WO2004010987A2

WO2004010987A2 - Use of s1p receptor agonists in heart diseases

Info

Publication number: WO2004010987A2
Application number: PCT/EP2003/008085
Authority: WO
Inventors: Volker Brinkmann; Gilles Feutren; Robert Paul Hof
Original assignee: Novartis Pharma GmbH Austria; Novartis AG
Current assignee: Novartis Pharma GmbH Austria; Novartis AG
Priority date: 2002-07-24
Filing date: 2003-07-23
Publication date: 2004-02-05
Anticipated expiration: 2005-01-24
Also published as: WO2004010987A3; US7910626B2; JP2005535679A; US20090029922A1; AU2003258534A1; JP2014037442A; JP2010241829A; US20050222092A1; US20110136739A1; GB0217152D0

Abstract

The invention relates to the use of a sphingosine-1-phosphate receptor agonist in the treatment of heart diseases.

Description

Use of S1 P receptor agonists in heart diseases

The present invention relates to a new use for a sphingosine-1 -phosphate (S1P) receptor agonist, particularly in the treatment of heart diseases.

S1 P receptor agonists are accelerating lymphocyte homing agents which elicit a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, without evoking a generalized immunosuppression. Naive cells are sequestered; CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's patches (PP), and thus for example infiltration of cells into transplanted organs is inhibited.

S1 P receptor agonists are typically sphingosine analogues, such as 2-substituted 2-amino- propane-1 ,3-diol or 2-amino-propanol derivatives, e.g. a compound comprising a group of formula X

wherein

Z is H; d-βalkyl; C₂-₆alkenyl; C₂-₆alkynyl; phenyl; phenyl substituted by OH; C_halky! substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃.₈cyclo- alkyl, phenyl and phenyl substituted by OH; or CH₂-R _z wherein R_4z is OH, acyloxy or a residue of formula (a)

wherein Z^ is a direct bond or O, preferably O; each of R_5z and R_6z, independently, is H, or C^alkyl optionally substituted by 1 , 2 or 3 halogen atoms;

R_1z is OH, acyloxy or a residue of formula (a); and each of R_2z and R_3z> independently, is H, Cι-₄alkyl or acyl.

Group of formula X is a functional group attached as a terminal group to a moiety which may be hydrophilic or lipophilic and comprise one or more aliphatic, alicyclic, aromatic and/or heterocyclic residues, to the extent that the resulting molecule wherein at least one of Z and Rι_z is or comprises a residue of formula (a), signals as an agonist at one of more sphingosine-1 -phosphate receptor.

S1 P receptor agonists are compounds which signal as agonists at one or more sphingosine- 1 phosphate receptors, e.g. S1 P1 to S1P8. Agonist binding to a S1 P receptor may e.g. result in dissociation of intracellular heterotrimeric G-proteins into Gα-GTP and Gβγ-GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signaling pathways/kinases. The binding affinity of S1 P receptor agonists may be measured as described at paragraph I. below. Preferred S1 P receptor agonists are those targeting e.g. S1P2 and/or S1P3.

Examples of appropriate S1 P receptor agonists are, for example:

- Compounds as disclosed in EP627406A1 , e.g.a compound of formula I

wherein Ri is a straight- or branched (Cι₂-₂₂)carbon chain

- which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR₆, wherein R₆ is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or

- which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or

- a phenylalkyl wherein alkyl is a straight- or branched (C₆.₂o)carbon chain; or

- a phenylalkyl wherein alkyl is a straight- or branched (C sojcarbon chain wherein said phenylalkyl is substituted by

- a straight- or branched (C₆-₂₀)carbon chain optionally substituted by halogen,

- a straight- or branched (C₆-₂₀)alkoxy chain optionally substitued by halogen,

- a straight- or branched (C₆.₂₀)alkenyloxy,

- phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl,

- cycloalkylalkyl substituted by C₆-₂oalkyl,

- heteroarylalkyl substituted by C₆-₂oalkyl,

- heterocyclic C₆-₂oalkyl or - heterocyclic alkyl substituted by C₂.₂oalkyl, and wherein the alkyl moiety may have

