-diphenyl-2-pyrrolidinone,~ with the lactam of the &-ethyl group is varied, Le., chloro, mercapto, carbonyl absorption occurring in each case a t 5.89 p. phenoxy. and acetoxy. Xore specificity does exist The similar six-membered ring lactam, 3,3-diphenyl-1i l l the amine compounds. When this group (NRZ', methyl-2-piperidinone, prepared from &dimethylaminoiii T, J f:ellanir, "The Infru-ed 9per tr.1 of ('oinpleu Rloleculea," 2n4 a ,a-diphenylvaleric acid, absorbs at the 1011,uer ~ a v r 1 ,I ,1011n \\ ~ I C I d m i Sons, Ini YP), J o r h \ Y , l!liS, p. 214. CH,C1
May, 1964
307
4-(@-SUBSTITUTED ETHYL)-3,3-DIPHENYL-2-PYRROLIDIKONES
Table IV) is dimethylamino and the nT-substituent is ethyl (8), the compound produces a marked and prolonged hypotension in the anesthetized dog; however, the corresponding morpholino compound (XII, 13) has proven to be one of the most interesting pressor
TABLEVI
EFFECTS OF 1-SUBSTITUTED 4-(8-SUBSTITUTED ETHYL)3,3-DIPHENYL-2-PYRROLIDINONESADMINISTERED
INTRAVEKOUSLY TO ASESTHETIZED DOGS
Compound
XII7
agents, respiratory stimulants, and C S S stimulants of the series. This compound has undergone extensive pharmacological evaluation which will be the subject of separate reports. It is currently being studied clinically* for various conditions involving hypoventilation or respiratory arrest. Sikethamide, studied for comparison, required intravenous doses of 40-80 mg./kg. to produce a modest effect on respiration. This effect was extremely brief in nature no matter what dose was used. In contrast, it was possible to stimulate respiration for several hours following a single injection of XII. It was impossible to elicit any observable analeptic effects with nikethamide at doses up to lethal. It can be seen from Table VI that the 4-(2-morpholinoethyl) compounds are unique among the aminosubstituted derivatives. Substitution with other heterocyclic amines [e.g., pyrrolidine (12), piperidine (14). and hexamethyleneimine (32) ] causes a marked diminution in activity. Hindrance of the nitrogen of the morpholino substituent, a probable site of metabolism, by methyl substitution in the morpholine nucleus (29, and 33) produced an increase in duration of effect. Substitution a t the nitrogen of the pyrrolidinone ring was necessary for antianesthetic activity and was optimum for the smaller alkyl groups. The S-unsubstituted compound (41) and the N-octyl derivative (40) were void of activity. Quaternization of XI1 produced an inactive compound (39).
Experimentalg Synthesis.-The 1-substituted 3-chloropyrrolidines were prepared by the method previously described4 for 3-chloro-1-isobutylpyrrolidine. The bases were characterized as their picrate or hydrochloride salts. Properties and analyses are detailed in Table I. 01-( 1 -Isopropyl-3-pyrrolidinyl)-cy,~-diphenylacetonitri~e.This method is typical of that used for each of the compounds of Table I1 in which the properties and analyses are reported. A suspension of the sodium salt of diphenylacetonitrile was formed by the addition of 193 g. (1.0 mole) of diphenylacetonitrile to a stirred suepension of 43 g. (1.1 moles) of sodamide in 1 1. of dry toluene. The mixture was refluxed for 4 hr., and then to the refluxing mixture 148 g. ( 1.O mole) of 3-chloro-I-ieopropylpyrrolidine was added a t a rapid dropwise rate with continuous stirring. After addition was complete, stirring and refluxing were continued for 3 hr. The mixture mas then cooled and extracted with 1 N hydrochloric acid. The aqueous layer together with the insoluble oily hydrochloride was separated, made basic with dilute sodium hydroxide, and extracted with ether. The ethereal solution was dried over sodium sulfate and concentrated, and the residue was distilled in vacuo; yield, 238 g. (78%). (7) Nonproprietary name of HC1 salt hydrate is doxapram hydrochloride. ( 8 ) See, f o r example, .i. J. Wasserman and TI. W. Richardson, J . Clin. Pharmacol. T l i e r a p . , 4 , 321 (1963); H. G . Canter, Am. Rev. Respirat. Diseases, 87, 830 (1963). (9) Melting points are correrted and were determined with a Drechsel apparatus. Boiling points are uncorrected.
Minimum dose observed t o stimulate respiration, mg./kg.
2 2 2 2
15 2a
3" 4b
5
5a
6" (HCl salt)
