WO2020044067A1 - Pharmaceutical combination to modify the effect of beta-receptor blockers and reduce side effects - Google Patents

Pharmaceutical combination to modify the effect of beta-receptor blockers and reduce side effects Download PDF

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Publication number
WO2020044067A1
WO2020044067A1 PCT/HU2019/000033 HU2019000033W WO2020044067A1 WO 2020044067 A1 WO2020044067 A1 WO 2020044067A1 HU 2019000033 W HU2019000033 W HU 2019000033W WO 2020044067 A1 WO2020044067 A1 WO 2020044067A1
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formula
general formula
beta
nitrogen atom
pharmaceutical combination
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PCT/HU2019/000033
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French (fr)
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Nagy Péter LITERATI
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N-Gene Research Laboratories, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to a pharmaceutical combination, which has reduced side effects.
  • 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.
  • 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.
  • a pharmaceutical preparation of the invention comprising a first pharmaceutical preparation comprising a beta-blocker as an active ingre transducer and a second pharmaceutical preparation containing as an active ingredient a hydroximic-acid derivative of the general formula I
  • Ar is pyridyl
  • A is a valence bond
  • X is -NH 2
  • R is a group of the general formula
  • 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
  • Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom, or its N- oxide, or
  • Ar is pyridyl
  • A is a valence bond
  • X is a group of the general formula
  • 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
  • Ar is phenyl
  • X is a group of the general formula
  • Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom.
  • R is a hydroxyl group
  • X is a group of the general formula
  • 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.
  • 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.
  • Ar When Ar is pyridyl, it is 2-, 3- or 4-pyridyl.
  • a 5- to 7-membered saturated heterocyclic group containing one ni- trogen atom, formulated in Ri is defined as pyrrolidyl, piperidyl or hexamethyleneimino.
  • 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.
  • 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.
  • 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- trans 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-carboximidoyl chloride (arimoclomol) of formula 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)
  • 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).
  • hydroximic-acid derivatives of formula I are known compounds.
  • 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.
  • 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.
  • 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.
  • a hydroximic-acid derivative such as BGP-15
  • U.S. Pat. No. 6,458,37l relates 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.
  • a hydroximic-acid derivative such as BGP-15
  • 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.
  • 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.
  • hydroximic-acid derivatives such as BGP-1
  • 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 Heights, 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.
  • 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.
  • BGP-15 can be used to reduce adverse psychiatric side effects of cannabinoid CBi receptor antagonists, such as ri- monabant.
  • BGP-15 may be used for the prevention and / or treatment of muscle atrophy.
  • 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.
  • bimoclomol of formula III according to (b) above is described in International Patent Application published under No. WO 90/04584.
  • 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.
  • the expres- sion or activity of molecular chaperones is enhanced by the use of various compounds, including bimoclomol.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions are understood to mean the follow- ing compositions:
  • each separate pharmaceutical composition is administered simultaneously or sequen tially to the patient who is in need of the treatment;
  • 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.
  • 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 ) .
  • 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.
  • 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.
  • 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.
  • compositions for parenteral administration are generally sterile solutions of the active compounds.
  • 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.
  • 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.
  • cardiovascular side effects such as bradycardia, hypotension, heart failure, cardiac arrest, dizziness, muscle weakness, fatigue, periph eral vasoconstrictor effect, etc. or aggravation of asthma.
  • 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.
  • the active ingredient may be present in separate pharmaceutical preparations or in a single pharmaceutical preparation, as described above.

Abstract

The invention relates to a pharmaceutical combination, which modifies the pharmaceutical effect of the beta-receptor blockers, has new pharmaceutical effects and reduced side effects. More particularly, the pharmaceutical combination of the invention consists of a first pharmaceutical composition containing a beta-receptor blocker as active ingredient, and a second pharmaceutical composition containing a hydroximic-acid derivative as active ingredient. An object of the present invention is to improve the therapeutic effect of beta-receptor blockers.

Description

Pharmaceutical combination to modify the effect of beta-receptor blockers and reduce side effects
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
Figure imgf000002_0001
or a pharmaceutically acceptable acid addition salt thereof.
In general formula I
a) Ar is pyridyl,
A is a valence bond,
X is -NH2,
R is a group of the general formula
OH
— O— CH2— 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
Figure imgf000003_0001
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— CH2— 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— CH2— CH— CH2— Ri
wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom.
R is a hydroxyl group, or
d2) X is a group of the general formula
Figure imgf000003_0002
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:
Figure imgf000005_0001
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)
Figure imgf000005_0002
III or one of its N-oxides, N-[2-hydroxy-3-(l-piperidinyl)-propoxy]-pyridine-l-oxide-3-carboximidoyl chloride (arimoclomol) of formula IV
Figure imgf000005_0003
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)
Figure imgf000005_0004
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).
Figure imgf000005_0005
or a pharmaceutically acceptable acid addition salt thereof,
and the 3-styryl-4-[3-(hexamethyleneimino)-2-hydroxypropyl]-A2-l,2,4-oxadiazolin-5-one of for mula VII (d2) above (abbreviated as NG-50)
Figure imgf000006_0001
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.

