164s
S.L. SI-IAPIRO, 1. Ill. ROSE,ERICROSKINAND LOUISr ’REEDMAN [CONTRIBUTION FROM THE
RESEARCH DIVISION,u. s. VITAMIN
Vol.
so
CORPORATION]
Pyridylethylated Oxazolidinedionesl BY SEYMOUR L. SIIAPIRO, IRAM. ROSE,ERICROSKINAND LOUISFREEDXIAN RECEIVED OCTOBER14, 1957 ‘1 series of pyritlylctliylated 2,4-oxasolidinedianes of the type I have been synthesized and screened for pharmacological activity. Significant responses found in animals include anticonvulsant activity, depression of motor activity and prolongation of Evipal sleeping time. The results have been assessed in terms of relationship of pharmacological response and chemical structure.
The cyanohydrin of 4-inethylcyclohcxa1ione, after conversion to the imino ester, afforded oil pyrolysis a mixture of amidesI2 which was not separated, but which on conversion to the oxazolidinedione could be separated readily into two products, form A, m.p. 107-10So,and form B, m p . 76-79’. The stereochemistry of these forms was not further characterized, but each condensed readily with the three vinylpyridine compounds to yield the corresponding I derivatives. Pharmacology.-The results have bcen collected in Table 11. Consideration of the response in the anticonvulsant test shows that the 4f compounds (14, 17, 23. 25, 46, 47, 48, 49, 50) have, with the exception of compound 23, two small alkyl groups, or are de0 R”)’. 0 rived from the spirostructure where the 5,5-substitRZ 1 13 + CI-I2=CHPy R2 uent is 3-methylpentamethylene. The 3+ re0 NH -+0 S-CII2CII2I’y sponse is confined to alkyl structures, while none of v 1 v the 5-phenyl substituted compounds showed inI1 ‘I2 teresting anticonvulsant activity. It is note0 11 0 1 R1, R 2 = I%, alkyl, alkyletic, aryl; P y = 2-pyridy1, 4- worthy that the series of compounds (4G-31) dcpyridyl, 5-ethyJ-2-pyridyl rived from 4-methylcyclohexanone were considerIn contrast to our observations2 with the pyri- ably more effective than those derived from cyclodylethylated benzoxazine-2,4-diones, the products hexanone (43-43) or cyclopentanone (40-42). When the compounds with high anticonvulsant of type I did not crystallize readily from the reaction mixture, and were either liquids or low-melting activity are related to the response in the Evipal solids. It was expedient when purifying to use sleeping test, it is noted that the majority also have short path distillation to avoid reversal of equation a high response in this test. However, coinpounds A to the initial reactants. When the bulk of the R1 46-49 with high antinietrazole activity, reflected or Itz groups (such as phenyl) was such that purifi- only little or no response in the Evipal test. Incation by distillation without considerable reversal terestingly, in the 5 , h u b s t i t u t e d 3-niethylpentaof the reaction could not be achieved, it was de- methylene spiro series, use of the products desirable to convert the impure product to the hydro- rived from 4-vinylpyridine (compounds 50, 3 l) resulted in high anticonvulsant activity or decided chloride for subsequent purification. The 3-pyridylethylated oxazolidinediones which prolongation of Evipal sleeping time, in contrast to products derived from 2-vinylpyridine and 2-vinylwere prepared are described in Table I. The required oxazolidinediones 11. unsubstittited 5-ethylpyridine (compounds 46-49). The response in the Evipal test, in turn, did not in the 3-position, were prepared by familiar procedures from either the cr-hydroxy esterL0or the CY- necessarily correlate with anticonvulsant acti\-ity. Thus, the following structures (compounds 5 , 20, hydroxy amide.” 