JPS59205382A - Amino disulfide - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to midomycin analogs with disulfide groups.

These compounds are mydomycin C derivatives having an organically substituted 7-amine group with a disulfide group. This compound is an experimental animal lung cancer inhibitor. Nomenclature - Family of mydomycin C 22 - Chemical Abstracts Name rlaR- (laα, 8
β, 8aα, 8bσ]]-6-amino-8-[:((aminocarbonyl)oxy)methyl]-1,1a,2,8
, 8a.

8b-hexahydro-8a-methoxy-5-methyl-alidino[2,'3. '3.4']pyrrolo[1,2-a
-:]] indole-4,7-dio, and thus the azilinoviroloindole ring system is numbered as follows: Common names for the nomenclature widely used in the midomicin literature are the various characteristic substituents of midomicin. The above ring system containing is identified as midosan.

Applicants use this system herein and refer to the azidino nitrogen atom as N2 and the amino nitrogen atom as N2. Regarding the stereochemical form of the product of the present invention, when identifying the product by its original name Midosan or by its structural formula, it is intended that its stereochemical form be identified as the same as that of midomycin C.

Mydomycin C is an antibiotic produced by fermentation, and is currently approved by the Food and Drug Administration for the treatment of infectious cancers of the stomach and pancreas in combination with other recognized chemotherapeutic agents. It is commercially available as a palliative treatment. , Nycoke 13201, Coelacus, Mutamycin from Bristol Laboratories, physicia
ns' Desk Preference 35 Edition,
1981. Pages 717-718] Midomycin C and its fermentation production method were published on May 2, 1972, in the 3rd edition of the US
No. 660,578 (April 6, 1957, priority claim including Japanese application).

The structures of midomycin A, BSC, and porphyromycin were provided by J. S. Webb et al.
Soc, 84.3185-3187 (1962
) was announced. One of the chemical transformations used in this structural study for midomycins A and C was the conversion of the former, 7-9a-dimethoximidosane, to the latter, 7-amino-9a-methoximidosane, by reaction with ammonia. Substitution of the 7-methoxy group of midomycin A has been found to be a very interesting reaction for producing derivatives of midomycin C with anticancer activity. The following miscellaneous patents each deal with the conversion of Midomicun A into 7-substituted aminomidomycin C derivatives with anticancer activity. The aim of this research was to produce more active and, in particular, less toxic derivatives of mydomycin C.

25- Mitsui et al.'s "l'he Journal of An"
tibiotics” XXI, 189-19B (19
68), ) Kinoshita et al., J. Med, Chem, 14.1
03-109 (1971, i.

JlMed, Chem, 24.9
75-981 (1981).

Jenger, Sami, Remmers and Bradner AJ'
rIer.

Chem, Soc, March 1982, No. 183
Yearbook, Boiled MEDI 72゜Jenger et al., Med, Chem, 198
3.26.16-20° Jenger et al. Amer, Chem, Soc, .
March 1983, 185th Pension Magazine, A MEDI
82 The following patents relate to the preparation of 26-7-substituted aminomidosane derivatives by reaction of Midomycin A, Midomycin B, and their 1m N-substituted derivatives with primary or secondary amines. U.S. Patent No. 3゜33 published in Japan
No. 2.944, Mitsui et al., published January 1, 1969, U.S. Patent No. 3,420.846, Mitsui et al.
U.S. Patent No. 3,450,705, published on March 17, 1970; Mitsui et al., U.S. Patent No. 3,514, published on March 26, 1970.
, No. 452, Nakano et al., U.S. Pat.
U.S. Patent No. 4,268°676, published May 19, 1982; Remmers Belgian Patent No. 893,1 published May 12, 1982.
No. 62.

Midomycin C derivatives with a substituted amino group in the 7-position have also been produced by direct biosynthesis, ie by adding a series of primary amines to the fermented broth and carrying out a conventional midomycin fermentation. (Amer, Soc, of Microb
C in iology, 1982 annual journal 028,
A. Report by Claridge et al.] Midomycin C is a major midomycin produced by fermentation and is a commercially available form. A recent technique for converting midomycin C to midomycin A used in the production of semi-synthetic substituted amino analogues of midomycin C in Joki patents and compositions involves the hydrolysis of midomycin C to the corresponding highly unstable 7-hydroxymidozane. This method involves methylation using diazomethane, a substance that is difficult to handle. One way to avoid the use of diazomethane for methylation is the use of 7-alkyloximidosane for the synthesis of midomycin C homologues. (Kyowa Hakko ■, Japan Patent Law J
5 6073-085, FarmdocA56227'
D/31) The present invention relates to a group of mydomycin C homologues with a dithioorganic substituent on the amino nitrogen atom in the 7-position.

In the formula 9, R9 is an organic group, i.e., a layering component of an organic thiol having the formula R'SH, and the compound in which 2 and R in A1 have the following childishness is also represented by the formula I: and the formula ■ : In the above formula, A1 has carbon atoms 1 to 6 when R7 is connected through its carbon atom, and R7 has its S, 0
Or if N is connected through 29-, it has 2 to 6 carbon atoms (
In this case, B7 and -SS- represent a straight-chain or branched alkylene group (attached to a different carbon atom); a straight-chain or branched alkylene group having 2 to 6 carbon atoms with an R7 substituent at Alk2 and if there is a sulfur or nitrogen atom connected to it and an R7 f substituent connected to it through an oxygen, sulfur or 9 chain, it is Alk.

