DE1803892A1 - New naphthacene derivatives and their preparation - Google Patents

Description

Dr. R. Koenigsberg « ^RHlbau

hy

PalenlanwöHe

2, Bräuhausstralje

SC 3204

RHONE-POULENC S.A., Paris / France New Naphthacene Derivatives and Their Manufacture The present invention relates to new naphthacene derivatives

the general formula:

(D

rf-

UfU Λ1

HDn UJ

OH

-0-

9822/1343

as well as their salts and their quaternary * ammonium derivatives, the Preparation of these compounds and the pharmaceutical compositions, which they quaternary in the form of bases »acids Contain ammonium derivatives or salts.

Xn in the above formula 1 denotes R ₁ and Rg, which can be the same or different from one another, oxygen atoms or radicals of the formula

Ji-N

and R represents a radical of the formula

N-N

^H 5

represents, where R ^ is a hydrogen atom or an alkyl-j alkanoyl- *, ThioalkanoyX-, aryl-, aroyl-, carbamoyl-, thiooarbamöyl- or Represents amidino radical, these radicals optionally substituted may be, and Rc represents a hydrogen atom or together with% forms a piperazine ring whose second nitrogen atom is optionally substituted Alkyl radical is substituted.

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BATH ORIGINAL

^i: iiii! ^{l ;: in :::::} ■ 1 !!! "Hi ': - ¹ "' -. ¹ "■ ^{: ι} '■" ¹ ^ "; *

The substituents represented by the radicals R ^ and Re are preferably substituents with acidic or basic Character that are able to improve the solubility of the products of general formula I. As preferred groups one can especially consider the quaternary aomonium groups and name the sulfonic acid groups or the best of amino acids and peptides.

According to the invention, the new naphthacene derivatives general formula Z by reacting a product of the all common formula

R ₁

(II)

with a naphthacene derivative of the formula

(III)

- CH - Cl OH

ί -

909822/1343

according to the usual methods for converting ketones into their functional derivatives are produced.

It is preferable to work in an inert organic Solvent, such as an alcohol (e.g. ethanol) or DJUnethylformamide, with gentle heating of the reaction medium.

The Naphthaoenderlvat used as the starting substance Formula III is the one with grief 13 037 H.P. designated Antibiotic that has been given the name Dauno ruble in. Its manufacture and its physicochemical properties are in Belgian patent 6j52 591 (Examples 6 and 7) described «In earlier publications it was referred to as" Rubidomycin ".

The new products produced according to the invention can optionally in addition salts with acids or with nitrogenous ones Bases, are converted into metal salts or into quaternary ammonium derivatives.

The salts can be obtained by reacting the new compounds with acids or bases in suitable solvents will. The organic solvents used are, for example, alcohols, ethers, ketones or chlorinated solutions

909822/1343

¹¹¹¹¹¹ ■: «■■ '- ■■■ * Ε | ϊ || PSIB

middle. The salt formed precipitates, if necessary after diluting its solution, and is filtered or removed Separated decanting.

The quaternary ammonium derivatives can be converted into durob of the new compounds with esters, optionally in one organic solvent, at ordinary temperature or can be obtained more quickly by gentle heating.

The new naphthacene derivatives of the general formula I, as well as their salts and quaternary ammonium derivatives interesting anti-tumor properties and exhibit a low toxicity.

They have proven to be particularly effective against L 1210 leukemia proven in mice (intraperitoneal administration) « The experiments were carried out on 1 month old mice weighing 18 to 20 g; those by the intraperitoneal route were inoculated with ICK cells from leukemia L 1210 and at doses between 0.5 and 5 mg / kg i.p. were treated.

For therapeutic use, the novel naphthacene derivatives according to the invention can be used either in free form or in the form of pharmaceutically usable, i.e. non-toxic salts and quaternary ammonium derivatives in brewing doses.

909822/1343

Ala examples of pharmaceutically usable salts can nest the salts of inorganic acids (such as the hydrochloride * sulfates, nitrates, phosphates) or of organic acids (such as the acetates, propionates, sucoinates, bensoates, fumarates, malelnates, tartrates, theophylllnacetates, S & lioyl & te * Phenolphth & li- * nate, methylen-hifi-e-oxynaphtoate) ₀ Metallsala © (such as the Nfttriurasalse) or salts with nitrogenous bases. .

