U.S. patent application number 13/310941 was filed with the patent office on 2012-09-27 for use of s1p receptor modulator.
Invention is credited to Yves-Alain Barde, Graeme Bilbe, Ruben Deogracias, Rainer R. Kuhn, Tomoya Matsumoto, Anis Khusro Mir, Anna Svenja Schubart.
Application Number | 20120245129 13/310941 |
Document ID | / |
Family ID | 39588961 |
Filed Date | 2012-09-27 |
United States Patent
Application |
20120245129 |
Kind Code |
A1 |
Barde; Yves-Alain ; et
al. |
September 27, 2012 |
USE OF S1P RECEPTOR MODULATOR
Abstract
Use of an S1P receptor modulator in the treatment or prevention
of a disease or condirion dependent on brain-derived neurotrophic
factor (BDNF) expression.
Inventors: |
Barde; Yves-Alain; (Basel,
CH) ; Bilbe; Graeme; (Neuchatel, CH) ;
Deogracias; Ruben; (Basel, CH) ; Kuhn; Rainer R.;
(Riehen, CH) ; Matsumoto; Tomoya; (Basel, CH)
; Mir; Anis Khusro; (Bartenheim, FR) ; Schubart;
Anna Svenja; (Basel, CH) |
Family ID: |
39588961 |
Appl. No.: |
13/310941 |
Filed: |
December 5, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12598771 |
Nov 4, 2009 |
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PCT/EP2008/055405 |
May 1, 2008 |
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13310941 |
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60915985 |
May 4, 2007 |
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Current U.S.
Class: |
514/114 ;
514/443; 514/640; 514/653 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/137 20130101; A61P 25/00 20180101; A61P 25/24 20180101;
A61P 3/04 20180101; A61P 3/10 20180101; A61P 25/16 20180101; A61K
31/145 20130101; A61P 25/14 20180101; A61P 25/20 20180101; A61P
37/00 20180101; A61P 17/02 20180101; A61P 25/22 20180101; A61P
25/28 20180101; A61K 31/397 20130101; A61P 43/00 20180101; A61K
31/138 20130101 |
Class at
Publication: |
514/114 ;
514/653; 514/640; 514/443 |
International
Class: |
A61K 31/661 20060101
A61K031/661; A61K 31/15 20060101 A61K031/15; A61K 31/381 20060101
A61K031/381; A61P 25/24 20060101 A61P025/24; A61P 25/00 20060101
A61P025/00; A61P 25/28 20060101 A61P025/28; A61P 3/04 20060101
A61P003/04; A61K 31/137 20060101 A61K031/137; A61P 3/10 20060101
A61P003/10 |
Claims
1. A method for preventing, inhibiting or treating a condition
effected by brain-derived neurotrophic factor, production, in a
subject in need thereof, comprising administering to said subject a
therapeutically effective amount of an sphingosine-1 phosphate
receptor modulator other than
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a
pharmaceutically acceptable salt thereof, wherein said S1P receptor
modulator is selected from: (a) Compounds of the formula I
##STR00019## wherein X is O, S, SO or SO.sub.2; R.sub.1 is halogen,
trihalomethyl, OH, C.sub.1-7alkyl, C.sub.1-4alkoxy,
trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy,
cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH.sub.2--OH,
CH.sub.2--CH.sub.2--OH, C.sub.1-4alkylsulfonyl, benzylthio, acetyl,
nitro or cyano, or phenyl, phenylC.sub.1-4alkyl or
phenyl-C.sub.1-4alkoxy each phenyl group thereof being optionally
substituted by halogen, CF.sub.3, C.sub.1-4alkyl or
C.sub.1-4alkoxy; R.sub.2 is H, halogen, trihalomethyl,
C.sub.1-4alkoxy, C.sub.1-7alkyl, phenethyl or benzyloxy; R.sub.3H,
halogen, CF.sub.3, OH, C.sub.1-7alkyl, C.sub.1-4alkoxy, benzyloxy,
phenyl or C.sub.1-4alkoxymethyl; each of R.sub.4 and R.sub.5,
independently is H or a residue of formula (a) ##STR00020## wherein
each of R.sub.8 and R.sub.9, independently, is H or C.sub.1-4alkyl
optionally substituted by halogen; and n is an integer from 1 to 4;
(b) Compounds of formula II ##STR00021## wherein R.sub.1a is
halogen, trihalomethyl, C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, C.sub.1-4alkyl-sulfonyl, aralkyl, optionally
substituted phenoxy or aralkyloxy; R.sub.2a is H, halogen,
trihalomethyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, aralkyl or
aralkyloxy; R.sub.3a is H, halogen, CF.sub.3, C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio or benzyloxy; R.sub.4a is H,
C.sub.1-Alkyl, phenyl, optionally substituted benzyl or benzoyl, or
lower aliphatic C.sub.1-5acyl; R.sub.5a is H, monohalomethyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy-methyl, C.sub.1-4alkyl-thiomethyl,
hydroxyethyl, hydroxypropyl, phenyl, aralkyl, C.sub.2-4alkenyl or
-alkynyl; R.sub.6a is H or C.sub.1-4alkyl; R.sub.7a is H,
C.sub.1-4alkyl or a residue of formula (a) as defined above, X, is
O, S, SO or SO.sub.2; and n.sub.a is an integer of 1 to 4; (c)
Compounds of the formula III ##STR00022## wherein R.sub.1 is a
straight- or branched (C.sub.12-22)chain which may have in the
chain a bond or a hetero atom selected from a double bond, a triple
bond, O, S, NR.sub.6, wherein R.sub.6 is H, C.sub.1-4alkyl,
aryl-C.sub.1-4alkyl, acyl or (C.sub.1-4alkoxy)carbonyl, and
carbonyl, and/or which may have as a substituent C.sub.1-4alkoxy,
C.sub.2-4alkenyloxy, C.sub.2-4alkynyloxy, arylC.sub.1-4alkyl-oxy,
acyl, C.sub.1-4alkylamino, C.sub.1-4alkylthio, acylamino,
(C.sub.1-4alkoxy)carbonyl, (C.sub.1-4alkoxy)-carbonylamino,
acyloxy, (C.sub.1-4alkyl)carbamoyl, nitro, halogen, amino,
hydroxyimino, hydroxy or carboxy; or R.sub.1 is a phenylalkyl
wherein alkyl is a straight- or branched (C.sub.6-20)carbon chain;
or a phenylalkyl wherein alkyl is a straight- or branched
(C.sub.1-30)carbon chain wherein said phenylalkyl is substituted by
a straight- or branched (C.sub.6-20)carbon chain optionally
substituted by halogen, a straight- or branched (C.sub.6-20)alkoxy
chain optionally substituted by halogen, a straight- or branched
(C.sub.6-20)alkenyloxy, phenyl-C.sub.1-14alkoxy,
halophenyl-C.sub.1-4alkoxy,
phenyl-C.sub.1-14alkoxy-C.sub.1-14alkyl, phenoxy-C.sub.1-4alkoxy or
phenoxy-C.sub.1-4alkyl, cycloalkylalkyl substituted by
C.sub.6-20alkyl, heteroarylalkyl substituted by C.sub.6-20alkyl,
heterocyclic C.sub.6-20alkyl or heterocyclic alkyl substituted by
C.sub.2-20alkyl, 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 NR.sub.6, wherein R.sub.6
is as defined above, and as a substituent C.sub.1-4alkoxy,
C.sub.2-4alkenyloxy, C.sub.2-4alkynyloxy, arylC.sub.1-4alkyloxy,
acyl, C.sub.1-4alkyl-amino, C.sub.1-4alkylthio, acylamino,
(C.sub.1-4alkoxy)carbonyl, (C.sub.1-4alkoxy)carbonylamino, acyloxy,
