WO1999018948A1

WO1999018948A1 - New use of npy antagonists

Info

Publication number: WO1999018948A1
Application number: PCT/SE1998/001791
Authority: WO
Inventors: Kajs-Marie SCHÜTZER; Bengt ÅBLAD
Original assignee: Astra AB
Current assignee: AstraZeneca AB
Priority date: 1997-10-10
Filing date: 1998-10-05
Publication date: 1999-04-22
Anticipated expiration: 2000-04-10
Also published as: AU9469298A; SE9703692D0

Abstract

There is provided the use of an NPY antagonist in the manufacture of a medicament for aiding diuresis.

Description

NEW USE OF NPY ANTAGONISTS

Field of the Invention

This invention relates to a new use of NPY antagonists.

Background of the invention

NPY Antagonists

Neuropeptide Y (NPY) is a peptide consisting of 36 amino acids. In recent years it has been established that NPY is an important co-tra--^mitter in the peripheral sympathetic nerve system.

Released NPY is known to elicit marked constriction of blood vessels both in the heart and in most peripheral organs. This vasoconstrictive effect of NPY is believed to be mainly mediated by a receptor sub-type known as Yj. Released NPY may also act on autonomic nerve endings to inhibit the release of neurotransmitters, which may thereby reduce the cardiac vagal tone. This effect of NPY is believed to be mediated by a receptor sub-type known as Y₂.

Other NPY receptor sub-types have been identified, namely the Y₃, Y₄, Y₅ and Y₆ sub-types. The precise function of these sub-receptors has not been elucidated in any detail, but it has been widely postulated that the Y₅ subtype is involved in the regulation of feeding and eating (see, for example, Exp. Opin. Invest. Drugs, vol. 6, pp. 437-445 (1997)). Antagonists of NPY have been indicated as being of potential use in the treatment of many different conditions, including cardiovascular diseases such as hypertension, myocardial ischaemia, myocardial infarction, cardiac failure, vasospasm and arrhythmia, as well as in the treatment of kidney failure, cerebral haemorrhage, pain, migraine, anxiety, depression, inflammation, Alzheimer's disease, asthma, epilepsy, diabetes, sleeping disorders, obesity and eating disorders.

Diuretics

During the course of certain diseases, including some hepatic, renal or pulmonary diseases, cardiovascular disorders and hypertension, it is desirable to preserve renal function. This is because a reduction in the production of urine may lead to oedema formation (in which excess fluid is formed in the tissue), resulting in disturbances in water and electrolyte balance. Such disturbances may also result from more subtle changes, which may be related to the development of hypertension.

Diuretics promote the excretion of water and electrolytes from general circulation by the kidneys and are thus employed climcally in situations where it is intended to keep urine production high (i.e. to preserve renal function) or, more importantly, to mobilise oedema fluid in order to create a negative fluid balance.

Some diuretics are known to lower blood pressure and may therefore play a pivotal role in the direct treatment of hypertension. However, all diuretics have the effect of potentiating almost all other antihypertensive treatments. Known classes of diuretic agents include carbonic anhydrase inhibitors, "loop" or "high ceiling" diuretics, mercurial diuretics, osmotic diuretics, potassium-sparing diuretics and thiazides. Problems which are associated with known diuretics include those listed below:

With the exception of osmotic diuretics, diuretics act directly on the tubular epithelia. Most of these modes of action are site specific and will act on one or a few (but not all) tubular segments. Nonetheless, because of the serial arrangement of tubules, a drug affecting one site may indirectly affect other segments, resulting in the problem of a lowering of the antinatriuretic effect. Moreover, this site-specific action of diuretics results in a change of tubular electrolyte composition downstream from the segment involved. Most re-absorptive processes in the tubular epithelia are driven by, or are affected by, the concentration of, other electrolytes, such as sodium. A change in electrolyte composition may influence absorption of critical ions, such as potassium or hydrogen ions, and thereby result in a source of unwanted plasma electrolyte composition, leading to adverse events or effects.

A further problem associated with several diuretics is the renal adaptation that occurs, resulting in a lowering of the diuretic effect as a result of long-term treatment. Several diuretics are also known to stimulate renin production, which is believed to be directly involved in pathophysiological changes in end-organs such as the kidney, heart and brain.

Prior Art

Known NPY antagonists, including benextramine, CC2137, arpromidine, BIBP3226, NGD 95-1, SR120819A, SR120107A, 1229U91 and PD 160170, are described in DDT, vol. 2 pages 19-24 (1997), which provides a general review of patents and patent applications in the NPY area.

A general review of NPY antagonists is also provided in Peptides, vol. 18, No. 3, pages 445-57 (1997).

