LU86062A1 - 7-SUBSTITUTED OXOMITOSANES - Google Patents

Description

V. *

Field of the invention.

The present invention relates to new mitomycin analogs containing a disul-? fure (class 260f. subclass 325.24) and processes for preparing them. These compounds are analogs of mitomycin A in which the 7-alkoxy radical carries an organic substituent comprising a disulfide radical. The present invention also relates to a process for producing mitomycin A and its derivatives (class 260, subclass 326.24). Mitomycin is an antibiotic of recognized utility and 7-0-substituted analogs of mitosan have similar utility.

The systematic name of mitomycin; A according to Chemical Abstracts, on the basis of the recent revision £ Shirhata et al., J. Am. Chem. Soc., 105, 7199 ~ (1983) 7 is: £ laS- (lap, 8 / i, 8aot, 8b / i) J-9- £ ((aminocarbonyl) oxy) m: thyl7 ”6,8a-dimethoxy -l, la, 2,8,8a, 8b-hexahydro-5-methylarizino / "2 ', 3', 4 7pyrrolo7 1,2-a 7indole-4,7-dione the azirinopyrroloindole ring system being therefore numbered as follows st X 8

6 lOr ^ V

I> - \ 8b N Π-1 4 \ ^^ · 2 la

Chemical Abstracts

The above cyclic system carrying different substituents characteristic of mitomycins is called mitosan according to the systematic nomenclature current in the literature relating to mito- /

- ·. CD.YM.F - 2 - SY-1740-A

mycines.

10 5 0 CH2OCONH2 7 1 5 ïi ^ TSnAa ch3 ^ y ^ \ y o y «

Mitosan

According to this system, mitomycin A is 7,9a-. Dimethoxymitosan and mitomycin C is 7-amino-9a- * methoxymitosan. When the products of invention 5 are identified by the term "mitosan" or by the structural formula, their stereochemical configuration r is that of mitomycin A or C.

o ch2oconh2 Κ | ΪΓ% ^

ΙΓ ^ NH O

Mitomycin A R = Ri = OCH3 Mitomycin C R = NH2, Ri = OCH3

Mitomycin C is an antibiotic produced by fermentation currently marketed for the treatment of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other recognized chemotherapeutic agents and for palliative treatment when other therapeutics

-. CD.YM.F - 3 - SY-1740-A

v * have failed (Mutamycin ® Bristol Laboratories, „Syracuse, New York 13221, Physicians' Desk Reference, 37th edition, 1983, pages 747 and 748). Mitomycin C and its production by fermentation are the subject of the E.U.A. No. 3,660,578, May 2, 1972, based on earlier patent applications, notably of April 6 (1957 in Japan.

The structures of mitomycins A, B and C and profiromycin were published for the first time by J.S. V7ebb et al. from Lederle Laboratories Division American Cyanamid Company, J. Am. Chem. Soc., 84, 3185-3187 (1962). One of the chemical transformations carried out for this structural study aimed at; establish the relationship between mytomycin A and mito- *. . . , Λ mycin C is the conversion of the first compound, 7,9a- dimethoxymitosan, by reaction with ammonia into the second compound, 7-amino-9a-methoxymitosan. The displacement of the 7-methoxy radical of mitomycin A has proved to be a reaction of considerable interest for the preparation of the antitumor derivatives of mitomycin C. Recently, the stereochemical configurations at positions 1, la ^ 8a and 8b have been found to be those indicated above according to the nomenclature of Chemical Abstracts Sh Shirhata et al., J. Am. Chem. Soc., 105, 7199-7200 (1983) J. Previous literature refers to the enantiomer.

The following articles and patents deal, inter alia, with the conversion of mitomycin A to a 7- (substituted amino) -mitomycin C derivative having anti-tumor activity. The aim of the present research was to prepare derivatives which are more active and, in particular, less toxic than mitomycin C:

Matsui et al., J. Antibiotics, XXI, 189-198 (1968);

Konishita et al., J. Med. Chem., 14, 103-109 CD.YM.F - 4 - SY-1740-A

f * (1971);

Iyengar et al., J. Med. Chem., 24, 975-981 (1981); > Iyengar, .Sami, Remers and Bradner, Abstracts o £

Papers, 183rd Annual Meeting of the American Chemical Society, Las Vegas, Nevada, March 1982, Abstracts No. MEDI 72;

Cosulich et al., E.U.A. ne 3.332.944, July 25, 1967;

Matsui et al., E.U.A. No. 3,420,846, January 7, 1969;

Matsui et al., E.U.A. no 3,450,705, June 17, 1969;

Matsui et al., E.U.A. No. 3,514,452, May 26, 1970;

Nakano et al., E.U.A. No. 4,231,936, November 4, 1980; - Remers, E.U.A. No. 4,268,676, May 19, 1981.

The following patent applications relate to the preparation of derivatives of 7- (substituted amino) -mitomycin, the substituent of which comprises a disulfide radical.

Kono et al., European patent application No. 116.208 (1984);

Vyas et al., English patent application No. 2,140,799 (1984).

The 7-alkoxy-mitosans related in structure to mitomycin A are described as being useful antibiotics which demonstrate activity against experimental tumors in animals in an article by Urakawa et al., J. Antibiotics, 23, 804-809 (1980).

Mitomycin C is the main mitomycin produced by fermentation and is the commercial form

CD.YM.F - 5 - SY-1740-A

specialized. Current techniques for converting mitomycin C to mitomycin A have various disadvantages. The hydrolysis of mitomycin C to the corresponding 7-hydroxy-9a-methox.ymitosan and the subsequent methylation of the latter make use of diazo-methane, which is dangerous to handle on an industrial scale, and 7-hydroxy- intermediate, which is very unstable £ Matsui et al., J. Antibiotics, XXI, 189-198 (1968) J. To try to avoid these drawbacks, we used 7-acyloxymitosans (Kyowa Hakko Kogyo KK Japanese patent does J5 6073-085, Farmdoc n ° 56227 D / 31). The alcoholysis of mitomycin A as described by Urakawa et al., J. Antibiotics, 23, 804-809 (1980) is limited to the preparation of certain specific 7-alkoxy derivatives by availability and reactivity starting spirits.

v OVERVIEW OF THE INVENTION.

The "present invention relates to a group of mitomycin A analogs carrying an organic dithi-substituent in the alkoxy radical at position 7. These compounds correspond to the following general formula: ï ° CH2OCNH2 1! Os4,

O

where r2 represents an organic radical, in this case the constituent radical of an organic thiol of formula R2SH, and Alk2 and Ri have the meanings indicated below. These compounds can also be represented

- CD.YM.F - 6 - SY-1740 — A

I.

* by formulas II and III.

B

o ch2ocnh2

R3-Alk- -SS-Alk0 - Ovs / '' * \ ^ A II

1 2 d | yoc ^ <: Η3 "ΛχΐΤ ^ Ν \ 1> r1 0 \ 0 ° 5 C ^ oc ^

R -SS-Alk, -Q ____ \ III

Il Tk3 chîsv / ^ 'Nk ^ »- R1 WHERE A1 ^ i represents an alkylene radical in a straight or branched chain of 1 to 6 carbon atoms, when K3 is joined to it by a carbon atom of the latter and 2 to 6 carbon atoms when R3 is joined to it by a sulfur, oxygen or nitrogen atom of the latter, and R3 and -SS- are, in this case, united to different carbon atoms, A11C2 represents a radical straight or branched chain alkylene of 2 to 6 carbon atoms optionally carrying a substituent A, where the sulfur and oxygen atoms which are linked to it and any optional substituent A which is linked to it by oxygen, sulfur or of nitrogen are united to carbon atoms different from ΑΠ <2, where the substituent A is chosen from one or two (Cl-6) -alkyl, (Cl-6) -

J

__ · CD.YM.F - 7 - SY-1740-A

ί * alkanoyl, (Cl-6) -alkoxy, halo, (Cl-6) -alkoxycarbonyl, cyano, (Cl-6) -alkoylamino, (Cl-6) -dialcoylamino, (Cl-6) -alkanoylamino and (Cl -6) -alkoxycarbonyl ,.

Allci and Alk2 may contain a double bond, R1 represents a hydrogen atom or lower alkyl, lower alkanoyl, benzoyl or substituted benzoyl radical, the substituent of which is a lower alkoxy, halo, amino or nitro radical, R 3 represents a halo radical, carboxyl, alkanoyloxy of 1 to 7 carbon atoms, hydroxyl in which the oxygen atom is united to Alk ^ having 3 to 6 atoms; carbon, alcoylamino or dialcoylamino of 1 to 12 carbon atoms, 1-N-alkoxyalkyllamino of 2 to 7 carbon atoms, alkanoylamino of 1 to 7 carbon atoms, benzoylamino or benzoylamino B-substituted, naphthoylamino or naphthoylamino B- substituted, B-substituted phenylamino or phenyl-amino, B-substituted cycloalkyl or cycloalkyl each of 3 to 8 members in a ring, B-substituted cycloalkenyl or cycloalkenyl each of 5 to 8 members in a ring, phenyl or B-substituted phenyl, ^ B-substituted aphthyl or naphthyl, a heterocyclic radical chosen from heteroaromatic and heteroalicyclic radicals with 1 or 2 rings, from 3 to 8 members in each ring and from 1 or 2 hetero atoms chosen from oxygen, nitrogen and sulfur in each ring, pyridylainino or thiazolylamino, alkoxy or alkylthio each of 1 to 6 carbon atoms, alkoxycarbonyl or alkylamocarbonyl each of 2 to 7 carbon atoms, aminocarbonyl, phenoxycarbonyl or phenoxycarbonyl B-substituted, phenoxy or phenoxy B-substituted, naphthoxy or B-substituted naphthoxy, alkoxycarbonylamino of 2 to 6 carbon atoms, ureido (-NHCONH2) 'N ”alkylurylene (-NHCONHalcoyl) of 2 to 7 atoms of

