SOTES
SCHEME I RNHi
-
4
3
HINNHi
N(CH,),SO,NHR
H,N(CH,),SO,NHR 6
CH 1
CHJ
I
I
CHj-CH-C-CHOHCONH(CHJ,SOZNHR I t
HOCH,-C--CHOHCONH(CH,),SO,NHR
I
CH i
bH kHJ 9
10. I)-(+)
T ~ R LI E SITnSTITL-TED S U L F . ~ M O Y L I . T H S L P H T H A L I ~ ~ I D l (, S5 )
0
No.
Mp,
oc
141-143' 151-153 161-163 168-170' 148-149' 194-196 188-192 137- 159 162-163
5a b C
d e f g h 1
P
O
c
H
q
208-209
Yield,
%
A
51
. 0i
57 53 49 83
0
CH,O&
m
CH O
S=N
-a
n 1-Adamant yl rl, E t O H ; B, AcOH, C, 31e2CO-H20.
B A A4 B C B A
A
B
B
203-207" 1
Porifn solvent'
CLaHnN40aS
178-1 80
35
B
150-152
59
A
CisHi5xi30,S
C, H, N
A
C2oH??XLj?OaS
C, H , X
190-19 1 See ref 3.
C, H , N
See ref I%.
Substituted Sulfamoylethylphthalimides ( 5 , Table I).-All the compounds except 5m were prepared by adding slonily 0.1 mol of finely powdered 2-phthalimidoethanesiilfonyl chloride ( 4 ) to a stirred and ice-cooled mixtiire of 0.1 mol of the amine in 80 ml of dry pyridine. After the reaction mixture had been stirred for 1 hr a t room temperature, it was poured into excess 15yc HCl with stirring and the precipitate was filtered and washed (HzO). After drying the solid was crystallized from an appropriate solvent. Compound 5m was prepared by heating a mixture of 19.8 g (0.16 mol) of 5-amino-2-methoxypyridine and 22.8 g (0.08 mol) of finely powdered 2-phthalimidoethanesiilfonyl chloride ( 4 ) in 64 ml of refluxing P h H for 1 hr. The precipitate
that had formed during the reaction was filtered off, stirred with 600 ml of 107, N a H C 0 3 solution, filtered, and washed ( H 2 0 ) . After drying the solid was crystallized from EtOH. 2-Aminoethanesulfonamides (6, Table II).-A mixture of 0.04 mol of the appropriate sulfamoylethylphthalimide ( 5 ) in 26-100 ml of EtOH and 9.4 g (0.04 mol) of 85yChydrazine hydrate wa:, heated a t reflux for 3 hr. T h e solvent wab removed under vacuum and the residue was suspended in warm H2O and acidified to congo red with the minimum amount of 10% HC1. The mixture was stirred, cooled in an ice bath, and filtered. The filtrate was concentrated to dryness to give the hydrochloride. The salt was added to boiling EtOH arid neutralized with 1 equiv of a freshly
li
li
i'
pwpared KOEt soliitii)ii. The soliitioti was filtered hot. C'ooliiig the filtrate gave the ~ o l i t iwhich was c*ry>tallized from the i i i tiicsated solvents. a-Hydroxy-p,p-dimethyl--,-valerolactone( 7 ) was prepared avviirdirig to the method of Drell and I ) i i i i i i , 4 i 1 mp 58-60", Amides of w-Methylpantoyltaurines (9, Table III).-To a mixtiire i i f 0.02 niol of the reqiiisite 2-amitioethariesiilfollamide ( 6 ) i i i EtOH, an Et011 soliitinn coritaiiiiiig 1 eqiiiv of freshly prepared KOEt was added. After refliixing for 0.5-1 hr, the .*ohitioii was vooled a i d EtOH was removed iirider vaciium. The K lialt thiih obtained wa6 further dried overnight in. tmcuo. The solid wa. powdered arid heated with 0.021-0.03 niol of a-hydroxy-p,p-dimethyl-y-valerolactone ( 7 ) at 110-120" for 4-5 hr with occasional stirring. The residue was dissolved in the minimum quantity of H 2 0 and neutralized with dilute HCI. I t was extracted with EtOAr, dried, and evaporated to leave a gum which was chrnmatographed throiigh a column of silicic acid (100 mesh) with the indicated solveiit system and followed by tlc. The later. frartioii whirh showed only one spot on tlrj was cnnrentratd
i n ocrc:lto t l l Ir:1ve it gllrli W h i l ~ t lwas ( tallizeti f i ~ o n iI tie itidi(*:it(vl >cllvelI t . Amides of Pantoyltaurine (10, Table I V ) . - ~ ( ' o n i ~ ~ ~ i 10a i i ~ dei were prepared by heating a mixture of 0.01 mol of the appropi,i;itc. 2-amirioethanesiilfoiiamide(6) and 1.4 g ( 0 .10s mol) ill' I)-( - 1pantolac8totie( 8 ) i t i a meh at 115-120" f o i , 2-4 hr with ( J c t % S i l ) l i ; i l atirritig. The reFiilting clear viscwii.* liquid w-as chromatographed atid crystallized as described above. Compound 1Oi was prepared by addiiig 0.01 mol of freshly prepared KOEt solutioii i t i EtOH to a mixture of 2.44 g i O . 0 1 mol) of 2-amino-Y-( 1-adamaiity1)-ethaiiesiilforiamidein Et0l-I. After refluxing for 0.5 hr, 2 g (0.0154 mol) of 8 was added. -4fter the solution had refluxed for 4 hr t,he solvent was removed iinder vacuum and the residue war dissolved in HIO. The solution wa.. iieutralized arid then was extracted with Et,OAc. The combined extrarts were washed HrOi, dried, and evaporated to leave a solid
Journal of 3fcdieinnl Chcmistry, 1.970, 1'01. l.;, .2'n. .7 549
TABLE IV AMIDESO F
PANTOYLPAURINE
(10)
CK
I I
OHCHI-C-CHOHCON
H (CHs)&O*NHR
CHI Yield,
R
?io.
