The invention relates to a pharmaceutical combination, which has reduced side effects.

More particularly, the pharmaceutical combination of the invention consists of a first pharma- ceutical composition containing a beta-receptor blocker as active ingredient, and a second pharma- ceutical composition containing a hydroximic-acid derivative as active ingredient.

Beta-receptor blockers or beta-receptor antagonists are widely used active pharmaceutical in gredients primarily for the treatment of hypertension, heart failure and certain cardiac arrhythmias. [Frishman, W.H.: beta-Adrenergic blockers: a 50-year hystorical perspective, Am. J. Ther., 15(6), 565-76 (2008)]. These active ingredients act on beta-adrenergic receptors, preventing the adrenaline and noradrenaline from binding to the receptors. The use of beta-receptor blockers is limited by their certain unwanted effects, including their cardiovascular side effects or exacerbation of asthma. Car diovascular side effects may include bradycardia, hypotension, heart failure, cardiac arrest, dizziness, muscle weakness and fatigue due to decreased blood circulation. Peripheral vasoconstrictor effect may also occur.

It is an object of the present invention to modify the activity of beta-receptor blockers, to induce new pharmacological effects, and to reduce side effects and thereby improve their therapeutic use.

It has now been found that this object is achieved by a pharmaceutical preparation of the invention comprising a first pharmaceutical preparation comprising a beta-blocker as an active ingre dient and a second pharmaceutical preparation containing as an active ingredient a hydroximic-acid derivative of the general formula I

I

or a pharmaceutically acceptable acid addition salt thereof.

In general formula I

a) Ar is pyridyl,

A is a valence bond,

X is -NH ₂ ,

R is a group of the general formula

OH

— O— CH ₂ — CH— CH2— Ri wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom, or b) Ar is pyridyl-,

A is a valence bond,

X is -halogen,

R is a group of the general formula

wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom, or its N- oxide, or

c) Ar is pyridyl,

A is a valence bond,

X is a group of the general formula

Y

-NH— O— CH2— CH— CH ₂ — Ri wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom,

R taken together with Y form a valence bond between the nitrogen atom adjacent to R and the carbon atom adjacent to Y to form a six-membered oxadiazine ring, or

d) Ar is phenyl,

A is -CH = CH-, and

di) X is a group of the general formula

OH

-NH— CH ₂ — CH— CH ₂ — Ri

wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom.

R is a hydroxyl group, or

d ₂ ) X is a group of the general formula

wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom, Y’ taken together with R form a valence bond between the oxygen adjacent to Y’ and the nitrogen adjacent to R to form a five-membered l,2,4-oxadiazoline ring. The first pharmaceutical composition comprising a beta-receptor blocker used as an ingredient in the pharmaceutical combination of the present invention comprises, for example, one of the fol- lowing:

acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bucindolol, butoxamine, carteolol, carvedilol, celiprolol, cyanopindolol, esmolol, labetalol, landiolol, levobunolol, methipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, or, if chemically possible, a pharmaceutically acceptable acid addition salt or a metal salt of the active ingredients listed. Preferably, the metoprolol is used in the form of its tartrate or succinate.

A preferred beta-receptor blocking agent is the bisoprolol.

The active ingredient of the pharmaceutical composition used as another component of the pharmaceutical combination according to the invention is a hydroximic-acid derivative of general formula I or a pharmaceutically acceptable acid addition salt thereof.

When Ar is pyridyl, it is 2-, 3- or 4-pyridyl.

In the general formula I, a 5- to 7-membered saturated heterocyclic group containing one ni- trogen atom, formulated in Ri is defined as pyrrolidyl, piperidyl or hexamethyleneimino. Preferably, the pyrrolidyl, piperidyl or hexamethyleneimino group is attached via its nitrogen atom to the carbon atom adjacent to Ri.

The N-oxide of the compound of general formula I as defined in (b) above is understood to mean the N-oxide formed on the nitrogen atom of the pyridyl group according to the meaning of Ar, and / or the N-oxide, which is formed on the nitrogen atom present in the 5-7 membered saturated heterocyclic group according to the meaning of Ri.

Pharmaceutically acceptable acid addition salt is an acid addition salt formed with a pharma- ceutically acceptable inorganic or organic acid, such as hydrochloride, acetate, fumarate, maleate, etc.

