1244
Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 18
New Compounds demonstrated a zone of inhibition equal to tolriaftate when evaluated at the equiv coricn.
Synthesis of Thiocarbamate S-Ester Derivatives ROBERT J. ADAMSKI,* SATORU XUMAJIRI, RICHARD P O E , LARRY J. SPEARS, Medicinal Chfmzstrg Research
FRI.:DI:RICK C. BiCH
AND
Microbiology Research, Alcon Laboratories, I n c Fort W o r t h , T e x a s 76101 Received J u n e 1 , 1971
We have synthesized a number of substituted thiocarbamates of the general formula R$CO?\"RZ (see Table I). Our attempt was to generate a thiocarba-
KO. Ri
R2
r-s
2 CjHj N
,)yH,209-210
RePro- action cedure solvent
.4
THF
Thiocarbamates. Method A.-To a soln of the amine in the reaction solvent (see Table I ) was added dropwise 0.5 equiv of the appropriate chlorothioformate dissolved in the react'ion solvent'. The mixt was allowed to stir for 18 hr. The amine salt was isolated by filtration and the thiocarbamate by evapri of the filtrate under reduced pressure. The product, was recrystd from EtOH or PhH-EtzO. Method B.3-To a soln of amine in the reaction solvent (see Table I ) was added dropwise 0.5 equiv of the appropriate chlorothioformate dissolved in the reaction solvent. After stirring overnight the mixt was poured into ice water. The solid thiocarbamate was collected by filt'ration, washed successively with 2 N HC1 and HzO, and recrystd from H20 or Me2CO-HZ0.
Acknowledgments.-Grateful acknowledgment is made of the valuable assistance of John D. Hansard.
TABLE I hlp, OC
Experimental Section
(3) D.G . Crosby and C. Niemann, J . Amer. Chem. Soc., 76,4458 (1954). Formulas*
Ci,HiJSiaOS
4I'
Potential Folic Acid Antagonists. 6. Potential Irreversible Folate Reductase Inhibitors Derived from 2,4-Diamino-5-arylazopyrimidines S S C H ~ T T E RI J, FJ F MORA",D J 4ND
4 C& .i C6Hj 6 CsHj 7 CsHj
2-Naphthyl C6H40H CH2CsHaCl i-Prsa
145-147 148-130 127-129 104-107
.4 T H F C1THlsNOS A A B
THF THF THF
CllHliNOiS CiaHizClNOS Ci3HigNOS
5 Et
N\14?
127-130
A
THF
CjHsN40SC
103-105
A
THF
C7HiaN20Sz
142-143
-4
THF
C7HioNzOSz
160-162 FChH
B
')1
CiiHizN4OS
189-191
A
I>
TRIGGLI
j *
.%. W i Y N t
Department of Btochcnzzstry, Schools of Mfdtczne, Dentistry, and Pharmacy, Department of Biochemzcal Pharmacology, School of Pharmacy and the Center f o r Theoretzcal Baology, State Unzvfrsziy of S e w York at Buflalo, Buflalo, Xew Y o r k 24.214 Rrcritvd J u n c 10, 1,971
H
9
n-Pr
F N
sd sd /-9
10 i-Pr 11 Et
r x
N,
N
H
ii 13 i-Pr
14 E t CH,CsHj 61-62 A 11 ClaHiaNOS a Disubstituted amide resulted as shown by elemental analysis and spectral data. All compds were analyzed for C, H, N D, dioxane. unless otherwise noted. Also S anal.
mate derivative of a tolnaftate-like compound having both antifungal and antibacterial1 activity. The compounds were evaluated* in a primary in vitro screen (agar strip) against bacteria and fungi. None of them (1) R . E. Ortli. \V, I . Darhy, and ?i. F. Billups, Can. J . Pharm. Sei.. 2 , 48 (1968). ( 2 ) M . Harris, "Pharmaceutical Microbiology," Bailliere, Tindall, and Cox, London, 1964, p 171.
