IE54373B1 - Pharmaceutical compositions comprising, 7,8-dihydroxy-1(hydroxyphenyl)-2,3,4,5-tetrahydro-ih-3-benzanepine derivatives and a beta-adrenergic blocking compound - Google Patents

Description

This Invention comprises a composition containing one or more compounds having renal vasodilating activity after oral or parenteral administration which, does not by itself elevate glomerular filtration, that is a renal dopamine-like agent, combined with one or more compounds having ^-adrenergic blocking activity. The composition which contains this new combination of medicinal agents demonstrates an Improved efficiency of kidney function and an improved antihypertensive effect. A novel synergistic increase in the glomerular filtration rate has also been demonstrated with the new combination product. Improved kidney function will be beneficial to hypertensive patients, hut this result can also be useful in patients who may or may not be hypertensive especially elderly patients.

The renal dopamine-like agents in the claimed compositions are described In U.S. Patent Nos. 4,160,765, 4,265,889 or 4,171,359. The β-blocking agents are old In the art and are described here by their accepted generic names. No prior art mention of the claimed compositions is known to the applicants.

The renal vasodilator component will be a compound of the structure: tn which X is methyl or halogen and Y ia hydrogen, methyl or halogen. The position of the phenolic or floating hydroxy group in Structure 1 will be preferably para. The term halogen Includes fluoro, chloro, bromo and iodo.

Also included are derivatives of these compounds which may either give rise to the parent compounds in vivo or be useful themselves such as the nontoxic, pharmaceutically acceptable acid addition salts, for example, hydrochloride, hydrobromide, sulfate, phosphate, sulfamate, methyl sulfonate, maleate oe fumarate salts; O-esters especially the tri-O-lower alkanoyl ester having from 2 to 8 carbon atoms in each alkanoyl group; 0-methyl esters; sulfate esters or glucuronate esters. The separated stereoisomers are also useful.

The amounts of the compounds of Formula I present in the antihypertensive compositions are calculated on the base form although the acid addition salts are most conveniently used especially the hydrochloride, hydrobromide or methyl sulfonate. The prodrug, isomeric or salt forms are prepared by methods well known to the art.

The 3-benzazepine compounds of Formula I are described in the prior literature to have an antihypertensive effect in subjects having, or prone to have, elevated blood pressure. The compounds work by means of a specific drug action at the peripheral dopaminergic receptors especially in the kidney thereby increasing renal blood flow and decreasing renal vascular resistance. The quantity of the renal dopaminergic agent in the compositions of this invention will vary with the potency of its biological activity as well as with its pharmacodynamic characteristics. Such quantity is chosen from the dose ranges of the renal dopaminergic agent in the literature useful for treating patients alone or combined with a diuretic agent. Generally the quantity of renal dopaminergic agent in a dosage unit of this invention will be selected from the range of about 15-500 mg. Using, for example, 6-chloro-7,8-dihydroxy-l-(£-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine as the methyl sulfonate salt from about 25-300 mg of base equivalent is used in the composition. Preferably the quantity of renal agent will be chosen from the range of 50-150 mg. The resulting composition is administered from 2-5 times a day. Other renal dopaminergic agents may be used basing their unit dosages on this daily regiment with consideration of their quantitative efficacy compared with the given compound. 3. 3437 3 In the standard test procedure for determining renal dopamine-like activity by infusion in anesthetized normotensive dogs, the preferred and standard species, 6-chloro-7,8-dihydroxy-l-(£-hydroxyphenyl)-2,3,4,5tetrahydro-lH-3-benzazepine ae the methylsulfonic acid salt, has a renal vascular resistance ED^^ of 0.3 ug/kg. The details of this test procedure are presented in the literature references mentioned above. The tri-O-acetyl derivative of the preferred compound has an EDof 25 Ug/kg, the tri-O-isobutyryl derivative, 16 ug/kg, Other 3-henzazepine species having renal dopaminergic activity of Formula I may he used by comparing their activity in the anesthetized dog protocol with that of the named standard species in preparing hypotensively effective and nontoxic dosage regimens. For example, referring to Formula I: A. X - Cl, Y = H, m-OH RVR-ED^O.35 Ug/kg B. X " Br, Y = H, p-OH RVR-ED^j 5ug/kg C. x - ch3, Y = H, p-OH RVR-ED15 2.8 ug/kg D. X » Cl, Y = Cl, p-OH RVR-ED^ 620 ug/kg E. x - ch3, Y Cl, p-OH RVR-ED15 30 ug/kg F. X - 1, Y = H, p-OH RVR-ED15 4.2 ug/kg G. X - Cl, Y - H, p-OH RVR-ED15 0.31 ug/kg d- -isomer H. X - Cl, Y - H, p-OH RVR-ED15 0.94 Ug/kg 1-isomer The active 3-benzazepine ingredients of the medical compositions of this invention are chemically prepared as described in the cited literature The renal vascular resistance ED^^ values in the infused anesthetized dog given above are useful to assess quantitative and qualitative biological properties of the l-hydroxyphenyl-7,8-dihydroxy2,3,4,5-tetrahydro-lH-3-benzazepine compounds of Formula I. These compounds are most useful following oral administration. They are rapidly absorbed from the gastrointestinal tract. Therefore, the renal dopaminergic agent must be matched with conventional dosage regimens of the β-nlocking agents considering the pharmacokinetic properties of each active component. This is accomplished by combining the renal dopaminergic agent with a β-blocker in standard dosage unit forms for administration from 1-5 times daily. Oral administration is preferred but the two basic compounds of these new compositions are also useful as parenteral products.

