DE4037693A1 - 13-DEOXO-4'-DEOXY-4'-JODANTHRACYCLINE - Google Patents

Description

The present invention relates to anthracyclines Process for their preparation, pharmaceutical Compositions containing them and their use in the treatment of human malignancy.

The present invention relates to anthracycline glycosides, which have the general formula I.

wherein R₁ is a hydrogen atom or a hydroxy group, and their pharmaceutically acceptable acid addition salts. A suitable salt is the hydrochloride salt. The invention thus provides 13-deoxodaunorubicin and doxorubicin analogs which have an iodine atom in the C-4 'position of the sugar residue. In particular, the present invention relates to the following anthracyclines:
Ia: 13-deoxo-4′-deoxy-4′-iododunorubicin (R₁ = H)
Ib: 13-deoxo-4'-deoxy-4'-iododoxorubicin (R₁ = OH).

The methods according to the invention are carried out using a Process prepared, which comprises:

• (i) protecting the 3'-amino group of 4'-deoxy-4'-iodo-daunorubicin, 4'-deoxy-4'-iodo-doxorubicin or an acid addition salt thereof, thereby forming a protected amino derivative of the formula (III ') becomes: where X represents an amino protecting group;
• (ii) reacting the protected amino derivative of formula (III ') with a benzenesulfonylhydrazine which has an electron attractive group on the aromatic ring to form a hydrazone of formula (IV'):
• (iii) reducing the hydrazone of formula (IV ') to form the 13-deoxo derivative of formula (V'):
• (iv) removing the amino protecting group from the 13-Deoxoderivat of formula (V '), where a Anthracycline glycoside of the formula (I) is formed, and
• (v) if desired, converting the Anthracycline glycosides of the formula (I) in one pharmaceutically acceptable acid addition salt thereof.

The intermediates of formula (II '), (IV') and (V ′) and their manufacture are also part of the present invention.

The raw materials for the production of the new Anthracycline glycosides are 4'-deoxy-4'-iododunorbuicin (IIa, R₁ = H) and 4'-deoxy-4'-iododoxorubicin (IIb, R₁ = OH). Both are described in US-A-44 38 105. These Compounds can be in the form of their pharmaceutical suitable acid addition salts, for example as Hydrochloride can be used.

The 13-deoxo derivatives Ia, b are prepared by a similar procedure to that described by T. H. Smith et al  (see: J. Med. Chem., 21, 178 (1978)) for the preparation of the 13 deoxodrivate of daunorubicin and doxorubicin is used. However, we have with that present method found that when using a Benzenesulfonylhydrazine, which is an electron attractive Group on the aromatic ring carries, such as p-fluorine or p-nitrobenzenesulfonylhydrazine, the reduction of 13-hydrazone derivative, IVa, b in 30 minutes instead of 6 Hours as described by T. H. Smith et al for the reduction of 13-tosylhydrazone of daunorubicin or doxorubicin described.

In order to produce 13-deoxo derivatives 1a, b, the Starting 4'-iodoanthracyclins IIa, b first, for example protected as N-trifluoroacetamido IIIa, b. In the X is therefore preferred in the present invention -COCF₃. The protected amino derivative is then in the corresponding hydrazone like 13- (p-fluorobenzenesulfonyl) hydrazone IVa, b or 13- (p-Nitrobenzenesulfonyl) hydrazone converted. The Benzenesulfonylhydrazine, which is an electron-withdrawing Group on the benzene ring is protected with the Amino derivative brought to reaction. For example, in one embodiment with the protected amino derivative an excess of p-fluorobenzenesulfonylhydrazine in Methanol and in the presence of a catalytic amount of p-Toluenesulfonic acid at temperature for 6 days Reaction.

The resulting hydrazone, such as that p-fluorobenzenesulfonyl hydrazones IVa, b can be obtained using Crystallization can be recovered. Usually then treated it with a cyanoborohydride. The Hydrazone can therefore be used with an equimolar amount of  alkaline cyanoborohydride salt such as sodium cyanoborohydride and be treated by 10-camphorsulfonic acid. This will effected by refluxing methanol for 40 minutes is cooked, with 13-deoxo-4'-deoxy-iodine-N-trifluoroacetyl derivatives Va, b are obtained from which after aqueous alkaline treatment the compounds Ia and Ib can be obtained. These connections can then be in the form their pharmaceutically acceptable salts are isolated. A Hydrochloride salt can be treated with methanolic Hydrogen chloride can be obtained.

