Journal of A\ledicinul C h m i s t r y , 1Y70, Bol. 13, A\To. 4 645
T.AEILE I
R
Ke-
NO.
1 2 S 4 )
6 7 8 9 10 11 12 13 14 13 16 17 18 19 20 21 2% 2s 24 25 26 27 28
s
R
c1 3Ie 3leS AC H
n-BuS C1
H H H I€ H H Me €1 H H H
e1 CF3
c1
crystn solMethod' vent
RI
CN
CN CN CN
CN
Ai At
d e
A3
C
A3
e
A2
f
A3
e
CH~NIIAC CHZNHAC COKCaH, COKH, COzEt Ac
A3
C
Ai A3
H
0€I
43
c1
€I H
OH OH OH OH OH ORIe I1 H CONHz CONH, CONH? CONHz CONHz CONHz CONHz CONHz
A3 Az
c1 Cl
H H Me H H H
e e e e h e h e h e e h
SIeO
CI
c1
e1
RleO
c1
c1 c1
H H H €I
Are hIe0 LIeS C Fa AC H hleO
H H 11 Ale
AI A3
A3
Ai A3 A2 A3
f f
A3 A3
k d k k k k h
A3 A3 A3
-43 A3
A3
A3
Yield ,
RIP,
70
"C
49 52 43 46 s4 51 62 43 62 R3 51 55 66 56 47 61 .5 1 58 70 43 42 59 39 34 48 51 39 57
120 103 dec 110 dec 106 dec 235 137-140 13.5 120 104-110 82-84 105-1 10 113 75-80 196 130-160' 185 11*5-120 123-130 287 217 dee 263 248 252 247 236 247 256 210
See Experiniental Sectioii. h Rlost of the yields indicated in this and subsequent tables are based on a single run and they do not EtOH. e EtOH-EtpO. f MeOH. iiecessarily reflect the optimum attainable. c All compounds were analyzed for C, H, N. g Nmr(CFaCO2H) T 6.05, equivalent to 0.5 mole of MeOH. h RIeOH-Et20. NC4Hs, pyrrolidino; XCsHlo, piperidino. 1 Acid 90y0 EtOH. 2 Nmr(CF3C02H) quartet r 5.90, 6.01, 6.12, 6.25, triplet 8.54, 8.65, e.7.5, equivalent to 1 mole of EtOH. Inaleate. Karl Fisher titration H20 = l.?17~. m Nmr(CF3COtH) quartet T 5.89, 6.00, 6.11, 6.24, triplet 8.52, 8.63, 8.73, equivalent to 1 mole of EtOH. Karl Fisher titration H 2 0 = 1.6%.
TABLE I1
No.
s
Ri
29 30 31 3% 33 34 35 36 37
I1 I1
C:II2SHAc OH OH OH CONHz CONH? H COPU'Hz CONHz
II H H H H c1
c1
a See Experiniental Section. NeOTI. h RleOH. EtOII.
Rz
Recrystn solvent
Yield,b
7d 67 70 64
A3
c
A3
d
A3
e
A3
c
A3 A3 Ai
9 9
A3
9 h
A3
i
See Table I, footnote b. lleOH-EtzO. Acid maleate. k See Table I, footnote c.
h I
hIethoda
%
81 83 78 47 32
AcOEt.
Mp.
oc
75-80 226 128-136 112-114 260 265 300 259 145-150 EtOH-EtzO.
Experimental Section hleltiiig points were determined in an open capillary tube iri a H2SO4 bath apparatus and are not corrected. Ir and nmr spectra were obtained oil Nihon Bunko IRG and C-60 instruments, respectively. The synthesis of these compouiids followed that shown ill Scheme I.
