DE4230755A1 - Phosphodiesterase IV inhibitors for kidney and ureter disease treatment - with eg (4-(3-(cyclopentyl oxy) 4-methoxyphenyl-2-pyrrolidinone) being specific for kidney and ureter tissue relaxation - Google Patents

Abstract

Use of inhibitors of phosphodiesterase (PDE) IV for the treatment of kidney and ureter diseases is new. Also claimed is the use of e.g, denbufylline (1,3-dibutyl-3,7- dihydro-7- (2-oxopropyl)- 1H-purine-2,6-dion), Ro 20-1724 (4-(3-butoxy-4- methoxyphenyl) methyl)-2- imidazolidinone), Rolipram (4-(3-(cyclopentyloxy) 4-methoxyphenyl)- 2-pyrrolidinone), Tibenelast (5,6-diethoxy benzo(b)thiophen-2-carbonic acid) or their physiologically acceptable salts in this treatment. Parenteral applications contain 0.5microg to 2mg, pref. 5 to 500microg of the component. ADVANTAGE - Current treatment of e.g, colics of the ureter involves the admin. of painkillers without treating the cause of the disease. The new medicaments treat the cause of colics of the ureter and kidney.

Description

The invention relates to the use of inhibitors of Phosphodiesterase IV (sPDE IV) for the treatment of kidney and Ureter disorders.

The physiological information transfer for relaxation (Sagging) smooth muscle cells is caused by transfer agents blood (hormones) or nerves (neurotransmitters) causes. These neurotransmitters work within the smooth Muscle cell an increase in cAMP and cGMP, which is a Relaxation. cAMP and cGMP are in turn Phosphodiesterases (PDE) are broken down. Inhibitors of the PDE in turn decrease the breakdown of cAMP and cGMP, leading to an increase of these molecules within the cell and thereby one Relaxation of the smooth muscle cell leads. This is for example described by Torphy, and others in thorax 46, 512, 1991.

From this publication and from TIPS 12, 19, 1991 and Br. J. Pharmacol. 104, 471, 1991 is still a distinction the PDE into different sub-esterases, the specific ones Phosphodiesterases (sPDE), known. It is in five different sPDE differentiated, in the individual organs and Organ systems are distributed differently and depending on Distribution in the cell has different levels of effectiveness have. In the publications mentioned and in J. Histochem. Cytochem. 35, 72, 1987, J. Urol. 139, 1988 and J. Pharmacol. Exp. Therap. 247, 630, 1988 also the occurrence the different isoenzymes in various tissues discussed, including the presence of sPDE I in the ureter (Ureter).  

Kidney or ureter colic have after old wine and Jacobi, urology, Enke Verlag Stuttgart, 1987, the character a common disease. The colic pain arises from one intrarenal pressure increase due to impaired urine transport as well as through ureter spasms. Treating these diseases is currently known to take place only secondarily through strong acting Analgesics for pain relief. A therapy of the causal Symptoms have so far not been possible because there are no ureter-relaxing ones Substances without unwanted, serious systemic Side effects are known.

The object of the invention is therefore to provide highly effective specific therapeutic agents for causal Treatment of kidney and ureter colic.

Surprisingly, it has now been found that there are two more sPDE's in the human ureter, namely sPDE III and sPDE IV, and furthermore that the sPED IV is of particular importance. A targeted inhibition of this isoenzyme leads to the application of even the smallest doses of a specific inhibitor, e.g. B. the sPDE IV inhibitor rolipram in a dosage of 10 ^-7 mol / l ( Fig. 4) to relax the ureter without noticeable effects on other organs, especially on vessels, were observed. They are therefore extremely effective in the treatment of kidney and ureter colic and in the promotion and relief of kidney and ureter stone exits.

The invention therefore relates to the use of specific inhibitors of sPDE IV in the treatment of Kidney and ureteral diseases, especially colic, which Use of the inhibitors for the preparation for this purpose suitable medicinal products and those containing sPDE IV inhibitors Medicines for the named task.

