SK279136B6 - Hydrazones, pharmaceutical compositions containing the same and their use for the preparation of medicament - Google Patents

Abstract

Compounds of the formula I are described, wherein A represents a direct bond or -CH2- group, X represents -C(=Y)-NR6R7 formula residual, formula of NH group, Z represents formula of NH group, R1 represents a hydrogen atom, or one or two substituents taken from alkyl group with 1 to 7 carbon atoms, hydro group or alkyl group with 1 to 7 carbon atoms, R2 represents a hydrogen atom or alkyl group with 1 to 7 carbon atoms, R3, R4 and R6 residuals represent hydrogen and R5 and R7 independently of one another represent a hydrogen atom or hydroxy group, tautomers or pharmaceutically acceptable salts thereof, having rare pharmaceutical properties and being particularly active against tumours.

Description

The invention relates to hydrazones of formula (I), to pharmaceutical compositions containing them and to their use for the preparation of a medicament for their preparation.

BACKGROUND OF THE INVENTION

In European patent application EP 0 163 888, in US patent no. No. 4,076,726 and in J. Ind. Chem. Soc. 37, 443-450 (1960) disclose certain compounds which are clearly distinct from the compounds of the present invention (at least in each case the X moiety contained in the compounds of the present invention is absent). These known compounds are also not described as agents for inhibiting the enzyme S-adenozymethionine decarboxylase.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula (I):

where

A is a direct bond or -CH2-, X is a radical of formula -C (= Y) -NR6r7, wherein Y is NH, Z is NH,

R 1 represents a hydrogen atom or one or two substituents selected from the group consisting of alkyl of 1 to 7 carbon atoms, hydroxy and alkoxy of 1 to 7 carbon atoms,

R 2 represents a hydrogen atom or a C 1 -C 7 alkyl group, the radicals r 3, R ⁴ and r 6 represent hydrogen and

R 8 and R 7 independently of one another represent a hydrogen atom or a hydroxy group, their tautomers or pharmaceutically acceptable salts.

The compounds of the present invention also find use in the therapeutic treatment of human or animal bodies in addition to the aforementioned characteristic uses.

For example, tautomers may occur where Z is NR 1 and R 3 and / or R ⁴ and / or R 3 are hydrogen: the corresponding guanyl radical in formula (I) is -N (r 3) -C (= Z) - NR ⁴ r 5 _and may also be in tautomeric forms -N = C (ZH) -NR ⁴ r 5, -N (R 3) -C - (- ZH) = NR 5 or -N (R 3) -C - (- ZH) = NR4. Another example: Y represents NH and R 7 and / or R 7 represents hydrogen, the corresponding amidine structure in formula (I) may be defined as X = -C (= Y) -NR 6 R 7, where tautomeric forms -C (-) may also exist YH) = NR 7 or -C (-YH) = NR 6. Such and similar tautomeric forms will be apparent to those skilled in the art. All of these tautomers are within the scope of the compounds of formula (I).

When A is - (CH 2) _n - and R 2 is not hydrogen, the corresponding R 2 substituent or substituents may also be attached to - (CH ₂ ) n R 1 is, for example, hydrogen or one or two substituents other than hydrogen.

General terms have the following meanings:

Lower alkyl having 1 to 7 carbon atoms is, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and especially methyl.

The alkyl group in the alkoxy group has any of the meanings given above.

The salts of the compounds of the invention are primarily pharmaceutically acceptable, non-toxic salts. For example, compounds of formula (I) with basic groups may form acid addition salts with, for example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfo acids, such as acetic acid, fumaric acid or methanesulfonic acid, or, for example, amino acids such as arginine or lysine. If more than one basic group is present, mono- or polysalts may be formed. Compounds of formula I with one acidic group, for example a carboxylic acid group and one basic group, for example an amino group, may for example be in the form of inner salts, i.e. in the form of an amphoteric ion, or it is possible salts of normal.

Pharmaceutically unsuitable salts such as picrate or perchlorate may also utilize isolation and purification. Only pharmaceutically usable, non-toxic salts are suitable for therapeutic use and are therefore preferred.

The compounds of the invention may be in the form of mixtures of isomers or as pure isomers. For example, when R2 represents a substituent other than hydrogen, the compounds of formula (I) may exist as racemates or pure enantiomers.

The compounds of the invention have valuable, particularly pharmacologically useful properties. In particular, the inhibition of the enzyme S-adenosylmethionine decarboxylase (SAMDC) is particularly potent. SAMDC has an important role as a key enzyme in polyamine synthesis that occurs in virtually all mammalian cells, including humans. The concentration of polyamine in the cell is controlled by SAMDC. Suppression of the SAMDC enzyme results in a decrease in the polyamine concentration. Reducing the concentration of polyamine will suppress cell growth and thus can be suppressed by treatment with SAMDC suppressing substances, both the growth of eukaryotic and prokaryotic cells and even kill or suppress cell differentiation.