- in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR₆, wherein R₆ is as defined above, and

- as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R₂, R₃, R₄ and R₅, independently, is H, C^ alkyl or acyl or a pharmaceutically acceptable salt thereof;

- Compounds as disclosed in EP 1002792A1, e.g. a compound of formula II

wherein m is 1 to 9 and each of R'_2> R'₃, R' and R'₅, independently, is H, alkyl or acyl, or a pharmaceutically acceptable salt thereof;

- Compounds as disclosed in EP0778263 A1, e.g. a compound of formula III

wherein W is H; C_halky!, C₂-₆alkenyl or C₂-₆alkynyl; unsubstituted or by OH substituted phenyl; R"₄O(CH₂)_n; or C^alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃-₈cycloalkyl, phenyl and phenyl substituted by OH; X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p-1) of carbon atoms, e.g. substituted by 1 to 3 substitutents selected from the group consisting of C^e alkyl, OH, C- ^alkoxy, acyloxy, amino, Ci-ealkylamino, acylamino, oxo, haloCi-βalkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C_halky!, OH, C^alkoxy, acyl, acyloxy, amino, C^alkylamino, acylamino, haloCι-₆alkyl and halogen; Y is H, C_halky!, OH, C^alkoxy, acyl, acyloxy, amino, d. ₆alkylamino, acylamino, haloC^alkyl or halogen, Z₂ is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6<p+q<23, m' is

1 , 2 or 3, n is 2 or 3, each of R" R"₂, R"₃ and R"₄, independently, is H, C^alkyl or acyl, or a pharmaceutically acceptable salt thereof,

- Compounds as disclosed in WO02/18395, e.g. a compound of formula IVa or IVb

wherein X_a is O, S, NRι_s or a group -(CH₂)_na-, which group is unsubstituted or substituted by 1 to 4 halogen; n_a is 1 or 2, R_1s is H or (C^Jalkyl, which alkyl is unsubstituted or substituted by halogen; R_1a is H, OH, (C₁.₄)al yl or

wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R_1b is H, OH or (d^alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R_2a is independently selected from H or (C^alkyl, which alkyl is unsubstituted or substitued by halogen; R_3a is H, OH, halogen or OfC^alkyl wherein alkyl is unsubstituted or substituted by halogen; and R_3b is H, OH, halogen, (C^alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or ©(Chalky! wherein alkyl is unsubstituted or substituted by halogen; Y_a is -CH₂-, -C(O)-, -CH(OH)-, -C(=NOH)-, O or S, and R_4a is (C₄. ι )alkyl or (C₄.₁₄)alkenyl; or a pharmaceutically acceptable salt or hydrate thereof; - Compounds as disclosed in WO 02/076995, e.g. a compound of formula V

wherein m_c is 1 , 2 or 3;

Xc is O or a direct bond; Ric is H; -₆ alkyl optionally substituted by OH, acyl, halogen, C₃-ι₀cycloalkyl, phenyl or hydroxy-phenylene; C₂-₆alkenyl; C^alkynyl; or phenyl optionally substituted by OH; R_2c is

wherein R_5c is H or C_halky! optionally substituted by 1 , 2 or 3 halogen atoms, and R_6c is H or ^alkyl optionally substituted by halogen; each of R and R_4c, independently, is H,

optionally substituted by halogen, or acyl, and R_e is C₁₃.₂oalkyl which may optionally have in the chain an oxygen atom and which may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)

wherein R_7c is H, ^alkyl or C^alkoxy, and R_8c is substituted d-^alkanoyl, phenylCι-ι₄alkyl wherein the Ci-πalkyl is optionally substituted by halogen or OH, cycloalkylC^alkoxy or phenylCι-₁ alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, C_halky! and/or