It is bonded to a different carbon atom inside; A l kl
and Alk2 may have a double bond; R represents hydrogen, lower alkyl, lower alkanoyl, benzoyl; or benzoyl substituted with lower alkyl, lower alkoxy, halo, amino or tf, nitro; R7
Kehydroxy, halo, amino, alkylamino or dialkylamino having 1 to 12 atoms, alkanoylamino, benzoylamino or A-tm benzoylamino,
Na30-phthoylamino spanning A-substituted naphthoylamino, each 3'
cycloalkyl or A-substituted cycloalkyl having 7' 1 to 2 rings,
A heterocyclic group selected from the group consisting of a heteroaromatic group and a peteroalicyclic group having 3 to 8 ring members and 1 to 4 heteroatoms selected from oxygen, 9 groups, and sulfur in each term, a carbon atom Alkoxy or alkylthio, carboxy, each having 1 to 6 carbon atoms, alkoxycarbonyl having 1 to 7 carbon atoms, phenoxycarbonyl or HA-substituted phenoxycarbonyl, phenoxy or A-substituted phenoxy, naphthoxy or A-substituted naphthoxy, carbon atoms Alkoxycarbonylamino with 2 to 6, guanidino, ureido (-NHCONH2), N- with 2 to 7 carbon atoms
Alkylureylene (-NHCONHHCONHN3-haloalkylureylene with 3 to 7 alkyl atoms, -haloalkyl-manitrosourylene with 3 to 7 carbon atoms and dialkylaminocarbonyl with 3 to 13 carbon atoms (as above) The A substituent group represents a group selected from the group consisting of one or two lower alkyl, lower alkanoyl, lower alkoxy, halo, amine, hydroxy, or nitro groups. R8 alkoxy with 1 to 12 carbon atoms, alkenyl or alkynyl with 3 to 12 carbon atoms, cycloalkyl and A-substituted cycloalkyl with 3 to 8 members, cycloalkenyl with 5 to 8 members; phenyl, h
-ttm phenyl, naphthyl, 8-substituted naphthyl, 1 to 2@, heteroaromatic and heteroalicyclic groups each having 3 to 8 ring members and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur A heterocyclic group selected from the group consisting of (wherein the above A-substituents are selected from the group consisting of one or two lower alkyl, lower alkanoyl, lower alkoxy, halo, amino, hydroxy or nitro groups) do)
represents a group selected from the group consisting of, and R8 can be esterified together with the adjacent sulfur atom.

It constitutes an S-cysteinyl group that can be salt-formed or attached within a peptide bond.

The substance of the invention is a tumor suppressor based on animal experiments.

These are prepared by reacting an amino disulfide with the formula ■ or ■: Y in the above formula is easily substituted by reaction with a primary amine group to form N'-f
This is a group that becomes an f-converted mydomycin Cv conductor. The midosan derivatives include midomycin A and its homologs in the formula (1) where Y is lower alkoxy having 1 to 6 carbon atoms. Others are derivatives having the formula (2) in which Y is an amidino group having the formula (2): 5 1M R3R4N-C=N-.

However, R5 of formula (2) represents hydrogen (preferred), lower alkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl, aminophenyl, or hanitrophenyl; Pyrrolidine, '2- or 3-lower alkyl-pyrrolidine, piperidine, 2'-13-34-crossover 4-lower alkyl-piperidine, 2,6-di-lower with the 9 atoms to which they are attached or Alkylpiperidine, piperazine, 4-substituted piperazine (
However, the 4-substituent is alkyl or carbalkoxy, phenyl, methylphenyl, methoxyphenyl, halophenyl, nitrophenyl, or pensyltosul, each having 1 to 8 carbon atoms, azepine, 2-13-14- or 5-lower alkylazepine. , morpholine, thiomorpholine, thiomorpholine-1-oxide, or thiomorpholine-1,1-dioxide. The lower alkyl, lower alkanoyl and lower alkoxy groups each have 1 to 6 carbon atoms. The latter is an amidino derivative of mydomycin C and is described in Application No. 385,149 filed on June 4, 1982.

Midosan derivative with formula ■ and amino 2 with formula ■ or ■
The sulfide reaction takes place in an anhydrous organic liquid medium width of approximately -15 to total +15
Occurs in the temperature range of °C. A humidity of 0 to 20°C is preferred. The organic liquid medium is also very stable under the reaction conditions and can be used as long as it is harmful to the reaction. It is preferred to use an equimolar proportion of the □2 reactant using 1 to 4 moles of the formula □2 amino 2 reactant for the midosane reactant having the formula □. A reaction time of several hours, preferably about 8 to 50 hours, is used. The product is recovered by evaporating the liquid organic reaction medium and chromatographically treating the residue.

The amino dihydride compounds of formula (1) and formula (2) are known compounds and can be prepared by various methods. For example, these include the appropriate thiol R'Alkl SH or R'5I-1 of the formula:
NH2A 1 kg S S Os Na
Butene salt having formula (1) or formula (2): Can be produced by reacting NH2A1 with sulfenylthiocarbonate having 2SSCOCHs (2).

Kleiman et al. (J, of Org, Chem,
29.3737-3738 (1964)) The following compounds were prepared by the butene salt method: 2-aminoethyl n-butyl disulfide 2-aminoethyl n-hexyl disulfide 2-aminoethyl n-
Octyl disulfur, compound 2-aminoethyl n-decyl
Disulfide 2-Aminoethyl Phenyl Disulfide 2-Aminoethyl Benzyl Disulfide Methanol was found to be the preferred reaction solvent for the reaction of Punte salt with thiol. A reaction temperature of 0 to -10°C was found to be preferable for using this solvent. Other solvents required high temperatures. The main drawback of this process is the formation of symmetric 37-binarization as a by-product, possibly as a result of the disprobation of the desired mixed disulphide.

The starting mixed disulfides of formulas (1) and (2) may be prepared by reaction of the appropriate thymol with a sulfenylthiocarbonate of formula W. This is S,J. Preuss C) (
J,of theAmer,Chem,Soc,,9
2.7269-7270 (1970)).

Generally, in this production method, a thiol is added to a methanol solution of an amino-alkylsulfenylthiocarbonate having the formula (1), and the reaction is allowed to proceed at a temperature in the range of 0 to 25°C. Reaction times vary from virtually instantaneous to several hours depending on the particular thiol used. The progress of the reaction can be followed by measuring the presence of unreacted thiol in the reaction vessel. If the reaction is slow, a contact amount of triethylamine can be added as a reaction accelerator.

The following are converted into the intermediates formulas ■ and ■ by reaction with butene salts ■ or sulfenylthiocarbonates ■, and then 38- and formula R' which are converted to the half-boloids of the invention as described above in P.
A number of hidden thiols with R85H across the AI kISH. In the case of the amino-containing thiols in the following list, they are generally first converted into their preserved form, prior to conversion to intermediates of formula ■ or ■ and reaction with midosan intermediates of formula ■.
It is preferable to change to β-(trimethylsilyl)ethoxycarbonylamino derivative. Then, β-(
The trimethylsilyl]ethoxycarbonylamino group is subsequently cleaved by treatment with tetraethylammonium fluoride in acetonitrile.

Carpino et al., J, C, S, Chem, Comm,, 35
8 (1978)), a free amino compound having the desired formula (1) or (2) can be produced.