The compounds of general formula I contain a C = N double bond structural part and therefore may exist both in form of Z and E geometric isomers. Compounds of general formula I, wherein in the formula A is a group of formula -CH=CH-, may have additional geometric isomers too. Corn- pounds of general formula I generally have a chiral centre as well, so that their optically active iso- mers R and S are also possible. In the description and the claims, any compound of general formula I is understood to include their geometric and/or optical isomers as well and an optional mixture of isomers.

A preferred subgroup (a) of the compounds of general formula I are those wherein Ar, A, X and R are as defined in (a) above. A particularly preferred compound in this subgroup is the 0-(3- piperidino-2-hydroxy-l-propyl)-nicotinic acid amidoxime (abbreviated as BGP-15), which is expe- diently used in the form of its dihydrochloride of formula II:

A preferred subgroup (a) of the compounds of general formula I are those wherein Ar, A, X and R are as defined in (b) above. A particularly preferred compound in this subgroup is the N-[2- hydroxy-3-(l -piperidinyl)propoxy]pyridine-3-carboximidoyl chloride (bimoclomol) III or one of its N-oxides, N-[2-hydroxy-3-(l-piperidinyl)-propoxy]-pyridine-l-oxide-3-c arboximidoyl chloride (arimoclomol) of formula IV

and a pharmaceutically acceptable acid addition salt of the compound of general formula III or IV.

A preferred subgroup (c) of the compounds of general formula I are those wherein Ar, A, X and R are as defined in (c) above. A particularly preferred compound in this subgroup is 5-(piperidin- l-ylmethyl)-3-(pyridin-3-yl)-5,6-dihydro-2H-l,2,4-oxadiazine (iroxanadine)

or a pharmaceutically acceptable acid addition salt thereof.

A preferred subgroup (d) of the compounds of general formula I are those wherein Ar, A, X and R are as defined in (d) above. A particularly preferred compound in this subgroup is the N-[3- (hexamethyleneimino)-2-hydroxypropyl]-cinnamic acid amidoxime of the formula (VI), (di) above (abbreviated as NG-094).

or a pharmaceutically acceptable acid addition salt thereof,

and the 3-styryl-4-[3-(hexamethyleneimino)-2-hydroxypropyl]-A ² -l,2,4-oxadiazolin-5-one of for mula VII (d ₂ ) above (abbreviated as NG-50)

VII

or a pharmaceutically acceptable acid addition salt thereof.

The hydroximic-acid derivatives of formula I are known compounds.

The amidoxime derivatives of formula I wherein Ar, A, X, and R are as defined in (a) above, may be prepared by the process described in U.S. Patent No. 4,187,220.

The hydroximic-acid derivatives of formula I according to (a) above generally have PARP inhibitory activity. Among them, many of the pharmacological effects of BGP-15 of formula II are known.

From the aforementioned U.S. Pat. No. 5,123,121, the use of the BGP-15 for the treatment of diabetic angiopathy is known.

U.S. Patent No. 6,306,878 relates to a method for protecting the mitochondrial genome and / or mitochondria from damage leading to myopathies and neurodegenerative diseases by administer ing an effective, non-toxic dose of a hydroximic-acid derivative, such as BGP-15, to a patient sus ceptible to such damage.

U.S. Pat. No. 6,458,37lrelates to a formulation containing as active ingredient 0.1-30% of a hydroximic-acid derivative, such as BGP-15 and a carrier, which is capable of reducing the occur rence of light damage caused by UV-B radiation.

U.S. Patent No. 6,884,424 relates to a method for inhibiting actinic keratosis by applying a hydroximic-acid derivative, such as BGP-15, to the affected skin.

U.S. Patent No. 6,451,851 relates to a method for treating a patient suffering from a viral infection by treating the patient with a therapeutically effective amount of a known antiviral agent and a hydroximic-acid derivative such as BGP-15.

U.S. Patent No. 6,440,998 relates to a pharmaceutical composition having a reduced side ef- fect having an antitumor effect comprising cisplatin or carboplatin and a hydroximic-acid derivative such as BGP-15. U.S. Patent No. 6,656,955 relates to a pharmaceutical composition having a reduced side effect having an anticancer effect comprising paclitaxel or docetaxel and a hydroximic-acid de- rivative such as BGP-15. U.S. Patent No. 6,720,337 relates to a pharmaceutical composition having WO 2020/044067 . . . . . , . PCT/HU2019/000033 a reduced side effect having an anti cancer effect comprising oxaliplatm and a hyaroximic-ac deriv ative such as BGP-15. U.S. Patent No. 6,838,469 relates to a pharmaceutical composition having a reduced side effect having an antitumor effect, comprising pyrimidine derivatives and BGP-15.