phenylC₁.₁₄alkoxy- d-ualkyl, phenoxyd-₁₄alkoxy or phenoxyd-ι₄alkyl,

R₀ being also a residue of formula (a) wherein R_8c is Cι- ₄alkoxy when Rι_c is d.₄alkyl, C₂-₆alkenyl or C₂-₆alkynyl, or a compound of formula VI

wherein n_x is 2, 3 or 4 R_1x is H; optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; C₂-₆alkenyl; C₂^alkynyl; or phenyl optionally substituted by OH;

R_2x is H, C alkyl or acyl each of R_3x and R_4x, independently is H, C^alkyl optionally substituted by halogen or acyl,

R_5x is H, d^alkyl or Ct^alkoxy, and

R_6x is 0^₂₀ alkanoyl substituted by cycloalkyl; cyloalkylC_M^Ikoxy wherein the cycloalkyl ring is optionally substituted by halogen, C^alkyl and/or ^alkoxy; phenylCι.₁₄alkoxy wherein the phenyl ring is optionally substituted by halogen, C_halky! and/or d^alkoxy,

R_6x being also C -₁₄alkoxy when R_1x is C^alkyl substituted by OH, or pentyloxy or hexyloxy when R_1x is C^akyl, provided that R_6xis other than phenyl-butylenoxy when either R_5x is H or R_1x is methyl, or a pharmaceutically acceptable salt thereof;

- Compounds as disclosed in WO02/06268AI, e.g. a compound of formula VII

wherein each of R_1d and R_2d, independently, is H or an amino-protecting group; R_3d is hydrogen, a hydroxy-protecting group or a residue of formula

_ _{p <}OR_9d

|| OR_8d o R_4d is lower alkyl; n_d is an integer of 1 to 6;

X_d is ethylene, vinylene, ethynylene, a group having a formula - D-CH₂- (wherein D is carbonyl, - CH(OH)-, O, S or N), aryl or aryl substituted by up to three substitutents selected from group a as defined hereinafter;

Y_d is single bond, C^oalkylene, Cι-₁₀alkylene which is substituted by up to three substitutents selected from groups a and b, d.₁₀alkylene having O or S in the middle or end of the carbon chain, or C^oalkylene having O or S in the middle or end of the carbon chain which is substituted by up to three substituents selected from groups a and b; R_5d is hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl substituted by up to three substituents selected from groups a and b, aryl substituted by up to three substituents selected from groups a and b, or heterocycle substituted by up to three substituents selected from groups a and b; each of R_6d and R_7d, independently, is H or a substituent selected from group a; each of R_8d and R_9d, independently, is H or d^alkyl optionally substituted by halogen;

<group a > is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono-lower alkylamino, di-lower alkylamino, lower aliphatic acylamino, cyano or nitro; and

<group b > is cycloalkyl, aryl, heterocycle, each being optionally substituted by up to three substituents selected from group a; with the proviso that when R_5d is hydrogen, Y_d is a either a single bond or linear d-ι₀ alkylene, or a pharmacologically acceptable salt or ester thereof;

-Compounds as disclosed in JP-14316985 (JP2002316985), e.g. a compound of formula VIII:

wherein Rι_e,R2e. 3e,R β» 5e.R6e. 7e, n_β, X_θ and Y_θ are as disclosed in JP-14316985; or a pharmacologically acceptable salt or ester thereof;

-Compounds as disclosed in WO 03/29184 and WO 03/29205, e.g. compounds of formula

IX

wherein X_f is O or S, and R_1f, R_2f, R_3{ and n_f are as disclosed in WO 03/29184 and O3/29205, each of R_4f and R_5f, independently is H or a residue of formula

wherein each of R_8f and Rg_f, independently, is H or C^alkyl optionally substituted by halogen; e.g. 2-amino-2-[4-(3-benzyIoxyphenoxy)-2-chlorophenyl]propyl-1 ,3-propane-diol or 2-amino-2-[4-(benzyloxyphenylthio)-2- chlorophenyl]propyl-1 ,3-propane-diol, or a pharmacological salt thereof.