-. CD.YM.F - 8 - SY-1740-A

I l carbon, N3-haloalkylenylene of 3 to 7 carbon atoms, N3-haloalkoyl-N3-nitrosoureylene of 3 to 7 carbon atoms, dialkoylaminocarbonyl of 3 to 13 carbon atoms, dialkoylaminoalkoxy of 4 to 13 carbon atoms, alkanoylaminoalkoxy of 3 to 7 carbon atoms and hydroxyalkylamino or N, N-dihydroxyalcoylami.no each of 2 to 8 carbon atoms, where the substituent B is chosen from one or two lower alkyl, lower alkanoyl, lower alkoxy, halo, amino, carboxyl radicals , hydroxyl and nitro, and R4 represents an alkyl radical of 1 to 12 carbon atoms, alkenyl or alkynyl each of 3 • to 12 carbon atoms, cycloalkyl or cycloalkyl B-substituted each of 3 to 8 ring members, cyclo-alkenyl or B-substituted cycloalkenyl each of 5 to 8-membered rings, phenyl or B-substituted phenyl, naphthyl or B-substituted naphthyl, a heterocyclic radical chosen from heteroaromatic and heteroalicyclic radicals with 1 or 2 rings of 3 to 8 members in chain as a cycle and from 1 or 2 hetero atoms chosen from oxygen, nitrogen and sulfur in each cycle, with the restriction that the heterocyclic radical is linked by a carbon atom which is united to at least one other carbon atom ( that is to say that the carbon atom united to -SS- cannot itself be united to two other hetero atoms), where the substituent B is chosen from one or two radicals lower alkyl, lower alkanoyl, lower alkoxy , halo, amino, carboxyl, hydroxyl and nitro, and R4 and the adjacent sulfur atom together constitute an S-cysteinyl radical, which S-cysteinyl radical can be: esterified, salified or combined in a non-toxic and non-allergenic peptide , which may exist as non-toxic salts r

CD.YM.F - 9 - SY — 1740 — A

3 Λ pharmaceutically acceptable.

The compounds of the present invention are inhibitors of experimental tumors in animals. In particular, the compounds obtained in Examples 17, 20 and 21-34 are new. They are used like mitomycin C. The doses administered i are adjusted in proportion to their toxicity compared to that of mitomycin C. When the new compound is less toxic, the dose administered is higher.

According to another aspect, the present invention relates to a new process for the production of mitosans of formulas II and III. This new process involves the reaction of a mitosan of formula IV: 11 0

o II

dd CH2OCNïï2 OCH_

I I 3 IV

N \ -RX 0 \ with a triazene of formula .y or VI:

Ar-N = N-NH-Alk2 “SS-Alk1-R3 Ar-N = N-NH-Alk2“ SS-R4

V .VI

where R1, r3, R4, Alk ^ and Alk2 are as defined above and Ar represents the organic residue of a diazotizable aromatic amine.

According to a variant, the present invention relates to another process for the production of mitosans of formulas II and III. This process comprises the reaction of a thiol of formula Vil or VIII:

AT

CD.YM.F - 10 - SY-1740-A

\

R3Alk! SH R4SH

VII. VIII

with a mitosan derivative of formula IB:

ÖX ÇH duH

ES-Alk - C> Vv .__ I * h if \ OCH- I I Ib * 1

Mitosanes comprising a disulfide radical which correspond to formula Ib are prepared by the above triazene process. More specifically, the mitosan of formula Ib where Alk2 represents an ethylene radical and R1 represents a hydrogen atom and described in Example 20.

According to another aspect, the present invention relates to an improved process for the preparation of the compounds of formula IX: 0 n 11 0 CH2OCNH2, 0CHa

I IX

N lî — R5

T

where R5 represents a hydrogen atom or a radical (C.1-6) -alkyl, and

R6 represents a radical (C.1-12) -alkyl or __ CD.YM.F - 11 - ’SY-1740-A

, 1 (Cl-12) -alkyl substituted, (C.3-12) -cycloalkyl or (C.3-12) -cycloalkyl substituted with the carbon atom which is linked to the oxygen atom in position 7 of mitosan carries 1 or 2 hydrogen atoms and the substitutes? killing agents are chosen from the halo, (Cl-6) -alkoxy, (Cl-6) -alkanoyl, (C.6-14) -aroyl, cyano, trihalomethyl, amino, (C. 1-6) -monoalkylamino radicals, (C.2-12) -dialcoylamino, (C.6-12) -aryl, (C.6-12) -aryloxy, (Cl-6) -alkanoyloxy, (C.7-14) -aroyloxy, heterocyclo to 1 or 2 rings and from 5 to 12 ring atoms comprising up to 4 heteroatoms chosen from nitrogen, oxygen and sulfur, and where each of these alkoxy, alkanoyl, aroyl, aryl, aryloxy, alkanoyloxy, aroyl radicals - • oxy and heterocyclo optionally carries 1 or 2 substituents chosen from the halo, (Cl-6) -alkoxy, (Cl-6) -alkanoyl, cyano, trihalomethyl, amino, (C.1-6) -alkylamino radicals and ( C.2-12) -dialcoylamino.

Many of the compounds of formula IX are known compounds which exert inhibitory activity against experimental tumors in animals in vivo. A number of new compounds of formula IX have also been prepared by this process and "r> t are the subject of the invention. In particular, the compounds obtained in Examples 14, 15, 16 and 19 are new and also exhibit anti-tumor activity with regard to experimental tumors in animals. These compounds are the subject of the invention. They are used like mitomycin C. The doses administered are adjusted in proportion to their toxicity compared to that of mitomycin C. When the new compound is less toxic, the dose administered is higher.

; The new process for the preparation of the compounds of formula IX comprises the reaction of a mitosan of formula X

CD.YM.F - 12 - SY-1740-A

s 0 "

1 Λ II

0 CH2OCNH2 HOv ^ \ ^ OCH3 N ^ -R5 with a triazene of formula XI:

Ar-N = N-NH-R6 XI

where R5 and R6 are as defined above and Ar; represents the organic residue of a diazotizable aromatic * amine.

By "lower alkyl", "lower alkoxy" and "lower alkanoyl" radicals is meant for the purposes of the invention (unless the context otherwise indicates) radicals alkyl, alkoxy or alkanoyl in a straight or branched chain of 1 to 6 atoms of carbon, such as methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, t-butyl, amyl, hexyl, etc. Preferably, these radicals have 1 to 4 carbon atoms and more preferably 1 or 2 carbon atoms. Unless otherwise indicated in the particular case, by "halogen" means for the purposes of the invention chlorine, fluorine, bromine and iodine. By "pharmaceutically acceptable non-toxic salt" is meant the salts of the compounds of formulas I and II with any non-toxic pharmaceutically acceptable acid or base. Such acids are well known and are in particular hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphorigue acid, nitric acid, maleic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid,

CD.YM.F - - 13 - SY-1740-A

t • ί i methanesulfonic acid, tartaric acid, citric acid, camphosulionic acid, levulinic acid, etc. Such bases are well known and give, for example,. salts with non-toxic metals, such as sodium, potassium, calcium and magnesium, ammonium salt and salts with non-toxic amines, such as trialkoylamines, procaine, dibenzylamine, pyridine, N- methylmorpholine, N-methylpiperidine, etc. The salts are prepared according to conventional methods.

DETAILED DESCRIPTION OF THE INVENTION.

The subject of the invention is a new process for the preparation of compounds of formula IX which comprises the reaction of a mitosan of formula X with a triazene of / * formula XI, as illustrated in scheme 1.

Diagram 1 0 11 0 CH2OCNH2 OCH3 I] + Ar “N * NH-R6 ^ Î-R5 XI,”

IX

where r5 and R6 are as defined above and Ar represents the organic residue of a diazotizable aromatic amine.

The 1-substituted 3-aryltriazenes of formula XI and more specifically the 1-alkyl-3-aryltriazenes

I. CD.YM.F - 14 - SY-1740-A

j.

* ft constitute a class of reactants of known utility for the reaction with carboxylic acids leading to the corresponding lower alkyl esters.

- 1-methyl-3 - (- 4-methylphenyl) triazene can be prepared according to the general methods described by E.H. White et al., In Org. Syn., 48, 102-105 (1968), as well as described in procedure 1. However, this procedure gives good results only with water-soluble amines and a second procedure, described by EH VThite and al., Tetrahedron Letters, n ° 21, 761 (1961) as well as in operating mode 2 below, is more suitable for preparing the triazenes of amines which are not soluble in water.

The 1-methyl-3- (4-methylphenyl) triazene prepared in the above manner has been used previously for preparing methyl esters of carboxylic acids such as 2,4-dinitrobenzoic acid / "EH White et al. ., Org. Syn., 48., 102-105 (1968) _7 and cephalosporanic acids leading to the desired Δ ^ -compound without isomerization to the Δ 2-isomer £ Mangia, Tetrahedron Letters, n ° 52, pages 5219-20 (1978) J. This reagent has been used in the si si., To produce a derivative of 3-methoxycephalosporin by reaction with the corresponding 3-hydroxy-4-cephem-4-carboxylate in benzene solution at reflux temperature (Wiederkeher et al., EUA patent n ° 4.069.324 - 17 January 1978).

Other 1- (lower alkyl) -3-aryltriazenes of formula XI can be similarly prepared by reacting other lower alkylamines with aryl diazonium salts in a similar manner. Any arylamine of 6 to 12 carbon atoms which readily forms a diazonium salt is suitable as a source of the aryl part of the 1,3-disubstituted triazene. Various triazenes produced in this way and used for the purposes of the invention are, for example:

I CD.YM.F - 15 - SY-1740-A

1- (n-butyl) -3- (4-methyl) triazene; - 1- (1-methylethyl) -3- (4-methylphenyl) triazene; 1- (4-methylpheny1) - 3- / "2- (4-morpholinyl) ethyl Jv triazene; l- (4-methylphenyl) -3- /” 2- (2-pyridyl) ethyl J-triazene; 1- (2-benzylthioethyl) -3- (4-methylpheny1) triazene; 1- (4-chlorophenyl) -3- (2-methoxyethyl) triazene; 1- (4-chlorophenyl) -3- (1,3 -dioxol-2-ylmethyl) -triazene; 1- (4-chlorophenyl) -3- (tetrahydrofuran-2-ylmé-thyl) triazene.