Non-peptide based (which term includes amino acid-based) antagonists of NPY have been disclosed in European patent applications EP 614 911 , EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos. 5,552,411 , 5,663,192 and 5,567,714 and Japanese patent application JP 09157253, as well as in the applicant's unpublished co-pending Swedish patent application No. 9703414-4 (the latter application includes full details of the synthesis of various novel NPY antagonists, including (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)ethyl]arginine amide).

European patent application EP 614 911 (which discloses sulphamoyl substituted derivatives of phenylalanine amidine) and international patent application WO 94/17035, do not mention the receptor sub-type upon which the disclosed compounds act.

European applications EP 747 357, EP 747 356 and EP 747 378 disclose dihydropyridine derivatives as sub-receptor Y, antagonists. International patent applications WO 96/12489, WO 96/12490, WO 97/09308, WO 97/25041 and US patents Nos. 5,567,714 and 5,663.192 disclose benzothiophene, benzimidazole and indole derivatives as sub-receptor Y, antagonists.

International patent applications WO 96/40660, WO 98/03492, WO 98/03493 and WO 98/03494 disclose benzylamine derivatives as sub-receptor Y_l antagonists and/or partial sub-receptor Y, agonists.

US patent No. 5,552,411 discloses quinoline derivatives as sub-receptor Yj antagonists.

International patent applications WO 97/34872 and WO 98/07420 disclose 2,4-diaminopyridines and mono- or disubstituted ureas respectively.

Japanese patent application JP 09157253 discloses amino acid derivatives as NPY antagonists.

International patent applications WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823 and WO 97/46250 disclose arylsulfonamide and quinazoline derivatives as sub-receptor Y₅ antagonists and thus for use in the treatment of eating disorders.

The compounds disclosed in international patent application WO 96/22305 are described as having Y₂ sub-receptor antagonist activity and are indicated for use in the treatment of eating disorders. Amongst the compounds specifically disclosed are phenylalanine amide derivatives of N-(diphenylpropionyl)arginine . International patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 97/19914 disclose certain amino acid derivatives as antagonists of NPY. WO 94/17035 discloses BIBP3226.

Peptide derivatives as NPY antagonists are disclosed in international patent applications WO 94/00486, WO 93/12139, WO 95/00161, US Patent No. 5,328,899, German patent application DE 393 97 97, European patent applications EP 355 794 and EP 355 793 and Japanese patent applications JP 06116284 and JP 07267988.

None of the aforementioned prior art documents mention or suggest that the NPY antagonists disclosed therein may be useful as diuretics.

Published prior art relating to the effect of NPY itself on diuresis appears to be contradictory. For example, early literature reports a reduced diuresis as a result of NPY administration (see, for example, Am. J Physiology, vol. 256, pp. F524-F531 (1989), J. Physiol., vol. 444, pp 289-302 (1991)). Conversely, more recent publications (including Brit. J Pharmacol., vol. 120, pp. 1335-43 (1997), Pflugers Archiv. European. J Physiology, vol. 434, pp. 57-62, (1997) and J. Physiology, vol. 495, pp 525-34 (1996)) demonstrate that infusion of NPY in rats produces diuretic and natriuretic effects. Although this latter view may be regarded as being that currently held by those skilled in title art, the situation is by no means clear cut.

In particular, Brit. J. Pharmacol. , vol. 120 pp. 1335-43 (1997) discloses that, although the administration of NPY produced a clear diuretic effect in rats, the administration of the NPY antagonist, BIBP3226, had no antidiuretic effect in rats infused with NPY. The use of BIBP3226 as a diuretic was neither mentioned nor suggested.

Disclosure of the Invention

Surprisingly we have found that NPY antagonists possess diuretic properties (for example, as demonstrated in the Example described below).

According to the invention there is provided the use of a NPY antagonist in the manufacture of a medicament for use in aiding diuresis.

We have found that NPY antagonists may be used to aid diuresis (i.e. may be used as diuretics) in preferably mammalian, and especially human, patients.

By "aiding diuresis" we mean the promotion of the excretion of urine to a statistically significant degree within 1 to 24 hours following the administration of a medicament to a patient, e.g. as demonstrated in the Example described below.