In each case where citations of patent applications are given, the subject matter relating to the compounds is hereby incorporated into the present application by reference.

Acyl may be a residue R_y-CO- wherein R_y is C_halky!, C₃-₆cycloalkyl, phenyl or phenyl-Ci- ₄alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.

When in the compounds of formula I the carbon chain as Ri is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.

Preferred compounds of formula I are those wherein Ri is C₁₃.₂₀alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R_n is phenylalkyl substituted by C₆.₁₄-alkyl chain optionally substituted by halogen and the alkyl moiety is a d.₆alkyl optionally substituted by hydroxy. More preferably, R^ is phenyl-Cι-₆alkyl substituted on the phenyl by a straight or branched, preferably straight, C₆-ι₄alkyl chain. The C₆.ι alkyl chain may be in ortho, meta or para, preferably in para.

Preferably each of R₂ to R₅ is H.

A preferred compound of formula I is 2-amino-2-tetradecyl-1 ,3-propanediol. A particularly preferred S1P receptor agonist of formula I is FTY720, i_e. 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1 ,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:

A preferred compound of formula II is the one wherein each of R'₂ to R'₅ is H and m is 4, i.e. 2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1 ,3-diol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound B), e.g the hydrochloride. A preferred compound of formula III is the one wherein W is CH₃, each of R"ι to R"₃ is H, Z₂ is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound C), e.g. the hydrochloride. The R-enantiomer is particularly preferred.

A preferred compound of formula IVa is the FTY720-phosphate (R_2a is H, R_3a is OH, X_a is O, R_1a and R_1b are OH). A preferred compound of formula IVb is the Compound C-phosphate (R_2a is H, R_3b is OH, X_a is O, R_1a and R_1b are OH, Y_a is O and R_4a is heptyl). A preferred compound of formula V is Compound B-phosphate.

A preferred compound of formula V is phosphoric acid mono-[(R)-2-amino-2-methyl-4-(4- pentyloxy-phenyl)-butyl]ester.

A preferred compound of formula VIII is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)- benzo[b]thien-6-yl]-2-methylbutan-1-ol.

When the compounds of formulae I to IX have one or more asymmetric centers in the molecule, the present invention is to be understood as embracing the various optical isomers, as well as racemates, diastereoisomers and mixtures thereof are embraced. Compounds of formula III or IVb, when the carbon atom bearing the amino group is asymmetric, have preferably the R-configuration at this carbon atom.

Examples of pharmaceutically acceptable salts of the compounds of the formulae I to IX include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine. The compounds and salts of the methods of the present invention encompass hydrate and solvate forms.

The S1P receptor agonists have, on the basis of observed activity, e.g. homing of lymphocytes, e.g. as described in EP627406A1 or USP 6,004,565, been found to be useful e.g. as immunosuppressant, e.g. in the treatment of acute allograft rejection.

It has now been found that S1 P receptor agonists have a beneficial effect in heart diseases, e.g. in chronic heart failure, congestive heart failure, complications of cardiovascular surgery, peri-operative hypertension, unstable angina or acute myocardial infarction.

Chronic heart failure is a clinical syndrome characterized by distinctive symptoms and signs resulting from disturbances in cardiac output, e.g. inadequate for the body's needs. It is often associated with other changes such as cardiac hypertrophy and myocardial ischemia. Congestive heart failure (CHF), or heart failure, is a condition in which the heart cannot pump enough blood to the body's other organs. As blood flow out of the heart slows, blood returning to the heart through the veins backs up, causing congestion in the tissues.

