September 1967
SlS
ANTIDEPRESSANT l-AMINO-4-.4RYL-$-PIPERIDINOLS
l-Arnino-4-aryl-4-piperidinols as Potential Antidepressants K.J. HARPER,C. W. T. HUSSEY,31, E. PEEL,A. C. RITCHIE,'ASD JULIET 11. WARING Rescurch Diviszon, Allen 82 Hanhurys Ltd., M.'are, Hertjordshire, England Receioed February 10, 1967 l-Xmiiio-4-pheny1-4-piperidinol is more active than imipramine in animal tests against the depression caused by reserpine. Thirty-six related piperidines have beeii synthesized and evaluated as potential thymoleptics. Striicture-activity relationships are discussed.
In a search for an antidepressant drug of the imipramine type a number of compounds were screened for their ability t o prevent the onset of ptosis and hypotherniia induced by reserpine in rodents. This test has been advanced as diagnostic of clinically effective thyniolepticBs.2 One compound3 that we found to be more active than imipramine wa5 l-amino-4pheiiyl-4-piperidinol (I), originally prepared by Beckett and Greerihill.4 The theme of the present paper is the synthesis of analogs of I and the correlation of structure with antireserpine activity.
I
I1
Chemistry.-The nitroso compounds listed in Tables I and I1 were obtained by nitrosation of the appropriate secondary base and then reduced with zinc and acetic acida to 1-aminopiperidines (Tables I11 and IV), An attempt to prepare the amide 10 from the ester 14 with 1-pyrrolidinylniagnesium iodide5 gave instead the 1,2-diazabic.yrlo[2.2.2]octanone II.'j Reductive alkylation of I with aldehydes or ketones gave 15, 16, and 17. Further reaction of the isopropyl compound 16 with acetaldehyde failed, presumably for steric reawlis. The monomethyl compound 19 was obtained by hydrogenation of the methylidene derivative 18. The propiophenones 20-22 resulted from amine exchange between the appropriate aminopiperidine and 2-benzoylethyltrimethylammoniumiodide.' 1Iono- and diacyl derivatives of I (Table V) were obtained by conventional methods (see Experimental Section). The diacyl rompounds (33-37) showed unexpected properties. They did not titrate in acetic acid with perchloric acid. The acyclic imides 33 and 34 hiid C=O bands at very high frequencies (ca. 171.5 m - l ) and all compounds showed very strong and unexplained absorption at 1220-1 280 cm-'. These features mere reproduced in the model com(1) T o whom correspondence should h e addressed. (2) F.Siilser, .J. Jl-atts, and R. l3. Brodie, Ann. S. Y . Acad. Sei., 96, 279 (1Y62). (3) Siipplied 11y L)r, \V, T. LVakama, Univemity of Nigeria, Nsukka,
pound 111 and were absent in IV which was a monoacidic base and had an infrared spectrum with normal amide C=O absorption (1670 em-') and no major peaks in the 1200-130O-cm-' region. The integrity of the hydroxyl group in the diacyl compounds was shown by a strong band at ca. 3610 cm-'. (CIIj)INN(COCI-IJ)~ I11
MeJ NH COCHI
I\-