Preferred inhibitors of sPDE IV are:

• 1.) 1,3-dibutyl-3,7-dihydro-7- (2-oxopropyl) -1H-purine-2,6-dione (Denbufylline, BRL 30892),
• 2.) 4 - [(3-butoxy-4-methoxyphenyl) methyl] -2-imidazolidinone (Ro 20-1724),  
• 3.) 4- [3- (Cyclopentyloxy) 4-methoxyphenyl] -2-pyrrolidinone (Rolipram, ZK 62711),
• 4.) 5,6-Diethoxybenzo [b] thiophene-2-carboxylic acid (Tibenelast, LY 186655),
• 5.) 3-Ethyl-1- (3-nitrophenyl) -2.4 (1H, 3H) -quinazoline dione (Nitraquazone, TVX 2706),
• 6.) 6- (3,6-Dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4,4-dimethylquinoline (EMD 54622),
• 7.) 1-ethyl-4 - [(1-methylethylidene) hydrazino] -1H-pyrazolo [3,4- b] ethyl pyridine-5-carboxylate (etazolates),
• 8.) N-Hydroxy-5,6-dimethoxy-benzo [b] thiophene-2-carboximidamide (Org 30029),
• 9.) 2-Amino-6-methyl-4-propyl- (1,2,4) triazolo [1,5-a] pyrimidine- 5 (4H) -on (ICI 63197) or
• 10.) 6- [4- (Difluoromethoxy) -3-methoxyphenyl] -3 (2H) pyridazinone (Zardaverine)

and their pharmacologically acceptable salts.

The compounds are known to be effective in diseases of the Respiratory tract, anti-inflammatory or diseases of the Central nervous system.

The pharmacologically acceptable salts are more common Way by neutralizing the bases with inorganic or get organic acids. As inorganic acids come to Example hydrochloric acid, sulfuric acid, phosphoric acid or Hydrobromic acid, as organic acids for example Carboxylic, sulfonic or sulfonic acids such as acetic acid, tartaric acid, Lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, Fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2- Phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, Mandelic acid, citric acid, malic acid, salicylic acid, 3- Aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, Isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2- disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid in question.

The drug is manufactured in addition to the usual Auxiliaries, carriers and additives an effective dose  the inhibitors of sPDE IV or their salts for the treatment of mentioned diseases used. The dosage is dependent of species, body weight, age, individual condition and Application type.

Oral, intravenous, intrautereal are the forms of application Preparations in question. The latter are mostly solutions and Preparations such as those for parenteral administration Find application.

Preparations for parenteral administration contain 0.5 µg to 1 mg, preferably 5 to 500 µg of the compounds of the general Formula II per dose unit and can be in separate Dosage unit forms such as B. ampoules or vials. Solutions of the active ingredient are preferably used, prefers aqueous solutions and especially isotonic solutions, but also suspensions. These injection forms can be used as Finished product can be made available or only directly before use by mixing the active compound to Example of the lyophilizate, optionally with other solid ones Carriers, with the desired solution or Suspensions are prepared.

The usual galenic ones are used for oral use Forms of preparation such as tablets, coated tablets, capsules, dispersible powders, granules, aqueous or oily Suspensions, syrups, juices or drops.

Solid dosage forms can be inert excipients and carriers included, such as B. calcium carbonate, calcium phosphate, Sodium phosphate, lactose, starch, mannitol, alginates, gelatin, Guar gum, magnesium or aluminum stearate, methyl cellulose, Talc, highly disperse silicas, silicone oil, higher molecular weight Fatty acids (such as stearic acid), gelatin, agar or vegetable or animal fats and oils, solid high molecular weight Polymers (such as polyethylene glycol); for oral application Suitable preparations can, if desired, additional Contain flavor and / or sweeteners.  

Liquid dosage forms can be sterilized and / or optionally auxiliaries such as preservatives, Stabilizers, wetting agents, penetrants, emulsifiers, Spreading agents, solubilizers, salts for regulating the osmotic pressure or for buffering and / or Viscosity regulators included.

Such additives are, for example, tartrate and citrate buffers, Ethanol, complexing agents (such as ethylenediamine tetraacetic acid and their non-toxic salts) come to regulate the viscosity high molecular weight polymers such as liquid Polyethylene oxide, carboxymethyl celluloses, polyvinyl pyrrolidones, Dextrans or gelatin. Solid carriers are for example Starch, lactose, mannitol, methyl cellulose, talc, highly disperse Silicas, higher molecular fatty acids (such as stearic acid), Gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers (like polyethylene glycol).