34, 36, 38) showed significant prolongation of (1) Presented a t the 132nd Meeting of the American Chemical Society, New York, N. y . , September. 1957. Evipal sleeping time with little or no anticonvulsant (2) S.L. Shapito, I. A I . Rose and L. Freedman, THISJ O U R N A L , 79, activity (0 or 1+) being noted. Of this group only 2811 (1957). compound 36 is not derived from 4-vinylpyridinc. (3) B. Elpern, L. N. Gardner and I.. Crumhach. ibid., 79, 1851 In fact, an analysis of the findings shown in Table (1957). (4) A. R. Katritzky, J . Chrnt. S O L ,2381 (133d). I1 indicates that the 3-(4-pyridylethyl) substituent ( S ) A. H. Sommers, hl. Vreirelder, H. B. Wright and A. W. Weston. on I is a requisite within this series (compounds 5 , T I I I J~O U R N I L , 7 6 , 57 (1953). 17, 20, 23, 26, 20, 34, 3S, 42, 43, 50, 51). \Vhen 3( 0 ) L. A . Walter, R. H. Barry and j.R . Clark, U. S. Patent 2,713,051 (2-pyridylethyl)-substitutedI showed decided pro(July 12, 1955). ( i ) &I. A. Spielman, THISJ O U R N A L , 66, 12-14 (1944). longation of Evipal sleep time the corresponding 3(8) &I. A. Spielman and G A I . Everett, ibid , 70, 1021 (1848). (4-pyridylethylated) derivative was equal or supc( 8 ) S. I,. Shapiru, H. Soloway and L. I;reedman, .I. A n t . Pitaurn. rior (see compounds 14 as. 17; IS vs. 20; 21 71s.23). Assoc., Sci. Ed., 46, S.33 (1957). The finding of significant pharmacological activity in a wide variety of pyridylethylated products2-6 suggested the synthesis and pharmacological investigation of the pyridylethylated oxazolidinediones. Suitable derivatives of oxazolidinediones7-~ have found wide clinical utility, particularly as anticonvulsants, and the compounds prepared in this work were screened pharmacologically in animals as anticonvulsaiits and for their effectiveness as depressors of motor a ~ t i v i t y . ~ Pyridylethylation2 of the oxazolidinediones I1 proceeded readily without catalyst to yield the 3pyridylethylated oxazolidine-2,4-diones (I) according to the equation A.
R’>;lf
(10) R. W. Stoughton, TNISJOURNAL. 63, 2370 (1941). (11) V. H. Wallingford, h l . A . Thorpe and R. W. Stoughton, iDid., 67, 522 (1945).
(12) B. ’Tchoubar, Bull. soc. chim. F ~ n n c e ,160 (1949); C. A , , 44, 4431 (l950), separated the mixture of t h e corresponding o-hydroxy acids.
PYRIbYLETIiYLATED OXAZOLIDINEDIONES
April 5 , 1958
R1)_/0 R2 TABLE I : PYRIDYLETHYLATED OXAZOLIDINEDIONES 0 NCHZCHZX(Y.2)
I I
1ti49
X = 2-pyridyl Y = 5-ethyl-2-pyridyl Z = 4-pyridyl
0
x, y or Z
Cmpd.
X
1 2 3 4 5 6 7 8 9 10 11 12 13 14
CH3I
Y CHaI 2
x
CH.d Picrate
Y Picrate 2
Picrate HCl
x
15 16 17
Y
18
X Y
Picrate 2
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46'" 47" 48" 49" 50'" 51"
Salth
z
X Y
z
x Y 2
X Y 2
X I-ICI
Y HCI
z
x
CIIJ
Y Z X Picrate
Y 2
-(CHz)zCHCHt(CHz)z-(CHz)CHCH3(CH*)2-( CHz)zCHCHs(C H i ) r -(CH2)aCHCHj(CHz)z-(CHz)zCHCHa(CHz)z-(CHz)zCHCHa(CHz)Z-
X Y Z X X Y Y Z Z
M.p. i or b.p., "C. (mm.)