Other triazenes already described are • reactants useful for preparing according to the invention 7- (alkoxy) -substituted mitosans of formula IX. Those described by T.A. Daniels et al., Can. J. Chem., 55, 3751-3754 (1977) are examples.

N = N-NH-CH2-Y

a X = H, Y = CN b X = N02, Y = CN c X = C02Me, Y = CN d X = Ac, Y = CN e X = N02, Y - C02Et f X = C02Me, Y = C02Et g X = C02Me, Y = COPh h X = N02, Y = -CH (PCH3) 2 Other starting triazenes of formula XI suitable for the purposes of the invention are, for example, the following: 1- (n-butyl ) -3- (o <-naphthyl) triazene, l- (n-hexyl) -3-phenyltriazene, l-ethyl-3- (2,4-dimethylphenyl) triazene, 1- (1-methylethyl) - 3- (4-methoxyphenyl) triazene.

! if I

1 _ CD.Yfl.F - 16 - SY-1740-A

*

For the preparation of mitomycin A, the Applicant prefers to use 3-methyl-1- (4-methyl-phenyl) triazene as a methylation reagent. Preferably, at least two molecular proportions of the triazene are taken per molecular proportion of 7-hydroxy-9a-methoxymitosan and the reaction is preferably carried out in an organic liquid which is a solvent for the starting 7-hydroxy-9a-methoxymitosan. Preferred solvents are lower alkanols, lower alkyl esters of lower alkanoic acids, | lower dialkyl ethers, cyclic aliphatic ethers and polyhalogenated lower aliphatic hydrocarbons. These solvents count up to! 6 carbon atoms, but those boiling below 100 ° C are preferred. Specific preferred solvents are methylene chloride, methanol, ether | diethyl, ethyl acetate and mixtures thereof. The | reaction can be carried out at the reflux temperature of the reaction mixture or up to about 60cC. At higher temperatures, mitosan tends to decompose, which lowers yield. It is preferred to carry out the reaction at room temperature or at a lower temperature (e.g. <0 to 25 ° C.

Thin layer chromatography is a convenient means of evaluating the progress of the reaction. Mitomycin A is dark purple in color and can be readily discerned from the starting compound and by-products. In the methylene chloride methanol system (90/10), mitomycin A has an Rf of 0.36. Chromatography on neutral alumina is suitable for purifying the product.

The above reaction conditions and precautions are generally applicable to the preparation of other 7-R6o-mitosans of formula IX by the process o '

CD.YM.F - 17 - SY-1740-A

of the invention.

2- The new process of the invention by means of 1-substituted 3-aryltriazenes also makes it possible to prepare compounds of formula II or III by reaction of a mitosan of formula IV with a triazene of formula V or VI as illustrated in figure 2.

Diagram 2 O Alk2-SS-Alki-R3

'9 ch2ocnh2 HN-N = N-AR V

^ OCH- I 1 + or 3 Π \ X * Alk2-SS-R4

HN-N = N-AR VI IV

II OU.JII

where R ^, R3, R4, Alkx and Alk2 are as defined above and Ar represents the organic residue of a diazotizable aromatic amine.

The aryltriazenes of formula V or VI can be prepared in a manner analogous to that indicated above for the preparation of the aryltriazenes of formula XI, except that the alkylamines are replaced by the aminodisulfides of formula XII: R2-SS-Alk2NH2 XI1 represented also by formulas XIII and XIV: o

CD.Yîl.F - 18 - SY-1740-A

3-Alk1-SS-Alk2NH2 and R4-SS-Alk2 "NH2

XIII XIV

The aminodisulfides of formulas XIII and XIV are known compounds which can be prepared according to various methods. For example, they can be obtained by reacting the appropriate thiol RsAlk ^ SH or R4SH with a Bunte salt of formula:

NH2Alk2SS03Na XV

; or with a sulfenyl thiocarbonate of formula: * 0

II

NH2Alk2SSCOCH3 XVI

Klayman et al., J. Org. Chem., 29, 3737-3738 (1964) prepared the following compounds by the Bunte salt process: 2-aminoethyl and n-butyl disulfide, 2-aminoethyl and n-hexyl disulfide, 2-aminoethyl and n-octyl disulfide, 2-aminoethyl and n-decyl disulfide, 2-aminoethyl and pfrenyl disulfide, 2-aminoethyl and benzyl disulfide.

Methanol has been shown to be the preferred solvent for the reaction of the Bunte salt with thiol. Reaction temperatures from 0 to -10 ° C have been found to be preferable with this solvent. Higher temperatures are required with other solvents. The main drawback of this procedure is the formation of symmetrical disulfides appearing as by-products, probably by disproportionation of the disul-

CD.YM.P - 19 - SY-1740-A

»Mixed fure sought.

= The mixed starting disulfides of formulas XIII and XIV are preferably prepared by reaction of the appropriate thiol with a sulfenyl thiocarbonate of formula XVI. This is the method of S.J. Brois et al., J. Am. Chem. Soc., 92, 7629-7631 (1970). Normally, according to this procedure, the thiol is added to a methanolic solution of the aminoalkylsulfenyl thiocarbonate of formula XVI and the reaction is carried out at a temperature of 0 to 25 ° C. Depending on the particular thiol, the reaction can be virtually instantaneous or last a few hours. The progress of the reaction can be followed by detection of the unchanged thiol in the reaction vessel.

*

In case the reaction is slow, a catalytic amount of triethylamine can be added as an accelerator.

The 1- (substituted disulfide) -3-aryltriazenes of formula V or VI are obtained by reaction of the no-disulfide friends of formula XII with aryldiazonium salts as described above with regard to the preparation of the aryltriazenes of formula XL " Any arylamine of 6 to 12 carbon atoms which readily forms a diazonium salt is suitable as a source of the aryl part of the triazene-1,3-disubstituted. Disulfide-triazenes prepared in this way and used according to the invention are, for example, l- £ 2- (2-acetamidoethyldithiol) ethyl_7-3- (4-methyl-phenyl) triazene, l- £ 2- ( 3-nitro-2-pyridylthio) ethyl J-3- (4-methyl-phenyl) triazene.

Other starting triazenes of formula V or VI suitable for the purposes of the invention are, for example, the following: 1-jT 2- (3-nitro-2-pyridylthio) ethyl J7 “3- (4-chloro -:>

^ CD.YM.F - 20 - SY-1740-A

î% phenyl) triazene, l- £ 2- (3-nitro-2-pyridyldithio) propyl_7-3- (4-mé-thylphenyl) triazène, l- / ~ 2- (2-pyridyldithio) ethyl. 3- (4-methylphenyl) -triazene, 2- (phenyldithio) ethyl J-3- (4-methylphenyl) - triazene, 1-C2- (butyldithio) ethyl J7 “3- (4-methylphenyl) -triazene , 1- / ~ 2- (4-methoxyphenyldithio) ethyl_7-3- (4-methyl-phenyl) triazene; 1-C 2- (4-nitrophenyldithio) ethyl _7 ~ 3- (4-methyl lphenyl) triazene, • 1- ^ 2 - / - (2-benzoylaminoethyl) dithio_7éthylj · -3- (4-methylphenyl) triazene, 'l- / ~ 2- (4-chloro-2-naphthyldithio) ethyl J7-3- (4-me-thylphenyl) triazene, 1-Z "2- (cÿclopropylmethyldithio) ethyl _7-3- (4-methyl -phenyl) triazene, 1- ^ 2 - / ”(2-phenoxyethyl) dithio_7éthyl ^ -3- (4-methyl-phenyl) triazene.

According to a preferred embodiment, the subject of the present invention is another process for the preparation of the disulfide-mitosans of formula la: P ch2ocnh2 R-SS-CH, CH, 0 _____ \ T Ia

IhlH

where r2 represents an organic radical, in this case the constituent radical of a thiol of formula r2sh,

J

, _, CD.YM.F - 21 - SY-1740-A

alternatively represented by R ^ Alkj or R ^, where r3, r4 and Alki are as defined above.

For the preparation of the disulfide-mitosans of formula la, it is preferred to subject the 9a-methoxy- 7- £ '2- (3-nitro-2-pyridyldithio) ethoxyJ7nii't-osane <3rd formula XVII thiol with an appropriate organic thiol of formula R ^ sH as illustrated in reaction scheme 3. The chemical potential favoring the formation of the disulfides of formula la is the stability of the by-product, namely 3-nitro-2-mercaptopyridine, which only exists in the form of thione XVIII.

Diagram 3 fi - ^ ° 2 0 CH2OCNH2

Se- »2 2 d | + R SH

XVII

"Y

2 X T2 ^ 2 R -SS-CH-CH-0 T Tl VX3 3 T \ ^ y

the XVIII

Alternatively, to prepare mitosans of formula II or III, where Alk2 represents a radical other

—- CD.YM.F - 22 - SY-1740-A

than ethylene, for example trimethylene or propylene, the appropriate triazene of formula V or VI is used in the procedure of scheme 2 in order to obtain the disulfide-mitosans of formula Ib ·.

_, K02 P

/ ΓΛ, v At 9¾0 ° 0¾ (/ ') -SS-Alk, -0_X \ ^ - \ Ib \ = / Τι ιΓ / ζ * CH3' \ / ^ - N ^ j-r1 where Alk2 and R1 are such that defined above.

