U.S. patent application number 10/583106 was filed with the patent office on 2008-06-12 for use of sphingosine-1-phosphate (s1p) receptor agonists for the treatment of brain degenerative diseases.
Invention is credited to Volker Brinkmann, Nicole Kaneider, Christian J. Wiedermann.
Application Number | 20080139662 10/583106 |
Document ID | / |
Family ID | 30776138 |
Filed Date | 2008-06-12 |
United States Patent
Application |
20080139662 |
Kind Code |
A1 |
Brinkmann; Volker ; et
al. |
June 12, 2008 |
Use of Sphingosine-1-Phosphate (S1P) Receptor Agonists For the
Treatment of Brain Degenerative Diseases
Abstract
Disclosed is the use of sphingosine-1-phosphate (S1P) receptor
agonists, preferably
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in the
treatment of progressive dementia or brain degenerative
diseases.
Inventors: |
Brinkmann; Volker;
(Freiburg, DE) ; Kaneider; Nicole; (Innsbruck,
AT) ; Wiedermann; Christian J.; (Innsbruck,
AT) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
30776138 |
Appl. No.: |
10/583106 |
Filed: |
December 17, 2004 |
PCT Filed: |
December 17, 2004 |
PCT NO: |
PCT/EP04/14436 |
371 Date: |
July 19, 2006 |
Current U.S.
Class: |
514/646 |
Current CPC
Class: |
A61K 31/133 20130101;
A61P 43/00 20180101; A61K 31/00 20130101; A61K 31/135 20130101;
A61K 31/551 20130101; A61K 31/4745 20130101; A61K 31/137 20130101;
A61K 31/502 20130101; A61P 29/00 20180101; A61K 45/06 20130101;
A61K 31/4725 20130101; A61K 31/675 20130101; A61K 31/7024 20130101;
A61K 31/5513 20130101; A61K 31/498 20130101; A61K 31/661 20130101;
A61P 25/00 20180101; A61K 31/5025 20130101; A61K 31/4245 20130101;
A61P 25/28 20180101; A61K 31/55 20130101 |
Class at
Publication: |
514/646 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61P 25/28 20060101 A61P025/28 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 19, 2003 |
GB |
0329498.0 |
Claims
1-3. (canceled)
4. A pharmaceutical composition for use in treating progressive
dementia or brain degeneration, R-amyloid-related inflammatory
diseases or disorders or for reducing or inhibiting loss of
cognitive abilities comprising a sphingosine-1-phosphate (S1P)
receptor agonist or a pharmaceutically acceptable salt thereof
together with one or more pharmaceutically acceptable diluents or
carriers therefore.
5. A pharmaceutical combination comprising a) a first agent which
is a S1P receptor agonist or a pharmaceutically acceptable salt
thereof and b) a co-agent useful in the alleviation or treatment of
brain degenerative diseases or progressive dementia.
6. A combination according to claim 5, wherein co-agent b) is
selected from an AMPA receptor agonist, a noortropic or
anti-inflammatory agent or a painkiller.
7. A method for treating progressive dementia or brain degeneration
or .beta.-amyloid-related inflammatory diseases or disorders or for
reducing or inhibiting loss of cognitive abilities in a subject in
need thereof, comprising administering to said subject a
therapeutically effective amount of a sphingosine-1-phosphate (S1P)
receptor agonist or a pharmaceutically acceptable salt thereof.
8. A method according to claim 7 comprising co-administration, e.g.
concomitantly or in sequence, of b) a co-agent useful in the
alleviation or treatment of brain degenerative diseases or
progressive dementia.
9. A composition, according to claim 4, wherein the S1P receptor
agonist is compound of formula I ##STR00019## wherein R.sub.1 is
straight- or branched (C.sub.12-22)carbon chain which may have in
the claim 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, 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, hydroxyl 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, phenylalkoxy, halophenylalkoxy,
phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, 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.6-20alkyl, 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 alkoxy,
alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,
acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy,
alkylcarbamoyl, nitro, halogen, amino, hydroxyl or carboxy, and
each of R.sub.2, R.sub.3, R.sub.4 and R.sub.5, independently, is H,
C.sub.1-4alkyl or acyl or a pharmaceutically acceptable salt
thereof.