Alternatively the renal dopaminergic agent may be incorporated into a timed release dosage unit form in which several doses are treated for delayed or sustained release of the medicament. Such dosage units may comprise sustained release granules, sugar centered spheres or multilayered tablets in each of which the availability of the active ingredient is controlled by coating with a lipid or polymeric material. In such compositions, the βblocking component would usually be present in immediately available form.

The β-blocking component of the antihypertensive compositions of this invention will be any such standard agent known to the art which will be present in the composition in quantities within its normal dosage unit and daily regimen ranges as detailed in the medical literature. Propranolol and its pharmaceutically acceptable acid addition salts, especially propranolol hydrochloride is the preferred β-blocker component of this new combination product. Normally the β-blocker will be selected to give a daily quantity selected from the range of about 1 mg to 400 mg depending on its known potency. A particularly effective nontoxic quantity of the β-blocking compound in a dosage unit will be chosen from about 5-300 mg, preferably 5-80.

Such known β-adrenergic blocking agents by their generic names, their dosage unit quantities and daily dose ranges are: β-blocking agent Unit form Unit dose (mg) propranolol tablets ampule 10-80 1-3 alprenolol tablets ampule 50 1 atenolol tablets 50-100 bemetizide tablets 10 bupranolol tablets 40-100 bunitrolol tablets 10 butidrin tablets 50 metoprolol tablets 50-100 nifenalol tablets 50 oxprenolol tablets ampule 20-80 2 pindolol tablets 5-15 sotatol tablets 160-640 timalol tablets 5-15 toliprolol tablets 10-50 Other compounds which have β-adrenoceptor blocking activity as part of their pharmacodynamic spectrum are practoiol, prizidilol, acebutolol, labetalol, mepinalol, bunalol or bufetalol. In fact any compound whose chemical structure contains the β-blocking fragment, OH I (-CH2CH-CH-N<^ usually attached to an aromatic nucleus, and also usually with a N-isopropyl or tert.-butyl containing substituent) and whose pharmacological activity includes a β-adrenergic blocking component can be used comparing its relative potency as a β-blocker to that of the preferred propranolol.

Each of the compounds of the composition of this invention have been described in the literature to he useful combined with diuretics, for example see European Patent Publication No. 22,330 published 14 January 1981, and R.T. Owen, Pharmacy International 1981, 17-21. The EPO reference describes the specifically acting renal dopaminergic agents of Formula I to have a synergistic natruretic effect with thiazide diuretics but not with diuretics acting at sites other than the diluting segment of the renal tubules.

The Owen article discloses that R-hlockers combined with diuretics are a useful combination in treating various cardiovascular conditions but that synergism cannot be demonstrated reproduclhly.

He have now found that the administration to a patient in need of Improvement in kidney function of a specifically acting renal dopaminergic agent together with a R-adrenergic blocking agent, each administered in accepted clinically effective quantities, synergistically increases the glomerular filtration rate (GFR) of the designated patient. This unexpected biological effect which has not been previously reported in the renal dopaminergic-diuretic combination study of the EPO reference is important in (1) increasing the sodium load presented to the tubules and (2) increasing the materials eliminated from the body by filtration such as metabolic waste products especially those of a nitrogenous nature such as urea. The compositions of this invention are therefore useful for example in improving kidney function of the elderly patient without increasing blood pressure or in treating the hypertensive patient.