Two general synthetic procedures are described for preparing the mitosanes, both lipophilic and hydrophilic, of formula la. The general procedure A is applied to the preparation of lipophilic or moderately soluble disulfides of formula la and the general procedure B is applied to the water-soluble disulfides of formula la which are preferably isolated in the form of sodium salts or in the form zwitterionic. Preferably, at least one equivalent of the mercaptan R ^ SH is used per equivalent of the mitosan of formula XVII and the reaction is carried out in the presence of approximately one equivalent of base per equivalent of mercaptan R2sH. The preferred bases are tertiary amines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, pyridine, 2,6-lutidine, and inorganic bases, for example sodium carbonate, potassium carbonate, potassium bicarbonate, etc. Inert solvents suitable for the reaction of the starting compounds of formula XVII and r2sH are the lower alkanols, the

CD.YM.F - 23 - SY — 1740-A

lower alkyl esters of lower alkanoic acids, lower aliphatic ketones, cyclic aliphatic ethers, polyhalogenated lower aliphatic hydrocarbons and water. Organic solvents have up to 8 carbon atoms, but those boiling below 100eC are preferred. The specific preferred solvents are methylene chloride, methanol, acetone, water and mixtures thereof. The reaction can be carried out at the reflux temperature of the reaction mixture or up to about 60 ° C. It is preferred to carry out the reaction at room temperature or at a lower temperature, for example from 0 to 25 ° C.

The above reaction conditions and precautions are generally applicable to the preparation of other disulfide-mitosans of formula la and Ib according to the general procedure of scheme 3.

Below is a list of representative thiols of formula R ^ AlkiSH or R ^ SH which can be converted by reaction with Bunte salt XV or sulfenyl thiocarbonate XVI to intermediates of formulas XIil and XIV, which in turn can be converted to the products of the invention as described. In the preferred embodiment, the representative thiols can be used for the reaction with the mitosans of formula la or Ib to give the products according to the invention. However, the only limitations to the methodology of the present invention are the use of thiols containing terminal primary alkylamines which can lead to a mixture of products and the use of heteroaromatic thiols which may not react with the compounds of the formulas la or Ib.

| \ - ^ j

CD.YM.F - 24 - SY-1740-A

t hsch3 HSCH2CH3 HSCH2CH2CH3 HSCH (CH3J2 HS (CH2) 3CH3 HS ~ CH-CH2CH3 CH3 HSCH2CH {CH3) 2

H

CH, I 3 HS-C-CH, i "3 3 HS <]

HS

“O

CD.YM.P - 25 - SY-1740-A

/ - "X

NOT A WORD - ' ' . "Ο -Ο

bb- ^ hQ

HS-CH2-CH = CH2 HS-CH2-CH = C (CH3) 2 HS-CH2-C = CH HS-CH2-C = C-CH3 o HS (CH2) n0Rl n - 2-4; R1 = H, CCHj, CH3 HS (CH2) nCXR n = 1-3? X = 0, NH, NR1; R / r1 = H, CH3 HS (CH-) NHR1 n = 2-4? 2 n '0 R1 = CH3, CH2CH3, CH2CH2CH3, ÜcH3

CD.YM.F - 26 - SY-1740-A

<HS (CH2) ^ NR ^ R2 n = 2-4; R1 / R2 “CH3, CH2CH3 c i I HS-CH2CH2SCH3 H S-CH2CH2NHC (CH3) 3 <fH3 9 HS-O ^ -C-CH ^ HR1 R1“ CH3, CCH3 Î: h3

-wA

/ C "2 HS-CH2CH2-N n * 3-5 N" CH2, n CH2NR1R2 HS-CH-CH2NR1R2 R1 "CH3? R2 = h, CH3 HS-CH n-CH-CH-NHR1 R1 = „CH, 2 I i 2 3 NHR · 1 HS-CH2-CH-NH2 + co2h peptides HS-CH2-CH-CH2-NH2 + co2h peptides HS-CH2-CH-CH2-C02H + λπ2 peptides

CD.YH.F - 27 - SY-1740-A

<’(J: h2co2h HS-CHjCHjCH + peptides‘ nh2 NH ~ 1 2 NHCOCH-CH-CHCO-H | 2 2 2

HS-CELCH

2 (

C0NHCH2C02H

O

II

HS-CH = CH-NHCCH3 HS-CH ““ CH-CHo0H 2 | 2

OH

ÏH3

HS-CH2CH-CH2OH

HS-CH ^ H-CH ^ R ^ 2 R1 = CH3; R2 * H, CH3 och3 hs-çh2ch2-n-ch3 OCH3 k HS-CH2CH2NH- ^ ^ HS-CH2CH2NH- ^ ^

Nm /

_ CD.YM.F - 28 - SY-1740-A

N ^

HS-CH2CH2-NH - <^ I

s ^ (CH3 H £ -CH_CH ^ -Ot-CH _ 2 2 I 3 iH3 hs- ^ ^ -n (ch3) 2 H £ ^ ^^ - OCH3 NHCH3 / "V s HS-r xV-NHCCH3 hs- ^ ^^) - ^ o2h NH2

. -O

J

• CD.YM.F - 29 - SY-1740-A

"'J>

O

AT,-*"

HS

n (ch3) 2 û ° HS-CH2CH2 - // \ V NHCCH3 HS- (CH2) n - ^^> n = 1, 2 hs.ch ^

'- NOT

CD.YM.F - 30 - SY-174Q-A

HS- (CH2) n - ^ "~ ^ N η = 1, 2

/ ^ N

HST (CH,) -N · Ι n “2, 4

2 n \ ^ M

/ ^ N 1 HS- (CH2) n-N I n = 2 - 4; R = OCH2CH3 J * HS-ICHjln - ^. ^ N = · 1, 2

H

HS- (CH,) ^ n »1, 2; X = 0, S, NH

2 n Xx

HS- (CH2) n O n * = 1, 2; X = 0, S, NH

HS- (CH,) ^ ,, n = 1, 2; X = 0, S, NH

2 n X

HS- (CH,) <^) - NH, n = 1, 2; X = 0, S, NH

2 η ^ χ / 2 "

HS- (CH2) n - <^^ J n = 1, 2; X = 0, S, NH

HS- (CH,) <^ -NH. η = 1, 2; X = 0, S, NH

2 n N 2

CD.YM.F - 31 - SY-1740-A

_.N (CH3) 2

hs-c "2 \\ J

HS-CH, 4. y R1 = H, CH, 2 t ΓΛ i! .

KS-CH2-L, KR Rx - H / CH3

HS-ÇH, -CH, -N X 0, NH, NCH-, S

22 \ _ / _ HS-CH2- ^ \ R1 e H, ch3 N.— '

RA

· **

Hs-œX) R1 = H, ch3 'N <

R

HS ~ CH2- ^ \ rX R1 = H, CH3 HS-Q ^ R1 - H, CH3 R1 - h, CH3 R1

_ 09 _ SY -: "40-A

PD. YM. F -5 ^ y 'Γ \, HS-C NR1 R = H, CH3 / ^ (ch2) HS- (CH2) n- ^ ra n = 1-3; m = 1-3 / H 2 HS-CH2- / I R2 * = H, CH3? R1 - Hr CH3

N ^ “R

HS-CH2 - [^^ NR1 R1 = Hr CH3

O

HS-CHj · / ^ N «1 R1 - H, CHj H S (CH3) 2 hs / ^^ ° ^^ nhcch3 0 hs / ^ NH ^ -oh

Vsv // ^ Vv0H

CD.YK.F - * SY-1740-A

The usefulness of the compounds of formulas I and IX in the antineoplastic treatment methods of the invention is demonstrated by the results of in vivo descrambling experiments in which the compounds are administered in different doses to mice in which leukemia P-388 or melanoma B16 have been induced.

The compounds according to the invention are believed to have antibacterial activity against Gram-positive and Gram-negative microorganisms in a manner analogous to that observed on natural mitomycins and are therefore potentially useful as therapeutic agents for treatment of bacteria • infections in humans and animals. Activity against P-388 leukemia in mice.

Table I contains the results of laboratory experiments on CDFj mice carrying, by intraperitoneal implantation, a tumor inoculum of 106 cells of ascites of mouse P-388 leukemia and which received different doses of a test compound of formula I or II or mitomycin C. The compounds were administered by intraperitoneal injection. Groups of six mice were taken for each dose and the animals received a single dose of the compound on the day of the inoculation. A group of ten control mice receiving physiological saline was included in each experimental series. The mice receiving mitomycin C constituted the positive control. An experiment duration of 30 days was chosen, with determination of the average survival time in days for each group of mice and the number of survivors at the end of 30 days The mice were weighed before the treatment and again on the sixth day. The change in weight was c considered as a measure of drug toxicity. We used

CD.YM.F- - 34 - SY-1740-A

mice weighing 10 g and weight loss of approximately 2 g was not considered excessive. The results were expressed in% T / c, that is to say 100 times the ratio of the average survival time in the treated group to the average survival time in the control group receiving the physiological saline solution. Control animals receiving saline are usually dead within nine days. The "maximum effect" indicated in the table is expressed in% T / C and the dose exerting this effect is indicated. The values in parentheses are those noted on mitomycin C as a positive control during the same experiment. It is therefore possible to estimate the relative activity of the compounds of the invention in comparison with mitomycin C. It is considered that a minimum effect expressed by% T / C is 125. The dose exerting the minimum effect mentioned in the table below is that leading to a% T / C of approximately 125. The two values indicated in each case in the column entitled "average change in weight" are respectively the average change in weight per mouse at the dose maximum effective at dose

·· * I

effective minimum.

h, -j

CD.YM.F - 35 - SY-1740-A

_ * _μ * <τ "—ι in cm co

CflJöP, Nr '· ** ^ · "> ι Q) έ ο ο ο ο ο Ε ·> +» + + 0) c 0)

Ci <ϋ Ό · * ·· · * · ··> · * C> ι · η ”η r- ~“ β · η *

Hl 0 0 ^ κ · ο • ί Ε ft Ο Ο · —I ΓΜ Ο U + III ι * Η IÜ Ε -Η c ιη m in in • η <D cm ο Ο Ο ni £ 0) »n · \» n ** Ο ο ο ο ο ο

"3 +" D V V

.3 φ Γ »w

Π "H

0. *

Μ CM ΓΜ CM CM CM

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^ £ S / \ E Q Φ Φ CM

° r \ - r ι U f A · Η · * · * · * ^ * \ CO δ H \ * -4 ^ M 40 CO ni χ_ \ 2 CO «/ \ / c I rVr 2 H * ^ / t!