(C.sub.1-4alkyl)carbamoyl, nitro, halogen, amino, hydroxy or
carboxy, and each of R.sub.2, R.sub.3, R.sub.4 and R.sub.5,
independently, is H, C.sub.1-4 alkyl or acyl; (d) Compounds of the
formula IV ##STR00023## wherein m is 1 to 9 and each of R'.sub.2,
R'.sub.3, R'.sub.4 and R'.sub.5, independently, is H,
C.sub.1-6alkyl or acyl; (e) Compounds of the formula V ##STR00024##
wherein W is H; C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl; unsubstituted or by OH substituted phenyl;
R''.sub.4O(CH.sub.2).sub.n; or C.sub.1-6alkyl substituted by 1 to 3
substituents selected from the group consisting of halogen,
C.sub.3-8cycloalkyl, 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.sub.1-6alkyl, OH, C.sub.1-6alkoxy, acyloxy, amino,
C.sub.1-6alkylamino, acylamino, oxo, haloC.sub.1-6alkyl, halogen,
unsubstituted phenyl and phenyl substituted by 1 to 3 substituents
selected from the group consisting of C.sub.1-6alkyl, OH,
C.sub.1-6alkoxy, acyl, acyloxy, amino, C.sub.1-6alkylamino,
acylamino, haloC.sub.1-6alkyl and halogen; Y is H, C.sub.1-6alkyl,
OH, C.sub.1-6alkoxy, acyl, acyloxy, amino, C.sub.1-6alkylamino,
acylamino, haloC.sub.1-6alkyl or halogen, Z.sub.2 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.ltoreq.p+q.ltoreq.23, m' is 1, 2 or 3, n is 2 or 3,
each of R''.sub.1, R''.sub.2, R''.sub.3 and R''.sub.4,
independently, is H, C.sub.1-4alkyl or acyl; (f) Compounds of the
formula VIa or VIb ##STR00025## wherein X.sub.a is O, S, NR.sub.1s
or a group --(CH.sub.2).sub.na--, which group is unsubstituted or
substituted by 1 to 4 halogen; n, is 1 or 2, R.sub.1s is H or
(C.sub.1-4)alkyl, which alkyl is unsubstituted or substituted by
halogen; R.sub.1a is H, OH, (C.sub.1-4)alkyl or O(C.sub.1-4)alkyl
wherein alkyl is unsubstituted or substituted by 1 to 3 halogen;
R.sub.1b is H, OH or (C.sub.1-4)alkyl, wherein alkyl is
unsubstituted or substituted by halogen; each R.sub.2a is
independently selected from H or (C.sub.1-4)alkyl, which alkyl is
unsubstituted or substituted by halogen; R.sub.3a is H, OH, halogen
or O(C.sub.1-4)alkyl wherein alkyl is unsubstituted or substituted
by halogen; and R.sub.3b is H, OH, halogen, (C.sub.1-4)alkyl
wherein alkyl is unsubstituted or substituted by hydroxy, or
O(C.sub.1-4)alkyl wherein alkyl is unsubstituted or substituted by
halogen; Y.sub.a is --CH.sub.2--, --C(O)--, --CH(OH)--,
--C(.dbd.NOH)--, O or S, and R.sub.4a is (C.sub.4-14)alkyl or
(C.sub.4-14)alkenyl; (g) Compounds of the formula VII ##STR00026##
wherein each of R.sub.1d and R.sub.2d, independently, is H or an
amino-protecting group; R.sub.3d is hydrogen, a hydroxy-protecting
group or a residue of formula ##STR00027## R.sub.4d is
C.sub.1-4alkyl; n.sub.d is an integer of 1 to 6; X.sub.d is
ethylene, vinylene, ethynylene, a group having a formula
-D-CH.sub.2-- (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.sub.d is single bond,
C.sub.1-10alkylene, C.sub.1-10alkylene which is substituted by up
to three substitutents selected from groups a and b,
C.sub.1-10alkylene having O or S in the middle or end of the carbon
chain, or C.sub.1-10alkylene 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.sub.5d is hydrogen,
C.sub.3-6cycloalkyl, aryl, heterocyclic group, C.sub.3-6cycloalkyl
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 heterocyclic group substituted by up to three
substituents selected from groups a and b; each of R.sub.6d and
R.sub.7d, independently, is H or a substituent selected from group
a; each of R.sub.8d and R.sub.9d, independently, is H or
C.sub.1-4alkyl 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-C.sub.1-4alkylamino,
acylamino, cyano or nitro; and <group b> is
C.sub.3-6cycloalkyl, aryl or heterocyclic group, each being
optionally substituted by up to three substituents selected from
group a; with the proviso that when R.sub.5d is hydrogen, Y.sub.d
is a either a single bond or linear C.sub.1-10alkylene; (h)
Compounds of the formula VIII ##STR00028## wherein R.sub.1e,
R.sub.2e, R.sub.3e, R.sub.4e, R.sub.5e, R.sub.6e, R.sub.7e,
n.sub.e, X.sub.e and Y.sub.e are as disclosed in JP-14316985; or a
pharmacologically acceptable salt, ester or hydrate thereof; (i)
compounds of the formula IX ##STR00029## wherein Ar is phenyl or
naphthyl; each of m.sub.g and n.sub.g independently is 0 or 1; A is
selected from COOH, PO.sub.3H.sub.2, PO.sub.2H, SO.sub.3H,
PO(C.sub.1-3alkyl)OH and 1H-tetrazol-5-yl; each of R.sub.1g and
R.sub.2g independently is H, halogen, OH, COOH or C.sub.1-4alkyl
optionally substituted by halogen; R.sub.3g is H or C.sub.1-4alkyl
optionally substituted by halogen or OH; each R.sub.4g
independently is halogen, or optionally halogen substituted
C.sub.1-4alkyl or C.sub.1-3alkoxy; and each of R.sub.g and M has
one of the significances as indicated for B and C, respectively, in
WO03/062252A1; (j) Compound of the formula X ##STR00030## wherein
Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH,
1H-tetrazol-5-yl, PO.sub.3H.sub.2, PO.sub.2H.sub.2, --SO.sub.3H or
PO(R.sub.5h)OH wherein R.sub.5h is selected from C.sub.1-4alkyl,
hydroxyC.sub.1-4alkyl, phenyl, --CO--C.sub.1-3alkoxy and
--CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionally
substituted; each of R.sub.1h and R.sub.2h independently is H,
halogen, OH, COOH, or optionally halogeno substituted
C.sub.1-6alkyl or phenyl; R.sub.3h is H or C.sub.1-4alkyl
optionally substituted by halogen or OH; each R.sub.4h
independently is halogen, OH, COOH, C.sub.1-4alkyl, S(O).sub.0,1 or
2O.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.3-6cycloalkoxy, aryl or
aralkoxy, wherein the alkyl portions may optionally be substituted
by 1-3 halogens; and each of R.sub.h and M has one of the
significances as indicated for B and C, respectively, in
WO03/062248A2; (k) Compounds of the formula XIa or XIb ##STR00031##
wherein A.sub.k is COOR.sub.5k, OPO(OR.sub.5k).sub.2,
PO(OR.sub.5k).sub.2, SO.sub.2OR.sub.5k, POR.sub.5kOR.sub.5k or
1H-tetrazol-5-yl, R.sub.5k being H or C.sub.1-6alkyl; W.sub.k is a
bond, C.sub.1-3alkylene or C.sub.2-3alkenylene; Y.sub.k is
C.sub.6-10aryl or C.sub.3-9heteroaryl, optionally substituted by 1
to 3 radicals selected from halogene, OH, NO.sub.2,
C.sub.1-6alkoxy; halo-substituted C.sub.1-6alkyl and
halo-substituted C.sub.1-6alkoxy; Z.sub.k is a heterocyclic group