Oily suspensions for parenteral or topical (in this Case intraureteral) applications can be vegetabile synthetic or semi-synthetic oils such as liquid fatty acid esters with 8 to 22 carbon atoms in each Fatty acid chains, for example palmitin, laurin, tridecyl, Margarine, stearin, arachine, myristic, behen, pentadecyl, Linoleic, elaidic, brasidic, erucic or oleic acid to trihydric alcohols with 1 to 6 carbon atoms such as for example methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol are esterified. Such fatty acid esters are, for example, commercially available Miglyols, isopropyl myristate, isopropyl palmitate, Isopropyl stearate, PEG 6-capric acid, caprylic / capric acid ester of saturated fatty alcohols, polyoxyethylene glycerol trioleates, Ethyl oleate, waxy fatty acid esters such as artificial Duckling glandular fat, isopropyl coconut fatty acid, Oleic acid oleyl ester, oleic acid decyl ester, lactic acid ethyl ester, Dibuthyl phthalate, adipic acid diisopropyl ester, polyol Fatty acid esters a. Silicone oils are also suitable different viscosity or fatty alcohols like Isotridexyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or  Oleyl alcohol, fatty acids such as oleic acid. Farther Vegetable oils such as castor oil, almond oil, olive oil, Use sesame oil, cottonseed oil, peanut oil or soybean oil Find. The substances mentioned also have the properties a spreading agent, that is, it is a particularly good one Distribution on the skin.

As solvents, gelling agents and solubilizers come in Question water or water-miscible solvents. Suitable are, for example, alcohols such as ethanol or Isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, Polyethylene glycols, phthalates, adipates, propylene glycol, Glycerin, di- or tripropylene glycol, waxes, Methyl cellosolve, cellosolve, ester, morpholines, dioxane, Dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, Cyclohexanone etc.

Cellulose ethers can be used as film formers in both water and organic solvents can dissolve or swell and after drying a kind of film form, such as hydroxypropyl cellulose, Methyl cellulose, ethyl cellulose or soluble starches.

Mixed forms between gel and film formers are quite also possible. Ionic macromolecules in particular come here to use such. B. sodium carboxymethyl cellulose, Polyacrylic acid, polymethacrylic acid and their salts, Sodium amylopectin semiglycolate, alginic acid or propylene glycol Alginate as sodium salt, gum arabic, xanthan gum, guar Gum or carrageenan.

The following can be used as additional formulation aids: Glycerin, paraffin of different viscosity, Triethanolamine, collagen, allantoin, novantisol acid, Perfume oils.

Also the use of surfactants, emulsifiers or wetting agents may be necessary for the formulation, such as Na- Lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-β- iminodipropionate, polyoxyethylated castor oil or sorbitan  Monooleate, sorbitan monostearate, cetyl alcohol, lecithin, Glycerol monostearate, polyoxyethylene stearate, Alkylphenol polyglycol ether, cetyltrimethylammonium chloride or Mono / dialkyl polyglycol ether orthophosphoric acid monoethanolamine salts.

Stabilizers such as montmorillonites or colloidal silicas to stabilize emulsions or to prevent the Breakdown of active substances such as antioxidants, for example tocopherols or butylated hydroxyanisole, or Preservatives such as p-hydroxybenzoic acid esters can also for the preparation of the desired formulations may be required.

Contain intraureteral to promote penetration Formulations preferably organic, well tolerated Solvents such as ethanol, methylpyrrolidone, polyethylene glycol, Oleyl alcohol, octanol, linoleic acid, triacetin, propylene glycol, Glycerin, Solketal or Dimethylsulfoxid.

The manufacture, filling and sealing of the preparations takes place under the usual antimicrobial and aseptic Conditions. Also for topical or transdermal If possible, they are packaged in separate packages Dose units to facilitate handling, also here how in the case of parenteral forms, if necessary for reasons of stability by separate packaging of the active ingredients or their Combinations as a lyophilisate, optionally with solid ones Carriers, and the necessary solvents etc.

Example 1 - solution for injection

50 mg rolipram are mixed with 750 mg NaCl in distilled water dissolved, adjusted to pH 3.7 with 1N HCl and with distilled Make up to 100 ml of water and pack it in 0.5 ml ampoules.  

Example 2 - Solution for topical application

From 500 mg rolipram, 2 ml isopropyl myristate and 10 ml ethanol a solution for topical application is prepared and prepared Packed dose units of 2 ml each.