D ®) = \ S

g J o = (· Vo "U S S g g g \ - / Σ2 C C2 w Î2 ^ <l) '' _ rto n * ni co io ^ r-i O JP 09 i £> ό ni co m

(S ~ · —I * - <CM cm <—I

ro U

! Π r ^ i ^

h L J * CM

-H X / 2 = Ê t ^ s

H K ‘aT aT

d u Ucm Hm G

Q o, K = ™

Cl -Hl V V V

Φ Ό Φ

H

"'Φ £ ffi E n n 0 <U n; ro _ ._ m - - ξ s s Ε Φ pH ^ O - U h

.CD.YM.F - 36 - SY-1740-A

po n p 'm »h C <D CW ~ ph' r-Γ pT o? I10 _? + + + +

0) C CD

S5S .N Ό ^

13 Ο ° ~ _T -T _T O

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rd

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£ ÏÏ 0 »“ oj oj oj co co ® r \ rs · \ rs.

t m ro m rr

H i-l 03 "β · V TT tj · CO

(0O »S · >> * \ * s * N

rS E C VD O O VD OJ

^ -H ri n * * i g * 7

• H Λ +> -L -L

^ ^ ~ ~ m ro

03 O Hj VD OJ OJ PO PO

“-H T; o r- ο * n po w E ^ V, Γ0 rX fH Λ Λ MO> .U ~ - τ-> - - U r7 PO «- (P * vd · co P. P ^ © f-X VD O r-

OJ OJ OJ «-X

J ^ CD _ <, 5 ™

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m 2 0).

Z "Λ 5 βνβν„ glsj2 Wk S O-® = / - \ s r z; w s u / \ w w

r W 2 O _ -, W M

Χ oj C oj Q. O oj oj i_] X U SC \ X / * X s

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oj X oj psi oi OJ

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ο ω ^ œ ^ ° e 0 ^ ^ ^ ^ oj oj E 0) 0 -

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/

CD. YM. F - 37 - '5Y-1740-A

C (Do'f J? "

"03 ^ + E

Ê -r-i m C œ ... x

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¢ 00 ^ ί E ft. 7 + j u 1 <c ai

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Pi ni D £ D 0)

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.CO g "h - E

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m - 1-1 ü g ic tu £ H Pi en - +)

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co) _ tr _r -P d ai x P X œ E rJ 03 D P! 03

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GD.YM.F - 38 - SY-1740-A

• · s

Activity against melanoma B16

Table II includes the results of anti-tumor experiments on melanoma B16 in mice. BDFi mice were used which received the tumor implant in subcutaneous inoculation. The duration of the experiment was 60 days. Groups of ten mice were taken for each dose and the mean survival time was determined in each group. Control animals inoculated like the experimental animals and receiving a drug injection without the drug had an average survival time of 24 days. The survival time compared with that of the controls (% Τ / c) makes it possible to evaluate the efficacy and the dose - of maximum effect and the dose of minimum effect for each experimental compound have been determined. The minimum effect dose is defined as that leading to a value of 125 for% T / C. For each dose, the animals received the test compound on days 1, 5 and 9 intravenously.

/ ÎS \ / ** ";

CD.YM.F - 39 - SY-1740-A

»-! ιΰ ε

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+> 'i w in ΰ rd

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Φ ’ÜOi H H O O

E ra + i + l +> Φ β * 0 φ φ φ -h ........ m e C> iO cn ^ invD iH «u

m 0 ft »» »» φ E

A E O CN O O

U I l + I * c id

H

Φ

CO CO

0 ß • V id • σ μ 10

"WH -" U

fl) m U W

"F ^ VDOIVD ^ ^ Ό-g O H n H. 8,’ ü

φ-H V V V u E

“Ε ß ο ο Ο -μ C · Γ-> · Η Ε

μ X

ιΰ cd & γΗ

VD

Η Η CD μ

W CQ φ S

β> Φ, ™ ~ ~ ~ Î R

<Ë β η η η η ιΰ KO î, tn Kß g ^ ^ cn vd · σ> φ ÇQ i3 h ο ^. “W <^ φ Η“ η Η φ Η Ε <'Φ Ρ ^ Ό φ 2 Η ο “. ®, Λ £ + ί Ε Λ ß Ε 0 -Ρ "2,“ φ β "Η (η" "μ '_ - ^ ^ 3 φ KU g ° ν ι ιΗ Qj r— {éQ) c_ | Η Η Η Η ^ 1 Ü1 IÖ ί ^ ~ ~ - ο * σ ε + ΐ t #> ^ ο OJ Φ Ή Ή β νο η η ιη Ο ß Φ ^ OJ Η Η Λ Ό g 10 φ α · κ Ό +) Ό Φ Φ -η π "μ μ Φ η, ο Φ" μ +> Όη α,> ί φ ß Ο Q - Φ 'Φ ρ φ £ Ό ® m 00 Ο VD «Π (0 ο yl \ CN ΓΜ +) φ μ φ £ φ cn β 10 β υ Ε. Αί Φ 0 Φ β p η Ε ό -μ φ ο μ φ φ -η ιο οι id> μ - di β η »φ (0 cd d

Ο £ 4D 0) X

Ε U Φ Κ Φ • - · · * Η CM C0

Z * J

/ _ ‘CD.YM.F - 40 - SY-1740-A

%

Due to the antitumor activity observed on experimental tumors in animals, the invention also relates to the administration of the compounds in accordance with the invention for inhibiting tumors in mammals. For this purpose, they are administered systemically to the mammal carrying a tumor in an effective anti-tumor dose which is substantially non-toxic.

The compounds of the invention are principally suitable for administration by injection substantially like mitomycin C and in some of the same indications. Slightly higher or lower doses may be administered depending on the particular sensitivity of the tumor. The compounds are readily presented in the form of dry pharmaceutical compositions containing diluents, buffers, stabilizers, solubilizers and constituents conferring good pharmaceutical properties. These compositions are then diluted with an injectable liquid immediately before being administered. Suitable injectable liquids include water, isotonic saline, etc. ,

Description of specific embodiments

In the procedures and examples below, all the temperatures are in degrees Celsius and the melting points are not corrected. The proton nuclear magnetic resonance spectra (1 h NMR) are those recorded on a Varian XL100, Joel FX-90Q or Bruker Ï7M 360 spectrometer in pyridine-d5 or D2O, as indicated. When pyridine-d ^ is the solvent, the resonance of pyridine at 0 = 8.57 serves as an internal standard, while when 1 * 20 is the solvent, the TSP serves as an internal standard. The chemical shifts are explained in units and the coupling constants in Hertz. The multiplicities z>

CD.YM.F - 41 - SY-1740-A

are expressed as s = singlet, â = doublet, t = triplet, q = quadruplet, m = multiplet, si = broad singlet, dd = doublet of doublet and dt = doublet of triplet. The infrared spectra are recorded on a Beckman model 4240 or Nicolet 5DX FT — IR spectrometer and are explained in reciprocal centimeters. Ultraviolet (UV) spectra are measured on a Cary model 290 or Hewlett Packard 8450A spectrometer with multiple diode detector. Thin layer chromatography (TLC) is carried out on 0.25 mm GF Analtech silica gel plates. Flash chromatography is carried out on neutral Woelm alumina (DDC quality) or Woelm silica gel (32-63J * -m) with the solvents indicated. All evaporations of solvents are carried out under reduced pressure below 40 ° C.

, 1-Alkyl-3-aryltriazenes are reagents of utility recognized for forming the lower alcoholic esters of carboxylic acids. 1-Methyl-3- (4-methylphenyl) triazene can be prepared as described below.

1 ”procedure / B.H. White et al., Org. Syn., 48, 102-195 (1968).

l-Methyl-3-p-tolyltriazene.

P-toluidine (50.2 g, 0.47 mole) is introduced into a 2 liter flask fitted with a 200 ml stopcock and an effective stirrer and the flask is immersed in an ice bath and salt at around -10 °. A solution of 46.8 g (0.55 mole) of potassium nitrite is introduced into the ampoule! 150 ml of water and, with stirring, a mixture J of 250 g of crushed ice and 140 ml of concentrated hydrochloric acid with p-toluidine is added. The potassium nitrite solution is added slowly with continuous stirring over 1 to 2 hours until the CD test. YM. F _ An o \ r inAn ”.

The potassium starch iodide is positive (note 1) and the mixture is stirred for an additional hour to ensure reaction of all of the toluidine.

The p-toluenediazonium chloride solution at pH 6.8-7.2 is brought to 0 ° at 0 ° using cold concentrated aqueous sodium carbonate, the solution then turning from red to orange, while a small amount of red substance is deposited. The cold neutral solution is poured into a stopper ampoule and slowly added to a vigorously stirred mixture of 150 g of sodium carbonate, 300 ml of 30-35% aqueous methylamine (note 2) and 100 g of crushed ice in a 3 liter flask. We maintain the mixture of! reaction at about -10 e during the addition which requires a duration of about 45 minutes (note 3). The solution is extracted with 3 aliquots of 1,000 ml of ether. The ethereal extracts are dried over anhydrous sodium sulfate and evaporated on a rotary evaporator at room temperature to obtain 65 g of crude l-methyl-3-p-tolyltriazene (note 4). The latter is introduced into a water-cooled sublimation apparatus and the triazene is sublimated at 50 ° (^ L mm Hg)

to obtain 43.3 g (0.29 mole or 62%) of a yellow crystalline sublimate, m.p. 77-80 ° (note 5). The sublimed can be recrystallized from hexane to obtain triazene in white needles, P..F. 80.5-81.5 °. More conveniently, it is dissolved in the minimum amount of ether and the solution is diluted with 2 volumes of hexane, then cooled to 0 ° to obtain flat plates of a product with slightly yellow reflection, PF 79 -81 °. The production of pure triazene is 33-37 g (47-53%) (note 6). s NOTES

1. The various tests with potassium starch iodide paper must be carried out 1 to T4

CD.YM.F - 43 - SY-1740-A

"2 minutes after the end of the addition of potassium nitrite.