as indicated in WO 04/103306A, e.g., azetidine; R.sub.1k is
C.sub.6-10aryl or C.sub.3-9heteroaryl, optionally substituted by
C.sub.1-6alkyl, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.3-9heteroaryl, C.sub.3-9heteroarylC.sub.1-4alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-4alkyl,
C.sub.3-8heterocycloalkyl or
C.sub.3-8heterocycloalkylC.sub.1-4alkyl; wherein any aryl,
heteroaryl, cycloalkyl or heterocycloalkyl of R.sub.1k may be
substituted by 1 to 5 groups selected from halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy and halo substituted-C.sub.1-6alkyl or
--C.sub.1-6alkoxy; R.sub.2k is H, C.sub.1-6alkyl, halo substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl: and each of
R.sub.3k or R.sub.4k, independently, is H, halogen, OH,
C.sub.1-6alkyl, C.sub.1-6alkoxy or halo substituted C.sub.1-6alkyl
or C.sub.1-6alkoxy; and the N-oxide derivatives thereof or prodrugs
thereof; and the pharmacologically acceptable salts, solvates and
hydrates of compounds of the formulae I, II, III, IV, V, VIa, VIb,
VII, VIII, IX, X, XIa and XIb.
2. The method of claim 1, where the condition affected by BDNF
production is selected from one or more of diabetes, nervous system
injured by wound, congenital conditions, neurodegenerative
diseases, sensory nerve dysfunction, obesity, cognitive impairment,
attention deficit disorders, sleep disorders or depressive
disorders.
3. A method according to claim 2, wherein the condition affected by
BDNF production is depression.
4. A method according to claim 1 comprising co-administration,
concomitantly or in sequence, of a therapeutically effective
non-toxic amount of a S1P receptor modulator and a second
therapeutic substance.
5. A method according to claim 1, wherein the condition affected by
BDNF production is diabetes mellitus, obesity, inherited convulsive
paraplegia associated with retina degeneration, Kjelin syndrome,
Barnard-Scholz syndrome, retinitis pigmentosa, Stargardt disease,
Usher syndromes and Refsum syndrome.
6. A method according to claim 1, wherein the S1P receptor
modulator that is administered is BAF312.
7. A method according to claim 1, wherein the S1P receptor
modulator that is administered is KRP203.
Description
[0001] The present invention relates to the use of an S1P receptor
modulator in the treatment or prevention of a peripheral nervous
system disorder, such as Guillan Barre syndrome (GBS)
[0002] One of the neurotrophic factors, a brain-derived
neurotrophic factor (hereinafter, often referred to as BDNF), is a
protein, which is provided from target cells or neurons and glial
cells and Schwann cells in the living body, and shows activities to
maintain the survival and differentiation of neurons.
[0003] It has now been surprisingly shown that S1P receptor
modulators can induce BDNF production.
[0004] BDNF has been known as a therapeutic agent for treatment of
neurodegenerative diseases (e.g., ALS) or diabetic peripheral
neuropathy. BDNF has also been described to be useful as a
therapeutic agent for treatment of diabetic mellitus.
[0005] Therefore, by inducing BDNF production (or stimulating BDNF
expression) S1P receptor modulators can be employed to treat such
conditions affected by BDNF, i.e. conditions which can be treated,
delayed or prevented by the increased expression of BDNF.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1: FIG. 1 shows the induction of BDNF in the cortex of
female DA rats after a 9-day treatment period with 0.3 mg/kg/d
FTY720 measured by Western blot. Shown on the y-axis is the
relative intensity of BDNF signal of animals treated with FTY720 vs
control animals that had received vehicle (i.e., ratio of signal
from FTY720-treated rats divided by signal from vehicle-treated
rats, n=3 rats/group). On the x axis, the first two bars come from
the frontal cortex, the second two from the parietal cortex and in
each case the white bar represents the vehicle treated animals and
the black bar represents the FTY720 treated animals.
[0007] FIG. 2: Similar to FIG. 1, FIG. 2 shows the induction of
BDNF in the cortex of female DA rats after a 9-day treatment
period, but using multiple doses of FTY720. N=3 animals each were
treated with either vehicle, 0.1 mg/kg/d FTY720, 0.3 mg/kg/d FTY720
or 1 mg/kg/d FTY720.
[0008] FIG. 3: FIG. 3 shows the results of a study wherein neuronal
cultures were established using neurons from different brain
regions. The cells were cultured for a total period of 21 days and
FTY720-P was added for the last 6 days of the culture period. As
with the results shown in FIGS. 1 and 2, BDNF levels were measured
by Western blot and normalised to the level observed in the vehicle
control.
[0009] FIG. 4: FIG. 4 shows the results of a study similar to that
shown in FIG. 3, but using a broader range of concentrations of
FTY720P (all in nM)
[0010] FIG. 5: FIG. 5 shows the mean BDI-II (Beck Depression
Inventory, second edition) scores of patients participating in a 6
month, placebo controlled Phase II trial of FTY720 in 281 patients
having relapsing multiple sclerosis, at the beginning and end of
such study (i.e., at t=0 months and t=6 months).
[0011] FIG. 6: FIG. 6 shows the changes from baseline in the BDI-II
scores of the 281 patients in the study referred to above in the
description of FIG. 5.
[0012] S1P receptor modulators 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 Y.
[0013] Sphingosine-1 phosphate (hereinafter "S1P") is a natural
serum lipid. Presently there are eight known S1P receptors, namely
S1P1 to S1P8. S1P receptor modulators 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 Y
##STR00001##
wherein Z is H, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
phenyl, phenyl substituted by OH, C.sub.1-6alkyl substituted by 1
to 3 substituents selected from the group consisting of halogen,
C.sub.3-8cycloalkyl, phenyl and phenyl substituted by OH, or
CH.sub.2--R.sub.4z wherein R.sub.4z is OH, acyloxy or a residue of
formula (a)
##STR00002##
wherein Z.sub.1 is a direct bond or O, preferably O; each of
R.sub.5z and R.sub.6z, independently, is H, or C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 halogen atoms;
[0014] R.sub.1z is OH, acyloxy or a residue of formula (a); and
each of R.sub.2z and R.sub.3z independently, is H, C.sub.1-4alkyl
or acyl.