PCT Patent Application published under No. WO 00/07580 discloses experimental data on the antidiabetic effect of BGP-15 in the treatment of type 1 diabetes.

PCT Application published under No. WO 03/007951 relates to a pharmaceutical combination of hydroximic-acid derivatives such as BGP-1 and an antidiabetic or antihyperlipidemic agent for the prevention or treatment of pre-diabetes, metabolic X-syndrome or diabetes, and disorders associ ated with these conditions, such as endogenous metabolic disorders, insulin resistance, dyslipidae- mia, baldness, diffuse effluvium, and / or female endocrine disorders based on androgen overweight.

PCT Application published under No. WO 2005/122678 relates to the use of BGP-15 in a pharmaceutical composition having prokinetic activity (i.e., inducing activity in the stomach and in testines).

PCT Application published under No. WO 2005/123049 relates to the use of BGP-15 for mi tochondrial genesis, that is, to increase the number of mitochondria present in cells, resulting in a robotizing effect.

PCT Application published under No. WO 2006/079910 relates to the use of BGP-15 in the treatment of oral cavity lesions, particularly in periodontal disease.

European Patent No. 2,089,031 discloses that BGP-15 can be used to reduce overweight or obesity.

European Patent No. 2,089,032 discloses that BGP-15 reduces the side effects of known anti- psychotics, antidepressants and antiepileptics leading to overweight or obesity.

PCT Patent Application published under No. WO 2009/074835 discloses that BGP-15 can be used to reduce adverse psychiatric side effects of cannabinoid CBi receptor antagonists, such as ri- monabant.

PCT Patent Application published under No. WO 2013/024311 discloses that BGP-15 may be used for the prevention and / or treatment of muscle atrophy.

PCT Patent Application published under No. WO 2013/024312 discloses that BGP-15 can be used to improve the tissue regeneration effect of adult stem cells, to promote the survival, adhesion, and regulation of adult stem cells.

The bimoclomol of formula III according to (b) above is described in International Patent Application published under No. WO 90/04584. According to the description the bimoclomol appli cable in the treatment of diabetic angiopathy can be prepared by reacting 3-pyridyl aldoxime with 3- piperidino-2-hydroxy-l-chloropropane, then by the chlorination of the obtained 0-(3-piperidino-2- hydroxy-l -propyl) with thionyl chloride.

International Patent Application published under No. WO 97/16439 discloses that the expres- sion or activity of molecular chaperones is enhanced by the use of various compounds, including bimoclomol. Based on the mechanism of action described, the compound may be used in the treat- ment of pathological conditions related to cell membranes or cellular organelles such as diabetes mellitus, diseases associated with mitochondrial damage, diseases of toxic origin, cardiovascular, vascular, allergic diseases, immune and autoimmune diseases, viral infections, bacterial infections, tumorous diseases, skin diseases, diseases caused by physiological stress.

International Patent Application published under No. WO 00/50403 discloses arimoclomol of formula IV, its stereoisomers and its use in the treatment of insulin resistance and related pathological conditions. The industrially applicable preparation of the latter compound and its stereoisomers is described in International Patent Application Publication No. WO 01/79174.

International Patent Application published under No. WO 2005/041965 discloses the use of arimoclomol or its optical isomers in the treatment of neurodegenerative diseases. The anteriority does not include comparative test data to compare the pharmacological activity of the optically active enantiomers with that of the racemic compound.

International Patent Application published under No. WO 2008/137149 discloses that bimoclomol and arimoclomol promote wound healing in diabetic patients.

International Patent Application published under No. WO 2008/070010 discloses that bimo- clomol and arimoclomol can be used to treat stroke.

International Patent Application published under No. WO 2009/155936 discloses that bimo- clomol and arimoclomol can be used to increase the intracellular concentration and / or activity of Hsp 70 in a lysosomal storage disease, such as for the treatment of Niemann-Pick disease, Gaucher disease, Farber disease, Rrabbe disease, Fabbre disease, or sialidosis.

International Patent Application published under No. WO 2013/045962 discloses the use of bimoclomol and arimoclomol for the prevention and / or treatment of muscle atrophy, e.g. muscle dystrophy in long-term akinesia.