For example, inhibition of the SAMDC enzyme can be detected by the method of H. G. Wiliams-Ashmann and A-Schenone, Biochem. Biophys. Res. Communs. 46, 288 (1972). The compounds of the invention have an IC? Value of at least about 0.005 μΜ.

Further, there is evidence of the biological effect (A) of the compounds of the invention relative to a prior art comparative compound (methylglyoxal-bisguanylhydrazone), and in addition the compounds of the invention (B) are classified for their toxicity.

(A) inhibition of the enzyme S-adenosylmethionine decarboxylase (SAMDC) can be demonstrated by a method which

SK 279136-6 was described by Williams-Ashman and Schenone in Biochem. Biophys. Res. Commun. 46, 288 (1972). An IC50 value is determined as a measured value by measuring various concentrations of the suppressant, in which the activity of the enzyme S-adenosylmethionine decarboxylase is reduced to half that determined in the control assay without the suppressant. The comparative compound is methylglyoxal-bisguanylhydrazone (MGBG), a compound representative of the prior art. The stated values are given in tabular form below.

Table compound

IC ₅₀ <μΜ) for suppression

SAMDC

Reference substance

MGBG *

0.0047

0,022

0,087

0.65 (compound of formula

* see B.L. Freedlandcr and F.A. Frcnch, Cancer Res. 18, 360-363.

The compounds of the invention appear to outweigh the SAMDC suppression value of the comparative compound (methylglyoxalbisguanylhydrazone), which also has a significantly different structure from the compounds of the invention.

The compounds tested hitherto have a slight to moderate toxicity in animal studies. This evaluation was also confirmed on cell cultures.

A further advantage of the compounds of the invention is that they inhibit diaminoxidase and are well tolerated only to a small extent compared to their strong SAMDC depressant action. The diaminooxidase suppression is according to J. Jaenne and D.R. Morris, Biochem. J. 218, 974 (1984), since it may lead to accumulation of putrescine and indirectly to activation of SAMDC.

Therefore, the compounds of formula (I) are, for example, useful against the treatment of malignant and benign tumors. They can cause tumor regression and further prevent tumor cell proliferation and micrometastasis growth. They can furthermore serve, for example, for the treatment of protozoa infections such as Trypanosomiasis, malaria or Pneumocystis carinii-induced inflammation.

As selective agents acting to inhibit SAMDC, the compounds of formula (1) may be used alone or also in combination with other pharmacologically active substances. Combinations of, for example, a) with inhibitors of other polyamine biosynthase enzymes, for example ornithine carboxylase inhibiting agents, b) with protein kinase inhibitors c, c) tyrosine protein kinase inhibitors, d) cytokines, e) negative growth regulators, f) anti-oestrogens, aromatase inhibitors or (h) classical cytostatic active substances.

Preferably, the invention relates to compounds of formula (I) wherein A represents a direct bond, X represents a residue

-C (= NH) -NH 2, Z is NH, R * is hydrogen or one or two substituents selected from the group consisting of alkyl of 1 to 7 carbon atoms, hydroxy and alkoxy of 1 to 7 carbon atoms , the radicals R @ ² , R @ 1 and R @ 4 represent a hydrogen atom and R @ 1 represents a hydrogen atom or a hydroxy group, their tautomers or pharmaceutically acceptable salts.

Particularly preferred compounds of formula (I) are:

1. 4-Amidino-1-indanone-2'-amidinohydrazone;

2. 4-Amidino-1-indanone-2 '- (N-hydroxyamidino) hydrazone;

3. 5-Amidino-1-tetralone-2'-amidinohydrazone.

The present invention also relates to pharmaceutical compositions comprising as active ingredient a pharmacologically active compound of formula (I). Especially preferred are preparations for enteral, especially oral, as well as parenteral administration. The formulations comprise the active ingredient alone or preferably together with a pharmaceutically acceptable carrier material. The dosage of the active ingredient depends on the disease to be treated as well as on the individual, its age, weight and individual condition and the mode of administration.

The pharmaceutical preparations contain about 0.1% to about 95% of the active ingredient, with the individual dosage forms preferably comprising from about 1% to about 90% and non-unit dosage forms of from about 0.1% to about 20% of the active ingredient. Unit dosage forms such as dragees, tablets or capsules contain from about 1 mg to about 500 mg of the active ingredient.

The pharmaceutical compositions of the present invention may be prepared by known methods, for example by conventional mixing, granulating, dragee, dissolution or lyophilization methods. Thus, a pharmaceutical formulation for oral use can be obtained in which the active ingredient is combined with one or more solid carriers, the mixture obtained can optionally be granulated and the mixture or granulate, if necessary, optionally with the addition of excipients, processed into tablets or dragee cores.