[0015] Group of formula Y 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 R.sub.1z is or comprises a residue of
formula (a), signals as an agonist at one of more
sphingosine-1-phosphate receptor.
[0016] S1P receptor modulators are compounds which signal as
agonists at one or more sphingosine-1 phosphate receptors, e.g.
S1P1 to S1P8. Agonist binding to a S1P receptor may e.g. result in
dissociation of intracellular heterotrimeric G-proteins into Ga-GTP
and G.beta..gamma.-GTP, and/or increased phosphorylation of the
agonist-occupied receptor and activation of downstream signaling
pathways/kinases.
[0017] The binding affinity of S1P receptor modulators to
individual human S1P receptors may be determined in following
assay:
[0018] S1P receptor modulator activities of compounds are tested on
the human S1P receptors S1P.sub.1, S1P.sub.2, S1P.sub.3, S1P.sub.4
and S1P.sub.5. Functional receptor activation is assessed by
quantifying compound induced GTP [.gamma.-.sup.35S] binding to
membrane protein prepared from . . . transfected CHO or RH7777
cells stably expressing the appropriate human S1P receptor. The
assay technology used is SPA (scintillation proximity based assay).
Briefly, DMSO dissolved compounds are serially diluted and added to
SPA-bead (Amersham-Pharmacia) immobilised S1P receptor expressing
membrane protein (10-20 .mu.g/well) in the presence of 50 mM Hepes,
100 mM NaCl, 10 mM MgCl.sub.2, 10 .mu.M GDP, 0.1% fat free BSA and
0.2 nM GTP [.gamma.-.sup.35S] (1200 Ci/mmol). After incubation in
96 well microtiterplates at RT for 120 min, unbound GTP
[.gamma.-.sup.35S] is separated by a centrifugation step.
Luminescence of SPA beads triggered by membrane bound GTP
[.gamma.-.sup.35S] is quantified with a TOPcount plate reader
(Packard). EC.sub.50s are calculated using standard curve fitting
software. In this assay, the S1P receptor modulators preferably
have a binding affinity to S1P receptor <50 nM.
[0019] Preferred S1P receptor modulators are e.g. compounds which
in addition to their SW binding properties also have accelerating
lymphocyte homing properties, e.g. compounds 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).
[0020] The lymphocyte homing property may be measured in following
Blood Lymphocyte Depletion assay:
[0021] A S1P receptor modulator or the vehicle is administered
orally by gavage to rats. Tail blood for hematological monitoring
is obtained on day-1 to give the baseline individual values, and at
2, 6, 24, 48 and 72 hours after application. In this assay, the SW
receptor agonist or modulator depletes peripheral blood
lymphocytes, e.g. by 50%, when administered at a dose of e.g.
<20 mg/kg.
[0022] Examples of appropriate S1P receptor modulators are, for
example:
Amino alcohol compounds of formula I
##STR00003##
wherein X is O, S, SO or SO.sub.2, R.sub.1 is halogen,
trihalomethyl, OH, C.sub.1-7alkyl, C.sub.1-4alkoxy,
trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy,
cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH.sub.2--OH,
CH.sub.2--CH.sub.2--OH, C.sub.1-4alkylthio, C.sub.1-4alkylsulfinyl,
C.sub.1-4alkylsulfonyl, benzylthio, acetyl, nitro or cyano, or
phenyl, phenylC.sub.1-4alkyl or phenyl-C.sub.1-4alkoxy each phenyl
group thereof being optionally substituted by halogen, CF.sub.3,
C.sub.1-4alkyl or C.sub.1-4alkoxy; R.sub.2 is H, halogen,
trihalomethyl, C.sub.1-4alkoxy, phenethyl or benzyloxy; R.sub.3H,
halogen, CF.sub.3, OH, C.sub.1-7alkyl, C.sub.1-4alkoxy, benzyloxy,
phenyl or C.sub.1-4alkoxymethyl; each of R.sub.4 and R.sub.5,
independently is H or a residue of formula (a)
##STR00004##
wherein each of R.sub.8 and R.sub.9, independently, is H or
C.sub.1-4alkyl optionally substituted by halogen; and n is an
integer from 1 to 4; or a pharmaceutically acceptable salt thereof;
or a compound of formula II
##STR00005##
wherein [0023] R.sub.1a is halogen, trihalomethyl, C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, C.sub.1-4alkylsulifinyl,
C.sub.1-4alkyl-sulfonyl, aralkyl, optionally substituted phenoxy or
aralkyloxy; [0024] R.sub.2a is H, halogen, trihalomethyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy, aralkyl or aralkyloxy; [0025]
R.sub.3a is H, halogen, CF.sub.3, C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio or benzyloxy; [0026] R.sub.4a is H,
C.sub.1-4alkyl, phenyl, optionally substituted benzyl or benzoyl,
or lower aliphatic C.sub.1-5acyl; [0027] R.sub.5a is H,
monohalomethyl, C.sub.1-4alkyl, C.sub.1-4alkoxy-methyl,
C.sub.1-4alkyl-thiomethyl, hydroxyethyl, hydroxypropyl, phenyl,
aralkyl, C.sub.2-4alkenyl or -alkynyl; [0028] R.sub.6a is H or
C.sub.1-4alkyl; [0029] R.sub.7a is H, C.sub.1-4alkyl or a residue
of formula (a) as defined above, [0030] X.sub.a is O, S, SO or
SO.sub.2; and [0031] n.sub.a is an integer of 1 to 4; [0032] or a
pharmaceutically acceptable salt thereof.
[0033] With regard to the compounds of formulae (I) and (II), the
term "halogen" encompasses fluorine, chlorine, bromine and iodine.
The term "trihalomethyl group" encompasses trifluoromethyl and
trichloromethyl. "C.sub.1-7 alkyl" encompasses straight-chained or
branched alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, pentyl, hexyl or heptyl. The phrase "substituted or
unsubstituted phenoxy group" encompasses those that have, at any
position of its benzene ring, a halogen atom, such as fluorine,
chlorine, bromine and iodine, trifluoromethyl, C.sub.1-4alkyl or
C.sub.1-4alkoxy. The term "aralkyl group" as in "aralkyl group" or
"aralkyloxy group" encompasses benzyl, diphenylmethyl, phenethyl
and phenylpropyl. Any alkyl moiety as present in "C.sub.1-4alkoxy",
"C.sub.1-4alkylthio", "C.sub.1-4alkylsulfinyl" or
"C.sub.1-4alkylsulfonyl encompasses straight-chained or branched
C.sub.1-4alkyl, e.g. methyl, ethyl, propyl, isopropyl or butyl. The
phrase "substituted or unsubstituted aralkyl group" encompasses
those that have, at any position of its benzene ring, a halogen
atom, such as fluorine, chlorine, bromine and iodine,
trifluoromethyl, lower alkyl having 1-4 carbon atoms, or lower
alkoxy having 1-4 carbon atoms.