Yield,a
%
Formula
89-90 168-173 65 140-141 128-129 143-145 126-130 (0.10) 193-194 144-150 (0.01) 163-164 131-148 (0.015) 137-144 174-175 54-55 115-132 (0.01) 129-136 (0.01) 177-179 73 12&129 (0.04) 155 (0.05)' 155 (0.08)' 155 (0.01)' 144-162 (0.10)' 142-170 ( 0 .10)' 80-81 144-154 (0.10)' 160-170 (0.08)k 162 ( 0 .12)k 164 (0. 55)' 183-194 (0.06)' 39-43 107-109 Residue 154-170 Residue 145-156 107 166-1FS 166-174 ( 0 . 170-172 (0.06)k 167-172 (0.03)' 162-176 (0.06)' 188-191 34-36 77-78 63 99-100 108-109 60-61 110-120 52-53 45-65 107-108 84-87
71b 53d 5Sb 24d 41' 21d 95 73' 71 71' 89 45" 66d 74*
CiOHiONzOs CiiHiiINzOa CizHi4N203 CiaHi7Iru'zOt CioHioNzOa CiiHi~INz0a CiiHi2XzOP C17H16N6010 ClrHi6N2O3 CigHioICsOio CllHiZN203 CnHisN60io CilHiaClN~Oa CizHi4N20a
86 CirHisNlOa 71' CmH2iNd310 50b CnH14Nz0:
84 89
83 90 90 70' 85 85 80
25
sod 64d OSb 47O 85 85 85 85 75' 50' 64' 78' 77' 71b 75' 35' 46' 65' 76b 69'
C12HiIN201 CIIHISNZOI CizHiINzOt C1aHisN20: CisH20;\T203 CisHi~Nz03
C
Calcd. H
58.3 4 . 9
Analyses,j %
N
C
6.0 4.6 4.9 3.8
13.6 58.1 8.1 12.0 61.7 7 . 5 41.7 13.6 5 8 . 3 8.1 3 8 . 3
45.4 3.4
45.7
61.5 41.5 58.3 37.9
Found H
N
4 . 9 13.9 7.7 6 4 11.9 4 9 7.3 5 0 13.8 4.2 7.8 3.4
47.8 4 . 0
14.7 48.1 3 . 9 1 4 . 9
45.4 3 . 4 51.5 5 . 1 61.5 6.0
15.6 45.5 3 . 6 1 0 . 9 51.7 5 . 0 1 2 . 0 61.8 6 . 3
15.9 10.6 11.8
48.9 61.5
4.3 6.0
14.3 48.9 4 . 5 13.8 1 2 . 0 61.8 6 . 0 11.6
61.5 64.1 61.5 62.9 65.2 62.9
6.0 6.9 6.0 6.5 7.3 6.5
12.0 10.7 12.0 11.3 10.1 11.3
62.9 ClsHi6N~01 65.2 C16H20~203 62.9 Ci~H16N203 68.1 Cl6H 14p\T203 69.7 CIEH18"203 m.1 C16HiaNz03 CzzHiah-zOs C~2H18C1Nz03 06.9 CZJL"03 Cz4HzaClNz03 6 8 . 2 73.7 Cz2HigNZ03 C?aHzlIr\TzOa 55.2 67.1 Ci7Hzrr\'zOa C19Hzs~z03 6 8 . 6 67.1 C17H24T\Tz03 64.6 Ci4Hie~zOs 49.1 CzoHid6Oio 66.6 Ci6Hzo~zoa 64.6 Ci4HisNzOa 65.7 CisHiaNzOt 67.5 CnHz2NzOa 65.7 CisHi8NzOa 66.6 CisHzol\'203 66.6 Cl6H20NZO3 CieHuNzO3 68.3 68.3 ClsHuNzO3 66.6 Ci6HzoNzOa C I ~ H D N I O ~ 66.6
61.6 64.0 61.6 63.1 64.7 63.0
6.3 6.7 6.2 6.6 7.2 6.7
11.7 10.7 11.5 10.8 9.8 11.2
6 . 5 11.3 6 3 . 4 6 . 7 1 0 . 9 7 . 3 1 0 . 1 ti5.8 7 . 5 9 . 7 6 . 5 1 1 . 3 63.1 6 . 8 1 1 . 3 5 . 0 9 . 9 67.9 5.0 9 . 7 9.1 5 . 9 9 . 0 70.2 5 9 5 . 0 9 . 9 68.2 5 . 2 9 . 7 4.9 5.5 5 1 4.2 8.0 8.5 8.0 6.2 3.9 7.0 6.2 6.6 7.3 6.6 7.0 7.0 7.7
7.7 7.0 7.0
7.1 07.3 4.8
0.8
68.1 5 . 4
6.9 7.9 6.1 8.8 8.2 9.0 10.7 13.8 9.7 11.0 10.3 9.0 9.8 10.4 9.6 9.4 9.0 9.7 9.9
B.6 7.8 5.6 9.2 8.4 9.2 10.8 14.3 9.7 10.8 10.2 9.3 10.2 9.7 9.7 8.9 8.9 9.7 9.7
73.2 5 . 1 ,55.4 4 . 4 67.0 8 . 1 68.7 8 . 2 66.7 8 . 0 64.8 6.3 49.2 3 . 9 66.8 6 . 9 64.7 6 . 3 65.7 6 . 9 67.6 7 . 4 65.9 6 . 9 66.8 6 . 9 66.9 6 . 9 67.9 7 . 7 68.3 7 . 6 66.6 6 . 7 66.9 6 . 9
