EP0427762A1 - Substituted phenylacetonitriles used to overcome resistance to drugs in oncolytic therapy - Google Patents

Abstract

Use of substituted phenylacetonitriles having the formula (I) to prevent resistance to cancer-causing drugs.

Description

 Substituted phenylacetonitriles for use as resistance breakers in oncolybic therapy.

The present invention relates to the use of substituted phenylacetonitri len for the breakdown of resistance to cancerostatica.

Resistance to chemotherapy drugs, especially multiple resistance, has repeatedly proven to be a major medical problem. Proven drugs can become completely useless and there is often no satisfactory alternative available. The ways of developing resistance are still largely unclear.

The observation that verapamil resistance in cancer cells

(JP-US 83 624/1983) is able to break, has therefore quickly led to clinical applications in oncology. Here the well-known proved

Cardiovascular efficacy of the verapamil as a practical one

Applicability hindering side effect. The required high doses require use under special clinical conditions (intensive care unit) or prevent it at all. If, instead of the racemic verapamil, its cardially weaker (+) - antipodes are used, such cautery is not required or is not required to this extent

(EP-OS 268 100). It has now been found that certain substituted phenylacetonitriles can be used well to break the resistance of cancerostatics.

The invention relates to the use of such racemic and optically active substituted Phenylacetonitri len of formula I.

wherein

R ¹ , R ² , R ^{3 are} hydrogen atoms, halogen atoms, C ₁ - ₄ alkyl groups,

C _1-4 alkoxy, trifluoromethyl or two

neighboring substituents R ¹ and R ₂ or R ³ together form the

Radicals -CH ₂ -CH ₂ -CH ₂ -CH ₂ - or -CH = CH-CH = CH-, R ⁴ represents a saturated or unsaturated alkyl or cycloalkyl group having up to 15 carbon atoms or a phenyl group, R ⁵ is a hydrogen or a C _1-4 alkyl group, m and n

 each represent the numbers 2, 3 or 4 and

R ^{6 is} a saturated or unsaturated alkyl radical with up to

 20 carbon atoms, a cyclohexyl radical or the group

means where R ⁷ , R ⁸ and R ^{9 are the} same or different and

Hydrogen atoms, halogen atoms, C ₁ -C ₄ alkyl groups, C ₁ - ₄ alkoxy groups, trifluoromethyl groups or two adjacent substituents R ⁷ and R ⁸ or R ⁹ together form the radicals -CH ₂ -CH ₂ -CH ₂ -CH ₂ or -CH = CH-CH = CH- mean that in the in Advances in Myocardiology Vol. 4 (1983) on page 506

have an ECso value above 10 ^-7 M, with the exception of (±) -, (+) - and (-) - norverapamil, (±) - and (+) - verapamil, (+) -Gallopamil, (+) - Devapamil and (+) - Emopamil and their salts with physiologically tolerated acids, for the manufacture of medicines for the breakdown of resistance to cancerostatics.

As a compound of formula I, this has proven particularly effective

1,7-bis (3-methoxyphenyl) -3-methylaza-7-cyan-10,14-dimethylpentadecadiene of the formula

proven.

As cancerostatica, whose resistances are broken, come

in particular: a) antibiotics such as actinomycin D, doxorubicin (adriamycin), daunorubicin, mithramycin, pepleomycin, mitomycin C and bleomycin as well as other substances with an interchatory effect, such as amonafide and mitonafide, b) Alkaloids such as Vtncristin, Vinblastin, Vindesin, Etoposid and

 Teniposide, c) alkylating substances, such as cyclophosphamide, thiotepa,

 Melphalan, nitrosoureas and cisplatin, and d) antimetabolites such as methotrexate, 5-fluorouracil and its analogues,

 as well as 6-mercaptopurine, 6-thioguanine and cytarabine. If desired, the abovementioned substances can be present in the form of their salts with physiological acids or bases. The following are preferably considered as physiologically acceptable acids: hydrochloric acid,

Sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, sal icylic acid, maleic acid, fumaric acid, succinic acid, ascorbic acid, malic acid, methanesulfonic acid, lactic acid, gluconic acid, glucuronic acid, amidosulphonic acid, benzoic acid, tartaric acid.

Particularly suitable as physiologically acceptable bases are ammonia, alkali metal hydroxides - in particular sodium, potassium and lithium, alkaline earth metal hydroxides - especially calcium and magnesium, and organic bases such as lower alkylamines - e.g. Methylamine or ethylamine, cyclohexylamine, substituted lower alkylamines - e.g. Diethanolamine, triethanolamine, tris (hyroxymethyl) aminomethane -, piperidine or

Morphole in.

The compounds of formula I can be administered together with or separately from the anticancer drugs. However, separate, previous application is preferred. The compounds I are usually oral

administered while the cancerostatics (= active ingredients) are given orally or parenterally (e.g. i.V., i.p.).