2. 40% aqueous methylamine is also suitable.

3. The reaction is complete when a drop of solution no longer gives a red color with a solution of -naphthol in aqueous sodium carbonate.

4. The main impurity is 1,5-di-p-to-lyl-3-methyl-1,4-pentazadiazene (m.p. 148 °). This can be separated by fractional crystallization, but it is more convenient to sublimate the triazene out of the reaction mixture.

; 5. The sublimed contains a trace of 1,3-di-p-tolyltriazene which the thin layer chromatography shows. Recrystallization gives pure 1-methyl-3-p-tolyltriazene.

6. This procedure does not give good results. states than with water-soluble amines. Procedure 2 below is more suitable for preparing the triazenes of water-insoluble amines.

Procedure 2 E.H. White et al., Tetrahederon Letters, ne 21, p. 761 (1961).

l-n-Butyl-3-p-chlorophenyltriazene

A solution of p-chlorobenzenediazonium hexafluorophosphate (recrystallized from acetone-methanol) (2.87 g, 10.1 mmol) in dimethylformamide (free from dimethylamine) is slowly added to a stirred mixture of n- butylamine (0.73 g, 10.0 millimoles), powdered sodium carbonate (15 g) and dimethylformamide (30 ml) which are kept at -5 °. The diazonium salt solution can be used at room temperature, but a purer product is usually obtained when the salt solution is prepared:>

CD.YM.F - 44 - SY-1740-A

»* Of diazonium and that it is delivered by means of a separating funnel cooled to approximately -50 °. The mixture is warmed to 0 ° and stirred until a negative test is obtained with 2-naphthol (a few minutes are usually sufficient). Add ether and filter the mixture, then wash the filtrate thoroughly with water and dry. (Triazene can be isolated at this time and recrystallized from pentane at low temperature).

Procedure 3 7-Hydroxy-9a-methoxymitosan

Mitomycin C (2.2 g, 6.6 millimoles) is dissolved in 140 ml of 0.1N methanolic NaOH (50%) and the reaction mixture is stirred at room temperature for 30 hours. The solution is then adjusted to about pH 4.0 with 1N HCl and extracted with ethyl acetate (4 x 500 ml). The mixture of extracts is dried in ethyl acetate (Na2SO4.) And evaporated under reduced pressure at about 30-35 ° to obtain a solid residue giving, after dissolution in ether and addition of excess of hexane, a purple precipitate. The precipitate is collected and dried in air to obtain, in the form of a fine purple powder, the title compound (1.4 g, 63%).

! h NMR (pyridine-d5, 6 ·. 2.05 (s, 3H)., 2.14 (sl, 1H), 2.74 (si, 1H), 3.13 (d, 1H), 3, 24 (s, 3H), 3.56 (d, 1H), 4.00 (dd, 1H), 4.37 (d, 1H), 5.05 (t, 1H), 5.40 (dd, 1H ), 5.90 (if, 2H).

Procedure 4 Mitomycin A

100 mg (0.30 millimole) of 7-hydro-- xy-9a-methoxymitosan and 100 mg (0.67 millimole) of 3-methyl 1-1-p-tolyltriazene are dissolved in 2 ml of methylene chloride and 10 ml of diethyl ether. After heating

, CD.YM.F - 45 - SY-1740-A

* '

at moderate reflux for 6 hours, the solution is stirred at room temperature for 18 hours. The CCM

(methylene chloride: methanol (90:10)) reveals the appearance of a dark purple spot at Rf = 0.36 and a trace of impurity at Rf = 0.41. The reaction mixture is concentrated to dryness and chromatographed on neutral Woelm alumina using methylene chloride and methylenermethanol chloride (30: 1) as elution solvents. The fractions containing the component are pooled at Rf = 0.36 and concentrated to dryness. By precipitation of the dry residue from methylene chloride and hexane, the title compound (25 mg, 24%), m.p. 161e, is obtained in the form of a fine amorphous purple powder.

*

Analysis for C ^ gHig ^ Og

Calculated: C, 54.96; H, 5.44; N, 12.02%

Found: C, 53.96; H, 5.37; N, 11.99% IR (KBr), \? Max, cm "1; 3400, 3300, 2950, 1700, 1630, 1575, 1200, 1060.

XH NMR (pyridine-d5,6); 1.82 (s, 3H), 2.74 (dd, 1H), 3.12 (d, 1H), 3.24 "(s, 3H), 3.54 (dd, 1H), 3.96 ( dd, 1H), 4.02 (s, 3H), 4.22 (d, 1H), 4.84 (sl, 2H), 5.02, (t, 1H), 5.38 (dd, 1H) .

The yield of procedure 4 is brought to 63% by taking methylene chloride as reaction solvent at room temperature with a reaction time of 24 hours.

Procedure 5

A solid Na2CO3, a 35% aqueous solution of amine (same quantity as in procedure 1) and ice are introduced into a 250 ml round-bottomed flask with a single neck, and the suspension is stirred at -5 ° (salt and ice bath). A cold suspension of p-chlorobenzenediazonium hexafluoro-phosphate (Aldrich Chemical) is added dropwise to this suspension.

, - CD.YM.F - 46 ~ SY — 1740-A

ff *

Co.) in ice, water and Na2CC> 3 (solution. About pH 7). At the end of the addition, the reaction mixture is extracted with diethyl ether. The mixture of diethyl ether extracts is subjected to backward extraction with water, dried (Na2SO4) and concentrated. The solid yellowish residue is purified by chromatography on a Woelm alumina column taking as hexane eluting solvent: methylene chloride (1: 1) (observation by NMR spectrum).

EXAMPLES 1-10

The triazenes 1-7 in Table III below are prepared according to procedure 1 described above • which relates to the triazene of Example 1. The triazenes are purified by chromatography on a Woelm alumina column.

The triazenes 8-10 in Table III are prepared according to procedure 5 above.

K

/ b

J

CD.YM.F - 47 - qy — 1740-A

-, y

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• ψ EXAMPLE 11.- 1 ~ Ε 2- (3-Nitro-2-pyridyldithio) ethyl J7 ~ 3 ~ (4-methyl-phenyl) triazene

A 4-methylphenyl diazonium chloride solution is prepared from p-toluidine as described in procedure 1 and adjusted to pH 6 / 8-7.2 at 0 °, as described in this procedure. In this way, 45 ml of solution are prepared which contain 21.15 millimoles of diazonium salt and which are introduced into a stopcock ampoule suitable for a 250 ml round bottom flask with 3 necks containing 5/34 g (20 / 0 millimoles) of 2- (3-nitro-2-pyridyldithio) -ethylamine, 7 g of sodium carbonate and 150 ml of • dioxane which were introduced in this order into the Λ flask. 6 ml of a saturated aqueous sodium carbonate solution and 10 g of ice are added to the contents of the flask. The flask is cooled in an ice bath and the contents are mechanically stirred. The solution of the diazonium salt is then added dropwise over 1 hour using the stopcock ampoule. When the addition is complete, the reaction mixture is allowed to warm to room temperature and then entered three times with 400 ml of ether. By drying and evaporating the extracts, the desired product is obtained which is purified by chromatography on an alumina column with a diameter of 25 mm and * with a length of 250 mm using hexane: methylene chloride (4; 1), hexane: methylene chloride (3: 2), hexane: methylene chloride (1: 4) and finally methylene chloride containing 1% ethanol for development and l elution from the column. The appropriate fractions (identified by TLC) are combined and evaporated to collect 2.5 g of the title compound.

CD.YM.F - 50 - SY-1740-A

* 9 EXAMPLES 12-19.-

General procedure for the preparation of 7-alkoxy-9a-methoxymitosans (12-19)

A solution of triazene (2.4 equivalents) in methylene chloride: methanol (4: 1) is added to a solution of 7-hydroxy-9a-methoxymitosan (prepared according to procedure 3) in methylene chloride methanol (4 : 1). The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography (10% methanol in methylene chloride). 7-alkoxy-9a-methoxymitosan for / born appears in the form of a dark purple spot at the CCM. The reaction mixture was chromatographed on Uoelm alumina when the reaction appeared to be complete according to the TLC and the 7-alkoxy-9a-methoxy-mitosan was collected as an amorphous solid. The products obtained are identified by the number of Examples 12 to 19 in Table IV.

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i f * EXAMPLE 20.- 9a-Methoxy-7- / 2- (3-nitro-2-pyridyldithio) ethoxy / -xnitosan (20)

580 mg (1.73 millimole) of 7-hy-droxy-9a-methoxymitosan is introduced into a round-bottomed flask and the dissolution is carried out in 60 ml of methylene chloride. About 2.5 g (5.7 millimoles) of the triazene of Example 11 is added to the solution contained in the flask and the mixture is stirred at 5 ° for 14 hours, then at room temperature for 8 hours. The progress of the reaction is monitored by TLC on silica with methylene chloride: methanol (9: 1). The reaction mixture is kept at room temperature for another 26 hours, then the operations are completed by chromatography on an alumina column with a diameter of 8.5 mm and a length of 305 mm. For development and elution, methylene chloride, 0.5% methanol in methylene chloride, 1.0% methanol in methylene chloride are used successively as solvents, each in a volume of 200 ml. , 1.5% methylene in methylene chloride, 2% methanol in "methylene chloride and 4% methanol in methylene chloride. The appropriate fractions are combined and evaporated to collect 470 mg of the title compound.