As examples of pharmaceutically usable Ammonium derivatives can be the derivatives of inorganic ones or organic esters «such as the chlorine broat or Jodtne thy late, -äthyiate, -ally late or -benzylate, the ethyl or ethyl sulfates, the benxoisulfonates or substitution derivatives of these compounds.

The medicinal compositions containing at least one product of the formula Z in the wild or in the form of salts or quaternSren Ai & BioniuiDderivaten in pure form or in

The presence of a diluting agent or a coating agent is a further subject of the invention represents. In human therapy, the Mengan portion of effective Product in these drugs depending on what you want therapeutic effects vary. With intravenous

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BATH ORIGINAL

Administration is the use dose in general between 2 and 10 mg Ag d · day HIr an adult.

The following examples explain the invention without restricting it.

example 1

Add 0.5 g of daunorubicin hydrochloride in a mixture of 20 cnr dimethylformamide and 10 cnr water. One sets 0.42 g of sodium 2-aminocarbamoyl ethanesulfonate. One stirs 24 hours at room temperature. It is concentrated to dryness under reduced pressure (25 mm Hg). You take that residue obtained in 100 cnr water.

A small amount of insoluble material is removed by filtration and the filtrate is then lyophilized. This gives 0.875 g of the sodium salt of 4-methoxy-5- (or 12-) oxo-6,9, -11-trihydroxy ^ -Eß ^ ö-O-trideoxy-J-araino-L-lyxohexosyl- (1) 3 -9- [1- (3-sulfopropionylhydrazono) -äthylJ-12- (or 5-) (3-sulfopropionylhydrazono) -5 »7 * & # 9 $ 10,12-hexahydronaphtha ^ oen in a yield of 95 %

909822/134

S: 7.47 $> (Theoriet 7.36) ι Ν: 7.7 % (Theories 8.03 %)

Ultraviolet spectrum ^ m _8x »233 nm $ €» 29 200

N ^nra »^ * 20 920

Nnax · ² ^ ¹¹ ^ i C »6 100

Example 2

Add 0.6 g of Daunorubieln hydrochloride to 65 ears of ethyl alcohol; a content of 2.5 % acetic acid and uses 0.369 β Girardß reagent T asu. The mixture is heated under tubes at 40 ° C. for four hours. Dan concentrated to dryness under reduced pressure (25 B «na Hg). The residue obtained in 50 is taken cm 'water.

A small amount of insoluble material is removed by filtration and the filtrate is then lyophilized. Man this gives 0.855 g of 4-methoxy-5- (or 12-) oxo-6,9,11-trihydroxy-7-C2,3 # 6-0-trideoxy-3-amino-L-lyxohexosyl- (1)] - 9- (1-trimethylammonioaeetylhydrazono-ethyl) -12- (or 5-) trimethylaynmonioacetylhydrazono-5,7,8,9,10,12-hexahydronaphthaoene dichloride hydrochloride

Cl: 12.07 # (theory: 12.32 ^)

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ültravlolett spectrum ^ max * ² 33 ^ ³¹ * ^ε * 3 & ²⁰ °

- 252 «mi £ 27,500 ■ 290 nmj £ «7 720

Example 3

Maii dissolves 0.5 β daunorublcine hydrochloride lh 8θ cnr ethyl alcohol with a content of 2.5 % acetic acid. 0.084 g thiosemicarbazide is added and the mixture is heated at 40 ° C. for four hours while stirring. The mixture is then stirred for 72 hours at the tin temperature. It is concentrated to dryness under reduced pressure (25 mm Hg), and the dry residue is taken up in 80 cw water. A small mixture of insoluble material is filtered off and the filtrate is then lyophilized.

This gives 0.483 g of 4-methoxy-5,12-dioxo * 6,9,11-trii · hydroxy-7- [2 $ , 6-0-1rideoxy-3-amiho-L-lyxQhexosy1- (1) 3- 9r (1-thlosemicarbazono-ethyl) -5.7 * 8,9,10,12-hexahydronaphthacene hydrochloride.

