Cumpd" Z-I'lie-(NO?) Argd Z-iJ-Phe-(XO?j.Irg Z-DL-PII~-(NOI) .irx Z-Phe-(NO>)-u-.iri! Z-u-Phe-hla Z-D-Phe-i>-.'Ila Z-D-Phe-u-Leue Z-o-Phe-hfet Z-n-Phe-D-LIet Z-Phe-u-Phe Z-D-Phe-D-Phe' 2-D-Phe-Ser Z-D-Phe-II-Ser Z-u-Phe-o-Tlir Z-u-Plie-u-Trp Z-11-Phe-o-Tyr Z-0-Plie-u-\'a1 Z-u-Phe-Phe-i>-.\ la Z-u-Phe-Plie-(KO?) Arg Z-Phe-D-Phe-D-Tyr Z-o-Phe-Phe-~-Val
Np,
__ N , R--
oc
174-176 143-145 137-139 13.5-137 116-118 165-167 138-139 115- 117 106-109 100-102 156-157 136-138 155-157 168-li0 160-163 168-170 114-146 85-90 105-107 183- 185 95-100
188-1 89 Z-u-.isn-.\la Z-o-Phe-bla 82-85 Z--/.Ibll-(S-Uzl)Cys 170-172 fNO?)Z Ar~-(S-l3ai)Cys I l i Z - D L - L ~ ~ - ( S - B ~ ~ ) C ~ ~ - O C139-141 H~ Di Z-DL-LSS-(S-BZ~)-D-CSS-OCH~ 153-155 75-78 Z-D-Phe-(S-Bzl) Css Z-D-Phe-(S-Bzij-o-C,.s 86-89 137-139 Z-Ser-(S-Bzl) Cys 157-1 59 Z-o-Ser- (S-Rz1)Cys 65-70 Z-Trp-(S-UaljCys 135-138 Z-Tyr-(S-Uzl)Cys-OCHa 168-170 Z-Val-(S-l3zl)Cys 91-94 %-val-(S-f%Zl)-D-C3.s 73-77 Z-u-Phe-(S-Etj C y s 112-1 17 Z-D-Phe-(S-hIejCys 126-128 Z-Phe-o~-ethionine-OCHa 142-143 Z-Pro-GI?-0x11 104-105 Z-Phe-Ile-OC Ha 107- 109 Z-Pro-Met-OCHa Z-D-Phe-Met 130-132 (Ih;OzjZ-u-Plie-o-Met-OCHa 166-168 Z-(S-Ual) C p - u - P h e 120-122 Z-D-Pro-D-Phe 198-200 Z-i~-.Isn-o-Ser-OCHs 187-189 Z-u-.lsn-Val-OCHs 203-206 Z-DL-Glu-val 136-1 36 Z-Phe-~-Val-oCHa
Calcd 16.79 16.79 16.79 16.79 7.56 7.56 6.79 6.39 6.51 6.15 6.28 7.25 7.25 7.00 8.66 6.06 7.03 8.33 1 4 ,76 6.89 7.69
.1 '1
c C
.I A C
.i -4
C
h A .1 '1
.i
.I C
C
.\, C A, C
c
12.45
C 13
B I3 l3
.1 .I
c
C I3
I3 I3 A
.I
x C A A C
I3 h
.I C C C A
Found 16.81 16.89 16.96 16.76 7.67 7.59 6.88 6.39 6.30 5.98 6.44 i.23 7.12 7.01 8.67 6.03 7 . 13 8.13 14.70 6.93 7.92 12.38
Tiriis ratingC 2.2 2.1 2.3 2 4 1. B 1.2 0.95 1,s 2.8 0.5 1.7 2.9 2.3 1.6 1.3 3.6 1.1 1.8 2.4 0.7 1.5
6.51 l5,38 6.7i 6.77 5.69 j.69 6.18 6.48 7.90 5.36 6.30 6.30 6.51 6.73 6.11 9.83 6.57 7.10
6.48 15.34 T . 12 6.98 5.79 5.49 6.34 6.51 8.21 5.51 6.27 6.38 6.72 6.86 6.06 10.00 6.57 7.13
8.58 5.69 7.06 11.44 11.08 11.08 6.79
8.79 5 74 7.10 11.57 11.28 11.07
0.2 0.6 0 0.8 0 0.2 0.6 0 0 0 0 0 0.1 0 0 0 0.75 1.1 0.7 0.4 0.3 0.5 0 0.6 0.3 0.4 0.8
6.i9
1.1
____
LIeasles plailue t e s t " - - - - -
Undiluted 100 80 YY
3.2 x 100 52 TO
...
