Dosage regimen for a s1p receptor agonist

A method of treating a long chronic disease in a patient in need of such treatment, comprising administering to said patient an S1P receptor modulator or agonist in such a way that the patient's daily decrease in heart rate is approximatively 2 beats/min or less,

• wherein the S1P receptor modulator or agonist is
• a compound of formula I,
• wherein R1 is a straight- or branched (C12-22) 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, C1-4alkyl, aryl-C1-4alkyl, acyl or (C1-4alkoxy)carbonyl, and carbonyl, and/or
• which may have as a substituent C1-4alkoxy, C2-4alkenyloxy, C2-4alkynyloxy, arylC1-4alkyl-oxy, acyl, C1-4 alkylamino, C1-4alkylthio, acylamino, (C1-4alkoxy)carbonyl, (C1-4alkoxy)-carbonylamino, acyloxy, (C1-4alkyl)carbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy;
• or
• R1 is
• a phenylalkyl wherein alkyl is a straight- or branched (C6-20)carbon chain;
• or
• a phenylalkyl wherein alkyl is a straight- or branched (C1-30)carbon 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 substituted by halogen,
• a straight- or branched (C6-20)alkenyloxy,
• phenyl-C1-14alkoxy, halophenyl-C1-4alkoxy, phenyl-C1-14alkoxy-C1-14alkyl, phenoxy-C1-4alkoxy or phenoxy-C1-4alkyl,
• cycloalkylalkyl substituted by C6-20alkyl,
• heteroarylalkyl substituted by C6-20alkyl,
• heterocyclic C6-20alkyl or
• heterocyclic alkyl substituted by C2-20alkyl,
• 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 C1-4alkoxy, C2-4alkenyloxy, C2-4alkynyloxy, arylC1-4alkyloxy, acyl, C1-4alkyl-amino, C1-4alkylthio, acylamino, (C1-4alkoxy)carbonyl, (C1-4alkoxy)carbonylamino, acyloxy, (C1-4alkyl)carbamoyl, nitro, halogen, amino, hydroxy or carboxy;
• and
• each of R2, R3, R4 and R5, independently, is H, C1-4 alkyl or acyl
• or a pharmaceutically acceptable salt or hydrate thereof, or
• a compound of formula IIa or IIb
• wherein Xa is O, S, NR1s or a group —(CH2)na—, which group is unsubstituted or substituted by 1 to 4 halogen;
• na is 1 or 2, R1s is H or (C1-4)alkyl, which alkyl is unsubstituted or substituted by halogen;
• R1a is H, OH, (C1-4)alkyl or O(C1-4)alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen;
• R1b is H, OH or (C1-4)alkyl, wherein alkyl is unsubstituted or substituted by halogen;
• each R2a is independently selected from H or (C1-4)alkyl, which alkyl is unsubstituted or substituted by halogen;
• R3a is H, OH, halogen or O(C1-4)alkyl wherein alkyl is unsubstituted or substituted by halogen;
• and R3b is H, OH, halogen, (C1-4)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C1-4)alkyl wherein alkyl is unsubstituted or substituted by halogen;
• Ya is —CH2—, —C(O)—, —CH(OH)—, —C(═NOH)—, O or S, and R4a is
• (C4-14)alkyl or (C4-14)alkenyl;
• or a pharmaceutically acceptable salt or hydrate thereof.