a Recrystallizing solvents listed in footnotes b through g. Ethyl acetate-hexane. Ethyl acetate. Ethyl acetatealcohol. # Alcohol. f Hexane. ' Water. Unless otherwise indicated, compound is free base. Melting points are G H I ScorreIsolated by short path distillation. not corrected. f Analyses by Weiler and Strauss, Oxford, England. From oxazolidinedione isomer, m.p. 76-79'. sponds to 3-heptyl. From oxazolidinedione isomer, m.p. 107-108°.
'
S. L. SHAPIRO, I. M. ROSE,ERICROSKINAND LOUISFREEDMAN
1650
TABLE I1 PHARMACOLOGICAL S C R E E N I N G OF
Compd
1- Drn in."
TABLE 111 SUMMARY OF INITIAL REACTANTS
COMPOUNDS O F TABLE I
Xnticonvulsantb
Bvipal timec
Depression of motor activityd
1 > 1000 3+ 0 0 3 1000 0 1+ 15 5 >1000 0 514 18 7 > 1000 .. 0 3+ 9 >loon .. 1+ 0 11 > 1000 0 .. 29* 14 1000 300 4+ 0 15 > 1000 I+ 0 17 >1000 630 25 * 4 -I18 1000 300 0 2+ 19 1000 0 100 3+ 20 750 0 300 0 21 750 293 2+ 22 1000 191 2+ 23 750 1450 0 4 24 750 29 .. 3 -t 25 > 1000 153 4+ 26 500 0 300 2+ > 1000 27 0 (1 1+ 28 > 1000 0 0 1+ 29 500 (1 0 300' 30 1000 0 0 35 32 1000 0 0 18 "3 > 1000 34 0 300 36 1000 0 200 0 37 > 1000 0 0 0 38 400 300 24 1+ 39 500 0 0 24 41 > 1000 .. 115 0 42 300 333 0 2+ > 1000 43 .. 0 3+ 44 750 0 .. .. 45 500 570 0 2+ 46 > 1000 0 87 .I+ 47 > 1000 0 0 4+ 48 > 1000 0 67 4+ 1000 49 0 0 4+ 50 750 0 500 4 51 450 34742 If ' The LDmin. wets establislicd subcutaneously i i i inice using 8-16 animals per test and is expressed as mg./kg. not toxic to any of the test animals. If the compound was not toxic a t 1000 mg./kg., the response has been shown as > 1000 without establishing the LD,i,. * The anticonvulsant response was established a t one-half and one-fourth the LDmi,. subcutaneously in mice and evaluated in terms of protection afforded against metrazole seizures. A 4+ response indicates substantially complete protection when tested a t one-fourth the LDmi.. Tridione (LDmi, >lo00 mg./kg.) used as a control drug showed a 4 + response. Evipal sleeping time evaluated a t one-third L D min. subcutaneously in mice. The average sleeping time of a control group of 6 mice was divided into average sleeping time of the group similarly treated plus test compound, multiplied by 100. Results reflect percentage increase in sleeping time. Neprobamate , (LDmin 750 mg./kg.) tested in this manner gave 126y0 increase. Compounds tested a t 20 mg./kg. subcutaneously in rats. Compounds shown with asterisk were tested at 10 mg./kg.; see ref. 9 for procedure. Meprobamate under the conditions of this test was inactive at doses as high as 100 mg./kg. while Chlorpromazine (LDmin.400 mg./kg.) showed 71% decrease at 10 mg./kg. e Compound was toric in this test.