The ratio of compound I to active ingredient depends on the disease to be treated, the patient's condition and the one used

Active ingredient. As a rule, the ratio is approximately 1: 1 to 500: 1.

The compounds I are generally used in an amount of 200 to 2000 mg per patient and day with oral administration and 200 to 500 mg with intravenous or intraperitoneal administration per patient and day. The active substances are applied in the amount which is also intended for the sole administration of these substances and which e.g. from the "Rote

List 1988 "or the scientific brochures mentioned therein. The substances can be in the form of tablets, capsules or dragees for oral administration or as a solution for injection for parenteral (IV, IP, IM) application. Solutions can also be infused. The application forms are produced in a known manner by customary methods.

The calcium antagonistic activity test described in Advances in Myocardiology, Vol. 4 (1983) on page 506 is carried out as follows: On K ⁺ -polarized aortic spiral strips (20 mm long, 2 mm wide) from Sprague-Dawley rats (250-300 g body weight under ether anesthesia), two experimental contractions were induced with calcium. The preload was 1 g; relaxation was achieved in about 1 hour in 37 ° C warm Tyrode solution, through which a mixture of 95% O ₂ and 5% CO ₂ (pH 7.3-7.4) bubbled. The strips were rinsed three times for 5 minutes in Ca-free, Tyrode solution containing 0.2 mM NaEDTA. The Ca-free strips were washed with Tyrode solution in which 100 mM Na + had been replaced by K ⁺ .

depolarized. After 10 min, a first contraction with 0.5 mM Ca ^{2+ was} generated. 15 minutes later, the strips were washed for 10 minutes with Ca-free, Tyrode solution containing 0.2 mM NaEDTA and again depolarized.

Drugs were added 15 minutes before the second test contraction generated with calcium (0.05 mM). The tension became isometric

recorded. The percent inhibition of calcium contraction in

The presence of different drug concentrations was evaluated. Linear regressions were made from the linear part of the

 Concentration-effect curve calculated. The relative efficacies were estimated from the distance between these linear regression lines.

Manufacturing examples

1. 500 mg (±) -5- [N-methyl-N- (n-octyl)] amino-2- (3,4,5-trimethoxyphenyl) -2-isopropylvalerontril hydrochloride were dissolved in 250 ml of physiological saline dissolved, sterilized and under sterile conditions for the purpose of combined use with vincristine sulfate in one

 Infusiohs bottle filled.

2. 10 ampoules, each with 1.5 mg mithramycin "Pfizer" (cf. Rote Liste 1985, No. 85 038) and a blister pack with 20 oblong tablets with (±) -5- [N-methyl-N- (2-cyclohexylethyl )] amino-2- (3,4,5-trimethoxyphenyl) -2-isopropyl-valeronitrile hydrochloride were packed together in a box for joint application. The Oblonggt tablets were produced in the usual way and contained 250 mg of the above-mentioned active ingredient, 120 mg lactose, 60 mg cellulose, 3 mg magnesium stearate, 50 mg corn starch and 15 mg polyvinylpyrrolidone per tablet.

Claims

Claims

1. Use of such racemic and optically active substituted phenylacetonitriles of the formula I.

 wherein

R ¹ , R ² , R ^{3 are the} same or different and are hydrogen atoms,

Halogen atoms, C _1-4 alkyl groups, C ₁ -4 alkoxy, trifluoromethyl or two adjacent substituents

R ¹ and R ² or R ³ together represent the radicals -CH ₂ -CH ₂ -CH ₂ -CH ₂ - or -CH = CH-CH = CH-,

R ^{4 is} a saturated or unsaturated alkyl or

 Cycloalkyl group with up to 15 carbon atoms or one

Represents phenyl group,

R ⁵ is a hydrogen or a C _1-4 alkyl group, each of m and n the numbers 2, 3 or 4 and

R ^{6 is} a saturated or unsaturated alkyl radical having up to 20 carbon atoms, a cyclohexyl radical or the group

means where R ⁷ , R ⁸ and R ^{9 are the} same or different and

Hydrogen atoms, halogen atoms, C ₁ -C ₄ -alkyl groups, C ₁ - ₄ alkoxy groups, trifluoromethyl groups or two adjacent substituents R ⁷ and R ⁸ or R ⁹ together form the radicals -CH ₂ -CH ₂ -CH ₂ -CH ₂ or -CH = CH-CH = CH- mean which in the test for calcium antagonistic activity described in Advances in Myocardiology Vol. 4 (1983) on page 506 have an EC ₅₀ value of more than 10 ^-7 M, and also their salts with physiologically tolerable acids with the exception of (±) -, (+) - and (-) - norverapamil, (±) - and (+) - verapamil, (+) - gallopamil, (+) - devapamil and (+) - emopamil for the manufacture of medicinal products to reduce resistance to cancerostats.

2. Use of the compounds of formula I according to claim 1 for the breakdown of resistance to cancerostatica.