In a preferred embodiment of the current Process is 4'-deoxy-4'-iodine or or 4'-deoxy-4'-iododoxorubicin hydrochloride, dissolved in not aqueous methylene chloride, at a temperature of 0 ° C, for one hour with trifluoroacetic anhydride Reaction brought, the N-trifluoroacetyl derivative is obtained in methanolic solution Room temperature for 3 days with an excess of p-fluorobenzenesulfonyl hydrazine using p-Toluenesulfonic acid reacted as a catalyst becomes; the 13-p-fluorobenzenesulfonylhydrazine thus obtained is 30 with sodium cyanoborohydride and 10-camphorsulfonic acid Treated in methanol at reflux for minutes to obtain the relevant 13-deoxo derivative, the after mild alkaline hydrolysis with 0.1 N Sodium hydroxide at 0 ° C to the N-trifluoroacetyl protective group to remove the desired glycoside of formula I results from treatment with methanolic chloride is isolated as the hydrochloride.

The following reaction scheme illustrates the present Method:  

Reaction scheme

The invention provides pharmaceutical compositions which is an anthracycline glycoside of the formula I or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluents or carriers include, available.

Usual carriers and diluents can be used will. The composition can be in a conventional manner be formulated and administered.

The compounds according to the invention are used in processes for Treatment of the human or animal body suitable with therapy. They are used as an anti-tumor agent suitable. A therapeutically effective amount will be given Administered to patients. It can be administered a lot enough to stop the tumor from growing inhibit. The tumor can be a colon or adenocarcinoma Gross leukemia tumor.

The following examples illustrate the invention.

Example 1 Preparation of 13-deoxo-4′-deoxy-4′-iododunorubicin (Ia)

4'-Deoxy-4'-iododunorubicin (IIa, 0.67 g, 1 mmol), was in the form of its hydrochloride salt by treatment for 1 hour with trifluoroautanhydride (2 ml) in non-aqueous methylene chloride (100 ml) at 0 ° C using Standard procedures (see: F. Arcamone et al., Chim. Ind. (Milan) 51, 834, (1969)) were quantitatively converted into the corresponding N-trifluoroacetyl derivative IIIa. TLC on silica gel plate F₂₅₄ (Merck) solvent system methylene chloride / acetone (95: 5 by volume) R _f = 0.68; FDMS m / z 732 (M) ⁺.

Compound IIIa (0.7 g, 0.1 mmol) was dissolved in methanol (200 ml), p-fluorobenzenesulfonylhydrazine (0.7 g, 3.6 mmol) and a catalytic amount of p-toluenesulfonic acid were added and the reaction mixture was left in the dark at room temperature for 3 days. The solvent was then removed under reduced pressure and after crystallization from ether / hexane 1/1, 13- (p-fluorobenzenesulfonyl) hydrazone-4'-deoxy-4'-iodo-N-trifluoroacetyldaunorubicin (IVa, 0.82 g, yield : 90%). TLC on silica gel plate F ₂₅₄ (Merck), solvent system methylene chloride / acetone (95: 5 by volume) R _f = 0.35; FDMS m / z 920 (M) ⁺.

Compound IVa was dissolved in methanol (60 ml) under a Dissolved nitrogen stream, sodium cyanoborohydride (0.7 g) and 10-camphorsulfonic acid (0.7 g) was added and the The reaction mixture was refluxed for 30 minutes cooked. Then the reaction mixture was poured into water-ice, that contains sodium bicarbonate, there have been some Stirred for minutes and extracted with methylene chloride. The organic phase was separated off with water washed, dried over anhydrous sodium sulfate and filtered off.

The solvent was removed under reduced pressure and the remainder was chromatographed on silica gel using a methylene chloride / acetone mixture (95: 5 by volume) as the elution system, with 13-deoxo-4'-deoxy-4'-iodine-N -trifluoroacetyldaunorubicin (Va, 0.4 g, yield 55%) was obtained. TLC on silica gel plate F₂₅₄ (Merck) solvent system methylene chloride / acetone (95: 5 by volume) R _f = 0.82 FDMS m / z 718 (M) ⁺.