Although NPY antagonists may be used to aid diuresis as such, the present invention finds particular utility in, and/or as part of, the treatment of diseases for which the aiding of diuresis is desirable. Such diseases include hypertension and hepatic, renal or pulmonary diseases, as well as cardiovascular disorders (such as heart failure), and includes those wherein, for example, salt and water retention has resulted in, or may result in, oedema or ascites. The term "NPY antagonist" will be well understood by those skilled in the art to include all those compounds which inhibit the activity of NPY to an experimentally determinable degree, i.e. those compounds which bind to a NPY receptor without eliciting a biological response, for example those compounds which, by binding to NPY receptors, inhibit the functional activity of NPY with an IC₅₀ (as measured in, for example, rat-brain cortex membranes) of less man 10 μM. The term thus includes antagonists of all NPY receptor sub-types including the Y, , Y₂, Y₃, Y₄, Y₅ and Y₆ sub-types. However, we prefer that the NPY antagonist is a NPY Y, sub-receptor antagonist.

NPY antagonists which may be mentioned include those disclosed in European patent applications EP 614 911, EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos. 5,552,411, 5,663,192 and 5,567,714; Japanese patent application JP 09157253; Swedish patent application No. 9703414-4; international patent applications WO 94/00486, WO 93/12139, WO 95/00161; US Patent No. 5,328,899; German patent application DE 393 97 97; European patent applications EP 355 794 and EP 355 793; and Japanese patent applications JP 06116284 and JP 07267988, the disclosures in all of which documents are hereby incorporated by reference. Preferred NPY antagonists include those compounds which are specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide-based NPY antagonists. Amino acid and non-peptide-based NPY antagonists which may be mentioned include those disclosed in European patent applications EP 614 911, EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos. 5,552,411, 5,663,192 and 5,567,714; Japanese patent application JP 09157253; and Swedish patent application No. 9703414-4. Preferred amino acid and non-peptide-based NPY antagonists include those compounds which are specifically disclosed in these patent documents.

Particularly preferred compounds include amino acid-based NPY antagonists. Amino acid-based compounds which may be mentioned include those disclosed in International patent applications WO 94/17035, WO 97/19911, WO 97/19913 and WO 97/19914 or, preferably, Swedish patent application No. 9703414-4. Preferred amino acid-based NPY antagonists include those which are specifically disclosed in these patent documents, for example BIBP3226 and, especially, (R)-N²-(diphenylaceryl)-(R)-N-[l-(4-hydroxyphenyl)-ethyl]arginine amide (Example 4 of Swedish patent application No. 9703414-4).

Pharmaceutical Preparations

In accordance with the invention, the NPY antagonists may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the active ingredient either as a free base, or a pharmaceutical acceptable non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending on the disorder, and the patient, to be treated, as well as the route of administration, the compositions may be administered at varying doses (see below).

In the therapeutic treatment of mammals, and especially humans, the NPY antagonists may be given as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The preparation of suitable formulations for use in administering NPY antagonists is described in the literature, including European patent applications EP 614 911, EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041 , WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos. 5,552,411, 5,663,192 and 5,567,714; Japanese patent application JP 09157253; international patent applications WO 94/00486, WO 93/12139, WO 95/00161; US Patent No. 5,328,899; German patent application DE 393 97 97; European patent applications EP 355 794 and EP 355 793; and Japanese patent applications JP 06116284 and JP 07267988, the disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations will be well known to those skilled in the art. Combinations of NPY antagonists may be used.

The amounts of NPY antagonist in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed.

According to a further aspect of the invention there is provided a pharmaceutical formulation for use in aiding diuresis comprising an effective amount of a NPY antagonist.

The NPY antagonists may also be combined with other therapeutic agents which are useful in the treatment of diseases for which the aiding of diuresis is desirable, including agents which are useful in the treatment of cardiovascular diseases, for example β-adrenoreceptor antagonists, ACE-inhibitors, ANG II antagonists, renin inhibitors and calcium antagonists.

The NPY antagonists may also be combined with other diuretics including carbonic anhydrase inhibitors, "loop" or "high ceiling" diuretics, mercurial diuretics, osmotic diuretics, potassium-sparing diuretics and thiazides.

Suitable doses of the NPY antagonists in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients are 0.01 to 10 mg/kg body weight per day at peroral administration and 0.001 to 1.0 (e.g. 0.1) mg/kg body weight per minute at parenteral administration. According to a further aspect of the invention there is provided a method of aiding diuresis which comprises administering a therapeutically effective amount of a NPY antagonist to a patient.

For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the prophylaxis, of a condition.

The use and method described herein may have the advantage that, in the treatment of diuresis, NPY antagonists do not possess disadvantages of known diuretics, as discussed hereinbefore.

The invention is illustrated, but in no way limited, by the following example.

Example

The diuretic effect of NPY antagonists was demonstrated in clinical studies in man using the specific Y_l antagonist, (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)ethyl]arginine amide (me synthesis of which is disclosed in the applicant's co-pending Swedish patent application No. 9703414-4 at Example 4 and is described below).