)1scT(3 HS CH2CH3 HS CHz Cl CH3 H8CM(CHs )2 H3(CH2)3 CT(3 H8-CH-CH2NH2 CHa H8CH2CH(CH3)2 CH3 H8-C-CH3 tb HS -CH2CH= CH2 H 8-CH2 -CH=C(CH3)2 T(S CH2C”CH H8CH2C”CCHs CH3 H8(C)T2)nCXRn=1 3.X=O, NH,
NR”.

R, R1=H, CH3 HS (CHz) n NH2n= 24H8(CH
2) nNHR" n=24 + R' = C
H3T CH3CN (3+CH2CH2C city.

CHs H8CH-CH,zNH2 CHa H8CCH2NH2 CH3 CHa H8CHz CM NH2 41- 0 days 3 H8CH2C-NH2 CH3 HS CH2CI(2S CHs 148 C1, (2CH2NHC(CH3)3CH2
N R' R2 ■ H8CI CHz R'=H,CH
a; R”=H.

CH3 HS CH,2CHCH2NH2 [OHCHz NH2 H8CHz CCH2NHz 42- 1(S CT(2CT(CH2 1 02H FIS CH2CH-CH2NT(202H H8CH2-CHCH2C02H CH2 CH2C 02H H8CH2CT(2CT( CH2 1 T(S-CH=CH-NHCCH, 5 H8-CHz CHCH2O:H H 5-thio -D-glucose C output H8-CH2CH-C)T2NH2 II ■ H8C,tb C-CH20H CH2 CH3 HS CH2CH,CH20H HS -CH2CH2-N CHs CR3 R8- CH2CH-CH2NI( 2 0CT (3 1 H8-C-CH-C-CH2 CH3 H8-CH2-CH=CHCH2CH2HS CHz
CCI4z NH21 CH2 C) Ll CH3 ■ H8CH2-CHl OCCH3 CH3 45- Hs N(CH3) 2 -49- 50- H8 8syaNH2 To H8 △0, /NH2 H8~ゞTo N(-)・H8'' ``ゝNHCCH3 1? Hs to H8/H\△NH, 2) Is/"ゝ8i0H Activity against P-388 murine leukemia Table 3 shows C in which a tumor inoculum of 106 ascites cells of P-388 murine leukemia was implanted intraperitoneally. The results of an experiment in which female D Fl females were treated with either dose of a test compound of formula I or with midomycin C using pinned mice. The compounds were administered by intraperitoneal injection. Groups of 6 mice were used and treated with a single dose of compound at the inoculation site.

A group of 10 saline control mice were included during each series of experiments. The midomycin C treatment group was included as a voditib control. The average survival days measured for each group of mice and the number of survivors recorded at the end of the 30-day period can be examined.
The daily exam table was used. The body shape of the mouse was measured before the treatment and again 6
Measured on day one. Weight change was taken as a measure of drug toxicity. Using 202 mice each, the weight loss up to about 21 was not considered significant.

The results were measured as T/C% (the ratio of the mean survival time of the treated group to the mean survival time of the saline control group multiplied by 100).

Animals died within 9 days of saline treatment. The "maximum effect" in the table below is expressed as T/C, and the dose that achieves that effect is shown. Values in parentheses are those obtained with midomycin C as a boditip control in the same experiment. A measure of the comparative activity of the compounds of the invention against mydomycin C can therefore be estimated. The minimum effective dose at 170°C is 125
It seemed to be. The minimum effective dose shown in the table below is approximately 1
The dose is to give a T/C% of 25. “Average weight change #
The two numbers in each case in the column are the average body weight changes of mice at the maximum and minimum effective doses, respectively.

53- Table 1 1 (BL-6787) ) 333 (294)
3.2 (3,2)3 (BL-6796)
) 375 (250) 6.4 (3,2
) 4 (BL-6832) 172 (19
4) 6.4(3,2)5(BL-6790)
>333 (294) 12.8 (3
,2)6(BL-6789) 183(
294) 1.2.8(3,2)7(BL-67
88) 200 (294) 12
．． 8(3,2)8(BL-6795)
188 (250) 6.4 (3,2) 9 (BM
Y-25036) 219 (319)
3.2 (3,2) 11 (BMY-25066)
194 (194) 3.2 (1,6
) 12 (BMY-25067) 331 (1
94) 12.8 (1, 6) υ weight Kq drawing ■
0 2) Days 1 to 6, maximum and minimum effective dose of mice 2゜0.2 -1.2, -〇, 3(0
,2-2,5,-〇9 0.8 -2.8, -09 (0,2-2,4,0 0,4-0,6,+0.8 0,2 -0.6, - 〇、20.8
-0.8, 10.1 (0,2-・1.3, -06 (0,2-1,,8, -〇,7 (0,2-3,3, -1,1 54- Table 1 shows the budding of an anti-liver test using six B16 melanomas grown in one mouse. BDFI was inoculated subcutaneously by intratumoral implantation in mice. A 60-day report card was used. The mean survival days were determined using groups of 10 animals for each test drug dose.Paired animals were also graded in the same manner as the test animals and treated with the injection vehicle, and the mean survival days of the non-medicated animals were 24.5 days. Growth time (T/C %) for pairs of test mice was used as a measure of efficacy to determine the maximum and minimum effective doses of each test compound. Test animals received each dose of the test compound by intravenous injection on days 1.5 and 9.

Table ■ 1 (BL-6787) 122 3.0
3.0 -2.7, -2.76 (BL-6789)
163 3.0 (3,0-1,8,-18
6 (BL-6789) 3), 161 6.0
(3,0-1,4,-1,41) ■0 per body weight 2) 2°3 per mouse at maximum and minimum effective doses for days 1 to 15 5.9 and day 133 da device.

l3DF1 grows into a mouse*, and 1316 Miiro lI
The results of Compound 3 (BL-6796, 1) were examined for the medium. Animals in this experiment were inoculated intraperitoneally with the tumor and the test compound was also injected intraperitoneally. As before, 1.5 and 9 The average survival time was determined on the 1st day of treatment.The minimum effective dose was again determined to be the dose that would produce a T/C ratio of 125.
and 1JII at a dose of 9 to 1/10 compounds is 46
Survived 1-CT/Cchi 235) during 0-day test lay 5
On day 1, the average weight gain was +0.12. At a dose of 0.5 / 9, the average survival days were 42.0 (T/C Chi 165
) showed that the minimum effective dose was 0.5 my/KgJR. In the same test, midomycin C
/Kg showed T/C% 165. This was the maximum effective dose of midomycin C in this experiment.