10. A composition, according to claim 9, wherein the S1P receptor
agonist is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in
free form or in a pharmaceutically acceptable salt form.
11. A combination according to claim 5, wherein the S1P receptor
agonist is compound of formula I ##STR00020## wherein R.sub.1 is
straight- or branched (C.sub.12-22)carbon chain which may have in
the cain 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, 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, hydroxyl 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, phenylalkoxy, halophenylalkoxy,
phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, 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.6-20alkyl, 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 alkoxy,
alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,
acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy,
alkylcarbamoyl, nitro, halogen, amino, hydroxyl or carboxy, and
each of R.sub.2, R.sub.3, R.sub.4 and R.sub.5, independently, is H,
C.sub.1-4alkyl or acyl or a pharmaceutically acceptable salt
thereof.
12. A method according to claim 7, wherein the S1P receptor agonist
is compound of formula I ##STR00021## wherein R.sub.1 is straight-
or branched (C.sub.12-22)carbon chain which may have in the cain 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, 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, hydroxyl 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, phenylalkoxy, halophenylalkoxy,
phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, 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.6-20alkyl, 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 alkoxy,
alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,
acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy,
alkylcarbamoyl, nitro, halogen, amino, hydroxyl or carboxy, and
each of R.sub.2, R.sub.3, R.sub.4 and R.sub.5, independently, is H,
C.sub.1-4alkyl or acyl or a pharmaceutically acceptable salt
thereof.
13. A combination according to claim 11, wherein the S1P receptor
agonist is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in
free form or in a pharmaceutically acceptable salt form.
14. A method according to claim 12, wherein the S1P receptor
agonist is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in
free form or in a pharmaceutically acceptable salt form.
Description
[0001] The present invention relates to a new use for a
sphingosine-1-phosphate (S1P) receptor agonist, particularly in the
treatment of progressive dementia or brain degenerative
diseases.
[0002] S1P receptor agonists 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
G.alpha.-GTP and G.beta..gamma.-GTP, and/or increased
phosphorylation of the agonist-occupied receptor and activation of
downstream signaling pathways/kinases, or to
internalization/desensitization of the receptors as a result of
super-agonism and consequently an antagonism of receptor signaling
by the natural ligand S1P.
[0003] The binding affinity of S1P receptor agonists to individual
human S1P receptors may be determined in following assay:
S1P receptor agonist activities of compounds are tested on the
human S1P receptors S1P.sub.1, S1P.sub.3, S1P.sub.2, 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 agonists preferably have
a binding affinity to S1P receptor <50 nM.
[0004] Internalization and desensitization of S1P receptors is
determined using e.g. Chinese hamster ovary (CHO) cells transfected
with a myc-tagged human S1P receptor. Internationalization of the
receptor as a results of stimulation by agonists is determined by
FACS analysis using fluorescently labeled anti-myc antibodies.
[0005] Preferred S1P receptor agonists are e.g. compounds which in
addition to their S1P 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).
[0006] The lymphocyte homing property may be measured in following
Blood Lymphocyte Depletion assay:
A S1P receptor agonist 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 S1P receptor
agonist depletes peripheral blood lymphocytes, e.g. by 50%, when
administered at a dose of e.g. <20 mg/kg. Preferred S1P receptor
agonists are further compounds which in addition to their S1P
binding properties internalize/desensitize S1P receptors, thereby
antagonizing inflammatory processes driven by lysophospholipids,
including i.e. sphingosine 1-phosphate (S1P),
sphingophosphorylcholine (SPC), lysophosphatidic acid (LPA), and
others, on vasculature cells, e.g. endothelial cells. The
internalization/desensitization capacity of compounds will be
determined using CHO cells transfected with a human myc-tagged S1P
receptor.