In accord with previous work8 reduction of the moiioacyl compounds 27 arid 29 with LiAlH, was unsuccessful. The formyl compound 26 gave 18 in very poor yield. Nore complex results were obtained with the succinimide 37. Two molar equivalents of the hydride caused ring fission and, according to the conditions, gave the amide 30 or the alcohol 23. One molar equivalent gave the pyrrolidirione 32. Experimental Section9 General Procedure for l-Amino-4-piperidinoIs.-The iiitrosation and reduction of piperidines were effected essentially as reported by Beckett aiid Greenhill.4 4-Phenyl-1,2-diazabicyclo[2.2.2]octan-3-one (II).-A solution of 8.5 g of ethyl 1-amino-4-phenylisonipecotate (14) was refluxed for 2 hr in 90 ml of ether with 1-pyrrolidinylmagriesium iodide (from 4.9 g of pyrrolidiiie, 8.7 g of methyl iodide, and 1.7 g of LIg). Water was added aiid the pH was adjusted to 9 with 2 S HC1. The aqueous phase was extracted (CHClr) at pH 7 aiid the extract was dried (hIgS04) mid evaporated t o d lizatioii from ethyl acetate gave 1.7 g of white 2.i.io, lit.6 248.0-249.2" (cor). Anal. CalcdforCIJ114N20:C , 71.3; H, i . 0 : N , 13.85. Foiiiid: C, 70.8; H, 6.8: N, 14.2. l-Dimethylamino-4-phenyl-4-piperidinol (17).-A solutioii of 5 g of 1 in 20 ml of ethanol was shaken under hydrogen at room temperature and pressure with 5 ml of formalin and 2 g of lOs', Pd-C catalyst. After removal of catalyst and solvent the product was crystallized from cyclohexane to give 2.5 g of white crystals, mp 133-134.5", lit.* 137-138". The following were similarly prepared. l-Diethylamino-4-phenyl-4-piperidinol(15).-Hydrochloride mp 232.5-233.5". .4nal. Calcd for CljH&1N20: C, 63.25; H, 8.85; C1, 12.4; Tu', 9.8. Found: C, 63.4; H, 8.8: C1, 12.3; hT,9.9. l-Isopropylamino-4-phenyl-4-piperidinol (16).-Hydrochloride mp 211-212'. Anal. Calcd for C14H25C1?IT20: C, 62.0: H, 8.56: C1, 13.1; K-10.3. Found: C, 61.85; H, 8.5; CI, 13.25; N, 10.2. l-Methylideneamino-4-phenyl-4-piperidinol(18). Method A. -A mixture of 20 g of 1, 12 ml of formalin, aiid 100 ml of ethanol was allowed to stand at room temperature until solution was complete. Evaporation and crystallization from cyclohexane gave 17.9 g of colorless crystals, mp 99-100.5". Anal Calcd for C,2H,cN20: C, 70.6; H, 7.9; Tu', 13.1. Found: C, 70.4; H, 7.5; E,13.75.
Xigeria. (4) .L H. Beckett and J. V. Greenhill, .I. Med. P h a r m . Chem., 4, 423 (1961). ( 5 ) H. L1. I3assett a n d C. R. Thomas, J . Chem. Soc., 1188 (1951). ( 6 ) P. 11. Carahateas, .\. R . Surrey, and L. S. Harris, J . .?fed. C h e m . , 7, "3 (19ti4). ( 7 ) E. RI. Icry and E. L. M a y , J . O r y . Chem., 2 4 , 116 (l(l5Y).
(8) R. L. Hinman, J . A m . C h e m . Soc., 78, 1645 (1956). (9) Melting points were determined on a Townson-Mercer apparatus calibrated for exposed stem. RIicroanalyses were performed by .ilfred Bernliardt, 3Iiilheim, \Vest Germany, and Drs. TVeiler and Strauss, Oxford, England.
s21
September 1967 TIBLEI V l-.~hrl~'o-4-PHE;vYLPIPERIDISMS
%-----
---Calcd,
"C
XO,
R
9
CII,O
10Xh
E C O
22'3-230"
IO
JIp,
C
H
Ci,Hi&lNO
59.33
7.9
C16II,,ClX30
63.0
7.Y
Formula
vi-----
--Found,
x 11.6
.j9.6
8.2
11.2
+++
13.35
61.7
7.8
13.1
-
195-196h CiiHiiClN, 62.1 8.05 13.2 62.0 8.05 57.6 7.2 7.0 10.35 37.7 ClaHl&1S20n 189-190* 69.8 8.73 8.8 13.6 Ci?Hd20 69.9 HOCH? 126-128' C02C2Hj 179.5C ~ J l ? ~ C l E * 0 ? 59.0 7.4 9.8 58.6 7.3 180.3d See footnote a,Table 111. b Hydrochloride. c The hydrochloride, mp 169.5-171.5', is described by footuote hydrochloride, mp 172-175.5", is described in footnote c, Table 111.