Analysis for C22H23N5O8S2 (with correction for 0.5 mole% of CH2CI2)

Calculated: C, 45.65; H, 4.09, N, 11.82%

Found: C, 45.74; H, 4.14; N, 11.61% IR (KBr), max, cm-lj 3440-3200, 3060, 2930, 1720, 1570, 1510, 1395, 1335, 1210, 1055.

iH NMR (pyridine-d5, <5): 1.81 (s, 3H), 2.00 (sl, 1H), 2.61 (si, 1H), 2.98 (sl, 1H), 3.08 (s, 3H), 3.20 (m, 2H), 3.39 (d, 1H), 3.83 (dd, 1H), 4.07 (d, 1H), 4.59-4.89. ^ t ----- ^ m.VM P ce: _ pvr n * 7 Λ r._7 \ <* (m, 3H), 5.21 (dd, lH), 7.16 (dd, lH), 8.31 (dd, 1H), 8.71 (dd, 1H).

By adapting the operating methods of the examples; pies 11 and 20 for other U - (3-nitro-2-pyridyldithio) alkylamines having 2 to 6 carbon atoms in the alkyl radical, the mitosan derivatives of the following formula can be prepared: n fî NO CH2OCNH2 (ί <CR2> n '°

O

n = 2-6 R1 = H, or (C.1-6) -alkyl.

EXAMPLES 21-34.-

The 7-alkoxydithio-9a-methoxymito-sanes 21-34 of table V are prepared according to general procedure A or B below, as indicated in table V. The physical properties of mitosanes 21-34 are detailed in table VI below.

Procedure A

Under an argon atmosphere, stirring is added to a deoxygenated solution of the mitosan of Example 20 (<v0, 1 millimole) in acetone (3-5 ml) of triethylamine (ru 1.1 equivalent), then drop by drop or gradually a mercaptana (1 equivalent) in acetone (1-2 ml). In most cases, the progress of the reaction is monitored by thin layer chromatography on silica gel (10% methanol in methylene chloride). The completion of the reaction results in the disappearance of the stain corresponding to the starting compound and the appearance of CD.YM.e - aa _ cv_i72in_a * <a rition of that corresponding to the product. the reaction mixture is concentrated under reduced pressure (α> 30β) and the residue is chromatographed on a column of neutral Woelm alumina (6 mm x 254 mm) packed in dispersion, using 2-5% methanol in methylene chloride. This procedure separates the desired mitosan from pyridylthione which is the by-product which remains in the column. The product thus eluted is subjected to 2-5% methanol in methylene chloride to further careful purification I by flash chromatography on silica gel with 5-7% methanol in methylene chloride as elution solvent, the main band corresponding to the product is isolated and the 7-alkoxide is characterized therein. amorphous thio-9a-methoxymitosan.

a) When the starting mercaptan is impure, more than one equivalent of thiol is required.

b) When the mitosan of Example 20 and the product have Rf values very close to TLC, the reaction is monitored by high pressure liquid chromatography (HPLC) on a column (yu-Bondapak-C ^ g).

Procedure B

To a solution of the mitosan of example 20 (hJ0, 1 millimole) in 2 to 5% acetonea in methanol (10 ml) is added a saturated aqueous solution of NaHCO 3 ^ (<V 6 drops), then the mercaptan (1 equivalent) in methanolc (1 ml). The progress of the reaction is monitored by TLC (silica gel, 10% methanol in methylene chloride). At the end of the reaction, the reaction mixture is diluted with water (15 ml), then concentrated to about 10 ml under reduced pressure at about 30 °. The resulting solution is chromatographed on a phase inversion C-18 column by elution with progressive gradients (100% water; up to 80% methanol in water). We collect the | ! ^ *

CD.YM.F - 57 - SY-1740-A

* * product eluted in the form of a major red band and it is concentrated to obtain 7-alkoxydithio-9a-me-thoxymitosan which is an amorphous solid. If further purification is required, repeat the above chromatography.

a) Methylene chloride is also suitable, but acetone is preferred.

b) When the mercaptan is L-cysteine, this base is not used.

c) Water is used if the starting thiol is water-soluble.

d) Elution with water separates the yellow pyridylthione which is the by-product from the product, which remains 1 in the column.

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CD.YM.F - 58 - SY-1740-A

* *

TABLE V

, 7-Alcoxydithio-9a-niethoxyinitosanes ff ο CH2OCNH2 a or RSS ^ ° rsh + 20 -> XL / Λ ^ τ> μη B CH3

Ex. Thiol Mode Product No. (RSH) opera tory

O

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22 3-mercapto-l, 2- A R = CH2CH (0H) CH20H

propanediol 23 3-mercapto acid BR = -CH2CH2COO “Ha + propionic 24 cysteine BR = -CH2CH (NH3 +) COO“ 25 thiophenol A r _ ^ 26 p-nitrobenzenethiol AR = - ^ 27 p-methoxybenzene- AR ~ ^ V-ÖCH ^ thiol \ - / 28 p-aminobenzenethiol AR = -CD. YM. F - 59 - SY-1740- Â to * COO ~ Na + 29 acid 2-mercapto- B R = —y 'y benzoic. \ - / 30 acid 2-nitro-4- B R s y-NOj

mercaptobenzoic acid \ IT ~ J

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32 4-mercaptonethyl-l- A R = I

methylimidazole ^ ___ * CH3 R = NH, I ^ - + NHC0CH_CH_CHC00 Na I 2 2

33 glutathione £ -CH ^ CH

C0NHCH2C00_Na + 34 dimethylamino- B R = -CH, CH_N (CH,), ethanethiol. ^ ^! h \

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Claims (39)