[0007] Examples of appropriate S1P receptor agonists are, for
example
[0008] Compounds as Disclosed in EP627406A1, e.g. a Compound of
Formula I
##STR00001##
wherein R.sub.1 is a straight- or branched (C.sub.12-22)carbon
chain [0009] 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, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl,
and/or [0010] 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
R.sub.1 is
[0010] [0011] a phenylalkyl wherein alkyl is a straight- or
branched (C.sub.6-20)carbon chain; or [0012] a phenylalkyl wherein
alkyl is a straight- or branched (C.sub.1-30)carbon chain wherein
said phenylalkyl is substituted by [0013] a straight- or branched
(C.sub.6-20)carbon chain optionally substituted by halogen, [0014]
a straight- or branched (C.sub.6-20)alkoxy chain optionally
substituted by halogen, [0015] a straight- or branched
(C.sub.6-20)alkenyloxy, [0016] phenylalkoxy, halophenylalkoxy,
phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, [0017]
cycloalkylalkyl substituted by C.sub.6-20alkyl, [0018]
heteroarylalkyl substituted by C.sub.6-20alkyl, [0019] heterocyclic
C.sub.6-20alkyl or [0020] heterocyclic alkyl substituted by
C.sub.2-20alkyl, and wherein the alkyl moiety may have [0021] 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 [0022] as a substituent alkoxy,
alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio,
acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy,
alkylcarbamoyl, 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 or a pharmaceutically acceptable salt
thereof;
[0023] Compounds as Disclosed in EP 1002792A1, e.g. a Compound of
Formula II
##STR00002##
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, alkyl or acyl, or a pharmaceutically
acceptable salt thereof;
[0024] Compounds as Disclosed in EP0778263 A1, e.g. a Compound of
Formula III
##STR00003##
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.1-6
alkyl, 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.13 and R''.sub.4, independently, is H,
C.sub.1-4alkyl or acyl, or a pharmaceutically acceptable salt
thereof,
[0025] Compounds as Disclosed in WO02/18395, e.g. a Compound of
Formula IVa or IVb
##STR00004##
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.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; or a pharmaceutically acceptable salt or
hydrate thereof;
[0026] Compounds as Disclosed in WO 02/076995, e.g. a Compound of
Formula V
##STR00005##
wherein [0027] m.sub.c is 1, 2 or 3; [0028] X.sub.c is O or a
direct bond; [0029] R.sub.1c is H; C.sub.1-6 alkyl optionally
substituted by OH, acyl, halogen, C.sub.3-10cycloalkyl, phenyl or
hydroxy-phenylene; C.sub.2-6alkenyl; C.sub.2-6alkynyl; or phenyl
optionally substituted by OH; [0030] R.sub.2c is
[0030] ##STR00006## [0031] wherein R.sub.5c is H or C.sub.1-4alkyl
optionally substituted by 1, 2 or 3 halogen atoms, and R.sub.6c is
H or C.sub.1-4alkyl optionally substituted by halogen; each of
R.sub.3c and R.sub.4c, independently, is H, C.sub.1-4alkyl