AQ
I
*-N>O I
A
It:,
39 40 41 42 43 4,5 4ti 4s 49 52
_*_*-
Z S'
8 11 12 14 18 21 22 26 29 30 31 32 33 34 35 36 37 38
3 = (CHI),, (CHI),, CHzC€iAIeCH, (CH Br, C1, OlIe, OTs = H, C1, Me, OhIe, CF?, CF,, SMe, SBu, 8 Ac = S, CH2CH,, CH=CH, CMez = H, OH, COKI-Iz, CONC~HE,"e?, CH2NHAc, CN, Ac, Ohle, C02Et = C&, p- or m-C1 or p-Me or p - M e 0 01 p-FCtiH4, CHIC~H;, p-FCtiH4, __ CHIC& ,, XLIe,, N C ~ H B , h GsHio = C1, hIeO = Br, C1
uS = Y I&
No
Method A.-For coiideiisiiig a 4,4-disubstitiited piperidine with a halogen or an aryl and alkyl sulfonyloxyalkyl derivative of 2,20-26t,he following three met,hods were employed. ( 1 ) The components were dissolved in alcohol and heated to 100170" in a sealed tribe. ( 2 ) Compoiient,s were st,irred in I)MF solution a t 100" in the presence of a basic reagent. ( 3 ) The components were refluxed in EtOH in the presence of a basic compound. Method B.-Compound 1 was prepared from 327and a substituted PhhIgBr iii T H F . The compounds thus obtained were purified by column chromatography or recrystallization. Some of the compounds showed a tendency to form solvates. Representative procedures to obtain compounds listed in Tables I-IV are given below. 3-Chloro-10- [3-(4-p-chlorophenyl-4-hydroxypiperidino)propyl]phenothiazine Hydrochloride (14).-In 50 ml of EtOH were dissolved 1.8 g of 3-chloro-l0-( 3-chloropropy1)phenothiazine and 2.3 g of 4-p-chlorophenyl-4-hydroxypiperidine, and the solution was heated in a sealed tube a t 120-130" for 7 hr. After cooling, Et,OH was dist,d off. The oily residue was treated with 100 ml of H,O, and ext,racted with 100 ml of C6H6. After drying, CsH6 wad removed iuider vacu\im. The oily residii.e, after crystallizing as a hydrochloride, yielded 1.7 g (56%) of t,he C, H, N. product, mp 196". Bnal. (Cz6H18C1,N30S) 5 - [ 3 4 4-Acetylaminomethyl-4-phenylpiperidino)propyl] 5H-lO,ll-dihydrodibenzo[b,f]azepine Hydrochloride (29).-111 60 ml of abs EtOH were dissolved 2.7 g of ;i-(S-chloropropyl)-5H-
-
( 2 0 ) Societe des Usines Chimiqua* Rhone-Poulenc, British Patent 51Y,856 (1959); Chem. Abstr., 64, 5 7 l l a (1960). (21j Societe des Usines Cliimiques Rhone-Poulenc, French Patent 1,166,240 (1958); Chem. Abstr.. 66, 584, (1961). (22) Societe des Usines Chimiques Rhone-Poulenc. French Patent 1,215,600 (1960); Chem. Abstr., 66, 176718 (1961). (23) Societe des Usines Chimiques Rhone-Poulenc. Frencli Patent 1,215,599 (1960): Chem. Abatr.. 66, 14458d (1961). (24) J. R . Geigy Chem. Corp., German Patent 1,133,729 (1962); Chem. dhnlr.. 68, 1 0 2 1 9 ~(1963). ( 2 5 ) J. R. Geigy Chem. Corp., British Patent 905,788 (1962); Chem. d h t r . , 69, 10011n. (1964). (26) .J. R . Geigs Chem. Corp., Netherlands Patent Appl., 6,603,526 (1966): Chem. Ab.&.. 66, 55412 (ltcfji). ! 2 i ) I320
++
++
++
+ +
i i
++ +++
-
>320 >320 2 320 >320 SO
40 60 > 320 >SO 120 > c10 136
>x0 >SO
f
-
+++ +++ ++ +++ +++ +++ ++ +
-
160 60 >.NU
+ ++ i +
i
>32U 320 240 120 60 120 120 60 120 S0
160 59 320 61 320 62 5 320 f 63 zt i 100 64 i 1;,0 6.5 120 The potency of each activity is represented under the criterion as below. a As EDjo values (mgjkg p . 0 . ) < l o ; 10-40; 41-100; 101-150; i,>151; -. EDjo of chloropromazine = 6.3 mg/kg. p . 0 . * As ED>, values (mg/kg i . p . ) loo; -. EDjo of chloropromazine = 1.2 mgjkg i . p . As ED,o values (mgjkg i.v.) l o ; k. EDSO of prenylamine lactate = 3.6 mg/kg i . ~ . As ED50 values 50-100; 101-2.50; i >2.50: -. (mgjkg p . 0 . )