In accordance with the particular findings of the present invention, there is provided:

1.1 A method for treating chronic heart failure in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1 P receptor agonist;

1.2 A method for improving heart energy efficiency and/or reducing its oxygen needs in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1 P receptor agonist;

1.3 A method for improving cardiac output in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1P receptor agonist;

1.4 A method for treating arrhythmia or tachyarrhythmia, e.g. atrial fibrillation, atrial flutter or sinus ventricular tachycardia, in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1 P receptor agonist;

1.5 A method for treating congestive heart failure in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1P receptor agonist;

The method of the invention is also appropriate for patients with acutely decompensated congestive heart failure and patients with pre-existing arrythmias.

1.6 A method for treating complications of cardiovascular surgery, e.g. peri-operative hypertension, in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1 P receptor agonist;

1.7 A method for treating unstable angina in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1 P receptor agonist;

1.8 A method for treating acute myocardial infarction in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a S1 P receptor agonist. 2. A S1 P receptor agonist, e.g. a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method as defined under 1.1 to 1.8 above; or

3. A S1 P receptor agonist, e.g. a compound of formula I or a pharmaceutically acceptable salt thereof, for use in the preparation of a pharmaceutical composition for use in a method as defined under 1.1 to 1.8 above; or

4. A pharmaceutical composition for use in a method as defined under 1.1 to 1.8 above comprising a S1 P receptor agonist, e.g. a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable diluents or carriers therefor.

Utility of the S1 P receptor agonists, e.g. in the treatment of heart diseases, as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described.

A. Binding affinity of S1 P receptor agonists to individual human S1 P receptors may be determined in following assays:

Transient transfection of human S1P receptors into HEK293 cells S1 P receptors and Gj proteins are cloned, and equal amounts of 4 cDNAs for the S1P receptor, G_rα, G_rβ and G_rγ are mixed and used to transfect monolayers of HEK293 cells using the calcium phosphate precipitate method (M. Wigler et al., Cell. 1977;11;223 and DS. Im et al., Mol. Pharmacol. 2000;57;753). Briefly, a DNA mixture containing 25 μg of DNA and 0.25 M CaCI is added to HEPES-buffered 2 mM Na₂HPO₄. Subconfluent monolayers of HEK293 cells are poisoned with 25 mM chloroquine, and the DNA precipitate is then applied to the cells. After 4 h, the monolayers are washed with phosphate-buffered saline and refed media (90% 1:1 Dulbecco's modified essential media (DMEM):F-12 + 10% fetal bovine serum). The cells are harvested 48-72 h after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCI₂, 1 EDTA, pH 7.4) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer. After centrifugation at 800xg, the supernatant is diluted with HME without sucrose and centrifuged at 100,000xg for 1h. The resulting pellet is rehomogenized and centrifuged a second hour at 100,000xg. This crude membrane pellet is resuspended in HME with sucrose, aliquoted, and snap-frozen by immersion in liquid nitrogen. The membranes are stored at 70°C. Protein concentration is determined spectroscopically by Bradford protein assay.

GTPγS binding assay using S1P receptor/HEK293 membrane preparations GTPγS binding experiments are performed as described by DS. Im et al., Mol. Pharmacol. 2000; 57:753. igand-mediated GTPγS binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCI, 10 MgCI₂, pH 7.5) using 25 μg of a membrane preparation from transiently transfected HEK293 cells. Ligand is added to membranes in the presence of 10 μM GDP and 0.1 nM [³⁵S]GTPγS (1200 Ci/mmol) and incubated at 30°C for 30 min. Bound GTPγS is separated from unbound using the Brandel harvester (Gaithersburg, MD) and counted with a liquid scintillation counter.

B. In vivo

The effect of a S1P receptor agonist, e.g. a compound of formula I on chronic heart failure is tested in rabbits where heart failure is induced as a consequence of a large myocardial infarction (RP. Hof et al. J. Cardiovasc. Pharmacol., 1991, 18,361-368). The changes of atrial natriuretic factor or baroflex sensitivity are a reliable indicator of the status of the heart failure in this animal model. When administered i.v. at a dose of from 0.1 to 10 mg/kg, a S1P receptor agonist, e.g. the compounds of formula I, e.g. Compound A, have a beneficial effect on the heart failure.