optionally substituted by halogen, or acyl, and [0032] R.sub.c is
C.sub.13-20alkyl 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)
[0032] ##STR00007## [0033] wherein R.sub.7c is H, C.sub.1-4alkyl or
C.sub.1-4alkoxy, and R.sub.8c is substituted C.sub.1-20alkanoyl,
phenylC.sub.1-14alkyl wherein the C.sub.1-14alkyl is optionally
substituted by halogen or OH, cycloalkylC.sub.1-14alkoxy or
phenylC.sub.1-14alkoxy wherein the cycloalkyl or phenyl ring is
optionally substituted by halogen, C.sub.1-4alkyl and/or
C.sub.1-4alkoxy, phenylC.sub.1-14alkoxy-C.sub.1-14alkyl,
phenoxyC.sub.1-14alkoxy or phenoxyC.sub.1-14alkyl, [0034] R.sub.c
being also a residue of formula (a) wherein R.sub.8c is
C.sub.1-4alkoxy when R.sub.1c is C.sub.1-4alkyl, C.sub.2-6alkenyl
or C.sub.2-6alkynyl, or a compound of formula VI
##STR00008##
[0034] wherein [0035] n.sub.x is 2, 3 or 4 [0036] R.sub.1x is H;
C.sub.1-6alkyl optionally substituted by OH, acyl, halogen,
cycloalkyl, phenyl or hydroxy-phenylene; C.sub.2-6alkenyl; C.sub.2
alkynyl; or phenyl optionally substituted by OH; [0037] R.sub.2x is
H, C.sub.1-4alkyl or acyl each of R.sub.3x and R.sub.4x,
independently is H, C.sub.1-4alkyl optionally substituted by
halogen or acyl, [0038] R.sub.5x is H, C.sub.1-4alkyl or
C.sub.1-4alkoxy, and [0039] R.sub.6x is C.sub.1-20 alkanoyl
substituted by cycloalkyl; cyloalkylC.sub.1-14alkoxy wherein the
cycloalkyl ring is optionally substituted by halogen,
C.sub.1-4alkyl and/or C.sub.1-4alkoxy; phenylC.sub.1-14alkoxy
wherein the phenyl ring is optionally substituted by halogen,
C.sub.1-4alkyl and/or C.sub.1-4alkoxy, [0040] R.sub.6x being also
C.sub.4-14alkoxy when R.sub.1x is C.sub.2-4alkyl substituted by OH,
or pentyloxy or hexyloxy when R.sub.1x is C.sub.1-4alkyl, provided
that R.sub.6x is other than phenyl-butylenoxy when either R.sub.5x
is H or R.sub.1x is methyl, or a pharmaceutically acceptable salt
thereof;
[0041] Compounds as Disclosed in WO02/06268AI, e.g. a Compound of
Formula VII
##STR00009##
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
##STR00010##
R.sub.4d is lower alkyl; 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, 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.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-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.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 or ester
thereof;
[0042] Compounds as Disclosed in JP-14316985 (JP2002316985), e.g. a
Compound of Formula VIII:
##STR00011##
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 or ester
thereof;
[0043] Compounds as Disclosed in WO 03/29184 and WO 03/29205, e.g.
compounds of formula IX
##STR00012##
wherein X.sub.f is O or S, and R.sub.1f, R.sub.2f, R.sub.3f and
n.sub.f are as disclosed in WO 03/29184 and O3/29205, each of
R.sub.4f and R.sub.5f, independently is H or a residue of
formula
##STR00013##
wherein each of R.sub.8f and R.sub.9f, independently, is H or
C.sub.1-4alkyl optionally substituted by halogen; e.g.