Claims

Claims
1. Pharmaceutical preparation having reduced side effect, comprising a first pharmaceu- tical preparation comprising a beta-blocker as an active ingredient and a second pharmaceutical prep aration containing as an active ingredient a hydroximic-acid derivative of the general formula I
X
I
Ar— A— C=N— R
or a pharmaceutically acceptable acid addition salt thereof, wherein in general formula I a) Ar is pyridyl,
A is a valence bond,
X is -NH2,
R is a group of the general formula
OH
— O— CH2— 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
Figure imgf000011_0001
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— CH2— 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 adjacent to R and the carbon 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
Figure imgf000012_0001
wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom,
R is a hydroxyl group, or
d2) X is a group of the general fonnula
Figure imgf000012_0002
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 this way forms a five-membered l,2,4-oxadiazoline ring.
2. The pharmaceutical combination of claim 1, which modifies the pharmacological ef fect of beta-receptor blockers, results in novel pharmacological effects, including regulation of the functioning of hyperpolarization- activated cyclic nucleotide-gated channels (If channels).
3. The pharmaceutical combination of claim 1 , wherein the beta-receptor blocking active ingredient and the hydroximic-acid derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof are contained in one common pharmaceutical composition with one or more commonly used carriers.
4. The pharmaceutical combination according to claim 1 or 2, wherein the beta-receptor blocking agent is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, celiprolol, esmolol, labetalol, levobunolol, methipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, or, if desired, a pharmaceutically acceptable acid addition salt or metal salt thereof.
5. The pharmaceutical combination of claim 3, wherein the beta receptor blocking agent is bisoprolol.
6. The pharmaceutical combination of claim 1 or 2, containing 0-(3-piperidino-2-hy- droxy-l-propyl)-nicotinic acid amidoxime dihydrochloride of the fonnula II
Figure imgf000012_0003
as a hydroximic-acid derivative of the formula I. WO 2020/044067 . , . . . , . _ , · , , PCT/HTI2019/000033
7. t he pharmaceutical combination of claim 1 or 2, wherein the hyuiu un^-a^ u um»- ative of the formula I is the N-[2-hydroxy-3-(l-piperidinyl)-propoxy]-pyridine-3-carboximidoyl chloride of formula III,
Figure imgf000013_0001
or N-oxide thereof, the N-[2-hydroxy-3-(l -piperidinyl)propoxy]pyridine-l -oxide-3-carboximidoyl chloride of formula IV
Figure imgf000013_0002
IV or the pharmaceutically acceptable acid addition salt of the compound of formula III or IV.
8. The pharmaceutical combination of claim 1 or 2, wherein the hydroximic-acid deriv ative of formula I is 5-(piperidin-l-ylmethyl)-3-(pyridin-3-yl)-5,6-dihydro-2H-l,2,4-oxadiazine of formula V,
Figure imgf000013_0003
or a pharmaceutically acceptable acid addition salt thereof.
9. The pharmaceutical combination of claim 1 or 2, wherein the hydroximic-acid deriv- ative of formula I is the N-[3-(hexamethyleneimino)-2-hydroxypropyl] cinnamic acid amidoxime of formula VI,
Figure imgf000013_0004
or a pharmaceutically acceptable acid addition salt thereof.
10. The pharmaceutical combination of claim 1 or 2, wherein the hydroximic-acid derivative of formula I is the 3-styryl-4-[3-(hexamethyleneimino)-2-(hydroxypropyl)-A2-l,2,4-oxadia- zolin-5-one amidoxime of formula VII,
Figure imgf000014_0001
VII
or a pharmaceutically acceptable acid addition salt thereof.
11. The hydroximic-acid derivative of the general formula I
X
Figure imgf000014_0002
Ar— A— C=N— R
or a pharmaceutically acceptable acid addition salt thereof, wherein in general formula I
a) Ar is pyridyl,
A is a valence bond,
X is -NH2,
R is a group of the general formula
Figure imgf000014_0003
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
Figure imgf000014_0004
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— CH2— 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 adjacent to R and the carbon adjacent to Y this way forms a six-membered oxadiazine ring, or d) Ar is phenyl,
A is -CH = CH- and
di) X is a group of the general formula
Y
-NH— CH2— CH— CH2— Ri
wherein Ri is a 5-7 membered saturated heterocyclic group containing one nitrogen atom,
R is a hydroxyl group, or
d2) X is a group of the general formula
Figure imgf000015_0001
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 this way forms a five-membered 1,2,4-oxadiazoline ring, or a pharmaceutically acceptable acid addition salt thereof for use in reducing one or more side effects of a beta receptor blocking drug, wherein the side effects include, in particular, cardiovascular side effects such as bradycardia, hypo tension, heart failure, cardiac arrest, dizziness, muscle weakness, fatigue, peripheral vasoconstrictor effects, and the like, or worsening of asthma.
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