+-
+
Xa Xb Xc Xd
= = = =
RIRzC(OH)CN,(cyanohydrin) R1RzC(OH)COOC2H5,(a-hydroxy ester) RIR&(OH)CONH~,(a-hydroxy amide) (2,4-oxazolidinedione, 11) X
Xd )id Xd Xa XC Xd X d
xc Xd Xa xc Xd Xd Xb Xd Sb Xd Xa S C
Sa S C
Scl Xa XC
M.P. or b p.. OC. (rnrn.1
Yield,
90-92' 122 (2.0)? 76-78* 88 (12.0)' 105-107' 118 (0.7)" 86 (12.0)" 68-70'"5"" 98 (0,005)" 90 (10.0)' 105-1062 106-110 (0.1)"" 108"b 104-106 (1.0)"" 135-136"d 104-106 (4.0)"" 124-130 (0.05)"' 86 (0.7)=# 137-138"* 102 (3.0)"; 127-128"' 113-1 14"k 108 (7.0)"' 145-150""
50h 74h 50 62 23" 80 73 73" 86
%
89 92' 84
GO" 43 62h 32 86 77 Wr 72 39" 76* 69
Sf9
Acta Acad. RboinGs, Muth. et PlzyA., 11, Yo. 14 11939); C.A. 33, 6802 (1939), m.p. 89-90' (60%). * R. \Vi Stoughton, THISJOURNAL, 63, 2778 (1948), b.p. 147-148 Ref. p , m.p. 77". a C. L. Stcvens, (5.0 mm.) (81%). E. Farkas and B. Gillis, THIS JOURNAL, 76, 2697 (19541, b.p. 103-105" (20.0 &I.) (49y0). CH. Bredereck, It. Gompper and G. Theilig, Ber., 87, 537 (1954), m.p. 105'. "Ref. p , m.p. 55-56'. " E . C. Chapin and R. F. Smith, THW Tormxnr.. 7 6 . 4179 (1954), b.p. 87-88" (17.0 mln.) 7 n and P . Silber, Bcr., 47, 1814 Rrlciimeyer, A . Kleiber and r:. 21, 1010 (1938), m.p. 31 . A . Lipp, Ann., 205, 24 (1880), b.p. 106" (22.0 iiiiii.). Lipp, Ann., 205, 27 (1880), m.1). 104'. " h l . A . Spielman and G. M. Everett, TIirs JOURSAL,70, 1021 (1048), h.p. 118-119' (1.5 niin.). a b €I. hspeluiid, Finska k'rniistsc~t77~z~ntcts .\icdd., 49, 42 (194U); C.A., 3 5 , 3634 (1041), n1.p. 108-109O (74'7Gj. a c H. rldkins : ~ n d1 3 . Rd Rillica, THIS JOURNAL,70, 3124 (1948), h.p. 138-14C (1.0 nun.) (:I%). OdRef. q , i n . p . 1.15-136'. ""XO~ reported; used for preparing S d derivative without :malytical data. ef Ref. l l , b.p, l44-14iio (2.3 mm.) (78%). O g Ref. 12, b.p. 140' (40.0 nun.). It. Giuliano :tnd G. Leonardi, Farm. sci. c tcc. (I'aoia), 7 , 29 (1952); C-,1., 46, 1011311 (1952), 111.p. 131'. Ref. 12, b.p. 120-131" (16.0 mrn.). ai H . T. Buchercr and W. Rrnndt, J . p i a k t . Chem., 140, 129 (19:34'1, 1n.p. 130". .I. Lespagilol, 1. hZercier and J . Dupas, Bull. soc. phnrjit. Lillc, 4 , ;io (1!1471; C.A.. 43, 1406a (l949), ni.p. 110". Ref. 12, b.p. 120.1.30' (12.0 m m . ) . Mixture of t x q u itereoisomers. . l ? t d . C'tlcd. for CsHI,N02. C , G I .l;H , 9.6; S , 8.9. I'ound: C , 61.3: H , 9.9: 5 , 8.8. (L1' T. Verhulit, Bztil. SOL. c h t ? ~ . Balgcs, 39, 563 (1930'1, reports m.p. 51-57'.