2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diol
or
2-amino-2-[4-(benzyloxyphenylthio)-2-chlorophenyl]propyl-1,3-propane-d-
iol, or a pharmacological salt thereof;
[0044] Compounds as Disclosed in WO03/062252A1, e.g. a Compound of
Formula X
##STR00014##
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;
[0045] Compounds as Disclosed in WO 03/062248A2, e.g. a Compound of
Formula XI
##STR00015##
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 halogeno, OH, COOH, C.sub.1-4alkyl, S(O).sub.0,1
or2C.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.g and M has one of the
significances as indicated for B and C, respectively, in
WO03/062248A2;
[0046] Compounds as Disclosed in WO 04/026817, e.g. a Compound of
Formula XII
##STR00016##
wherein R.sub.1j is halogen, trihalomethyl, C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, aralkyl, or optionally
substituted phenoxy or aralkyloxy, R.sub.2j is H, halogen,
trihalomethyl, C.sub.1-4alkyl, C.sub.1-4alkoxy, aralkyl or
aralkyloxy, R.sub.3j is H, halogen, trifluoromethyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio or benzyloxy,
R.sub.4j is H, C.sub.1-4alkyl, phenyl, benzyl optionally
substituted, lower aliphatic acyl having 1 to 5 C or benzoyl
optionally substituted, R.sub.5j is H, monohalomethyl,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxyethyl,
hydroxypropyl, phenyl, aralkyl, C.sub.2-4alkenyl or
C.sub.2-4alkynyl, each of R.sub.6j and R.sub.7j, independently is H
or C.sub.1-4alkyl, X.sub.j is O, S, SO or SO.sub.2 and n.sub.j is
1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof;
[0047] According to a further embodiment of the invention, a S1P
receptor agonist for use in a combination of the invention may also
be a selective S1P1 receptor, e.g. a compound which possesses a
selectivity for the S1P1 receptor over the S1P3 receptor of at
least 20 fold, e.g. 100, 500, 1000 or 2000 fold, as measured by the
ratio of EC.sub.50 for the S1P1 receptor to the EC.sub.50 for the
S1P3 receptor as evaluated in a .sup.35S-GTP.gamma.S binding assay,
said compound having an EC.sub.50 for binding to the S1P1 receptor
of 100 nM or less as evaluated by the .sup.35S-GTP.gamma.S binding
assay. Representative S1P1 receptor agonists are e.g. the compounds
listed in WO 03/061567, the contents of which being incorporated
herein by reference, for instance a compound of formula
##STR00017##
[0048] When the compounds of formulae I to XIV 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.
[0049] 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.
[0050] The compounds of formulae I to XIV may exist in free or salt
form. Examples of pharmaceutically acceptable salts of the
compounds of the formulae I to XIII 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.
[0051] 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.
[0052] Acyl 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.
[0053] 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.
[0054] Preferred compounds of formula I 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.
[0055] Preferably each of R.sub.2 to R.sub.5 is H.
[0056] 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:
##STR00018##
[0057] A preferred compound of formula II 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.
[0058] A preferred compound of formula III 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.
[0059] A preferred compound of formula IVa is the FTY720-phosphate
(R.sub.2a is H, R.sub.3a 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.
[0060] A preferred compound of formula V is phosphoric acid
mono-[(R)-2-amino-2-methyl-4-(4-pentyloxy-phenyl)-butyl]ester.
[0061] A preferred compound of formula VIII is
(2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbuta-
n-1-ol.
[0062] Preferred compounds of formula XII are those wherein
R.sub.1j is CF.sub.3 or benzyloxy and R.sub.6j is H
[0063] Compounds of formulae I to XIV have, on the basis of
observed activity, e.g. as described in EP-A1-627,406, been found
to be useful e.g. as immunosuppressants, e.g. in the treatment of
acute allograft rejection or autoimmune disorders.
[0064] Brain degenerative diseases are becoming more common in
developed nations as the population includes more and more older
persons. There is no known cause for the diseases. It is not known
why some people present as early as 30 or 40 years of age with
dementia while others do not present until their late 70's or 80's.
Alzheimer disease is a progressive degenerative disease of the
brain characterized by the insidious onset of dementia. Impairment
of memory, judgment, attention span, and problem solving skills are
followed by global loss of cognitive abilities. There remains a
medical need for agents which are effective in the treatment of
such diseases and disorders, e.g. in reducing or preventing disease
progression and/or alleviating the symptoms and/or improving
quality of life. It has now been found that S1P receptor agonists
have interesting properties which make them useful for treating
progressive dementia and brain degeneration.