In addition to GFR synergism, the combination Increases renal blood flow, natruresis and balances plasma renin levels. The beneficial effect of the fr-blocking agent on the increased renin plasma effect of the dopaminergic agent is unexpected since g-blockers were reported to Increase the plasma renin activity of diuretics, see the noted Owen article although propranolol itself is known to inhibit renin release by the kidneys. Of course renin is a mediator in the angiotensin cycle with increased blood pressure when present in high levels in the plasma.

The g-blockers especially propranolol, have not been described in the prior literature to the best of our knowledge to have significant effects on the kidney other than as inhibitors or renin. They are better known to decrease cardiac output and diminish tonic sympathetic nerve outflow from the vasomotor centres of the brain.

As stated above, the active renal dopamine-like and R-adrenoceptor S4373 blocking components of the new compositions are not used in any particular ratio but each is used at one of its clinically effective doses. The resulting compositions exhibit the full spectrum of the biological activity of each of the ingredients with the unexpected synergistic effects discussed above and demonstrated hereafter.

The dosage unit compositions of this invention are prepared by standard pharmaceutical techniques by incorporation into a pharmaceutical carrier in the form of a dosage unit such as a tablet, troche, capsule or powder for either suspension or solution. For example, an effective quantity of a renal dopaminergic compound of Formula I selected from the dose ranges presented above together with an effective quantity of β-bloeking agent selected from the dose ranges presented above are screened, sized and mixed together with a filler if need he, for example, talc, lactose, terra alba, magnesium stearate, agar, pectin, acacia, gelatin or stearic acid. The active ingredients and filler are mixed and filled with a hard gelatin capsule. Alternatively, the ingredients are tabletted using lubricants and granulating agents. Also liquid carriers can be used, for example, peanut oil, sesame oil, olive oil or water. Such mixtures are encapsulated into soft gelatin capsules or, in case of a sterile, isotonic solution for parenteral use, in a unit or multidose vial.

If the renal dopaminergic agent is desired to be in a time release formulation, coating agents as glyceryl distearate, wax, polyvinylpyrrolidone, zein, ethylcelluloae, castor wax, polymethacrylates, cellulose acetate butyrate, a cross-linked polymeric film, for example, one formed from prepolymers of an unsaturated dicarboxylic acid and an ethylene compound, or acid copolymers formed from acrylic or methacrylic acid monomers.

The dosage unit compositions are administered orally to patients who have subnormal kidney function, abnormally high blood pressure or who are prone to have high blood pressure, usually from 1—6 times daily preferably from 2—3 times daily. In certain cardiovascular emergencies, the combined compounds in pharmaceutically acceptable salt form may be dissolved or suspended in saline and administered parenterally. It will be appreciated that the antihypertensive compositions of this invention combine clinically acceptable doses of a renal dopaminergic agent and a β-blocking agent with consideration for the half-life and peak therapeutic effect of each.

It may be desirable in certain patients for the primary care physician to administer the two agents individually to achieve the novel therapeutic effect described herein.

Also, under certain circumstances, a third agent from the 10 same or another class of compounds may be added such as an oral dosage unit containing clinically effective quantities of 6-chloro-l-(£-hydroxyphenyl)-7,8-dihydroxy-2,3,4,5tetrahydro-lH-3-benzazepine methyl sulfonate, ]5 propranolol hydrochloride an<* hydrochlorothiazide.

As treatment for cardiovascular emergencies, parenteral, usually intravenous, preparations are used for example containing doses selected from 1-3 mg/kg of propranolol and from 0.1-10 mg/kg of the preferred 6-chloro-l-(£-hydroxyphenyl)-7,8-dihydroxy-2,3,4,5-tetra20 hydro-lH-3-benzazepine methylsulfonic acid salt.

A modification of the phosphate-mannitol protocol, described in the prior art was used for renal clearance studies in adult, trained, unanesthetized, fasted, female mongrel dogs, lightly restrained on their backs on a cradle-like board constructed specifically for this purpose. The effect of compound upon kidney function was determined by measurement of effective renal plasma flow (RPF), glomerular filtration rate (GFR), and filtration fraction (FF). Orine volume, pH and electrolyte excretion were also determined. The clearance of free water was calculated from plasma and urinary osmolalities.