'rhe depression of niotor activity was indnifestetl a t very low dosages (10-20 nig.,'kg.) with these relatively non-toxic compounds. and depression wLt\ tlntecl \$rlth cotupoutlds, .'i, 1 1 , 17, 30, ij2, 31, 36, 39. Of thi9 group o i i l > conipoud 17 showed significant nnticonvulsmt activity, while in the Evipal sleeping time tcst compounds 3, 30, 32 t-~,
Compound 23 is outstandiiig in this category in that the sleeping times were prolonged over 14 times that observed with the control group.
VOl. 80
April 5, 1958
1-AZAPHENOTHIAZINE AND RELATED COMPOUNDS
1651
and 39 were negative, and compounds 5, 17,34 and g. (46%), m.p. 107-108° (form A), unchanged by recrys38 were active. I n view of our prime interest in tallization from ethyl acetate-hexane. Anal. Calcd. for CpHtaNOa: C, 59.0; H, 7.2; N, 7 . 7 . compounds which would function orally as depresFound: C, 59.2; H, 7.1; N,8.0. sors of motor activity, it was established that comOn complete acidification of the filtrate, 3.2 g. (15%) of pound 11, the 5-methyl-3-(4-pyridylethyl)-oxazoli-the low melting isomer was obtained, m.p. 76-79' (form B), dine-2,4-dione showed a 30% depression of motor unchanged by recrystallization from hexane. activity when evaluated orally a t 50 mg./kg. Anal. Calcd. for CgH13N03: C, 59.0; H, 7.2; N, 7.7. Experimental13 The many reactants prepared for this work which were not available commercially and which were previously described, have been gathered in Table 111. 3-Aza-1-oxaspiro [4,4]nonane-2,4-dione.-A mixture of 3.6 g. (0.157 mole) of sodium metal in 38 ml. of methanol and 20.2 g. (0.172 mole) of diethyl carbonate was heated under reflux, a solution of 19.4 g. (0.15 mole) of l-hydroxycyclopentane carboxamide in 50 ml. of hot methanol added, and heating continued for 4 hr. The methanol was removed and the residue was dissolved in 100 ml. of water and filtered. The filtrate was washed with two 50-ml. portions of ether and then aerated to remove the dissolved ether. ..lfter acidification with concentrated hydrochloric acid (13 xnl.) and standing 16 hr., the product was separated, washe? with water and dried, yielding 11.89 g., m.p. 132-133 On extraction of the filtrate with four 50-ml. portions of ether, an additional 3.7 g., m.p. 132-133", was obtained; total yield 67y0. Anel. Calcd. for C7HBN03: C, 54.2; H, 5.9; S , 9.0. Found: C, 54.4; H, 5.7; N,8.7. 3-Aza-l-oxaspiro-8-methyl[4,5]decane-2,4-dione (2 Isomers) .-The pair of stereoisomers was prepared as above from 18.5 g. (0.118 mole) of 1-hydroxy-4-methylcyclohexane carboxamide (mixture of isomers). In the final acidification step (careful addition of 3 N hydrochloric acid) the point of separation of the two isomers was taken as that point a t which further acid addition gave a semi-permanent cloudiness which did not clear in a few seconds by crystallization to the hard needles of the high melting isomer. This isomer was filtered off, washed with water, and dried, yielding 9.9
.
(13) Descriptive d a t a shown in the tables are not reproduced in the Experimental section.