Therefore, it is clear that Compound 3 is several times more potent than midomycin against BI3 melanoma in mice.

Compounds administered intravenously to total and specific white suppressor cell (WBc) counts in rats] (BL-6787) and 3 (BL-
6796) was tested. Both drugs were found to be medullary depressant, but significantly less so than mydomycin C. The results are shown in Table ■. The results for Compound 1 and Midomycin C were obtained in the same 58- experiment and can therefore be directly compared. Compound 1 is somewhat less medullary depressant. Although the results of Compound 3 seem to be a little more medullary suppressive than the results from Sen's experiment, direct comparison with the other two compounds was difficult.

59- Considering the antitumor group activity observed in experimental animal tumors and the extremely insufficient myelosuppressive activity compared to mydomycin C, the present invention has applications for suppressing P tumors in mammals. For this purpose, substantially non-toxic antitumor effective doses of the substances of the invention are systematically administered to tumor-bearing mammals.

The compounds of this invention are primarily used in injections in much the same way as midomycin C and in some cases for the same purpose as midomycin C. The dosage is adjusted depending on the sensitivity of the specific tumor.

The compounds are readily dispensed as dry smoke formulation compositions containing diluents, buffers, stabilizers, solubilizers and other pharmaceutically necessary ingredients.

The composition consists of a liquid vehicle ready for injection immediately prior to use. Suitable injectable fluids include water, isotonic salt solutions, etc. In the following experimental procedures, temperatures are given in degrees Celsius (°C) throughout. Proton magnetic resonance spectra (HNMR) were recorded on a Varian XL100 in pyridine d5 or on a Jeol6l-FX-900 (90 MHz) spectrum unless otherwise noted. Infrared i# (IR) spectra were recorded on a Betaman 4240 spectrophotometer. With the result, the IR count value νmax is /ff
Indicated by -1. Thin layer chromatography (TLC) uses ultraviolet light and (also) iodine vapor as embodying agents.
．． 25 mE was effective on Merck pre-coated silica gel plates. Flash chromatography method (J, Org, Ch
Em., 14.2923 (1978) was carried out using silica wool (32-63 um). The solvent was evaporated under reduced pressure below 50°C.

Method 1 S in methanol containing 300 μm of triethylamine
-Benzyldithioethylamine 20'Omg (0', 2
Add a solution of midomycin A62-99 (28.3mM) in 10m of methanol at 0-4°C. Polymerization solution at 20℃
The reaction was stirred for 25 hours at a rate of 1.0:90'7.
Monitored by TLC using methanol-chloroform solvent system. The reaction mixture was concentrated under reduced pressure and the dried solid residue was subjected to flash chromatography (35F silica gel) using 7:93 V/y methanol-chloroform as eluent to give the title compound as an amorphous pure solid of 87 μm (59%).
I got it.

'HNMR (90Hz, pyridine d5, δ): 2.08
(8,3H), 2.74 (m13H,), 3.16
(, d, IH, J=6Hz), 3.24 (s.

3H), 3.40-4.20 (m, 6H), 4.04
(s, 2H,), 4,56 (d, IH, J=1.4
)1z), 5.08 (t, IH1J=12Hz), 5.
40 (d d, 1'H, J=6.12Hz), 7.
44 (b s, 5H), IR (BKr), u
z-': 3440, 3350, max' 3290, 3060, 3020, 1720, 1635.
1560, 1325, 1060, Analysis value for C24H28N40 to 82: Calculated value: C
155,80:H15,46:N,10.84:S
, 1241, Measured value: C155,08:T(,5,31
:N, 10.52; S, 12.10° Method 2 N-'2-(2-aminoethyldithio)ethyl]acetamide (compound 2) a, Bunte salt method Sodium hydroxide 318■ (7,95mM) 695 2-aminoethanche sulfuric acid in 7 tn! of methanol containing
A solution of crn (4.59mM) was stirred at room temperature for 10 minutes and then cooled to 0°C.

Add 357μ of N-acetylcysteamine (3,43
mM) was added thereto, and the mixture was further stirred for 10 minutes. Acetyl 624 is made by diluting the accumulated liquid with about 60 methanol.
(7.95mM) was added to make it acidic. The waxy solid obtained by evaporation of the clear liquid was used for conversion to Compound 3.

b. Sulfenylthiocarbonate method S. J. Preuss et al. (Triethylamine promoter of methyl-2-aminoethylsulfenylthiocarbonate hydrochloride in methanol solution treated with acetylcysteamine at 0°C using the method described above) The reaction was virtually instantaneous.

Method Midomycin A1007v (0.29mM
) was added a solution of about 400 η of compound 2 in methanol 2 at about 0°C. The resulting precipitate was separated and the P solution was left at room temperature for 4 hours. The liquid was evaporated to dryness and flash chromatographed on silica gel 102 using a gradient elution method (4-8 timethanol in cyclized methicin). The desired product is the faster 65- moving blue zone component, which is 45 as an amorphous solid.
q (31,5%) separated. The solid was triturated with 5% dichloromethane in hexane and dried to provide an analytical sample.

"HNMR (100MITz, pyridine d5, δ): 2
．． 06(S, 3H), 2.10(s, 3T(), 2.7
6 (b s, IT-T), 2.80-3.20 (m
.

5H), 3.24(s, 3T(), 3.60 (d d
, IT (, J = 12 and 2H2), 3.70-4.10 (
m, 5H), 4.54 (d, IH, J=1.2Hz),
5.04 (t, IH, J=10Hz), 5.38
(dd, l'l(, J=4 and 10Hz), IR(KBr), "ffi, 3420.3350.32
90, max' 1720.1635.1656.1330.1060,
Analysis value for CztH2*N50g5z: Calculated value: C
149,26;H,5,67;N,13.68;S,1
2°51, measured value: C, 49,33; H, 6,04:
I'J, 13.20; S, 11.48°66- Method 4°7- in methanol 1-containing 0.2-triethylamine
2-(octyldithio)-ethylamine hydrochloride 139~(0.54mM) in a solution of 60q (0.15mM) of (dimethylaminomethylene)amino-9a-methoximidosane
added.

Thin layer chromatography using 10:90 v/v methanol-methylene chloride showed consumption of the green starting material and a major blue zone (RF=0.6) was visible.