Mildly alkaline treatment of the N-trifluoroacetyl derivative Va with aqueous 0.1 N sodium hydroxide at 0 ° C. gave, after standard work-up at pH 7.5 and methylene chloride extraction, 13-deoxo-4'-deoxy-4'-iodine dunorubicin (Ia 0.35 g ), which was converted into its hydrochloride salt by treatment with methanolic hydrogen chloride. TLC on silica gel plate F₂₅₄ (Merck) solvent system methylene chloride / methanol / acetic acid / water (30: 4: 1: 0.5 by volume):
R _f = 0.56; FDMS m / z 622 [M] ⁺.
¹HNMR (400 MHz, CDCl₃) δ:
13.99 (s, 1H, 6- OH ); 13.39 (s, 1H, 11- OH ); 8.05 (d, J = 7.6 Hz, 1H, 1- H ); 7.79 (dd, J = 7.6, 8.5 Hz, 1H, 2-H); 7:40 (d, J = 8.5 Hz, 1H, 3- H); 5.47 (d, J = 3.8 Hz, 1H, 1'- H ); 5.26 (m, 1H, 7- H ); 4.49 (m, 1H, 4'- H ); 4.10 (s, 3H, O CH ₃); 3.51 (q, J = 6.OHz, 1H, 5'- H ); 3.26 (d, J = 18.8 Hz, 1H, 10- H eq); 2.58 (d, J = 18.8 Hz, 1H, 10- H ax); 2.37 (m, 1H, 8- H eq); 2.17 (m, 1H, 3'- H ); 1.9-1.6 (m, 5H, CH ₂CH₃, 2'- CH ₂, 8- H ax); 1.34 (d, J = 6.0Hz, 3H, CH ₃CH); 1.08 (t, J = 7.3 Hz, 3H, CH ₃CH₂).

Example 2 Production of 13-deoxo-4′-deoxy-4′-iododoxorubicin (IIb)

4'-Deoxy-4'-iododoxorubicin (IIb, 0.5 g, 0.72 mmol) was first in the form of its hydrochloride salt in the corresponding N-trifluoroacetyl derivative IIIb (TLC on silica gel plate F₂₅₄ (Merck), solvent system: methylene chloride / acetone ( 8: 2 based on volume) R _f = 0.30; FDMS m / z 748 (M) ⁺ and then converted to 13- (p-fluorobenzenesulfonyl) hydrazone-4'-deoxy-4'-iodine-N-trifluoroacetyldoxorubicin ( IVb, 0.54 g, yield 80%), using the procedure described in Example 1. TLC on silica gel plate F₂₅₄ (Merck) solvent system: methylene chloride / acetone (8: 2 by volume) R _f = 0.12, FDMS m / z 936 (M) ⁺.

The hydrazone derivative IVb (0.54 g, 0.57 mmol) was, after treatment with sodium cyanoborohydride (0.5 g) and 10-camphorsulfonic acid (0.5 g) in methanol (100 ml) as described in Example 1, in the corresponding 13-Deoxo-4'-deoxy-4'-iodo-N-trifluoroacetyl derivative (Vb, 0.21 g, yield 50%) reduced. TLC on silica gel plate F₂₅₄ (Merck), solvent system:
Methylene chloride / acetone (8: 2 by volume)
R _f = 0.36; FDMS m / z 734 [M] ⁺¹HNMR (400 MHz, CDCl₃) δ: 14.01 (s, 1H, 6- OH ); 13.36 (s, 1H, 11- OH ); 8:07 (d, J = 7.7 Hz, 1H, 1H); 7.81 (d, J = 7.7, 8.4 Hz, 1H, 2-H); 7:41 (d, J = 8.4 Hz, 1H, 3- H); 6.29 (d, J = 8.4 Hz, 1H, NH COCF₃); 5.52 (d, J = 3.8 Hz, 1H, 1'- H ); 5.26 (m, 1H, 7- H ); 4.62 (m, 1H, 4'- H ); 4.10 (s, 3H, O CH ₃); 4.1-3.9 (m, 2H, CH ₂OH); 3.7-3.5 (m, 1H, 3'- H ); 3.53 (q, J = 18.9 Hz, 1H, 10- H eq); 3:09 (m, 1H, CH₂O H); 2.62 (m, 1H, 8- H eq); 2.35 [m, 1H, 14- CH (H)]; 2.04 [M, 2H, 14- CH (H) and 2'- CH (H)]; 1.9-1.8 [m, 2H, 8- H ax and 2'- CH (H)]; 1.34 (d, J = 6.OHz, 3H, 5'- CH ₃CH).