All dogs were given an oral water load of 500 ml of tap water thirty minutes prior to initiation of the study. Using a constant infusion pump, the dogs were infused intravenously at 3 ml/minute throughout the course of the experiment with a 4% mannitol-phosphate buffer solution, pH 7.4. Glomerular filtration rate was determined by the clearance of creatinine and effective renal plasma flow by the clearance of p-aminohippuric acid 5 (PAH). These clearances were determined simultaneously by including 0.4% creatinine and 0.08% p-aminohippuric acid in the infusion solution. Suitable plasma levels of creatinine and p-aminohippuric acid were obtained by a thirty minute infusion of this solution to obtain equili10 brium prior to starting of the initial urine collection (Up . In addition, 1.5 ml/kg of a 1% creatinine solution in phosphate buffer was injected intravenously fifteen minutes prior to collection of U^. Replicate urine collections were obtained at ten minute intervals ^5 throughout the experiment. The bladder was emptied by an indwelling catheter and complete urine collections were assured by rinsing the bladder with 10 mis of warm water at the end of each collection interval. This procedure was followed by an air washout. Venous blood samples were drawn from an indwelling catheter at the mid-point of each clearance period.

Plasma and urine osmolalities were determined by freezing point depression on freshly obtained samples. Urine volume and pH were recorded at the time of collects tion. Plasma and urine samples were stored frozen, after collection, until analyzed. Analyses for sodium and potassium were made by flame photometry and for chloride, creatinine and p-aminohippuric acid, by colorimetry, using standard AutoAnalyzer methodologies. These analyses were made simultaneously on each sample. Peak intensities were identified electronically, recorded on on-line teletype, stored and subsequently analyzed mathematically by timeshared computer against appropriate standards. Data were computed from linear least square regression lines, and 35 quality control standards were analyzed simultaneously to evaluate system reproducibility and reliability.

The bladder was emptied upon beginning the study and three control clearance (Hj-U^, Phase 1) were obtained.

SK&F 82526-J was given orally by stomach tube at a dose 10 mg/kg of the base after Phase 1.

Propranolol hydrochloride waa given Intravenously In order to obtain sufficient levels to ensure biological activity during the period of the test (in 4 ml of saline) after the third clearance (Phase 1) at doses of 20 g/kg, 0.5 mg/kg and 1.0 mg/kg.

Post-drug clearance C^-D^, C^-C^, Cio"C12 phases XI, III and IV) were collected immediately with no delay between C2 and C^. The total post-drug period observed was one and one-half hours.

Four dogs were used for each treatment.

All compounds were administered as the free base.

TABLE 1 Comparison of a combination of propranolol and 6-chloro-7,8-dihydroxy-l-(j>-hydroxyphenyl)-2,3,4,5-tetrahydro-lH3-benzazepine methyl sulfonate (SK&F 82526-J) with each component in the mannitol-phosphate treated dog. 11.

Treatment Control Phase I Clearances 1-3 Phase II Clearances 4-6 Phase III Clearances 7-9 Phase IV Clearances 10-12 Mean % Changes Post Drug RPF (ml/min) A. SK&F 82526-J 10 mg/kg p.o. 165.41 11.69 24.36* 27.58* B. Propranolol hydrochloride 0.5 ng/kg i.v. 162.48 - 1.111 - 7.111 - 10.671 C. Combination 158.60 20.73* 37.00* 31.15* GFR (ml/min) A. SKStF 82526-J 10 mg/kg p.o. 52.82 - 3.70 - 0.04 - 0.45* B. Propranolol hydrochloride 0.5 mg/kg i.v. 51.70 1.64 - 2.75 - 3.931 C. Combination 50.76 8.69* 8.76* 18.58* renin (ng/ml/min) A. SK8tF 82526-J 10 mg/kg p.o. 3.49 93.91 137.71 250.001 B. Propranolol hydrochloride 0.5 mg/kg i.v. 1.78 -11.20 - 49.91 - 55.00 C. Combination 3.08 1.01 28.0 49.0 5 Difference Between Post-Drug Phases and Control Na i % excreted A. SKStF 82526-J 10 mg/kg p.o. 0.82 - 0.32 - 0.08 - 0.175 Έ B. Propranolol hydrochloride 0.5 mg/kg i.v. 0.59 0.12 0.31 0.751 θ C. Combination 0.58 0.50 0.88* * 1.27 Differs significantly frcm historical control. 1 Differs significantly from combination.