14 healthy individuals were administered increasing doses (0.0002 to 0.0033 mg/kg/min) of the NPY antagonist as an infusion of the acetate salt over 20 minutes. As a comparison, 4 healthy individuals were given a 20 minute infusion of placebo (saline solution). The urine samples were collected 2 hours before dosing and 2 hours after the start of the infusion. The mean urine volume of the control group was 106 mL pre-dosing and 133.5 mL 2 hours after dosing. In the treatment group the pre-dosing urine volume was 128.4 mL and 192.8 mL 2 hours after dosing.

Thus, a marked increase of urine volume was observed after dosing of the NPY antagonist.

Synthesis of (R)-^ -(Diphenylacetyl)-(R)-N-fl-(4-hydroxyphenyl)ethyl]- arginine amide hydrochloride

(a) N^Boc-N^δ-Cbz-(R)-ornithine o-nitrophenyl ester

A solution N^Boc- -Cbz-(R)-oπιithine (25.0 g; 68.2 mmol; Boc is tert- butyloxycarbonyl and Cbz is benzyloxycarbonyl) and o-nitrophenol (19.0 g; 136.4 mmol) in pyridine (250 mL) was cooled to 0°C. Dicyclohexylcarbodiimide (13.4 g; 64.8 mmol) was added at 0°C. The solution was stirred at 0°C for several hours, warmed to room temperature and stirred overnight. The resulting heterogeneous solution was diluted with ethylacetate (EtOAc) and filtered. The filtrate was concentrated under reduced pressure to afford a thick oil. The oil was dissolved in a minimal amount of warm isopropanol and stirred. The resultant precipitate was collected via vacuum filtration and washed with isopropanol, then diethyl ether. Concentration of the isopropanol/ether filtrate and crystallization from isopropanol provided a second crop. The combined product was dissolved in EtOAc at room temperature and filtered. Concentration of the EtOAc gave the sub-title compound as a solid.

(b) (/?)-Ν²-(Boc)-Ν⁵-(Cbz)-( 2)-Ν-[l-(4-hydroxyphenyl)ethyl]ornithine amide

N^α-Boc-N^<LCbz-(R)-ornithine o-nitrophenyl ester (33 g; 66.8 mmol; from step (a) above) and (R)-4-hydroxy-α-methylbenzylamine (9.3 g; 68.2 mmol) were combined in CH₂C1₂ (600 mL). The resulting yellow solution was stirred at room temperature for 4 hours. When the coupling was complete, as determined by thin layer chromatography (TLC), the solution was concentrated under vacuum to give the crude product. The crude material was dissolved in EtOAc, washed with 0.5N NaOH (2 x 300 mL), saturated KHS0₄ (2 x 300 mL), brine (2 x 300 mL), dried over Na₂S0₄, filtered and concentrated to yield 30.1 g (61.9 mmol; 93 %) of the sub-title compound.

(c) (i?)-N⁵-(Cbz)-(Λ)-N-[l-(4-hydroxyphenyl)ethyl]ornithine amide hydrochloride

(R)-N²-(Boc)-N⁵-(Cbz)-(R)-N-[l-(4-hydrox>φhenyl)ethyl]ornithine amide (30.1 g; 61.98 mmol; from step (b) above) in EtOAc (250 mL) was treated with EtOAc saturated with hydrogen chloride (150 mL) at room temperature for 5 hours. The solution was concentrated under vacuum yielding (after chromatography on silica gel, eluting with CH₂Cl₂:methanol (80:20)) the sub-title compound (15.5 g; 60%).

(d) (jR)-N⁵-(Cbz)-N²-(Diphenylacetyl)-(Λ)-N-[l-(4-hydroxyphenyl)ethyl]- ormthine amide (R)-N⁵-(Cbz)-(R)-N-[l-(4-hydroxyphenyl)e l]ornithine amide hydrochloride (28.1 g; 66.6 mmol; from step (c) above) was dissolved in tetrahydrofuran (THF; 500 mL) and solid sodium bicarbonate (22.4 g; 266.4 mmol; 4 eq.) was slowly added. A solution of diphenylacetylchloride (21.4 g; 66.60 mmol) in THF was then slowly added dropwise over 30 minutes. The reaction was monitored by TLC analysis. After the reaction was judged complete, the solvent was removed under vacuum and the residue was dissolved in a mixture of THF, EtOAc and methanol and washed with saturated aqueous sodium bicarbonate, water, saturated KHS0₄ and brine. The organics were dried over Na₂S0₄, filtered and concentrated to dryness to yield 29.2 g (0.050 mol; 76%) of the sub-title compound.