Found: C, 59.4; H, 7.3; N, 7.8. Pyridylethylated Oxazolidinediones (Compounds of Table I).-Equivalent amounts of the oxazolidinedione and the vinylpyridine were heated a t 150' for 2 hr. If the residue solidified on cooling, i t was triturated with hexane (in cases of compounds 41, 48 and 49, it was necessary to use cold hexane). The crude product was then dissolved in dilute hydrochloric acid, the solution washed with ether, and the product, precipitated on the addition of excess sodium bicarbonate solution, was filtered, washed with water, dried and recrystallized. With compounds 29 and 34, the residue solidified on triturating with ether. Compound 29 was then worked up as above and compound 34 was recrystallized directly. Compounds 1 and 3, water-soluble solids, were extracted from the aqueous solution with ether, the ether evaporated and the products recrystallized. Compound 5 was triturated with water, filtered, washed with water, dried and recrystallized. Liquid residues were dissolved in dilute hydrochloric acid, the acid solutions washed with ether, the products extracted with benzene, the benzene evaporated and the products distilled under reduced pressures. In most cases where the boiling points anticipated would require a bath temperature high enough to reverse the reaction, purification was effected by short path distillation. In some cases (compounds 7, 11, 15, 30 and 32) the structures were characterized by the preparation of hydrochlorides or picrates. Methiodides were prepared in the usual manner (compounds 2,4, 6 and 35).
Acknowledgment.-The authors wish to thank Dr. G. Ungar and his staff for the pharmacologic results of the screening of the compounds. YONKERS, NEWYORK
[CONTRIBUTION FROM THE SQUIBB INSTITUTE FOR
MEDICAL RESEARCH]
10-(Dialkylaminoalky1)-pyrido[3,2-b ] [1,4]benzothiazine (1-Azaphenothiazine) and Related Compounds BY HARRYL. YALEAND FRANCIS SOWINSKI RECEIVED NOVEMBER 8, 1957 1-Azaphenothiazinehas been prepared via the Smiles rearrangement of 2'-(3-nitro-2-pyridylthio)-aceta1iilidc. 8-Chloro-lazaphenothiazine was prepared similarly from 5'-chloro-2'-(3-nitropyridylthio)-acetanilide. Reaction between these two azaphenothiazine derivatives and various dialkylaminoalkyl chlorides in xylene, using sodamide as the condensing agent, led to a series of 10-dialkylaminoalkyl derivatives, which were converted to mono- and dihydrochlorides, as well as salts with oxalic acid.
In our studies with substituted phenothiazinesl.2 and the relation of their structure to pharmacological activity, we thought it of interest to synthesize pyrido [3,2-b][ 1,4]benzothiazine (l-azaphenothiazine) and 8-chloropyrido [3,2-b][ 1,4]benzothiazine (8-chloro-1-azaphenothiazine)and their 10-dialkylaminoalkyl derivatives. These compounds have shown interesting pharmacological properties and several are now undergoing clinical evaluation. 1-Azaphenothiazine and 8-chloro-1-azaphenothiazine are new compounds; a few mono- and dini(1) H. L. Yale, THISJ O U R N A L , 7 7 , 2270 (1955). (2) H. L. Yale, F. Sowinski a n d J. Bernstein. ibid., 79, 4375 (1957).
tro- and mono- and diamino-substituted 3- and 4azaphenothiazines are known. 3.4 The synthesis of 1-azaphenothiazine is outlined below and has, as its critical step, the Smiles rearrangement5 of 2'-(3-nitro-2-pyridylthio)-acetanilide (I). Again, as reported in our previous paper2 we prefer the rearrangement procedure involving the use of one equivalent of alkali in a mixture of acetone and ethanol; this makes possible the isolation of the intermediate 10-acetyl-1-azaphenothia(3) V. A. Petrow and E. L. Rewald, J . Chem. Soc., 591 (1045). ( 4 ) T. Takahashi a n d E. Yoshii, Pharm. Bull. ( J a p a n ) ,2, 382 (1954). ( 5 ) W. J. E v a n s a n d S. Smiles, J. Chcm. Soc., 181, 1263 (1935).