The solid residue obtained by evaporating the liquid under reduced pressure was subjected to flash chromatography on silica gel 122 and eluted with 20:1'/yi methylene-methanol.
] was obtained as an amorphous solid. The “HNMR spectrum A
, (1, OOMHz) are shown in Table ■.

Methods 5 to 22 Applications of Various Dithioamines The amines shown in Table ■ are the If-! z-ic
can be reacted to form a product with T and ■.

Analysis and spectral data of some of the above substances and some of those shown in Table 2 are shown in Table 2.

Table ■ (continued) 16 ■ 4-chloro-2-naphthyl
-(CH2b-17HCH30□CCHCH2NH
2QC)TCH2C6H5(CH2)2-18
U CHsOzCCHCHz-NHCOCHCH
zC6I(s (CI(2)2-19 1
CH302C(CH2)6
(CH2)2-22 ■ 2-pyrimidyl
-(CH2)2-〇1 25 1 C2H50C-NHCHHzCHz
(CH2)2-amine reactant 2-aminoethyl 4-chloro-2-naphthyl disulfide 5-(2-aminoethylthio]cysteine methyl
Ester 5-(2-aminoethylthio)phenylalanylcysteine methyl ester 6-mercabutonanthate methyl ester 6-[
(cyclopropyl]methyldithio]hexylamine 2-
Aminoethyl 2-phenoxyethyl 2
(2-aminoethyldithio)pyrimidine 1-[2-(2
-Aminoethyldithio]ethyl]-2-pyrrolidone 2-[2-(aminoethyldithio)]]benzimidazole 2-aminoethyl 2-ethoxycarbonylaminoethyl disulfide 70- Table ■ (Continued) Study 26 T H2NC- NH (CH2)!
(CH2)2-N.

27 T el (CH2)2NcONH
(CH2)2 - (CH2)2-* Especially target 1
Unless otherwise specified, R in formulas I and 2 is hydrogen.

**Y, Nagao et al.'s fishing method (Tetrahedron
1etters A50, 2-nitrophenylsulfenyl at 500°C! The compound is also ij 2.4- dinitro.

Amine reactant H2NCH2CHz SS CH2ClCH2CH
2NC0NHCO2N.

2-aminoethyl 2-nitrophenyl 2m compound"2
-aminoethyl 2,4-dinitrophenyl 2 (j
ff compound"2-aminoethyl 3-nitro-2-pyridyl 2-sulfide 2-aminoethyl 5-nitro-2-pyridyl 2-image compound page 21-5024 (1978)) 71- Table ■ (Continued) 7b0.6 to 1.80 (m, 7T (), 2.12 (s
, 3T(), 3440.3350.2.72(
m, 3H), 2.96 (t, 2H18H'Z),
3290.2950.3.12 (d, IH),
3.24 (s, 3H), 3.60'2920
．． 1715, (dd, IH, 2, 14H7), 3.8
2 (m, 3H), 1635.1560.4.5
0 (d, IH, 14Hz), 5.36 (dd, IHl
1320.10606.12Hz) a, e 8- 2.05 (s, 3H), 2.13 (s, 3H)
, 2.15 (s, 3420.3350.3H)
, 3.00 (m, 4.H), 3.20 (s, 3)I
), 3290.2830.3.48 (d
d, IH,), 3.60 (dd, IH12, 1710
, 1650, 14I (, Z), 3.77 (d, in
, 5Hz), 3.90 (m, 1635.
1560.4H), 4.06(dd, IH, 4,10
Hz), 4.59 1320.1060(t,
LH, 10H, z ), 4.74 (d, IH, 14Hz
), 5.61 (dd, IH, 4, 10H7), 7.2
8.7.649b2.12(s, 3H), 2.76(b
s, 1) 1), 3.12. 3430.3360, (
m, 5H,), 3.24 (s, 3H), 3.60 (dd
, 3280.2920, IH12,14H
z, ), 4.00 (m, 6H), 4.52.
1710.1630, (d, IH, 14H, z),
5.04 (t, IH, 12Hz), 1550.1
325.5.40 (dd, 1) 1.6.12Hz)
10551143- Elemental analysis T, C, 52, 26: I (, 6, 26; N, 11.
61;S, 13.29F, C,52,78;H,
687;N, 9.89;S, 10.38T, C,
49,90:H, 5,64;N, 12.65;S,
11.58F, C, 48,95; H, 5,37; N
, 12.22;S, 12.54T, C,48,
50; H2S, 5'7; N, 11.91; s, 1
3.63F, C148,73;H,5,82;N,
11.06 ;s, 13.6773- Table ■ (continued) b 10 2.04 (S, 3H), 2.74 (bs, I
H), 3.08 3430, 3350° (m, 3
H), 3.24 (s, 3H), 3.60 (ddl
3280, 2930° IH12, 14Hz), 3.
92 (m, 3H), 4.52 1720,163
0゜(d, IH, 14Hz), 5.02(t, IH1
12Hz, ), 1555.1325.5.36
(d v, IH16, 12Hz), 7, 16.7, 5
6, 10608.72 11 2.04 (s, 3H), 2.72 (bs, I
H), 3.04 3440,3360° (m, 3
H), 3.22 (s, 3HJ, 3.58 (d d,
330012940°1H12,14Hz),
3.68 (S, 3H), 3.92 172
0,1,635, (m13H,), 4.52 (d, IH
, 14Hz), 5.04 1555.1335,
(t, in, 12Hz), 5.38 (d d, IH1
6, 106012Hz), 7.34 (AB quadruplet,
4H) 12 2.04 (s, 3H), 2.74 (b
s, IH), 3.08 3460, 3360° (m, 3H), 3.24Cs, 3H), 3.60 (dd
, 3300,2940゜IH12,14)
iZ ), 3.96 (m, 3H), 4.52
1720, 1635, (d, IH, 14Hz), s, 0
4 (t, IH, 12hz), 1555.1340
゜5.40 (dd, IH16, 12Hz), 8.04 (
AB 10604iL term, 4H) Elemental analysis T, C, 52,47; H, 500:N, 13.91
;S, 12.73F, C, 46,37;) 1.4
．． 42;N, 11.88:S111.26T,
C, 54, 12; I 15.30; N, 10.52; 5
112.04F, C153,30;H,5,32;N
, 106i1;S, 12.13T, C,50,
45; H, 4, 60; N, 12.79; S, 11
．． 71F, C149, 25; H, 4, 55; N, 1
278;S, 11.6974-Table V (Tsuzu 6) 28 2.0 (IC8,3H,), 2.17 (m
, IH), 2.77 (b 8. IH),
33.03 (t, 2H), 3.17 (b 8,
IH), 3.23 (s, 3H), 3.60 3 (d
, IH, 12,8Hz), 3.87 (d t,
2H), 4.00 (dd, IH114, 2Hz, 11
．． 1Hz), 4.51 (d, IH, 12,8Hz
), 5.10 (t, IIH), 5.40 (dd
, IH14,2Hz, 1.0.3)TZ), 7.3
2(m, 12■(), 7.71(t, I
H), 8.28 (dd, IH)
129 2.03 (s, 3H), 2.15 (bs,
IH), 2.75 (b s, IH-), 3
3.14 (t, 2H), 3.24 (s, 3
H), 3.24 (bs, IH), 3.60
3 (d, IH), 3.94 (d t, 2H), 4.0
0(dd, IL 4.1Hz, 211.2)t
Z), 4.50 (d, In, 1-2.7Hz
), 5.36 (dd, IH, 14, 1Hz, 10.3
Hz), 7.32 (m, IH,), 8.53 (m, L
H) 130 2.08 (s, 3H),
2.18 (m, IH-), 2.77 (b s, I
H), 3.17 3 (m, 3H), 3.24 (s,
3H), 3.61 (d, IH, 12,4Hz)
, 33.87 (d t12H,), 4.03
(d d, II (,4,1Hz, 11.1Hz)
, 24.55(d,H(,12,7Hz),5.
12 (t, IH), 5.42 (dd, IIH,
4.2Hz, 10.3Hz), 7.33(dd, IH
, 4,8Hz, 18.4Hz), 7.8
5 (t, 1H), 8.50 (d, IH18, 2H
z), 9.13 (d, IH, 4,8Hz) 11
44-460.3350, T, C, 48,33;
H, 4,47; N, l 2.04285.2940. 720.1635, F, C, 4B, 37; H,
4,56;N, 12.02560.1510・
(Corrected for 0.4M CI2 C12) 450.
1335, 60 460.3360, T, C, 4/1.5
1;I13.97;N, 13.251 9! 635・””” (0.5MCH2Cl2%
Corrected for] 340.1060 460.3350, T, C, 45,72
;H,4,26;N, 14.22F 9: 630・1550・ (corrected for 0.5MCH2Cl2) 335.1060 −75= 辷■ (continued) Compound IHNMR (pyridine d4, δ
)31 2.04(s, 3H), 2.04(bs,
IH5), 2.76 (bs, IH), 3.12 (m,
3B), 3.22(s, 3T(), 3.56(d
, IH114) (Z), 3.90 (m, 3H), 4.
48 (d, IH, 14H, z), 5.00 (t
, I T(, 12,0I(Z), 5.36 (d d
, IH, 4,,3Hz.