(e) (/?)-N²-φiphenylacetyl)-(Λ)-N-[l-(4-hydroxyphenyl)ethyl]ornithine amide acetate

A solution of (R)-N⁵-(Cbz)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)- ethyljornithine amide (26.8 g; 46.23 mmol; from step (d) above) in acetic acid (HO Ac; 1L) was flushed with nitrogen prior to the addition of 10% Pd/C (2.5 g). The heterogeneous solution was briefly flushed with hydrogen and then stirred under 1 atmosphere of hydrogen for 3 hours. When the deprotection was complete, as determined by TLC analysis, the solution was filtered through a pad of Celite to remove the catalyst. The filtrate was evaporated at reduced pressure to give 24.3 g of the sub-title compound (after azeotroping with toluene).

< ) </?)-N«,N«*-bis(Cbz)-N²-(Diphenylacetyl)-(/?)-N-[l-(4-hydroxyphenyl)- ethyljarginine amide

(R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)emyl]ornithine amide acetate (5.5 g; 11.8 mmol; from step (e) above) and diisopropylethylamine (DiPEA; 4.0 mL; 22.9 mmol) in N,N-dimethylformamide (DMF; 100 mL) was treated with N,N¹-bis(Cbz)-S-methylisothiourea (6.14 g; 17.1 mmol) and stirred for 60 hours. Concentration under vacuum gave the crude product which was chromatographed on silica gel eluting with CH₂C1₂, then EtOAc to give pure sub-title compound as a white foam (6.6 g).

(g) ( ?)-Ν²-(Diphenylacetyl)-(Λ)-Ν-[l-(4-hydroxyphenyl)ethyl]arginine amide hydrochloride

(R)-N^ω ,N^ω ' -bis(Cbz)-N²-(diphenylacetyl)-(R)-N-[ 1 -(4-hydroxyphenyl)ethyl]- arginine amide (6.6 g; from step (f) above) in HO Ac (160 mL) was flushed with nitrogen prior to the addition of 10% Pd/C (w/w; 1.1 g). The heterogeneous solution was briefly flushed with hydrogen and then stirred under 1 atmosphere of hydrogen for 4 hours. When the deprotection was complete, as determined by TLC analysis, the solution was filtered through a pad of Celite to remove the catalyst. The filtrate was evaporated at reduced pressure to give the crude product. The crude acetate salt was dissolved in HC1 saturated methanol, treated with activated carbon, filtered, concentrated, and dried under vacuum for 5 hours yielding 2.75 g of the title compound. mp 150-153°C

[α]_D ²³ = + 57.4° (c = 1.0, methanol)

R_f 0.44 (EtOAc: methanol: concentrated ammonium hydroxide; 47:47:6) 1H NMR (CD₃OD) δ 1.38 (d, 3H), 1.50 (m, 2H), 1.69 (m, 1H),

1.79 (m, 1H), 3.09 (m, 2H), 4.39 (m, 1H), 4.86 (q, 1H), 5.11 (s, 1H), 6.71 (d, 2H), 7.09 (d, 2H), 7.25 (m, 10H), 8.15 (d, 1H, NH), 8.38 (d, 1H, NH)

Claims

1. The use of a NPY antagonist in the manufacture of a medicament for aiding diuresis.

2. The use of a NPY antagonist in the manufacture of a diuretic.

3. The use as claimed in Claim 1 wherein the diuresis is aided as part of the treatment of a disease in which the aiding of diuresis is desirable.

4. The use as claimed in Claim 3, wherein the disease is a hepatic, a renal or a pulmonary disease.

5. The use as claimed in Claim 3, wherein the disease is a cardiovascular disorder.

6. The use as claimed in Claim 5, wherein the disease is heart failure.

7. The use as claimed in Claim 3, wherein the disease is hypertension.

8. The use as claimed in any one of the preceding claims, wherein the NPY antagonist is (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)- ethyljarginine amide or a pharmaceutically acceptable salt thereof.

9. The use of (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)- ethyl]arginine amide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for aiding diuresis.

10. A method of aiding diuresis which comprises administering a merapeutically effective amount of a NPY antagonist to a patient.

11. A pharmaceutical formulation for use in aiding diuresis comprising an effective amount of a NPY antagonist.

12. A formulation as claimed in Claim 11 , wherein the NPY antagonist is (R)-N²-(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)ethyl]argήτine amide or a pharmaceutically acceptable salt thereof.

13. Use of a NPY antagonist for aiding diuresis by administering a NPY antagonist to a patient.

14. The use of a NPY antagonist for aiding diuresis.