Table II In a similar procedure in four dogs, propranolol in a dose approximately that used intravenously in humans, pg/kg i.v., combined with 10 mg/kg p.o. of 6-chloro7,8-dihydroxy-l-(£-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3benzazepine methylsulfonate (SK&F 82526-J) gave similar synergistic effects on glomerular filtration rate (GFR) and renal plasma flow (RPF). Control Phase I Clearances 1-3 Phase II Clearances 4-6 Phase III Clearances 7-9 Phase IV Clearances 10-12 Mean % Changes Post Drug RPF (ml/min) 188.13 9.48 39.35* 38.42* GFR (ml/min) 50.23 -4.28 8.32* 19.74* ‘statistically significant Table III The following data were derived frcm using a high dose of propranolol,1 mg/kg,in combination with SK&F 82526-J.

With such a high dose of R-blocking agent, the synergistic effects of the combination are less striking because of other compensating cardiovascular action.

Ccntrol Treatment Phase I Clearances 1-3 Phase II Clearances 4-6 Phase III Clearances 7-9 Phase IV Clearances 10-12 Mean % Changes Post Drug KPF (ml/inxn) 15 A. Prcpranolol hydrochloride 1 mg/kg i.v. 204.92 - 2.39 -12.67 -16.69* B. Canbination with SK&F 82526-J 10 mg/kg p.o. 190.12 16.54* 25.24* 21.71* 20 GFR (ml/nin) A. Prcpranolol hydrochloride 1 mg/cg i.v. 53.69 7.49* 7.87* 7.20* 25 B. Conciliation with SK&F 82526-J 10 mg/kg p.o. 64.91 2.78 3.30 9.38* Difference Between Post-Drug Phases and Control Na ± % excreted 30 A. Prcpranolol hydrochloride 1 rog/kg i.v. 0.90 0.35* 1.36* 2.13* B. Canbinaticn with SK&F 82526-J 10 mg/kg p.o. 1.18 0.39* 0.89* 1.29* *statistically significant The data in the above tables demonstrate the synergistic effects of the R-blocker-renal dopaminergic agent combination on blood flow, renin, sodium ion excretion and especially the glomerular filtration rate.

The following examples are designed to teach the preparation and use of the compositions of this invention. β 1 EXAMPLE 1 Ingredients 6-Chloro-7,8-dihydroxy-l-(4-hydroxyphenyl) 2,3,4,5-tetrahydro-lH-3-benzazepine methyl- Amounts, mg: 100 5 sulfonate as base weight Propranolol hydrochloride 40 Sucrose 25 Calcium sulfate, dihydrate 50 Talc 5 10 Stearic acid 3 Starch 10 The active ingredients, sucrose, and calcium sulfate are mixed, granulated using hot 10% gelatin 15 solution, meshed and dried. After mixing with the remaining ingredients, the mixture is compressed into a scored tablet. The scored tablet, per se or broken, is administered orally to a hypertensive patient from 2-4 20 times daily. EXAMPLE 2 FORMULA Ingredients: mq/cap. 25 6-Chloro-7,8-dihydroxy-l-(4-hydroxyphenyl)2,3,4,5-tetrahydro-lH-3-benzazepine methylsulfonate 131.4* Gelatin 15.0 Microcrystalline Wax 5.0 Glyceryl Distearate 25.0 30 Non-Pareil Seeds 25/30 Mesh ♦Equivalent to 100 mg free base. 123.6 Commercial ethanol, methylene chloride and water are used in the coating operation but are removed during processing. 35 1. Place the non-pareil seeds in a coating pan. 2. Make an alcoholic gelatin solution (e.g., 10% gelatin in alcohol. 3. Spray the alcoholic gelatin solution onto the pellets until evenly wetted. 4. Disperse 10% of the benzazepine salt evenly on the wetted pellets.

. Roll pellets in the pan until they are dry enough to repeat the application of gelatin solution and drug powder. Continue coating in this matter until all of the drug powder has been applied. Roll the pellets until dry. 6. Make up a solution of microcrystalline wax and glyceryl distearate in methylene chloride. 7. Coat the stock medicated pellets from Step #5 with the appropriate amounts of wax-fat materials (Step #6) to give the desired release rate characteristics. Roll the pellets until dry. 8. Several such groups of wax-fat pellets from Step #7 are blended with stock medicated pellets to yield the sustained release mix. 9. Add meshed 60 mg of propranolol hydrochloride.