By mildly alkaline treatment of the N-trifluoroacetyl derivative Vb with aqueous 0.1 N sodium hydroxide at 0 ° C. and subsequent standard work-up with methylene chloride extraction at pH 7.5, 13-deoxo-4′-deoxy-4′-iododoxorubicin (IIb, 0.15 g ) obtained, which was converted into its hydrochloride salt by treatment with methanolic hydrogen chloride, TLC on silica gel plate F₂₅₄ (Merck), solvent system;
Methylene chloride / methanol / acetic acid / water (30: 4: 1: 0.5 by volume) R _f = 0.44; FDMS m / z 638 (M) ⁺.

Claims (12)

1. Anthracycline glycoside of the formula I in which R₁ is a hydrogen atom or a hydroxy group; and its pharmaceutically acceptable acid addition salts. 2. Connection according to claim 1, the 13-deoxo-4'-deoxy-4'-iodine dunorubicin or its Is hydrochloride. 3. Connection according to claim 1, the 13-deoxo-4'-deoxy-4'-iododoxorubicin or its Is hydrochloride. 4. A process for the preparation of an anthracycline glycoside of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, the process comprising:

• (i) protecting the 3'-amino group of the 4'-deoxy-4'-iodo-daunorubicin, the 4'-deoxy-4'-iodo-doxorubicin or an acid addition salt thereof, a protected amino derivative of the formula (III ') is formed: where X represents an amino protecting group;
• (ii) reacting the protected amino derivative of formula (III ') with a benzenesulfonylhydrazine which has an electron attractive group on the aromatic ring to form a hydrazone of formula (IV'):
• (iii) reducing the hydrazone of formula (IV ') to form the 13-deoxo derivative of formula (V'):
• (iv) removing the amino protecting group from the 13-deoxy derivative of formula (V ') to form an anthracycline glycoside of formula (I), and
• (v) if desired, converting the anthracycline glycoside of formula (I) into a pharmaceutically acceptable acid addition salt thereof.

5. The method according to claim 4, where X is COCF₃. 6. The method according to claim 4 or 5, the benzenesulfonyl hydrazine being p-fluorine or is p-nitrobenzenesulfonyl hydrazine. 7. The method according to any one of claims 4 to 6, wherein in step (iii) the hydrazone of formula (IV ') with Cyanoborohydride is treated. 8. The method according to any one of claims 4 to 7, where 4-Doey-4′-iododunorubicin or 4'-deoxy-4'-iododoxorubicin hydrochloride dissolved in anhydrous methylene chloride at a temperature of  0 ° C for one hour with trifluoroacetic anhydride is reacted, the N-trifluoroacetyl derivative is obtained, which in methanolic solution for 3 days at room temperature with an excess of p-fluorobenzenesulfonyl hydrazine using p-toluenesulfonic acid as Catalyst is reacted; and being that 13-p-fluorobenzenesulfonylhydrazone thus obtained with Sodium cyanoborohydride and 10-camphorsulfonic acid Reflux temperature in methanol for 30 minutes is treated, the relevant 13-deoxy derivative is obtained after mild alkaline hydrolysis using 0.1 N sodium hydroxide at 0 ° C to get the N-trifluoroacetyl protecting group to remove that desired glycoside of formula I results in that Treatment with methanolic hydrogen chloride as Hydrochloride is isolated. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or Diluent and as an active ingredient Anthracycline glycoside of the formula I as in claim 1 defined, or a pharmaceutically acceptable Acid addition salt thereof. 10. Anthracycline glycoside of the formula I as claimed defined, or a pharmaceutically acceptable Acid addition salt thereof for use as Antitumor agent. 11. Compound of formula (III '), (IV') or (V ') as in Claim 4 defined.   12. Process for the preparation of an anthracycline glycoside of formula I as defined in claim 1, or one pharmaceutically suitable acid addition salt thereof, the process being essentially as described above in Examples 1 or 2.