C. Clinical Trial

Patients with class IV congestive heart failure are selected: they have elevated intracardiac filling pressures (orthopnea, abdominal discomfort attributed to hepato-splenic congestion, peripheral edema, ascites, rales and jugular venous distension) and inadequate peripheral perfusion. Patients receive a daily dose of the S1 P receptor agonist to be tested, e.g. Compound A in free form or a pharmaceutically acceptable salt thereof, e.g. orally, during 2 or 4 weeks or 3 months. The dose may be escalated if necessary. Patients are followed-up for 6 months. Following data are collected during hospitalization and the 6 month follow-up: blood pressure, weight, electrocardiogram, echocardiogram, serum electrolytes, natriuretic hormone profile and exercise stress tests. A beneficial effect is observed.

Daily dosages required in practicing the method of the present invention will vary depending upon, for example, the compound used, the host, the mode of administration, the severity of the condition to be treated. A preferred daily dosage range is about from 0.03 to 2.5 mg/kg per day as a single dose or in divided doses. Suitable daily dosages for patients are on the order of from e.g. 0.5 to 50 mg p.o. Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 25 mg active ingredient, e.g. FTY720, e.g. in hydrochloride form, together with one or more pharmaceutically acceptable diluents or carriers therefor. As an altemative, the S1 P receptor agonist may also be administered twice or three times a week, e.g. at a dosage as indicated above.

The S1 P receptor agonist may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions. Pharmaceutical compositions comprising a S1 P receptor agonist, e.g. a compound of formula I may be manufactured in conventional manner, e.g. as described in EP-A1 -627,406 or in EP-A1 - 1,002,792.

The S1 P receptor agonists may be administered as the sole ingredient or together with other drugs, e.g. an angiotensin converting enzyme inhibitor, e.g. benazepril, captopril, quinapril, ramipril, enalapril, linisopril or moexipril, an angiotensin II receptor antagonist, e.g. valsartan, losartan, irbesartan, eprosartan, forasartan, olmesartan, ripisartan, saprisartan, candesartan, tasosartan or telmisartan, a synthetic form of B-type natriuretic peptide (BNP) or other human B-type natriuretic peptide, e.g. nesiritide, other drugs used in patients with heart failure, e.g. digoxin or digitalis preparations, a β-blocker, e.g. propanolol, atenolol, a β-adrenergic receptor agonist, e.g. salbutamol, an α-2 receptor agonist, e.g. dexmetomidine, a calcium antagonist, e.g. cilnidipine, or a diuretic, e.g. hydrochlorothiazide or spironolactone.

Where the S1 P receptor agonists are administered in conjunction with other drugs, dosages of the co-administered compound will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition to be treated, and so forth. The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

In accordance with the foregoing the present invention provides in a yet further aspect:

5. A pharmaceutical combination comprising a) a first agent which is a S1 P receptor agonist, e.g. a compound of formula I, e.g. FTY720, or Compound B or C or a compound of formula V or VIII, or a phosphate thereof, or a pharmaceutically acceptable salt thereof, and b) a co-agent, e.g. a second drug agent as defined above.

6. A method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a S1P receptor agonist, e.g. a compound of formula I, e.g. FTY720, or Compound B or C, or a compound of formula V or VIII, or a phosphate thereof, or a pharmaceutically acceptable salt thereof, and a second drug substance, e.g. as indicated above.

S1 P receptor agonists are well tolerated at dosages required for use in accordance with the present invention. For example, FTY720 has an acute LD_S0 > 10 mg/kg p.o. in rats and monkeys.