R
hip.
(--
oc
162-163
55
Purifn solvent
[alo" dee
26
EtOH-E t 201
+16.9
Formulah
Ci,HJJ,Ojl:
S-
i 1-Adamant yl 130-131 38 CHCls-Et>O h Ci,HuN?O,F ,411 comporindy were analyzed for C, H, Y.'* Cry-tallized after prirification b.7 chioC = I-ZC;, temp, 22-2.5", 9,5% EtOH. Eluted with 50: 50 EtOAc-C& e Eluted with 93: 3 EtOAc-> IeOH matography on silicic acid (100 mesh) and eluted wlth EtOAc. Eluted with 3: 1 CHCl3-1IeOH; Eluted with 9: 1 EtOAr-1leOH, the gum failed to cry-tallize. * It showed zero rotation. n
Q
.___
which was t,riturated with EtsO. The solid was filtered and recrystallized. Compounds 1Of-h were prepared following t,he condit,ions used for the preparation of amides of w-methylpantoyltaurinea. However, iii the case of log t,he K salt was heated with the lactone 8 for 24 h r and after neutralization with dilute HC1 t,he solution was evaporated to dryiiesv and the residue extracted with EtOH. T h e extract was evaporated to a brown gum. Trituration with E t O H gave a beige solid which was removed by filtration. The filtrat,e was conrentrated and chromatographed iri the usual way.
Synthesis and Microbiological Properties of Some Substituted Derivatives of 3-Amino-3,4-dihydrocarbostyril ALVIEL. D ~ V I S J ,a v ~ sW. HUGHES,* ROUF,RT L. HkNCE., V I C K I L. G I U L T , AXD TOMMY J. JICCORD Dtpartinent of Chemistry, dbilene Chiistian College, Abilene, Texas
Received Sovember 7 , 1969
The synthesis and microbiological properties of several reduction products of 0-nitrophenylalanine have been previously described to afford some rather interesting structure-activity relationships. For example, 0-aminophenylalanine specifically and competitively antagonizes the utilization of phenylalanine for the growth of Escherichia coli, whereas its corresponding lactam, 3-amino-3,4-dihydrocarbostyril, also causes growth inhibitions to E. coli and Leuconostoc dextranicum that are reversed by phenylalanine but in a noncompetitive mannere3 Another reductive cycliza(1) T h e support of this work by a research grant from t h e Robert A. Welch Foundation of Houston, Texas, is gratefully acknowledged. ( 2 ) Taken in part from t h e &I. S. Thesis of J . IT, Hughes, Abilene Christian College, hbilene, Texas. M a y , 1969. (3) A . L. Davis. R. Lloyd. J . Fletcher. and T . J . MrCord, Arch. Biochen. B i n p h ~ i s . lo%, , 48 (1963).
tion product, 3-amino-3,4-dihydro-l-hydroxyc:arbostyril, was demonstrated to exert potent inhibitory activity against the growth of E . coli, L. dextra? i c u m , and L. mesenteroides, and its toxicity is not appreziably affected by natural extracts or protein h y d r o l y ~ a t e s . ~ Our studies on tyrosine analogs demonstrated that 2-aminotyrosine VI is a specific arid competitive antagonist of tyrosine for E . coli and L. dextraTlicum, while 2-amino-4-methoxyphenylalanine V is an effective growth inhibitor of L . clexlranicum but not of E . As an extension of this work, the l-hydroxy-7methoxy-111, 1,7-dihydroxy-IV, 7-methoxy-VII, and 7-hydroxy-VI11 substituted derivatives of 3-amino-3,4dihydrocarbostyril were prepared and examinc d for microbiological growth-inhibitory properties in A'. coli, and L. dextra?zicunz as subsequently described. The catalyt'c hydrogenation of 4-methoxy-%nitrophenylalanine (I) and 2-nitrotyrosine (11)under rather exacting conditions of acidity gave the reduction cyclization products, 3-amino-3,4-dihydro-l-hydroxy-Tmethoxycarbostyril (111) and X-amino-3,4-dihydro-l ,Tdihydrocarbostyril (IV), respectively. AlternaI ively, 2-amino-4-methoxyphenylalanine (V) and %aminotyrosine (VI) ,5 were cyclized intramolecularly by treatment with acid to form their corresponding lac tams,
k I, R = OCH,; X = NO, 11.R OH; X =NO, V.R = OCH,; X = NH, VI, R = OH; X = S H . i=
111, R = OCH,;Y = O H I\.', R = O H ; Y = O H
VII, R = O C H , ; Y = H VIII. R = OH; Y = H
3-amino-3,4-dihydro-7-methoxycarbostyril (VII) and 3-amino-3,4-dihydro-7-hydroxycarbostyril(VIII), re(4) .%. L. Davis. 0. H. P. Choun, D . E . Cook and T. J. McCord J . .\fed. Chem., 7, 632 (1964). ( 5 ) A. L. Davis. J . W.Zaiin, P. C . Reeves, R. L. Hance, and T. J. ZIcPord, abad., 9, 828 (1086).