1.- Compound of formula II or III: 0 CH2OCNH2 R3-Alk.-SS-Alk-KK / ^^ A jf] T 0 O I = ¾0 ^ R -SS-Alk, -Û ___ \ There /! “3 111 U’-R1 2, - Compound according to claim 1, wherein Alk2 represents an ethylene radical and R1 represents a hydrogen atom. 3.- Compound according to claim 2 of formula II, where Alkj represents an ethylene radical and r3 represents an acetylamino radical. 3 T \ J * where Alki represents an alkylene radical in a straight or branched chain of 1 to 6 carbon atoms when R 3 is joined to it by a carbon atom of the latter and from 2 to 6 carbon atoms when R "3 is united by a sulfur, oxygen or nitrogen atom of the latter, and R3 and -SS- are, in this case, united to different carbon atoms, Alk2 represents an alkylene radical in a straight or branched chain of 2 to 6 carbon atoms optionally carrying a substituent A, where the sulfur and oxygen atoms linked to it and any optional substituent A which is linked to it by oxygen, sulfur or nitrogen are united to carbon atoms i /; - CD.YM.F - 6S - SY-1740-A Ιτ * different from Alk2, where the substituent A is chosen from one or two radicals (C.1-6) -alkyl, (Cl-6) -alkanoyl, ( Cl-6) -alkoxy, halo, (Cl-6) -alkoxycarbonyl, · cyano, (C.1-6) -âlcoylamino, (Cl-6) -dialcoylamino, (Cl-6) -alkanoylamino and (Cl-6 ) -alkoxycarbonyle, Alkj and Alk2 may contain a double bond, R1 represents a hydrogen atom or lower alkyl, lower alkanoyl, benzoyl or substituted benzoyl radical whose substituent is a lower alkoxy, halo, amino or nitro radical, R3 represents a halo radical, carboxyl, ^ alkanoyloxy of 1 to 7 carbon atoms, hydroxyl of which 11 oxygen atom is united to Alk ^ having 3 to 6 carbon atoms, alkylamino or dialkoylamino of 1 to 12 carbon atoms, N-alkoxyalkoylamino of 2 with 7 carbon atoms, alkanoylamino of 1. with 7 carbon atoms, benzoylamino or B-substituted benzoylamino, naphthoylamino or B-substituted naphthoylamino, phenylamino or phenyl-amino B-substituted, c B-substituted ycloalkyl or cycloalkyl each of 3 to 8 ring-cycled »B-substituted cyclo-alkenyl or cycloalkenyl each of 5 to 8-membered ring, B-substituted phenyl or phenyl, B-substituted naphthyl or naphthyl, a heterocyclic radical chosen from heteroaromatic and heteroalicyclic radicals with 1 or 2 cycles of 3 to 8 members in each cycle and of 1 or 2 heteroatoms chosen between oxygen, nitrogen and sulfur in each cycle, pyridylamino or thiazolylamino, alkoxy or alkylthio each from 1 to 6 carbon atoms, alkoxy-carbonyl or alkyllaminocarbonyl each of 2 to 7 carbon atoms, aminocarbonyl, phenoxycarbonyl or B-substituted phenoxycarbonyl, phenoxy or phenoxy B-substituted, naphthoxy or naphthoxy B-substituted, alkoxycar- ——— CD.YM.P - 7Π - CV-1 7ΛΠ-1 Il bonylamino of 2 to 6 carbon atoms, ureido (-NHCONH2) »N-alkylurylene (-NHCONHalkyl) of 2 to 7 carbon atoms, N3-haloalkylylene of 3 â 7 carbon atoms, N ^ -haloalkoyl-N ^ -nitrosouréyle ne s .. from 3 to 7 carbon atoms, dialkoylaminocarbonyl from 3 to 13 carbon atoms, dialkoylaminoalkoxy of 4 to 13 carbon atoms, alkanoylaminoalkoxy of 3 to 7 carbon atoms and hydroxyalcoylami.no or N, N-dihydroxyalkylamino each 2 to 8 carbon atoms, where the substituent B is chosen from one or two lower alkyl, lower alkanoyl, lower alkoxy, halo, amino, carboxyl, hydroxyl and nitro radicals, and R4 represents an alkyl radical of 1 to 12 atoms carbon, alkenyl or alkynyl each of 3 to 12 carbon atoms, cycloalkyl or cycloalkyl B-substituted each of 3 to 8 ring members, cyclo-alkenyl or cycloalkenyl B-substituted each of 5 to 8 ring members, phenyl or phenyl B -substituted, naphthyl or B-substituted naphthyl, a heterocyclic radical chosen from heteroaromatic and heteroalicyclic radicals with 1 or * 2 cycles of 3 to 8 members in each cycle and of 1 or 2 heteroatoms chosen between oxygen, nitrogen and sulfur in each cycle, with the restriction that the heterocyclic radical is linked by a carbon atom which is joined to at least one other. carbon atom, where the substituent B is chosen from one or two lower alkyl, lower alkanoyl, lower alkoxy, halo, amino, carboxyl, hydroxyl and nitro radicals, and r4 and the adjacent sulfur atom jointly constitute an S-cysteinyl radical , which S-cysteinyl radical can be esterified, salified or combined in a non-toxic and non-allergenic peptide, or a non-toxic pharmaceutically acceptable salt of „fin.VM P _ -71 _ CV_1 1Λ Ice compound. 4.- Compound according to claim 2 of formula II, where Alk ^ represents an ethylene radical and r3 represents an acetyloxy radical. 5- Compound according to claim 2 of formula II, where Alkj represents a methylene radical and represents a 1,2-dihydroxyethyl radical. 6, - Compound according to claim 2 of * formula II, where Alk ^ represents an ethylene radical and r3 represents a carboxyl radical, or a non-toxic pharmaceutically acceptable salt of this compound. 7, - Compound according to claim 2 of formula II, where Alk ^ represents a methylene radical and R3 represents a 1-carboxyaminomethyl radical, or a non-toxic pharmaceutically acceptable salt of this compound. "/ 8.- A compound according to claim 2 of formula II, where Alkl represents a methylene radical and represents an l-methylimidazol-2-yl radical. 9.- Compound according to claim 2 of formula II, where Alk ^ represents an ethylene radical and R3 represents a dimethylamino radical. 10 - A compound according to claim 2 of formula III, wherein R ^ represents a phenyl radical. 11.- A compound according to claim 2 of formula III, wherein R ^ represents a 4-nitrophenyl radical. 12.- Compound according to claim 2 of formula III, where R ^ represents a radical 4- ~ CD.YM.F - 72 - SY-1740-A <► methoxyphenyl. t, 13. A compound according to claim 2 of formula III, wherein R4 represents a 4-aminophenyl radical. 14. A compound according to claim 2 of formula III, wherein R4 represents a 2-carboxyphenyl radical, or a non-toxic pharmaceutically acceptable salt of this compound. 15. A compound according to claim 2 of formula III, wherein R4 represents a 4-nitro-3-carboxyphenyl radical, or a non-toxic pharmaceutically acceptable salt of this compound. 16. A compound according to claim 2 of formula III, wherein R4 represents a 4-pyridyl radical. 17. A compound according to claim 2, of formula: nü2 0 ho2cchch2ch2conh O ch2ocnh2 CHCH-SSCH ^ CH ^ O J ho2cch2nhco | J “> λτ O5" ·. B or a non-toxic pharmaceutically acceptable salt of this compound. 18. Compound according to claim 1 of formula Ib: - / ^ f :) CD.YM.F - 73 - SY-1740-A 4 * N02 Û VL A ÇH ° Lh \ = / j il / -! 3 CH3 ' j ^ -R1 where R1 and Alk2 are as defined in claim 1. 19. A compound according to claim 2 of formula: flO- fi / - (2 0 CH2OCNH2 \ ss1CH2CH2ä °% / ^ Ssvy ^ \ v> DCH. XVII seen N j j 20. A method for inhibiting the growth of a tumor in a mammal, characterized in that it comprises a systemic administration of a compound of formula I, in a substantially non-toxic effective anti-tumor dose, to a mammal carrying a tumor. 21. Pharmaceutical composition, characterized in that it comprises a compound according to claim 1 in combination with a solvent, diluent, adjuvant or pharmaceutically acceptable excipient. 22. Process for the preparation of a compound according to claim 1, characterized in that it comprises the reaction of at least one equivalent of a CD.YM.F - 74 - SY-1740-Ά * * triazene of formula V or VI: (ÿ. Ar-N = N-NH-Alk2-SS-Alki-R3 Ar-N = N-NH-Alk2 ~ SS-R4 V VI with an equivalent of a mitosan of formula IV: 0 O 11 ~ CH2OCNH2 H hiT ^ VC3 IV CH3 J> -Rl where R1, R3, R4, Alki and Alk2 are as defined in claim 1 and Ar represents the organic residue of a diazotizable aromatic amine, under reaction conditions in an inert organic solvent at a temperature of about 0 to 60 ° C until an appreciable amount of the product of formula II or III is obtained. 23. The process as claimed in claim 22, characterized in that the triazene of formula VI is 1-Γ2- (3-nitro-2-pyridyldithio) ethyl J / 3- (4-methyl-lyle-nyl) triazene. 24, - Process for the preparation of a compound according to claim 1, characterized in that it comprises the reaction of at least one equivalent of a thiol of formula: R3AlkiSH or R4SH with an equivalent of a mitosan of formula Ib : / 1 CD.YM.F - 75 - SY-1740-À · s NO, η ^ ί / -0 ^ j ΓΚ: "νγ ^ î> -r1 where R1, r3 # r4 # Alki and Alk2 are such that defined in claim 1 and optionally in the presence of at least one equivalent of a base in an inert solvent at a temperature of from about to 60 ° C until an appreciable amount of the product of formula II is obtained or III. "25.- A method according to claim 24, characterized in that Alk2 represents an ethylene radical and Rl represents a hydrogen atom. 26. The method of claim 24 or 25, characterized in that a base equivalent is used for the reaction. -, 27. The method of claim 24 or 25, characterized in that a lower alkanol, a lower alkyl ester of lower alkanoic acid, a lower aliphatic ketone, a cyclic aliphatic ether or a polyhalogenated lower aliphatic hydrocarbon is used as the reaction medium. with up to 8 carbon atoms or water. 28. Process for the preparation of a compound of formula IX:; / J CD - YM * F - 76 - QV-1 7ΛΠ-Ζ. Iw + * P ο ch2ocnh2 I IX N J ^ î-R5 0 where R5 represents a hydrogen atom or radical (C.l-6) -alkyl, and! R6 represents a radical (C.1-12) -alkyl ^ or (C.1-12) -alkyl substituted, (C.3-12) -cycloalkyl or (C.3-12) -cycloalkyl substituted whose atom of carbon -r which is linked to the oxygen atom in position 7 of the mitosan carries 1 or 2 hydrogen atoms and the substituents are chosen from the halo, (Cl-6) -alkoxy radicals, (C.1- 6) -alkanoyl, (C.6-14) -aroyl, cyano, * trihalomethyl, amino, (Cl-6) -monoalcoylamino, (C.2-12) -dialcoylamino, (C.6-12) —aryl, (C.6-12) - ^ ryloxy, {Cl-6) -alkanoyloxy, (C.7-14) -aroyloxy, heterocyclo with 1 or 2 rings and from 5 to 12 ring atoms comprising up to 4 selected heteroatoms between nitrogen, oxygen and sulfur, and where each of these alkoxy, alkanoyl, aroyl, aryl, aryloxy, alkanoyloxy, aroyl-oxy and heterocyclo radicals optionally carries 1 or 2 sübsti- • killers chosen from halo radicals, (Cl-6) -alkoxy, (C.1-6) -alkanoyl, cyano, trihalomethyl, - amino, (Cl-6) -alkoylamino and (C.2-12) -dialcoylamino,? characterized in that it comprises the reaction of a mitosan of formula X s CD.YM.P - 77 - RV-l 7ΔΠ-1 i Ο II * Ο CH2OCNH2 OCH, ΧΪΧ ^ 5 with a triazene of formula XI: Ar -N = N-NH-R6 XI where r5 and r6 are as defined above and Ar * represents the organic residue of a diazotizable aromatic amine. "29. Process according to claim 28, characterized in that the triazene of formula XI is 3-methyl-1- (4-methylphenyl) triazene. 30. Method according to claim 27 or 28, characterized in that at least two molecular proportions of the ·· * triazene are used, relative to the mitosan of formula X. 31. - Process according to claim 27 or 28, characterized in that an inert organic liquid which * is a solvent for the mitosan of formula X is used as the reaction medium. 32. Process according to claim 27 or 28, characterized in that a lower alkanol, a lower alkyl ester of lower alkanoic acid, a lower dialkyl ether, a polyhalogenated lower aliphatic hydrocarbon or an aliphatic ether is used as the reaction medium. cyclic with up to 8 carbon atoms. 33. Process according to claim 27 or / CD.YM.F - 78 - RY-17 / Ln-A 4 ·% * 28, characterized in that methylene chloride, methanol, l diethyl ether, ethyl acetate or a mixture of two or more of them. 34. Process according to claim 27 or 28, characterized in that the reaction temperature is from 0 to 60 ° C. 35. Process according to claim 27 or 28, characterized in that the reaction temperature is from 0 to 25 ° C. 36. A compound according to claim 28, wherein r6 represents a 2- (benzylthio) ethyl radical and represents a hydrogen atom. 37. A compound according to claim 28, wherein ^ represents a 2- (2-pyridyl) ethyl radical and represents a hydrogen atom. 38. A compound according to claim 28, in which R® represents a 2- (4-morpholinyl) ethyl radical and R ^ represents a hydrogen atom. 39.- Compound according to claim 28, in which R6 represents a methyl (1,3-dioxolane-2-yl) radical and R5 represents a hydrogen atom. , '\ I i; V V V. \ h - & ’j CD.YM.P - 79 - SY-1740-A