The effectiveness of the pharmaceuticals for the teaching according to the invention is proven by the following pharmacological examinations:

Human ureters freshly removed during the operation are cut into small strips (approx. 3 × 10 mm). These are then installed in a bath with a nutrient solution that ensures the survival of the organ strips. By coupling the organ strips to a sensor, changes in the length of the organ strip can be registered, and the effects of medications that are added to the organ bath nutrient solution can be examined based on the change in length (increase or decrease) of the organ strip. At the start of the experiment, the organ strips are z. B. contracted noradrenaline. After contraction of the organ strips has occurred, an inhibitor of a specific phosphodiesterase is then added to the organ bath solution in increasing doses (10 ^-7 , 10 ^-6 , 10 ^-5 etc. mol / l) and the relaxation triggered thereby is measured. The results obtained are essentially transferable to the whole organism, since human tissue has been used and the metabolic processes investigated in the whole organism are faster and therefore the medication works even faster.

In Fig. 1 to Fig. 5, the results of these are shown Organbadversuche.

Fig. 1 shows the relaxing effect of cumulatively increasing concentrations of papaverine, a non-specific phosphodiesterase inhibitor, on human, with 80 mM KCl precontracted ureter strips. The curve shows the mean values of measurements on 3 to 7 ureter strips each.

FIG. 2 shows the relaxing effect of cumulatively increasing concentrations of quazinone, an inhibitor of sPDE III, on human ureter strips pre-contracted with 80 mM KCl. The curve shows the mean values of measurements on 3 to 6 ureter strips each.

Fig. 3 shows the relaxing effect of cumulatively increasing concentrations of Zaprinast, an inhibitor of sPDE V, on human precontracted with 80 mM KCl ureter strips. The curve shows the mean values of measurements on 3 to 6 ureter strips each.

Fig. 4 shows the relaxing effect of cumulatively increasing concentrations of rolipram, an inhibitor of sPDE IV precontracted on human, with 80 mM KCl ureter strips. The curve shows the mean values of measurements on 4 to 7 ureter strips each.

Figure 5 shows a comparison of the relaxing effects of rolipram on renal and coronary artery strips.

The tests for FIG. 5 were carried out analogously to the examinations on ureteral strips and clearly demonstrate the specific relaxing effect on the ureteral tissue, while the renal vascular system is not influenced at all.

Evidence of whether a compound for the invention Purpose is d. H. is an inhibitor of sPDE IV by known methods, such as. B. described by Galwan et al., Arch. Pharmacol. 1990, 342, 221-227 or Nicholson, Br. J. Pharmacol., 1989, 79, 889-897, for example according to the following general method:

Fresh tissue obtained intraoperatively is homogenized and then ultracentrifuged. The supernatant is then pipetted off and chromatographed. Of the 100 fractions from 70 to 1000 mM (millimolar), 5 batches of 30 ul of the enzyme preparation are then prepared; Each enzyme preparation of a fraction is treated with a) radioactive labeled cAMP, b) radioactive labeled cGMP, c) radioactive labeled cAMP plus calcium plus calmodulin, d) radioactive labeled cGMP plus calcium plus calmodulin, d) radioactive labeled cGMP plus calcium plus calmodulin or e) radioactively labeled cAMP plus cGMP plus calcium plus calmodulin added. After incubation and completion of the reaction and centrifugation again, the radioactivity of the samples is measured. The determination of the radioactivity allows the calculation of the enzyme activity in pmol / ml × min. The plot of the activity curve allows the identification of fractions in which the phosphodiesterase activity is particularly high. The phosphodiesterase activity of each peak shows a different composition with regard to the activity of the 5 different batches. This special composition of the phosphodiesterase activity allows an assignment to a specific phosphodiesterase (sPDE). An inhibitor of an sPDE is now the substance whose concentration, which is necessary to inhibit 50% of substrate hydrolysis (IC ₅₀ ), is at least 20 times smaller for the relevant peak fraction, which contains the specific phosphodiesterase, than for other peak fractions. For this purpose, as described above, enzyme preparations are produced. Before the incubation of the enzyme batches according to a) to e) of the peak fractions, the compound to be tested is now added. The renewed determination and application of the enzyme activity then allows the identification of a substance as an inhibitor of the specific phosphodiesterase according to the definition given above.

Claims (2)

1. Use of inhibitors of phosphodiesterase IV in the Treatment of kidney and ureter disorders. 2. Use of Denbufyllin, Ro 20-1724, Rolipram, Tibenelast, Nitraquazone, EMD 54622, Etazolate, Org 30029, ICI 63197 or zardaverine and their pharmacological compatible salts according to claim 1.