The administration of a pharmaceutical combination of the invention results in a beneficial effect, e.g. a synergistic therapeutic effect, less side-effects or an improved quality of life compared to a monotherapy.

Claims

1. A S1 P receptor agonist for use in the preparation of a pharmaceutical composition for use in the treatment of chronic heart failure, congestive heart failure, arrhythmia or tachyarrythmia, unstable angina, acute myocardial infarction or complications from cardiac surgery or for improving heart energy efficiency or cardiac output.

2. A S1 P receptor agonist for use in the treatment of chronic heart failure, congestive heart failure, arrhythmia or tachyarrythmia, unstable angina, acute myocardial infarction or complications from cardiac surgery or for improving heart energy efficiency or cardiac output.

3. A pharmaceutical composition for use in the treatment of chronic heart failure, congestive heart failure, arrhythmia or tachyarrythmia, unstable angina, acute myocardial infarction or complications from cardiac surgery, or for improving heart energy efficiency or cardiac output, comprising a S1 P receptor agonist together with one or more pharmaceutically acceptable diluents or carriers therefor.

4. A method for treating chronic heart failure, congestive heart failure, arrhythmia or tachyarrythmia, unstable angina, acute myocardial infarction or complications from cardiac surgery or for improving heart energy efficiency or cardiac output in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a S1 P receptor agonist.

5. A pharmaceutical combination comprising a) a first agent which is a S1 P receptor agonist, and b) a co-agent selected from an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a synthetic form of B-type natriuretic peptide (BNP) or other human B-type natriuretic peptide, a β-blocker, a β-adrenergic receptor agonist, an α- 2 receptor agonist, a calcium antagonist and a diuretic.

6. A method according to claim 4 comprising co-administration concomitantly or in sequence, of a therapeutically effective amount of a S1P receptor agonist and a co-agent selected from an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a synthetic form of B-type natriuretic peptide (BNP) or other human B-type natriuretic peptide, a β-blocker, a β-adrenergic receptor agonist, an α-2 receptor agonist, a calcium antagonist and a diuretic.

7. Use, a pharmaceutical composition, a pharmaceutical combination or a method according to claims 1 to 6, wherein the S1 P receptor agonist is selected from a compound of formula I

wherein R^ is a straight- or branched (C₁₂.₂₂)carbon chain

R is

- a phenylalkyl wherein alkyl is a straight- or branched (Cι.₃o)carbon chain wherein said phenylalkyl is substituted by

- a straight- or branched (C₆.₂o)carbon chain optionally substituted by halogen,

- a straight- or branched (C₆.₂₀)alkoxy chain optionally substitued by halogen,

- a straight- or branched

- cycloalkylalkyl substituted by C₆.₂oalkyl,

- heteroarylalkyl substituted by C₆.₂₀alkyl,

- heterocyclic C₆.₂₀alkyl or

- heterocyclic alkyl substituted by C₂.₂₀alkyl, and wherein the alkyl moiety may have

- as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R₂, R₃, R and R₅, independently, is H, ^ alkyl or acyl; a compound of formula II

wherein m is 1 to 9 and each of R'₂₎ R'₃, R'₄ and R'₅₎ independently, is H, alkyl or acyl, a compound of formula III

NR-' R"

W -C ¹ -Z V⁼V

-^2~ ^~*xX

(CH₂)_m.OR"₃

wherein W is H; d-₆alkyl, C₂^alkenyl or C₂.₆alkynyl; unsubstituted or by OH substituted phenyl; R"₄O(CH₂)_n; or Cι-₆alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C₃.₈cycloalkyl, phenyl and phenyl substituted by OH;

X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p-1) of carbon atoms, e.g. substituted by 1 to 3 substitutents selected from the group consisting of d-₆ alkyl, OH, d.₆alkoxy, acyloxy, amino, d.₆alkylamino, acylamino, oxo, halod.₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C^alkyl, OH, d.₆alkoxy, acyl, acyloxy, amino, d-₆alkylamino, acylamino, halod.₆alkyl and halogen; Y is H, d^alkyl, OH, d.₆alkoxy, acyl, acyloxy, amino, d-