[0034] Other compounds of formula I are compounds of formula Ia
##STR00006##
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined
above; and R.sub.6 is hydrogen, halogen, C.sub.1-7alkyl,
C.sub.1-4alkoxy or trifluoromethyl.
[0035] Further preferred compounds of formula (Ia) are those
wherein R.sub.3 is chlorine, e.g.,
2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-propane-1,3--
diol,
2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane--
diol or
2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-1,3-pro-
pane-diol or a pharmacological salts or hydrates thereof and theirs
corresponding phosphate derivatives. Also exemplified is phosphoric
acid
mono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]est-
er. The phosphoric acid
mono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]est-
er can be prepared enantiomerically pure by the procedures
described in WO 2005/021503.
Other compounds of formula II are compounds of formula (IIa)
##STR00007##
wherein [0036] Y is O or S; and [0037] R.sub.2a, R.sub.3a,
R.sub.5a, R.sub.7a and n.sub.a are as defined above.
[0038] Preferred compounds of formula (IIa) are those wherein
R.sub.3 is chlorine, e.g.,
2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutane-1-ol;
the corresponding phosphoric acid
mono-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutyl]e-
ster;
2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethylbutane-1-
-ol; and the corresponding phosphoric acid
mono-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethylbutyl]es-
ter.
[0039] Compounds of formulae I and II are known and are disclosed
e.g. in WO03/029205, WO 03/029184 and WO04/026817, respectively,
the phosphorylated derivatives being disclosed e.g. in WO04/074297,
the contents of which being incorporated herein by reference in
their entirety. Compounds of formulae I and II may be prepared as
disclosed in above cited references.
[0040] Phosphorylated derivatives of compounds of formula (I),
e.g., phosphoric acid
mono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]est-
er, can be prepared utilizing the procedures for synthesizing
phosphorylated compounds described e.g., in WO 2005/021503 (see,
e.g., pages 11 and 12). Optically active compounds of structural
formula (I) and phosphorylated derivatives thereof, in particular
of formula (Ia) can be prepared in high purity utilizing the
procedure described, e.g., in Hinterding et al., Synthesis, Vol.
11, pp. 1667-1670 (2003). As an example, an optically active
compound of structural formula (Ia), phosphoric acid
mono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]est-
er, can be prepared as described in the scheme below utilizing the
procedures of Hinterding et al. (2003) supra. Also included are
compounds as disclosed in EP627406A1, e.g. a compound of formula
III
##STR00008##
wherein R.sub.1 is a straight- or branched (C.sub.12-22)chain
[0041] which may have in the chain a bond or a hetero atom selected
from a double bond, a triple bond, O, S, NR.sub.6, wherein R.sub.6
is H, C.sub.1-4alkyl, aryl-C.sub.1-4alkyl, acyl or
(C.sub.1-4alkoxy)carbonyl, and carbonyl, and/or [0042] which may
have as a substituent C.sub.1-4alkoxy, C.sub.2-4alkenyloxy,
C.sub.2-4alkynyloxy, arylC.sub.1-4alkyl-oxy, acyl,
C.sub.1-4alkylamino, C.sub.1-4alkylthio, acylamino,
(C.sub.1-4alkoxy)carbonyl, (C.sub.1-4alkoxy)-carbonylamino,
acyloxy, (C.sub.1-4alkyl)carbamoyl, nitro, halogen, amino,
hydroxyimino, hydroxy or carboxy; or [0043] R.sub.1 is [0044] a
phenylalkyl wherein alkyl is a straight- or branched
(C.sub.6-20)carbon chain; or [0045] a phenylalkyl wherein alkyl is
a straight- or branched (C.sub.1-30)carbon chain wherein said
phenylalkyl is substituted by [0046] a straight- or branched
(C.sub.6-20)carbon chain optionally substituted by halogen, [0047]
a straight- or branched (C.sub.6-20)alkoxy chain optionally
substitued by halogen, [0048] a straight- or branched
(C.sub.6-20)alkenyloxy, [0049] phenyl-C.sub.1-14alkoxy,
halophenyl-C.sub.1-4alkoxy, phenoxy-C.sub.1-4alkoxy or
phenoxy-C.sub.1-4alkyl, [0050] cycloalkylalkyl substituted by
C.sub.6-20alkyl, [0051] heteroarylalkyl substituted by
C.sub.6-20alkyl, [0052] heterocyclic C.sub.6-20alkyl or [0053]
heterocyclic alkyl substituted by C.sub.2-20alkyl, [0054] and
wherein [0055] the alkyl moiety may have [0056] in the carbon
chain, a bond or a heteroatom selected from a double bond, a triple
bond, O, S, sulfinyl, sulfonyl, or NR.sub.6, wherein R.sub.6 is as
defined above, and [0057] as a substituent C.sub.1-4alkoxy,
C.sub.2-4alkenyloxy, C.sub.2-4alkynyloxy, arylC.sub.1-4alkyloxy,
acyl, C.sub.1-4alkyl-amino, C.sub.1-4alkylthio, acylamino,
(C.sub.1-4alkoxy)carbonyl, (C.sub.1-4alkoxy)carbonylamino, acyloxy,
(C.sub.1-4alkyl)carbamoyl, nitro, halogen, amino, hydroxy or
carboxy, and [0058] each of R.sub.2, R.sub.3, R.sub.4 and R.sub.5,
independently, is H, C.sub.1-4 alkyl or acyl [0059] or a
pharmaceutically acceptable salt or hydrate thereof; [0060]
Compounds as disclosed in EP 1002792A1, e.g. a compound of formula
IV
##STR00009##
[0060] wherein m is 1 to 9 and each of R'.sub.2, R'.sub.3, R'.sub.4
and R'.sub.5, independently, is H, C.sub.1-6alkyl or acyl, or a
pharmaceutically acceptable salt or hydrate thereof; [0061]
Compounds as disclosed in EP0778263 A1, e.g. a compound of formula
V
##STR00010##
[0061] wherein W is H; C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl; unsubstituted or by OH substituted phenyl;
R''.sub.4O(CH.sub.2).sub.n; or C.sub.1-6alkyl substituted by 1 to 3
substituents selected from the group consisting of halogen,
C.sub.3-8cycloalkyl, 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.sub.1-6alkyl, OH, C.sub.1-6alkoxy, acyloxy, amino,
C.sub.1-6alkylamino, acylamino, oxo, haloC.sub.1-6alkyl, halogen,
unsubstituted phenyl and phenyl substituted by 1 to 3 substituents
selected from the group consisting of C.sub.1-6alkyl, OH,
C.sub.1-6alkoxy, acyl, acyloxy, amino, C.sub.1-6alkylamino,
acylamino, haloC.sub.1-6alkyl and halogen; Y is H, OH,
C.sub.1-6alkoxy, acyl, acyloxy, amino, C.sub.1-6alkylamino,
acylamino, haloC.sub.1-6alkyl or halogen, Z.sub.2 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.ltoreq.p+q.ltoreq.23, m' is 1, 2 or 3, n is 2 or 3,
each of R''.sub.1, R''.sub.2, R''.sub.3 and R''.sub.4,
independently, is H, C.sub.1-4alkyl or acyl, or a pharmaceutically
acceptable salt or hydrate thereof, [0062] Compounds as disclosed
in WO02/18395, e.g. a compound of formula VIa or VIb