Suitable carriers are, in particular, fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or dibasic phosphate, further binding agents such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl cellulose, , sodium carboxymethylcellulose and / or polyvinylpyrrolidone and / or disintegrating agents such as starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or salts thereof such as sodium alginate, if necessary.

The auxiliaries added are primarily flow control agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and / or polyethylene glycol or derivatives thereof.

Dragee cores may be coated with suitable or gastric juice-resistant coatings using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may be added to the tablets or dragee-coated tablets, for example to identify or distinguish different effective doses.

Orally administrable pharmaceutical preparations are also gelatin insertion capsules as well as soft, sealed gelatin capsules and plasticizers such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers such as corn starch, binders and / or glidants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients such as fatty oils, paraffinic oil or liquid polyethylene glycols, and optionally a stabilizer may be added.

For example, other oral dosage forms are syrups prepared in conventional manner which contain the active ingredient, for example, in suspended form and at a concentration of from about 0.1% to 10%, preferably about 1%, or a similar concentration which provides, for example, 5 or 10 ml. dose. Powder or liquid concentrates are also suitable. Such concentrates may be packaged in a unit dosage amount.

Suitable rectally usable pharmaceutical preparations are, for example, suppositories which consist of the active ingredient and the suppository base. Suitable bases for suppositories are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycol or alkanols.

For parenteral administration, aqueous solutions of the active compounds in water-soluble form, for example water-soluble salts, or aqueous injectable suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers, are suitable in the first place. The active ingredient, optionally together with an adjuvant, may also be in the form of a lyophilisate and is made into a solution by the addition of a suitable solvent prior to parenteral administration.

Solutions which are used, for example, for parenteral administration can also be administered as infusion solutions.

The invention also relates to a method of treating said disease states. The compounds of the present invention may be used prophylactically or therapeutically, and are preferably used in the form of pharmaceutical preparations. At a weight of about 70 kg, a daily dose of from about 1 mg to about 1000 mg, preferably from about 25 to 100 mg orally or 2 to 50 mg of the parenteral compound of the present invention is used.

DETAILED DESCRIPTION OF THE INVENTION

Capsules containing 0.25 g of an active ingredient, for example one of the compounds according to the invention, can be prepared as follows:

Ingredients (for 5000 capsules) active ingredient 1250 g talc180 g wheat starch120 g magnesium stearate80 g lactose20 g

The pulverulent substances are passed through a sieve with a mesh size

50.00 g 2535.00 g 125.00 g 150.00 g

40.00 g quantum satis

0.6 mm and mixed. The 0.33 g aliquots of the mixture are filled into a gelatin capsule using a capsule filling machine.

10,000 tablets are prepared, each containing 5 mg of the active ingredient, for example one of the compounds produced in Examples 1 to 22:

Ingredients active ingredient milk sugar corn starch polyethylene glycol 6000 magnesium stearate purified water

process:

All powder components are sieved through a sieve with a mesh size of 0.6 mm. The active ingredient, milk sugar, magnesium stearate and half of the starch are then mixed in a blender. A further half of the starch is suspended in 65 ml of water and the resulting suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The paste formed is added to the powder mixture and granulated with optional additional water. The granulate is dried at 35 ° C overnight, sieved through a 1.2 mm sieve and compressed into tablets that are scored.

Claims (7)

PATENT CLAIMS Compounds of general formula (I) wherein: A represents a direct bond or a -CH 2 - group, X is a radical of formula -C (= Y) -NR6r ^, wherein Y is NH, Z is NH, R 1 represents a hydrogen atom or one or two substituents selected from the group consisting of alkyl of 1 to 7 carbon atoms, hydroxy and alkoxy of 1 to 7 carbon atoms, R 2 represents a hydrogen atom or a C 1 -C 7 alkyl group, the radicals r 3, r 4 and R 6 represent hydrogen and R $ and R? independently represent a hydrogen atom or a hydroxy group, a tautomer thereof, or a pharmaceutically acceptable salt thereof. Compounds of formula (I) according to claim 1, wherein A represents a direct bond, X represents a radical -C (= NH) -NH 2, Z represents a group of the formula NH, R ¹ represents a hydrogen atom or one or two substituents selected from the group; R @ 1, R @ 2, R @ 3 and R @ 5 are hydrogen and R @ 5 is hydrogen or hydroxy, tautomers or pharmaceutically acceptable salts thereof. The 4-amidino-1-indanone-2'-amidinohydrazone of claim 1, or a pharmaceutically acceptable salt thereof. The 4-amidino-1-indanone-2 '- (N-hydroxyamidino) hydrazone of claim 1, or a pharmaceutically acceptable salt thereof. The 5-amidino-1-tetralone-2'-amidinohydrazone of claim 1, or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of diseases which depend on the inhibition of the enzyme S-adenosylmethionine decarboxylase.