According to International Patent Application published under No. WO 2013/045963, bimo- clomol and arimoclomol can be used to improve the tissue regeneration effect of adult stem cells, to promote stem cell survival, adhesion and differentiation.

The hydroxy acid derivatives of formula I according to (c) above are known from European Patent Application No. EP 801 649. Hungarian patent applications P 98 02896 and P 98 02897, published on November 28, 2000, disclose the (+) - and (-) - enantiomer of iroxanadine of formula V. The enantiomers are useful in the treatment of vascular diseases

The hydroxy acid derivatives of formula I according to (d) above may be prepared according to the methods described in PCT Application Published under No. WO 01/70674. The compounds are useful in the treatment of conditions deficient in oxygen and / or energy, diseases based on PARP inhibition, diseases of viral origin or diseases caused by toxic effects. The compounds are also disclosed in the aforementioned PCT Patent Applications published under Nos. WO 2013/02431 1 and WO 2013/024312.

The pharmaceutical combination according to the invention is understood to mean the follow- ing compositions:

a combination of the separate pharmaceutical composition comprising the beta-receptor blocking agent and a pharmaceutically acceptable carrier and the separate pharmaceutical composi- tion comprising the hydroximic-acid derivative of formula I and a pharmaceutically acceptable car rier, wherein each separate pharmaceutical composition is administered simultaneously or sequen tially to the patient who is in need of the treatment; or

a pharmaceutical composition comprising the beta-blocking agent and a hydroximic-acid de rivative of formula I and a pharmaceutically acceptable carrier at the same time, wherein either a mixture of the two agents is present, or each is present in a different location in the pharmaceutical composition, e.g. in the tablet core and the other in the tablet core coating.

Of course, any conventional carrier and any conventional pharmaceutical preparation proce dure may be used to prepare the individual pharmaceutical compositions or the single pharmaceutical composition.

The pharmaceutical combination may be any dosage form suitable for oral, parenteral or rectal administration or topical administration, or solid or liquid form. The weight ratio of active ingredients in the pharmaceutical combination is generally (1-1000) : ( 1000- 1 ) .

In principle, the pharmaceutical combination of the invention may contain more than one beta- receptor blocking agent.

Solid pharmaceutical compositions suitable for oral administration may be in the form of powders, capsules, tablets, film-coated tablets, microcapsules, sustained-release formulations, etc., and may contain binding agents as carriers, such as gelatine, sorbitol, polyvinylpyrrolidone, etc.; fillers such as lactose, glucose, starch, calcium phosphate, etc.; tabletting aids such as magnesium stearate, talc, polyethylene glycol, silica, etc.; wetting agents such as sodium lauryl sulphate, etc. Liquid pharmaceutical preparations for oral administration may be in the form of solutions, suspensions or emulsions and may include as carriers, for example, suspending agents, such as gela- tine, carboxymethylcellulose, etc.; emulsifiers such as sorbitan monooleate, etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol, etc.; preservatives such as methyl p-hydroxybenzoic acid, etc.

Pharmaceutical compositions for parenteral administration are generally sterile solutions of the active compounds.

The above dosage forms and other dosage forms are known per se, see, for example, Reming- ton's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).

The drug combination will generally contain a unit dose of the active ingredients. The daily dose may be administered in one or more portions. The actual dose will depend on many factors and will be determined by the doctor.

The pharmaceutical composition (s) forming the pharmaceutical combination of the present invention may be prepared in a manner known in the art (e.g., Remington's Pharmaceutical Sciences mentioned above).

The present invention relates to the use of a hydroximic-acid derivative of the Formula I or a pharmaceutically acceptable acid addition salt thereof for reducing one or more side effects of a beta- receptor blocking drug, wherein the side effects include particularly cardiovascular side effects such as bradycardia, hypotension, heart failure, cardiac arrest, dizziness, muscle weakness, fatigue, periph eral vasoconstrictor effect, etc. or aggravation of asthma.

Accordingly, to a patient treated with a pharmaceutical preparation having a beta-receptor blocking active ingredient is administered also a hydroximic-acid derivative of formula I or a phar maceutically acceptable acid addition salt thereof, preferably in the form of a pharmaceutical prepa ration. The two active substances may be administered simultaneously or sequentially. For administration, the active ingredient may be present in separate pharmaceutical preparations or in a single pharmaceutical preparation, as described above.