##STR00011##
[0062] wherein X.sub.a is O, S, NR.sub.1s or a group
--(CH.sub.2).sub.na--, which group is unsubstituted or substituted
by 1 to 4 halogen; n.sub.a is 1 or 2, R.sub.1s is H or
(C.sub.1-4)alkyl, which alkyl is unsubstituted or substituted by
halogen; R.sub.1a is H, OH, (C.sub.1-4)alkyl or O(C.sub.1-4)alkyl
wherein alkyl is unsubstituted or substituted by 1 to 3 halogen;
R.sub.1b is H, OH or (C.sub.1-4)alkyl, wherein alkyl is
unsubstituted or substituted by halogen; each R.sub.22 is
independently selected from H or (C.sub.1-4)alkyl, which alkyl is
unsubstituted or substituted by halogen; R.sub.3a is H, OH, halogen
or O(C.sub.1-4)alkyl wherein alkyl is unsubstituted or substituted
by halogen; and R.sub.3b is H, OH, halogen, (C.sub.1-4)alkyl
wherein alkyl is unsubstituted or substituted by hydroxy, or
O(C.sub.1-4)alkyl wherein alkyl is unsubstituted or substituted by
halogen; Y.sub.a is --CH.sub.2--, --C(O)--, --CH(OH)--,
--C(.dbd.NOH)--, O or S, and R.sub.4a is (C.sub.4-14)alkyl or
(C.sub.4-14)alkenyl; or a pharmaceutically acceptable salt or
hydrate thereof; [0063] Compounds as disclosed in WO02/06268AI,
e.g. a compound of formula VII
##STR00012##
[0063] wherein each of R.sub.1d and R.sub.2d, independently, is H
or an amino-protecting group; R.sub.3d is hydrogen, a
hydroxy-protecting group or a residue of formula
##STR00013##
n.sub.d is an integer of 1 to 6; X.sub.d is ethylene, vinylene,
ethynylene, a group having a formula -D-CH.sub.2-- (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.sub.d is single bond, C.sub.1-10alkylene, C.sub.1-10alkylene
which is substituted by up to three substitutents selected from
groups a and b, C.sub.1-10alkylene having O or S in the middle or
end of the carbon chain, or C.sub.1-10alkylene 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.sub.5d is
hydrogen, C.sub.3-6cycloalkyl, aryl, heterocyclic group,
C.sub.3-6cycloalkyl 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 heterocyclic group
substituted by up to three substituents selected from groups a and
b; each of R.sub.6d and R.sub.7d, independently, is H or a
substituent selected from group a; each of R.sub.8d and R.sub.9d,
independently, is H or C.sub.1-4alkyl 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-C.sub.1-4alkylamino, acylamino, cyano or nitro; and
<group b> is C.sub.3-6cycloalkyl, aryl or heterocyclic group,
each being optionally substituted by up to three substituents
selected from group a; with the proviso that when R.sub.5d is
hydrogen, Y.sub.d is a either a single bond or linear C.sub.1-10
alkylene, or a pharmacologically acceptable salt, ester or hydrate
thereof; [0064] Compounds as disclosed in JP-14316985
(JP2002316985), e.g. a compound of formula VII
##STR00014##
[0064] wherein R.sub.1e, R.sub.2e, R.sub.3e, R.sub.4e, R.sub.5e,
R.sub.6e, R.sub.7e, n.sub.e, X.sub.e and Y.sub.e are as disclosed
in JP-14316985; or a pharmacologically acceptable salt, ester or
hydrate thereof; [0065] Compounds as disclosed in WO03/062252A1,
e.g. a compound of formula IX
##STR00015##
[0065] wherein Ar is phenyl or naphthyl; each of m.sub.g and
n.sub.g independently is 0 or 1; A is selected from COOH,
PO.sub.3H.sub.2, PO.sub.2H, SO.sub.3H, PO(C.sub.1-3alkyl)OH and
1H-tetrazol-5-yl; each of R.sub.1g and R.sub.2g independently is H,
halogen, OH, COOH or C.sub.1-4alkyl optionally substituted by
halogen; R.sub.3g is H or C.sub.1-4alkyl optionally substituted by
halogen or OH; each R.sub.4g independently is halogen, or
optionally halogen substituted C.sub.1-4alkyl or C.sub.1-3alkoxy;
and each of R.sub.g and M has one of the significances as indicated
for B and C, respectively, in WO03/062252A1; or a pharmacologically
acceptable salt, solvate or hydrate thereof; [0066] Compounds as
disclosed in WO 03/062248A2, e.g. a compound of formula X
##STR00016##
[0066] wherein Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH,
1H-tetrazol-5-yl, PO.sub.3H.sub.2, PO.sub.2H.sub.2, --SO.sub.3H or
PO(R.sub.5h)OH wherein R.sub.5h is selected from C.sub.1-4alkyl,
hydroxyC.sub.1-4alkyl, phenyl, --CO--C.sub.1-3alkoxy and
--CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionally
substituted; each of R.sub.1h and R.sub.2h independently is H,
halogen, OH, COOH, or optionally halogeno substituted
C.sub.1-6alkyl or phenyl; R.sub.3h is H or C.sub.1-4alkyl
optionally substituted by halogen and/OH; each R.sub.4h
independently is halogen, OH, COOH, S(O).sub.0,1 or
2C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.3-6cycloalkoxy, aryl or
aralkoxy, wherein the alkyl portions may optionally be substituted
by 1-3 halogens; and each of R.sub.h and M has one of the
significances as indicated for B and C, respectively, in
WO03/062248A2 or a pharmacologically acceptable salt, solvate or
hydrate thereof. [0067] Compounds as disclosed in WO 04/103306A, WO
05/000833, WO 05/103309 or WO 05/113330, e.g. compounds of formula
XIa or XIb
##STR00017##
[0067] wherein A.sub.k is COOR.sub.5k, OPO(OR.sub.5k).sub.2,
PO(OR.sub.5k).sub.2, SO.sub.2OR.sub.5k, POR.sub.5kOR.sub.5k or
1H-tetrazol-5-yl, R.sub.5k being H or C.sub.1-6alkyl; W.sub.k is a
bond, C.sub.1-3alkylene or C.sub.2-3alkenylene; Y.sub.k is
C.sub.6-10aryl or C.sub.3-9heteroaryl, optionally substituted by 1
to 3 radicals selected from halogene, OH, NO.sub.2, C.sub.1-6alkyl,
C.sub.1-6alkoxy; halo-substituted C.sub.1-6alkyl and
halo-substituted C.sub.1-6alkoxy; Z.sub.k is a heterocyclic group
as indicated in WO 04/103306A, e.g. azetidine; R.sub.1k is
C.sub.6-10aryl or C.sub.3-9heteroaryl, optionally substituted by
C.sub.1-6alkyl, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.3-9heteroaryl, C.sub.3-9heteroarylC.sub.1-4alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-4alkyl,
C.sub.3-8heterocycloalkyl or
C.sub.3-8heterocycloalkylC.sub.1-4alkyl; wherein any aryl,
heteroaryl, cycloalkyl or heterocycloalkyl of R.sub.1k may be
substituted by 1 to 5 groups selected from halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy and halo substituted-C.sub.1-6alkyl or
--C.sub.1-6alkoxy; R.sub.2k is H, C.sub.1-6alkyl, halo substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl: and each of
R.sub.3k or R.sub.4k, independently, is H, halogen, OH,
C.sub.1-6alkyl, C.sub.1-6alkoxy or halo substituted C.sub.1-6alkyl
or C.sub.1-6alkoxy; and the N-oxide derivatives thereof or prodrugs
thereof, or a pharmacologically acceptable salt, solvate or hydrate
thereof.