100 80 100
97 100 100 98 80 98 94 100 100 90 53 100 95 98 44
82 89 24 7 -
13
66 94 60 36
-I /
Toxic 88 100 67 47 72 80 66 66 90 68 62 Toxic 85 27 54 85 85
10
x
90 0 11
32 x 41 10
100
x i
... ...
...
...
..
...
i8
81 28 68 78 T9 33 99 +5 82
i9
53
7 57
16 0
40 42 0 84
98 +l5 0 27 22 66
47 90 93 100 100 98 24 88 10 8T 100 92 40 100 71 87
0 44 100
46 35 100 43 50
17 61 0 0
... 0 0 0
0
25
..
...
94
..
66
...
3.5
-Herpes plaque testc-50 42 22 52 65 60 7 68 67 0 30 63 59 0 26 12 64 4i 55 80 26 26 19 22 7 12 23 16 19 7 51 12 58 62 73 6 $5.5 0 37 23 0 41 64 56 74 74 69 0 i6 .. 37 28 16 46 69 61 41 42 35 0 52 14 54 66 66 Toxic 63 48 30 72 64 53 50 42 49 39 30 16 0 4i 49 49
,
1
23 26 14 0
...
0 24
... ...
... 0 51 0 ,
.
0
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... 24
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19
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6
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34
The methyl esters were prepared hut are omitted here except for active compounds: Z = carbobenzoxy, Bzl = benzyl, ONp = p-riitrophenyl; for amino acid symbols used see J . Bzol. Chem., 241, 2491 (1966). Amino acids are the L configuration unless otherwise Reference 1. e Y. Xoda, S z p p o n h'agaku Zasshi, 80, 411 See ref 6. designated. * See Experimental Section for methods used. (19.59). J This peptide was reported as an oil: Z. J. Vejdzlek, Collectton Czech. Chem. Commun., 15, 929 (1951). a
Sone of the peptides tested was active against other viruses such as polio, rabies, or influenza. The nonpeptide amide derivatives were all inactive regardless of stereochemistry.* A few tripeptides possessed antimeasles activity. The in vivo antiviral activity of carbobenxoxyphenylalanylnitroarginine has been in~ e s t i g a t e d . ~The serum from rats or rabbits receiving the drug by injection or by oral administration was found to be active against measles virus in the plaque test. Oral administration to monkeys did not produce active serum. Injection into monkeys resulted in severe tissue irritation.
Experimental Section Melting points, taken with the Thomas-Hoover melting point apparatus, are corrected.
capillary
( 8 ) I t is of interest t h a t a recent patent has clairiied carliobenzoxy-Lto be active against herpes virus; T h e Upjolin Co., Netlierlandv Patent 6.510.25X (1Htiti). !illen>lalanylcytosainine
General Procedures for the Preparation of the Compounds Listed in Tables I and 11. Method A.-To a cold ( - l o o ) , stirred solution of i g (0.021 mole) of carbobenzoxy-D-t,ryptophan in 100 nil of CHgC12 was added 2.1 g (0.021 mole) of Et3N followed by 2.3 g (0.021 mole) of ethyl chloroformate. The solution was stirred 20 min a t -lo", and a solution of 3 g (0.021 mole) of n-alanine methyl ester hydrochloride and 2.1 g (0.021 mole) of Et3X in 100 ml of CH2C12a t 0" was added. The solution wa:, stirred for 3 hr a t 0" and a t room temperature overnight. The solution was washed with HZO, 5% NaHC03 solution, dilute HC1, and H2O and dried. The filtered solution was evaporated to a small volume, and petroleum ether ( b p 33-60") was added giving carbobenzoxy-D-t,ryptophyl-D-alanine methyl ester which was recryst,allized from CH2C12-petroleum ether; yield 8 g (90yc ), mp i9-81'. Anal. Calcd for Cs3H2,Xa06: C, 65.23; H, 5.95; N, 9.92. Found: C, 65.21; H, 5.91; N, 9.80. To a solution of 5 g (0.0118 mole) of the above dipeptide ester in 50 ml of MeOH was added 7 ml (0.014 mole) of 2 N KaOH. The solut.ion was kept for 1 hr a 25" and diluted with 100 ml of H20, then 7 ml of 2 S HC1. T h e carbobenzoxy-D-tryptophyl-D\V..I. Rightsel, h'. 11.Scliabel, ,Jr., aiid I . \V. NcLean, Jr.. -Y.1'. Bcurl. Yci., 130, 24 (1Y65j.
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