12.0Hz), 7.92(d, 1.H, 10,0H
z), 8.52 (d d.

IH14Hz, 10Hz), 9.52 <, d, 1H
14Hz) Note a. 100 MH2 NMR spectrum b, 90 M I(Z Nl'viR spectrum C1) Prepared by acylating compound 5 with hydroacetic acid and pyridine.

d, T=theoretical i1j+, F=measured value 6, 360
MB2 NMR spectrum 3465.3345,
T, C146,18; H, 4,29; N,
14.433280.3060. 293o, 172. F-C, 46, 19; H, 4
,32;N,13.911630・1585・
(Corrected for 0.4M Cl-12C12%) 1555
．． 1340, 055 Continued from page 1 Priority claim @February 24, 1984■United States (US)■
581291 0 Inventor Terrence William Doyle 224 Redfield Avenue, Fatsville, New York, USA 13066 0 Inventor Neelin Chan 24 Ejien Drive, Convent Station, New York, New York 07961 1145-76-

Claims (1)

[Claims] 1. Formula: (In the formula, lk2 represents a straight or branched alkylene group having an optional R7 substituent and 2 to 6 carbon atoms, and the sulfur and nitrogen atoms bonded thereto, Any R7 substituent attached to it through oxygen, sulfur or nitrogen is attached to a different carbon atom in Alkz; (Ilt alkyl, lower alkoxy,)
represents benzoyl substituted with amino, amino or nitro; R7 hydroxy, amino, amino, atoms 1 to 12
alkylamino or dialkylamino, alkanoylamino, benzoylamino or A-substituted benzoylamino, naphthoylamino or A-substituted naphthoylamino, cycloalkyl or A-substituted cycloalkyl each having 3 to 8 ring atoms, each Cycloalkenyl or A-substituted cycloalkenyl with 5 to 8 egg members, phenyl or A-substituted phenyl, naphthyl or A-substituted naphthyl, 1 to 2
A heterocyclic group selected from the group consisting of a heteroaromatic group or a heteroalicyclic group having a ring and having 3 to 8 ring atoms in each term and 1 to 4 heteroatoms extending from oxygen, 9 rings, and sulfur. , alkoxy or alkylthio with 1 to 6 atoms of each element, carboxy, alkoxycarbonyl with 1 to 7 carbon atoms, phenoxycarbonyl or 1A-fl
1-Phenoxycarbonyl, phenoxy or h-fEt-substituted phenoxy-shiftoxy-A-substituted naphthoxy, alkoxycarbonylamino with 2 to 6 carbon atoms, guanidino, ureido (-NHCONH2), with 2 to 7 carbon atoms N-alkylureylene, 3 to 7 carbon atoms
marhaloalkylureylene with 3 to 7 carbon atoms
represents a group selected from the group consisting of -haloalkyl-N3-nitrosoureylene and dialkylaminocarbonyl having 3 to 13 carbon atoms, provided that lower alkyl, lower alkanoyl, lower alkoxy with one or two substituents as above; , /-, amino, hydroxy, or nitro; and R9 represents an organic group. ) A compound characterized by the following. 2. Formula ■: ■ Or Formula ■: 1 (In the above formula, Alkl has 1 to 6 carbon atoms when R7 is bonded through its carbon XI, and R7 is oxygen or nitrogen A straight chain N with 2 to 6 carbon atoms represents a branched alkylene and is then linked to a carbon atom that is anisotropic to R7; Alk is optionally a substituent in R7. represents a W6fi or branched alkylene group having 2 to 6 carbon atoms with sulfur and 9 atoms bonded thereto and an optional R7 substituent bonded to every carbon atom of Alk2; Alk, and Alk2 may have a double bond; R
is hydrogen, lower alkyl, lower alkanoyl, benzoyl; or lower alkyl, lower alkoxy, halo, amino,
or nitro-substituted benzoyl; R7 is hydroxy, halo, amino, alkylamino or dialkylamino having 1 to 12 atoms, alkanoylamino,
benzoylamino-substituted A-substituted benzoylamino, naphthoylamino or A-ft substituted phthoylamino, cycloalkyl or A-substituted cycloalkyl each having 3 to 8 ring members, cycloalkenyl or 5-substituted cycloalkyl each having 5 to 8 ring members; - is A-substituted cycloalkenyl, phenyl or A-F substituted phenyl, naphthyl or A-substituted naphthyl, having 1 to 2 A and 3 to 8 occurrences in each A and selected from oxygen, nitrogen and sulfur; a heterocyclic group selected from the group consisting of heteroaromatic radicals or heteroaliphatic radicals having 1 to 4 heteroatoms, alkoxy or alkylthio, carboxy, each having 1 to 6 carbon atoms, carboxy, having 1 to 7 carbon atoms; Alkoxycarbonyl, phenoxycarbonyl or A-substituted phenoxycarbonyl, phenoxy or A-ft substituted phenoxy, naphthoxy or A-ftm naphthoxy, alkoxycarbonylamino, guanidino, ureido (NHCONH2) with 2 to 6 carbon atoms, carbon atoms N-alkylureylene having 2 to 7 (-NHCONHHC
ONH represents a well selected from the group consisting of N3-haloalkylureylene with 3 to 7 alkyl atoms, N3-haloalkyl-manitro6-soureylene with 3 to 7 carbon atoms and dialkylaminocarbonyl with 3 to 13 carbon atoms , and R8 is one carbon atom. alkyl having 3 to 12 carbon atoms, alkenyl or alkynyl each having 3 to 12 carbon atoms, 3
Cycloalkyl with 3 to 8 ring members, A-substituted cycloalkyl with 3 to 8 ring members, cycloalkenyl with 5 to 8 ring members, phenyl, A-substituted phenyl, naphthyl, A
Naphthyl, having 1 to 2 rings, 3 to 8 in each ring