----.~Ikyl
derivatives----
Ri
R?
19
H
20 21
C6HICO(Ckl2)?
C2Hr CsH7-i CHI CH2= CHs C%HsCO(CH?)z CoHaCO(CI1?)?
22
CHI
C6HaCO(C1f?)z
N 0. C2Hs H CH3
I5 16
17 18
tt
H
23 a
(CHdrOH
Graded activitya
+++ +++ +++ +++ +++ +t+ + + +
----,\~onortcyl SO.
24 25 26 27 28
29 :3 0 31 32
derir atives-
R1 COXH? C0 z C2 H 6 CHO CoHrCHKO CO?(CH*)rN(CHa)g CHaCO HO(CHdaC0 c HO 6HHj~XHCOC(C2HjjzC0 (CHz)sCO
-R? H H H H H H H H
Graded actiyity'
H
S
I3 CHaCOz
11 12 13 14
-
c
Graded activitya
+++
+ +++
+ + ++ +
12.9 10.5 13.5 9.8 c,
33 34 35 36 37
-
-
Table 111.
Diacyl derivatives
NO.
+$-+
R? Ri CHaCO CHaCO CHICO COK2Hs COC(C9Ha)LO COC(CHI)?CO CO iCHI)K O
a
The
Graded activity=
4-
+ -
-
-
+
See footiiote a in Table 111.
crystallized twice from beiizeiie-petroleuni et,her t o give 6 g of whit,e crystals, mp 115.5-11i0. Anal. Calcd or C,,H,,Nd&: C, 76.3; H, 7.1; N, 6.13. Found: 6,76.7. H, 7.0: N, 6.4. Similarly was prepared 1-[(2-benzoylethyl)methylamino]-4phenyl-4-piperidinol(22),mp 73-78'. . i n d . L:alc:d for ;321H2nN262: C, 74.3; IT, 7.7; S , 8.3. Foiuid: C. 74.8: FI. 7.65: S . 8.0. 1 [( 2-Benzoylethyl)amino] -4-phenyl-4-piperidinol Hydrochloride (2O).--Sitrogeii was passed for 16 hr through a suspension of 5 g of 1, 4 g of anhydrous Xa?COs, and 8.5 g of P-benzoylethyltrimethylammonium iodide in 100 ml of DUF. T h e mixture was poured into water aiid extracted (ether). The ether extract was dried (MgSOd) and treated with dry HCI. The precipitated gum was crystallized from ethyl acetate-methanol (4: 1) t o give 1.5 g of white crystals, mp 154-15.i0. Anal. Calcd for C;oH2jC1Xz02: C, 66.5: H, 7.0: C1, 9.8; N, 7.8. Foiuid: C, 66.75: H, 7 . 0 : C1, 9.8: N, 7.7. N-(4-Hydroxy.4-phenyIpiperidino)acetamide (29).-A solutioii of 3.37 g of acetic anhydride, 5.76 g of 1, aiid 50 ml of pyridine was heated for 3 hr a t 100". Removal of t,he solvent and crystallization from methanol-ethyl acetate gave 4.9 g of white 1111) 198-200°. Calcd for C13TI,,N;20~:C 66.7: H, 7.7; E, 11.9; 0 , 13.7. Foluid: C , 67.1: II, 7.7: K, 11.9: 0, 1i3.3. N-(4-Hydroxy-4-pheny1piperidino)diacetamide(33).-A solution of 100 ml of acetic anhj-dride and 5.76 g of 1 were heated at 100° for 4.5 hr. Removal of the excess of anhydride and crystallizatiou from benzene-petroleum ether gave 5 . 5 g of white solid, mp 142-144". I&2