[0068] The compounds of formulae III to XIb may exist in free or
salt form. Examples of pharmaceutically acceptable salts of the
compounds of the formulae III to VIII 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 combination of the present invention encompass hydrate
and solvate forms.
[0069] Acyl as indicated above may be a residue R.sub.y--CO--
wherein R.sub.y is C.sub.1-6alkyl, C.sub.3-6cycloalkyl, phenyl or
phenyl-C.sub.1-4alkyl. Unless otherwise stated, alkyl, alkoxy,
alkenyl or alkynyl may be straight or branched.
[0070] Aryl may be phenyl or naphthyl, preferably phenyl.
[0071] When in the compounds of formula I the carbon chain as
R.sub.1 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.
[0072] Preferred compounds of formula III are those wherein R.sub.1
is C.sub.13-20alkyl, optionally substituted by nitro, halogen,
amino, hydroxy or carboxy, and, more preferably those wherein
R.sub.1 is phenylalkyl substituted by C.sub.6-14-alkyl chain
optionally substituted by halogen and the alkyl moiety is a
C.sub.1-6alkyl optionally substituted by hydroxy. More preferably,
R.sub.1 is phenyl-C.sub.1-6alkyl substituted on the phenyl by a
straight or branched, preferably straight, C.sub.6-14alkyl chain.
The C.sub.6-14alkyl chain may be in ortho, meta or para, preferably
in para.
[0073] Preferably each of R.sub.2 to R.sub.5 is H.
[0074] In the above formula of VII "heterocyclic group" represents
a 5- to 7 membered heterocyclic group having 1 to 3 heteroatoms
selected from S, O and N. Examples of such heterocyclic groups
include the heteroaryl groups indicated above, and heterocyclic
compounds corresponding to partially or completely hydrogenated
heteroaryl groups, e.g. furyl, thienyl, pyrrolyl, azepinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl,
thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,
pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl or
pyrazolidinyl. Preferred heterocyclic groups are 5- or 6-membered
heteroaryl groups and the most preferred heterocyclic group is a
morpholinyl, thiomorpholinyl or piperidinyl group.
[0075] A preferred compound of formula III 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:
##STR00018##
[0076] A preferred compound of formula IV is the one wherein each
of R'.sub.2 to R'.sub.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.
[0077] A preferred compound of formula V is the one wherein W is
CH.sub.3, each of R''.sub.1 to R''.sub.3 is H, Z.sub.2 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.
[0078] A preferred compound of formula VIa is the FTY720-phosphate
(R.sub.2, is H, R.sub.1a is OH, X.sub.a is O, R.sub.1a and R.sub.1b
are OH). A preferred compound of formula IVb is the Compound
C-phosphate (R.sub.2a is H, R.sub.3b is OH, X.sub.a is O, R.sub.1a
and R.sub.1b are OH, Y.sub.a is O and R.sub.4a is heptyl). A
preferred compound of formula V is Compound B-phosphate.
[0079] A preferred compound of formula VIII is
(2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbuta-
n-1-ol.
[0080] A preferred compound of formula XIa is e.g.
1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-be-
nzyl]-azetidine-3-carboxylic acid, or a prodrug thereof.
[0081] It will be appreciated that the compounds as described
herein may be the direct active substances, or may be prodrugs. For
example, the compounds may be phosphorylated forms.
[0082] It has now been found that S1P receptor modulators have an
inhibitory, preventative or delaying effect on conditions
associated with or dependent on or affected by levels of BDNF.
[0083] In one particular aspect of the present invention, the
compounds as described herein, representing the genus of S1P
receptor modulators, increase the levels of BDNF, for example, the
compounds as described herein stimulate BDNF production.
[0084] A compound which induces brain-derived neurotrophic factor
(BDNF) expression can be used as a therapeutic agent for treatment
of nervous system disorders and diseases, or treatment of diabetes
mellitus.
[0085] More particularly, it is useful for nervous system injured
by wound, surgery, ischemia, infection, metabolic diseases,
malnutrition, malignant tumor, or toxic drug, etc. Especially, it
can be used in the treatment of conditions wherein sensory neurons
or retinal ganglion cells are injured.
[0086] More especially, the compounds can be used in the treatment
of congenital conditions or neurodegenerative diseases, for
example, Alzheimer's disease, Parkinson's disease (the symptoms of
Parkinson's disease may be caused by the degeneration of
dopaminergic neuron), Parkinson-Plus syndromes (e.g., progressive
spranuclear palsy (Steele-Richardson-Olszewski syndromes),
olivopontocerebellar atrophy (OPCA), Shy-Drager syndromes (Multiple
Systems Atrophy), and Parkinson dementia complex of Guam),
Huntington's disease (Huntington's chorea), and Rett Syndrome, but
are not limited thereto.
[0087] Further, the compounds can be used in the treatment of
sensory nerve dysfunction and congenital diseases or
neurodegenerative diseases being associated with degenerative of
retina.
[0088] In addition, the compounds can be used in the treatment of
inherited convulsive paraplegia associated with retina degeneration
(Kjellin and Barnard-Scholz syndromes), retinitis pigmentosa,
Stargardt disease, Usher syndromes (retinitis pigmentosa
accompanied by congenital hearing loss) and Refsum syndrome
(retinitis pigmentosa, congenital hearing loss, and
polyneuropathy).
[0089] Further, the compounds can be used to treat obesity.
[0090] The compounds may also be used to treat cognitive impairment
and/or attention deficit disorder, for example deficits and
abnormalities in attention and vigilance, executive functions and
memory (for instance working memory and episodic memory). Other
disorders relating to cognitive dysfunction include sleep related
breathing disorders (SRBD), behavioral impairments, information
processing deficits and age-related disorders, Attention-deficit
hyperactivity disorder (ADHD), childhood ADHD, adult ADHD, excess
daytime somnolence, sleep apnea, traumatic brain injury,
neurodegenerative disorders with associated memory and cognitive
problems (such as Alzheimer's disease, Lewy body dementia, senile
dementia, vascular dementia, Parkinson's disease), chronic fatigue
syndrome, fatigue associated with sleep deprivation or prolonged
wakefulness, age-related decline in memory and cognitive function
(such as mild cognitive impairment), cognitive impairment
associated with mood disorders (such as depression) and anxiety,
schizophrenia, day time sleepiness associated with narcolepsy.
[0091] In addition, the compounds can be used to treat sleep
disorders, e.g. narcolepsy, primary insomnia, sleep-awake rhythm
disorders (e.g., work-shift syndrome, time-zone syndrome
(jet-lag)).