a heterocyclic group selected from the group consisting of a heteroaromatic group having a ring member and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, and a heteroalicyclic group; represents a group, provided that the above A substituent is one or two selected from the group consisting of lower alkyl, lower alkanoyl, (f161b alkoxy, halo, amine, hydroxy or nitro group) and [2, adjacent to R8 The sulfur atoms together constitute an S-cysteinyl group which can be combined in an esterification, salt formation or peptide bond. 3. Compound 0 according to claim 2, having the formula (2) in which Alk2 in formula I is ethylene and R is hydrogen. 4. Claim 3, in which Ark is ethylene.
Compounds described in Section. 5. The compound according to claim 2, known by the chemical name 7-[2-(2-aminoethyldithio]ethylamino)-9a-methoximidosan. 6. The compound listed in t' in claim 2, known by the chemical name 7-(2-(2-acetylaminoethyldithio)ethylamino:]-]9a-methoximidosa. 7. In the formula (■), Alk, is ethylene and R is hydrogen;
``'' compound. 8. Compound according to claim 7, in which R8 is alkyl. 9. Patent known by the chemical name 7-(2-(octyldithio)ethylaminocou 9a-methoximidosan) The compound according to claim 2. 10. The compound according to claim 2 having the chemical name 7-[2-(n-butyldithio]ethylamino]-9a-methoximidosan. 11. The compound according to claim 2 having the chemical name 7-[2-(benzyldithio]ethylamino]-9a-methoximidosan. 9-128 Formula ■: or Formula ■: (In the above formula, Alk , is a straight chain having 1 to 6 carbon atoms if R7 is bonded through that carbon atom, and 2 to 6 carbon atoms if R7 is bonded through its oxygen or nitrogen atom. or represents a branched alkylene group, in which case R7 and SS are linked to different carbon atoms; represented, the sulfur and g purple atoms bonded thereto and the Rendo R71 group are A,
Alk2 is bonded to different carbon atoms; Alk and Alk2 may have a bifurcated bond; R
Represents hydrogen, lower alkyl, lower alkanoyl, benzoyl; or benzoyl substituted with lower alkyl, lower alkoxy, halo, amino or nitro; R7 hydroxy, halo, amino, alkylamino or dialkylamino having 1 to 12 atoms; , alkanoylamino, benzoylamino or A-substituted benzoylamino, naphthoylamino or A-f-substituted naphthoylamino, each 3 to 8
Cycloalkyl or A-substituted cycloalkyl having ring members, cycloalkenyl each having 5 to 8 ring members or A4tj
substituted cycloalkenyl, phenyl or 8-substituted phenyl,
Naphthyl-A-substituted naphthyl, a heteroaromatic group or a heterolipid having 1 to 2 A, 3 to 8 rare members in each ring, and 1 to 4 heteroatoms selected from oxygen, 9 atoms, and sulfur. Heterocyclic group selected from the group consisting of ring groups, alkoxy or alkylthio having each carbon atom -f1 to f6, carboxy, alkoxycarbonyl having 1 to 7 carbon atoms, phenoxycarbonyl or A-i substituted phenoxycarbonyl, fuunoxy A-substituted phenoxy, naphthoxy, A-substituted naphthoxy, alkoxycarbonyl having 2 to 6 carbon atoms, amine, guanidino, ureido (NHCONH2), N-alkylureylene having 2 to 7 carbon atoms (-NHCONH N3-haloalkyl-N3-nitrosoureylene having 3 to 7 carbon atoms, N3-haloalkyl-N3-nitrosoureylene having 3 to 7 carbon atoms, and dialkylaminocarbonyl having 3 to 13 carbon atoms. The above A substituent, which represents a group, shall be taken from the group consisting of a single or double alkyl, lower alkanoyl, combined alkoxy, halo, amine, hydroxy, or nitro group;
and R8 is alkyl having 1 to 12 carbon atoms, alkenyl or alkynyl having 3 to 12 carbon atoms, cycloalkyl having 3 to 8 ring members, A having 3 to 8 ring members;
-Substituted cycloalkyl, cycloalkenyl having 5 to 8 rare members, phenyl, A-substituted phenyl, naphthyl, h-
substituted naphthyl, consisting of a heteroaromatic group and a heteroalicyclic group having 1 to 2 rings, each ring having 3 to 8 ring members and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; a heterocyclic group selected from the group consisting of, provided that the above A substituent is one or two lower alkyl, lower alkanoyl, lower alkoxy, halo,
selected from the group consisting of amino, hydroxy, or nitro groups, and R8 and the adjacent sulfur atom are both esterified,
Forms an S-cysteinyl group that can be combined in salt formation or peptide bonds. ) An antitumor agent containing a compound as an active ingredient. 13, Formula m: R'-Alkl-8S"A1kzN
H2m or formula F/: 2NH2 to R8-5S-A1
1 to 4 mole parts of the amine represented by TV are combined with the formula ■:■ [In the formulas ■, ■, and ■, Alkl has 1 to 6 carbon atoms when R7 is bonded through its carbon atom; Sulfur,