Previous studies1m2 have described the irreversible inhibition of folate reductase produced by 5-arylazopyrimidines bearing an alkylating function at the G position (I). It appeared of interest in the light of our previous' 3 ' 4 rationalizations of the structure-nctivity relationships of 5-arylazopyrimidines to preparc and examine the activities of related cornpounds i n which the alkylating function is attached to the 5-ar) I group (11). In viex of the pronounced lack of activity of the compounds listed in Table I11 (I)/(S)",5> 5.0) the corresponding alkylating analogs (X = C1) ncre not prepared. Experimental Section5
2-Nitro-w-bromoalkylbenzenes(IV, n = 2-5).--These compdh were prepared by nitration and fractional dist,illation of 2-bromo(1) J. Hampshire. P. Hebborn, A . h'I. Triggle, and D . J. Triggle, , J , .\led. Chem., 8, 745 (1965). (2) J. Hampshire, P . Hehborn, A. B I . Triggle, and D . J . Trigule, . I . P h w m . Sei.. 65, 453 (1966). (3) S. S. Chatterjee, D. R. Garrison, R . Kaprove, J . F. hIoran. A . hX. Triggle, D. J. Triggle, and A. Wayne, J . M e d . Chem., 14, -199 (19il). (4) S.S.Chatterjee. 9.Ludwig. J. F. Moran, D. J. Triggle. and .IWayne. , i b i d . , 14, 1237 ( 1 9 i l ) . ( 5 ) Melting points were recorded on a Thomas-Kofler hot stage and are corrected. Analyses \\.ere performed by Dr. A . E. Bernhardt a n d , \ h e r e indicated only h y syrnhols of the elements, were within 0.47, of the tileuretical values.
Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 12 1245
Xmv COMPOUNDS
N
3
NAr
NH(CH2)nNEICH2CH2CI
HZN
H,N A N NY
l
I
i
2
9
(CH2ln NEICH2CH2X
II
Pyrazoles. 4. Analogs of 3-(3,3-DimethyI-ltriazeno)pyrazole-4-carboxamidel C. WAYNENOELLAND C. C. CHENG*
Midwest Research Institute, Kansas City, Missouri 64110 Received June 8, 1971
&(CH21.Br
m
Is!
ethyl-, 3-bromopropyl-, 4-bromobutyl-, and 5-bromopentylbenzene according to lit. procedures. 2-Nitro- (w-N-ethyl-N-2-hydroxyethylaminoalkyl)benzenes.-A soln of IV (0.1 mole) and N-ethylethanolamine (0.2 mole) in C6H6 (150 ml) was refluxed for 24 hr. The PhH layer was washed thoroughly (HzO) and then extd with 10% HCl. The acid ext was basified and extd with EtnO, dried, and distd in vacuo (Table I).
The antileukemic activity exhibited by 3-(3,3-dimethyl-1-triazeno)pyrazole-4-carboxamide2and its stability toward light and heat2 prompted a synthesis of closely related compounds for continued study. The isomeric 4-(3,3-dimethyl-l-triazeno)pyrazole-3-carboxamide (Ia) and a homolog of Ia, 4-(3,3-dimethyl-ltriazeno)-5-methylpyrazole-3-carboxamide(Ib) , as well as two amino acid derivatives of 3-diazopyrazole-4carbo~arnide,~ I1 and 111, were prepared as described in the Experimental Section. (CHJ,NN=N
TABLE I
R
EtO,CCH,NHN=N
~-NITRO-(W-N-ETHYL-~T-~-HYDROXYETHYL-
HZNOC
AMIPZOALKYL)BENZENES
BP (mm), OC
n
a
Yield,
%
Formulaa
1 145 (0.05) 72 2 138 (0.10) 68 3 152 (0.10) 70 4 116 (0.05) 66 5 165 (0.10) 52 All compds were analyzed for C, H, N.
CiiHdz03 CizHi8Nz03 CisHzoNz03 Ci4HzzNz03 Ci&Nz03
2-Amino-(w-N-ethyl-N-2-hydroxyethylaminoalkyl)benzenes (111, n = 1-5).-Solns of the nitro compd (0.05 mole) in EtOH (100 ml) were reduced a t 50" with 57' Pd/C catalyst (200 mg). The amines were isolated and characterized as the dihydrochlorides (Table 11).