[0092] In additions, the compounds can be used to treat depressive
disorder, e.g. manic-depressive psychosis.
[0093] In a further use, the compounds can be useful in making
patients feel better.
[0094] In a series of further specific or alternative embodiments,
the present invention provides: [0095] 1.1 A method for preventing,
inhibiting or treating a condition effected by BDNF production, in
a subject in need thereof, comprising administering to said subject
a therapeutically effective amount of an S1P receptor modulator,
e.g. a compound of formulae I to XIb. [0096] 1.2 A method for
alleviating or delaying progression of the symptoms of obesity, a
sleep disorder or depressive disorder, in a subject in need
thereof, in which method the BDNF-dependent factor associated with
said disease is prevented or inhibited, comprising administering to
said subject a therapeutically effective amount of an S1P receptor
modulator, e.g. a compound of formulae I to XIb. [0097] 1.3 A
method for inducing the production of BDNF, in a subject,
comprising administering to said subject a therapeutically
effective amount of an S1P receptor modulator, e.g. a compound of
formulae I to XIb. [0098] 1.4 A method for slowing progression of
obesity, a sleep disorder or depressive disorder, in a subject, in
which method the BDNF-dependent factor associated with said disease
is prevented or inhibited, comprising administering to said subject
a therapeutically effective amount of an S1P receptor modulator,
e.g. a compound of formulae I to XIb. [0099] 1.5 A method as
indicated above, wherein the S1P receptor modulator is administered
intermittently. For example, the S1P receptor modulator may be
administered to the subject every 2.sup.nd or 3.sup.rd day or once
a week. [0100] 2. A pharmaceutical composition for use in any one
of the methods 1.1 to 1.5, comprising an S1P receptor modulator,
e.g. a compound of formulae I to XIb as defined hereinabove,
together with one or more pharmaceutically acceptable diluents or
carriers therefor. [0101] 3. An S1P receptor modulator, e.g. a
compound of formula I to XIb as defined herein above, for use in
any one of the methods 1.1 to 1.5. [0102] 4 An S1P receptor
modulator, e.g. a compound of formulae I to XIb as defined herein
above, for use in the preparation of a medicament for use in any
one of the methods 1.1 to 1.5.
[0103] Utility of the S1P receptor modulators, e.g. the S1P
receptor modulators comprising a group of formula Y, in preventing
or treating a disease associated with BDNF as hereinabove
specified, may be demonstrated in animal test methods as well as in
clinic, for example in accordance with the methods hereinafter
described.
EXAMPLE 1
In Vivo: S1P Receptor Modulator Induced BDNF Production
[0104] Female DA rats were treated for 9 days (5 days, 2 day pause,
4 days) with FTY720 p.o.
[0105] Expt 1: 0.3 mg/kg/d vs. vehicle.
[0106] N=3 rats/group
[0107] One day after the last treatment, the rats were perfused
with ice-cold PBS and different CNS regions were isolated.
[0108] The results are shown in FIG. 1.
EXAMPLE 2
In Vivo: S1P Receptor Modulator Induced BDNF Production
[0109] Female DA rats were treated for 9 days (5 days, 2 day pause,
4 days) with FTY720 p.o. 0.1; 0.3 or 1 mg/kg/d vs vehicle
[0110] N=3 rats/group
[0111] One day after the last treatment, the rats were perfused
with ice-cold PBS and different CNS regions were isolated.
[0112] The results are shown in FIG. 2.
EXAMPLE 3
In Vitro: S1P Receptor Modulator Induced BDNF Production
[0113] Effect of FTY720 on BDNF expression in cultured CTX, STR,
and HIP neurons was investigated.
[0114] Neurons were treated with phosphorylated FTY720 (FTY-p) (1
and 10 nM) for the last 6 days. Cell lysates were collected at 21
days in vitro.
[0115] Y axis indicates levels of BDNF normalized to control.
[0116] *P<0.05 vs DMSO
[0117] The results are shown in FIGS. 3A, B and C.
EXAMPLE 4
In Vitro: S1P Receptor Modulator Induced BDNF Production
[0118] Effect of FTY720 on BDNF expression in cultured CTX and HIP
neurons was investigated.
[0119] Neurons were treated with FTY720 (FTY-p) (0.01, 0.1, 1 and
10 nM) for the last 6 days.
[0120] Cell lysates were collected at 21 days in vitro.
[0121] Y axis indicates levels of BDNF normalized to control.
[0122] The results are shown in FIG. 4,
EXAMPLE 5
Clinical Trial: S1P Receptor Modulator Made People Feel Better
[0123] In a 6-month, placebo controlled, Phase II trial involving
281 patients with relapsing MS, FTY720 reduced gadolinium-enhanced
magnetic resonance imaging (MRI) lesions by up to 80%, and the
annualized relapse rate by more than 50%, compared with placebo, at
doses of 1.25 and 5 mg once daily..sup.3 The resulting low disease
activity on both MRI and relapses was sustained in patients treated
with FTY720 for up to 24 months during a dose-blinded extension
phase. Patients who received placebo also had marked improvements
after switching to FTY720 in the extension.
[0124] In this study, depressive symptoms were assessed by means of
the Beck Depression Inventory second edition (BDI-II). These
results are presented here.
Method
[0125] Patients with relapsing MS (relapsing-remitting or secondary
progressive) were randomized to receive placebo or FTY720 1.25 or 5
mg/day, for 6 months (the core study). At the end of this period,
placebo-treated patients were re-randomized to one of the two
FTY720 doses, while those originally randomized to FTY720 continued
treatment at the same doses. After approximately 18-24 months,
patients receiving FTY720 5 mg, were switched to 1.25 mg in view of
evidence that the higher dose conferred no efficacy benefit over
the lower dose.
[0126] The BDI-II was administered at baseline, and at 3 and 6
months during the core study and at 12 and 24 months during the
extension phase (i.e. 6 and 18 months after the start of the
extension phase). This is a 21-item self-report scale measuring
various symptoms and attitudes associated with depression.
Respondents rate depressive symptoms experienced during the past
two weeks on a 4-point scale, coded 0 to 3 by increasing order of
severity. A total score across all 21 items can be generated, with
lower total scores indicating lower overall severity of depressive
symptoms. BDI-II total scores of 14 or above are indicative of
clinical depression. Ny reduction in the BDI-II score indicated an
improvement in depression.
Results
Patients
[0127] Of the 281 patients originally randomized to treatment, 255
completed the core study. BDI-II scores at baseline and 6 months
were available in 239 patients.
Changes in BDI-II Scores During the Core Study
[0128] Mean BDI-II scores during the core study are shown in FIG.
5, and changes in these scores from baseline during the core study
are shown in FIG. 6. BDI-II scores decreased from baseline in
patients receiving FTY720 1.25 mg/day, remained consistent in
patients receiving FTY720 5.0 mg/day, and increased in patients on
placebo. At 6 months, the change in BDI-II scores from baseline in
FTY720 1.25 mg/day treated patients was significantly greater than
in placebo-treated patients. The difference in changes in BDI-II
scores between the two doses of FTY720 was not significant at the
5% level.
* * * * *