₆alkylamino, acylamino, halod-ealkyl or halogen, Z₂ is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6<p+q<23, m' is

1 , 2 or 3, n is 2 or 3, each of R"_1f R"₂, R"₃ and R"₄, independently, is H, d^alkyl or acyl; a compound of formula IVa or IVb

wherein X_a is O, S, NR_1s or a group -(CH₂)na-ι which group is unsubstituted or substituted by 1 to 4 halogen; n_a is 1 or 2, Rι_s is H or (d-^alkyl, which alkyl is unsubstituted or substituted by halogen; R_1a is H, OH, (d-^alkyl or ©( -^alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R_1b is H, OH or (Cι-₄)alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R_2a is independently selected from H or (d.₄)alkyl, which alkyl is unsubstituted or substitued by halogen; R_3a is H, OH, halogen or O(C₁-₄)alkyl wherein alkyl is unsubstituted or substituted by halogen; and R_3b is H, OH, halogen, (d-^alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C_M)alkyl wherein alkyl is unsubstituted or substituted by halogen; Y_a is -CH₂-, -C(O)-, -CH(OH)-, -C(=NOH)-, O or S, and R_4a is (C₄. ₁₄)alkyl or (C₄.₁₄)alkenyl; and a compound of formula V

^l1C _4cR₃cN- (CH₂)m_c-X_cR '₂2c- V

wherein m_c is 1 , 2 or 3; X_c is O or a direct bond;

R_1c is H; d-₆ alkyl optionally substituted by OH, acyl, halogen, C₃-ι₀cycloalkyl, phenyl or hydroxy-phenylene; C₂-₆alkenyl; C₂-₆alkynyl; or phenyl optionally substituted by OH; R_2c is

wherein R_5c is H or C_halky! optionally substituted by 1 , 2 or 3 halogen atoms, and R_6o is H or d^alkyl optionally substituted by halogen; each of R_3c and R_4o, independently, is H, C_halky! optionally substituted by halogen, or acyl, and R₀ is C₁₃.₂₀alkyl which may optionally have in the chain an oxygen atom and which may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)

wherein R_7c is H,

and R_8c is substituted d-₂₀alkanoyl, phenyld-₁ alkyl wherein the C_halky! is optionally substituted by halogen or OH, cycloalkylCι-ι alkoxy or phenyld.₁ alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, d^alkyl and/or d^alkoxy, phenyld-₁₄alkoxy- d-ι₄alkyl, phenoxyCι. alkoxy or phenoxyd.₁₄alkyl,

R₀ being also a residue of formula (a) wherein R_8o is Cι-ι₄alkoxy when Rι_c is d. aikyl, C₂-₆alkenyl or C₂^alkynyl, or a compound of formula VI

wherein n_x is 2, 3 or 4

R_1x is H; Cι-₆alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; C₂^alkenyl; C₂.₆alkynyl; or phenyl optionally substituted by OH; R_2x is H, C .^ alkyl or acyl each of R_3x and R_4x, independently is H, d^alkyl optionally substituted by halogen or acyl, R_5x is H, C_halky! or C^alkoxy, and R_6x is d-2o alkanoyl substituted by cycloalkyl; cyloalkyld-₁₄alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, d^alkyl and/or d^alkoxy; phenyld-₁ alkoxy wherein the phenyl ring is optionally substituted by halogen, d^alkyl and/or d^alkoxy,

R_6x being also C₄.ι alkoxy when R_1x is C₂-₄alkyI substituted by OH, or pentyloxy or hexyloxy when R_1x is d^akyl, provided that R_6xis other than phenyl-butylenoxy when either R_5x is H or Rι_x is methyl, or a pharmaceutically acceptable salt thereof.