H
H.,NOC
Ia,R=H b,R=Me
I1
C02H
/
H,NOC' 111 Experimental Section4
4-Diazopyrazole-3-carboxamide.-To a suspension of 10 g of T.4BLE 11 finely divided 4-aminopyrazole-3-carboxamide6in 100 ml of Hz0 ~ - ~ M I N O - ( ~ - ~ ~ - ~ ~ T H Y L - l ~ ~ - ~ - H Y D R O X Y E T H Y L A M l N O . ~ L K Y L was )added 6 ml of coned HC1. To the resulting soln was added dropwise, at 5O, 5.4 g of NaNOz in 30 ml of HZO. A tan-colored BENZEPZE DIHYDROCHLORIDES ppt formed gradually. The mixt was stirred for 30 min, and the MP, Yield, solid was filtered off, washed with cold H20 and Me2C0, and n oca % Formulab dried at 80' to yield 7.5 g (69y0 yield) of product, which decompd 1 151 85 CiiHzoC1zNz03 violently with a sharp sound at 220' upon rapid heating, P 4.5 p 2 132 95 CizHmCIzN203 (diazo). Anal. (C4HaN50) C, H, N. 3 169 90 Ci3Hz4ClzNz03 4-Diazo-5-methylpyrazole-3-earboxamidewas prepd in a 4 142 91 Ci4Hz&l:Nz03 similar fashion from 4-amino-5-methylpyrazole-3-carboxamides 5 172 82 Ci&8CLNz03 in 47YG yield. In contrast to 4-diazopyrazole-3-carboxamide, this light yellow solid' decompd gradually upon heating above a Recrystn from i-PrOH-EtzO. All compds were analyzed 200'. Anal. (CsH5NjO)C, H, N. for C, H, C1, N . 4-(3,3-Dimethyl-l-triazeno)pyrazole-3-carboxamide(Ia).at 20" was added 2,4,6-Triamino-5- (2-w-N-ethyl-N-2-hydroxyethylaminoalkyl- To 125 ml of EtOAc, satd with anhyd Me2" 5 g of finely powdered 4-diazopyrazole-3-carboxamide. The pheny1)azopyrimidines (11, n = 1-5) were prepd by the coupling mixt was stirred for 3 hr a t room temp. The solid was collected procedure previously describedh3,4and are listed in Table 111. by filtration, washed with EtOAc, and recrystd from MeOH to give 1.6 of Ia, mp 215-216". Anal. (C6HloN60) c, H, IC'. TABLE I11 4-(3,3-Dimethyl-1-triazeno)-5-methylpyrazole-3-carboxamide ~,~,~-TRI.~MINO-~-(~-~-~~-ETHYL-~~'I-~'-HYDROXYETHYLAMINO(Ib), mp 193-194' (MeOH), was prepd in 25% yield from 4PHENYL)AZOPYRIMIDINES (11, n = 1-5) n
MP, OCQ
Yield, Solvent
7%
Formulab
1 185 EtOH 70 CibHzzN80 2 175 EtOH 75 CieHz4Ns0 3 16j i-PrOH 65 Ci,Hz6NsO 4 170 i-PrOH 80 CiaHmNs0 5 0. 67 Very hygroscopic: a satisfactory anal. could not be obtd. All compds except 5 were analyzed for C, H, N.
Enzyme Procedure.-Chicken liver dihydrofolate reductase (partially purified) was employed with the protocol previously described.3.4
(1) This investigation was supported b y Contract No. P H 43-65-94 with Chemotherapy, National Cancer Institute of t h e National Institutes of Health, Public Health Services. (2) C. W.Noel1 and C . C. Cheng, J . M e d . Chem., 12, 545 (1969). (3) C . C. Cheng, R . K. Robins, K. C. Cheng, and D. C. Lin, J . Pharm. Sci., 67, 1044 (1968). (4) All melting points (corrected) were taken on a Thomas-Hoover melting point apparatus. Where analyses are indicated only b y symbols of the elements, analytical results obtained for these elements were within &0.4% of the theoretical values. (5) R. K . Robins, F. W.Furcht, A. D. Grauer, and J. W. Jones, J . Amer. Chem. Soc., 78, 2418 (1956). (6) R . A. Long, J. F. Gerster, and L. B. Townsend, J . Heterocycl. Chem., 7, 863 (1970). (7) Although not isolated, the existence of this compd mas commented on in ref 6.