. Pill into opaque gelatin capsule.

Adminster such a capsule orally to a hypertensive patient 1-3 times daily.

EXAMPLE 3 The following compounds (expressed as base weight) are mixed together with 125 g of lactose and 5 mg of magnesium stearate then filled into a hard gelatin capsule. These capsules are administered to a patient in need of improvement in kidney function from 1-4 times daily.

A. 6-Chloro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydroΙΗ-3-benzazepine hydrobromide, 50 mg; propranolol hydrochloride, mg.

B. 6-Fluoro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-35 benzazepine hydrobromide, 75 mg; propranolol hydrochloride, 40 mg.

C. 6-Methyl-7,8-dlhydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3benzazeplne hydrobromide, 20 mg.

D. .6-Fluoro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3benzazepine hydrobromide, 125 mg, propranolol hydrochloride, 60 mg.

E. 6-Chloro-7,8-di-isobutyryloxy-l-(4-isobutyryloxyphenyl)-2,3,4,5tetrahydro-lH-3-benzazepine hydrobromide, 150 mg, propranolol hydrochloride, 40 mg.

F. 6,9-Dichloro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-lH3-benzazepine hydrochloride, 150 mg, propranolol hydrochloride, 40 mg.

G. 6-Chloro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydroΙΗ-3-henzazepine methane sulfonate-100 mg, metoprolol tartrate, 50 mg.

H. 6-Chloro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3benzazepine methane sulfonate-100 mg, propranolol hydrochloride40 mg, hydroehlorothiazlde-25 mg. 1· d-6-Chloro-7,8-dihydroxy-l-(4-hydroxypheny 1)-2,3,4,5-tetrahydroΙΗ-3-benzazepine methane sulfonate, 75 mg, propranolol hydrochloride40 mg.

Claims (15)

1. A composition in dosage unit form having antihypertensive activity or activity in improving kidney function comprising: (a) a nontoxic, renal dopaminergic quantity of a compound of the 5 formula: in which X is methyl or halogen and Y is hydrogen, methyl or halogen; one of its pharmaceutically acceptable acid addition salts, a stereoisomer thereof, or one of its tri-O-lower alkanoyl esters each lower alkanoyl 10 group having 2-8 carbon atoms; and (h) a nontoxic, clinically effective quantity of a S-adrenergic blocking compound.

2. A composition of claim 1 in which the quantity of the dopaminergic compound is selected from 15-500 mg. 15

3. A composition of claims 1-2 in which the quality of the dopaminergic compound is selected from 25-300 mg and the quantity of the (5-blocking compound is selected from 1-100 mg.

4. A composition of claims 1-3 In which Y is hydrogen and X is halogen.

5. A composition of claims 1-3 in which Y is hydrogen, X is chloro 18. and the floating hydroxy group is in the para position.

6. A composition of claim 1 in which X is Cl, Y is hydrogen and the floating hydroxy group is in the para position and the quantity of the dopaminergic compound is selected from 25-100 mg of base present in the acid addition salt form.

7. A composition of claims 1-6 in which the (3-bloeking compound is propranolol or pharmaceutically acceptable acid addition salt thereof.

8. A composition of claims 1-7 In which the quantity of the 0-blocking compound is selected from 5-80 mg.

9. The composition of claims 1-8 in which the dopaminergic compound is 6-chloro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3benzazepine methyl sulfonate in a quantity selected from 25-100 mg of base.

10. The composition of claim 1 comprising 75 mg 6-fluoro-7,8-dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5,tetrahydro-lH-3benzazepine hydrobromide and 40 mg propranolol hydrochloride.

11. The composition of claim 1 comprising 125 mg 6-fluoro-7,8dihydroxy-l-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3-benzazeplne hydrobromide and 60 mg propranolol hydrochloride.

12. The composition of claims 1-9 in which a clinically effective dose of hydrochlorothiazide is also present in the dosage unit.

13. The composition in dosage unit of claims 1 to 12 for oral or parenteral use in combating hypertension or improving kidney function.

14. The composition In dosage unit of claims 1 to 12 for oral use in combating hypertension or improving kidney function.

15. A composition according to any preceding claim substantially as described herein with reference to the Examples.