M ί 8.85 % (theory: 8.79 ^) i St 5.0% (theory j Ultraviolet spectrum max «232 nra; £ «32 250

^X max -257 nmj t - 32 225

909822/1343

Example 4

Dissolve 0.6 g · daunorubicin hydroehlorid lö% ö enr ethyl alcohol with a content of 2.5% acetic acid ", separately, a solution of O _y 1ffT g aminoguanidine in 1.09 cm 1n" hydrochloric acid forth. The two solutions and heated k hours mixing at 50 ⁰ C. The mixture is left for 72 hours at ordinary temperature anaohliesseiKä stand and then concentrated under reduced pressure (25 mm Hg) to dryness. It is taken up in 60 cirr water, a small amount of insoluble material is filtered off and the piltrate is lyophilized.

This gives 0.64 g ^ -

hydroxy-7- [2,3,6-0-trideoxy-3 »an3ino-L-lyxohexosyl- (

thacene dihydrochloride.

N * 10.73 % (theory % 10.66 %)

Ultraviolet spectrum ^x _m ax - 223 ™ a% ^ »45 500

^X max - 253 nmi £. 27 820 Nnax - 291 mn; £ - 8 515

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BAD ORiQINAL

18038S2

Example 5

0.4 g of daunorubicin hydrochloride is dissolved in 60 carbons of ethyl alcohol with a content of 2.5 % acetic acid, and 0.135 g of thiosemioarbazide is then added. The mixture obtained is heated at 45 ° C. for 12 hours with stirring. It is concentrated to dryness under reduced pressure and the residue is taken up in 50 ml of water. The solution obtained is lyophilized.

This gives 0.476 g of 4-methoxy-5- (or 12-) oxo-6,9,11-trihydroxy-7- [2,5,6-0-trideoxy-5-an'ino-L-lyxohexosyl- ( 1)] -9- (1-thiosemicarbazono-Sthyl) -12- (or 5-) thiosemicarbazone -5 »7,8,9,10,12-hexahydr.onaphthacene-hydrochloride in a yield of 89 5 ^ -

Cl: 4.97 % (theory: £ 4.99); S: 8.90 % (theory: 9 * 02 %)

Ultraviolet spectrum: \, ax - 233 nm; € »42,000

^X max - 257 nmj € «31 800

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Example 6 A solution of the following composition is prepared Product of Example 5 2.1 g

distilled water 100 ear

This solution is sterilized by filtering it through a bacteriostatic filter and then dispensed into ampoules in an amount of 10 cm per ampoule. The ampoules are then subjected to lyophilization in a nitrogen atmosphere and then locked.

To use the medicament by the parenteral route one injectable solution through to the tent of the brewery Add 5 oar physiological serum to the contents of the ampoule.

This gives 5 cnr of a solution containing 200 mg of active product.

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BATH ORIGINAL

Claims (1)

Claims 1. New naphthacene derivatives of the general form ice H-CH ₂ -CH-CH-1 OH ! H-CH ₁ in which R ₁ and R ₂ , which can be the same or different from one another «. Oxygen atoms or radicals of the formula N -N. Ri and R, a radical of the formula N - 909822/1343 daretelit, where R ^ denotes a hydrogen atom or an alkyl, alkanoyl, thioalkanoyl, aryl, aroyl, carbonyl, carbamoyl or amidino radical, these radicals may optionally be substituted, and H "© represents in hydrogen atom or Rj ₁ , a Piperazlnrlng "whose second nitrogen atom is substituted by an optionally substituted alkyl radical", as well as their Balze and quaternary ammonium derivatives " 2 process for the manufacture of the products according to claim 1, characterized in that a compound of the general formula B ₅ with a haphthaene derivative of the formula 909822/134 3 BATH ORIGINAL ^: 180389Ö OH 0 - CH ..- CSL - CH - CH - CH - CE ? ¹ NH ₂ OH implements and. optionally the products obtained in salt or quaternary ammonium derivatives. 3. Pharmaceutical compositions «characterized by a content of at least one of the products according to claim as an active ingredient. 90 9822/1343