Acid 14- represents a straight-chain or branched alkylene having 2 to 6 carbon atoms when bonded through an element or nitrogen and in which case R7 and SS are imprinted on a carbon atom; Alk2
represents a straight or branched alkylene group having 2 to 6 carbon atoms, optionally with an R7 substituent, which is bonded to a carbon atom and a nitrogen atom, and where the optional R7 substituent is bonded to two different carbon atoms in A1; Alkl and Alk2 may have 21 bonds; R
represents hydrogen, lower alkyl, lower alkanoyl, benzoyl; or benzoyl substituted with lower alkyl, lower alkoxy, halo, amino or nitro; R7 is hydroxy, halo, amino, alkylamino or dialkylamino having 1 to 12 atoms; , alkanoylamino, benzoylamino or 8-substituted benzoylamino, naphthoylamino or A-substituted naphthoylamino, each 3 to 8
cycloalkyl or A-cycloalkyl with 5 to 8 ring members, cycloalkenyl with 5 to 8 ring members or 1dA-f
tf-inhibited cycloalkenyl, phenyl or A-tj substituted phenyl, naphthyl or A-substituted naphthyl, having 1 or 2 terms and 3 to 8 ring members in each ring, and a heteroatom selected from oxygen, nitrogen and sulfur. a heterocyclic group selected from the group consisting of heteroaromatic groups or heteroaliphatic groups having 1 to 4 carbon atoms, alkoxy or alkylthio each having 1 to 6 carbon atoms, carboxy, alkoxycarbonyl having 1 to 7 carbon atoms, phenoxy carbonyl or A-substituted phenoxycarbonyl, phenoxy or A-substituted phenoxy,
naphthoxy or A-substituted naphthoxy, from 2 to 6 carbon atoms
alkoxycarbonylamino, guanidino, ureido (NHCONH2), N- with carbon atoms 2 to 7;
consisting of alkylureylene (-NHCONHalkyl), N3-haloalkylureylene having 3 to 7 carbon atoms, fecal-haloalkyl-N3-nitrosoureylene having 3 to 7 carbon atoms and dialkylaminocarbonyl having 3 to 13 carbon atoms. represents a group selected from the group consisting of lower alkyl, lower alkanoyl, lower alkoxy, halo, amine, hydroxy, or nitro groups with one or two substituents in A;
R8 is alkyl having 1 to 12 carbon atoms, alkenyl or alkynyl having 3 to 12 carbon atoms, cycloalkyl having 3 to 8 ring members, A having 3 to 8 ring members
-Substituted cycloalkyl, cycloalkenyl with 5 to 8 ring members, phenyl, A-fl phenyl, naphthyl, A-
fl naphthyl, 17 from heteroaromatic groups and heteroalicyclic groups having 1 to 2 members, 3 to 8 rare members in each ring, and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; - lower alkyl, lower alkanoyl, lower alkoxy, halo, amino, hydroxy or is selected from the group consisting of nitro groups, R8 and the adjacent sulfur atom together form an S-cysteinyl group that can be combined in an ester, salt formation, or peptide bond, and Y is 1 to 6 carbon atoms. Lower alkoxy or 2■:
5 1■ R3R'N-C=N- (In the above formula, R5 represents hydrogen, lower alkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl, aminophenyl, or nitrophenyl;
R3 and R4 independently represent lower alkyl, or together with the 9 atoms to which they are bonded, pyrrolidine, 2- or 18-3-lower alkyl-pyrrolidine, piperidine, 2-13
- or 4-lower alkyl-piperidine, 2,6-monodisacyl-alkylpiperidine, piperazine; 4-substituted with alkyl having 1 to 8 carbon atoms or carbalkoxy, phenyl, methylphenyl, methoxyphenyl, halophenyl, nitrophenyl or benzyl piperazine; azepine, 2-13-14- or 5-lower alkyl azepine;
Morpholine, thiomorpholine, thiomorpholine-
1-oxide or thiomorpholine-1,1-dioxide; and each of the lower alkyl, lower alkanoyl and lower alkoxy has 1 to 6 carbon atoms. In an organic solution inert to the reaction with 1 mol part of midosane represented by the group represented by ], formula ■: or formula ■: (where Alk+, Alk2, R, R7 and R
8 as defined above] under reaction conditions at a temperature of about -15 to +50° C. for a sufficient time to produce a suitable amount of a product having A method for producing the compound shown in 14. The compound according to claim 2 having the chemical name 7-C2-<phenyldithio]ethylamino]-9a-methoximidosan 15. The chemical name 7-[2-(2-hydroxyethyldithio) [ethylamino]-9a-methoximidosane.The compound according to claim 2 having the chemical name 7-[2-(2-pyridyldithio)ethylamino)-9a-methoximidosane. A compound according to claim 2. 17. The compound according to claim 2 having the chemical name 7-[2-(4-methoxyphenyldithio]ethylamino]-9a-methoximidosane. 1.8. Chemical name 7-C2-( 4-Nitrophenyldithio]ethylamino]-9a-methoxymidosane compound according to claim 2. 19. Chemical name 7-C2-(2-nitrophenyldithio]ethylamino)-9a -Claim 21- Scope year 2]'# Compounds with methoximidosan. 21. Claim 2 having the chemical name 7-[2-(3-nitro-2-pyridyldithio)ethylaminoco-9a-methoximidosan. Compound according to claim 2. 22. Compound 'lIP according to claim 2 having the chemical name 7-(2-(5-nitro-2-pyridyldithio)ethylaminoco-9a-methoximidosan).