[0065] In accordance with the particular findings of the present
invention, there is provided:
1.1 A method for treating progressive dementia or brain
degeneration in a subject in need thereof, comprising administering
to said subject a therapeutically effective amount of a
sphingosine-1-phosphate (S1P) receptor agonist, e.g. a compound of
formula I or a pharmaceutically acceptable salt thereof. 1.2 A
method for treating .beta.-amyloid-related inflammatory diseases or
disorders in a subject in need thereof, comprising administering to
said subject a therapeutically effective amount of a
sphingosine-1-phosphate (S1P) receptor agonist, e.g. a compound of
formula I or a pharmaceutically acceptable salt thereof.
[0066] Examples of such diseases and disorders are e.g. Alzheimer
disease, amyloidosis, Lewy Body diseases, Multi-Infarct dementia,
Pick's disease or cerebral atherosclerosis.
1.3 A method for reducing or inhibiting loss of cognitive abilities
in a subject in need thereof, comprising administering to said
subject a therapeutically effective amount of a
sphingosine-1-phosphate (S1P) receptor agonist, e.g. a compound of
formula I or a pharmaceutically acceptable salt thereof. 2. A
sphingosine-1-phosphate (S1P) 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 any
method as defined under 1.1 to 1.3 above. 3. A pharmaceutical
composition for use in any method as defined under 1.1 to 1.3 above
comprising a sphingosine-1-phosphate (S1P) 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.
[0067] Preferably the progressive dementia or brain degeneration is
other than senile dementia.
[0068] Utility of the sphingosine-1-phosphate (S1P) receptor
agonists, e.g. a compound of formula I, in treating 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.
[0069] A.1 Peripheral blood mononuclear cells are prepared from
peripheral venous blood of healthy volunteers (anticoagulated with
EDTA). After Lymphoprep.RTM. density gradient centrifugation,
peripheral blood mononuclear cells are collected and washed three
times with normal saline. Positive selection of monocytes is
performed by adding MACS colloidal superparamagnetic microbeads
conjugated with monoclonal anti-human CD14 antibodies to cooled,
freshly prepared peripheral blood mononuclear cell preparations in
MACS buffer (PBS with 5 mM EDTA and 0.5% bovine serum albumin)
according to the manufacturer's instructions. Cells and microbeads
are incubated for 15 min at 4-6.degree. C. In the meantime the
separation column is positioned in the MACS magnetic field and
washed with MACS buffer at room temperature. The cells are washed
with MACS buffer, resuspended, and loaded onto the top of the
separation column. The eluent containing CD14 cells is withdrawn
and after removal of the column from the magnet, trapped monocytes
(CD14.sup.+) are eluted with the sixfold amount of cold MACS
buffer, centrifuged, and resuspended in medium containing 0.5% BSA.
By immunocytochemistry, preparations yield a purity of
approximately 98%.
Chemotaxis Assay
[0070] Leukocyte migration is measured using a modified
48-blindwell microchemotaxis chamber equipped with 5 .mu.m
pore-sized nitrocellulose filters for monocyte chemotaxis. In some
experiments cells are incubated for 20 min with GFX [500 nM],
staurosporine [10 ng/mL], tyrphostin-23 [10 ng/mL], wortmannin [10
nM], cholera toxin [1 nM], DMS [20 pg/mL to 20 .mu.g/mL] or
pertussis toxin [1 nM]. For determination of A.beta.'s potency to
affect monocyte chemotaxis toward fMLP, cells with A.beta. [1 aM to
1 .mu.M] are incubated for 20 min. After washing twice, 50 .mu.l of
cell suspension [1.times.10.sup.6 cells/mL] is put into the upper
compartment of the chemotaxis chamber and cells are allowed to
migrate for 90 min toward fMLP. After these migration periods the
filters are dehydrated, fixed and stained with haematoxylin-eosin.
Migration depth is quantified by microscopy, the distance from the
surface of the filter to the leading front of three cells being
measured. Data are expressed as "chemotaxis index", which is the
ratio between the distance of directed and undirected
migration.
Semiquantitative RT-PCR
[0071] Total RNA is isolated from 8.times.10.sup.6 cells by
phenol-chloroform-isoamylalcohol extraction (RNAClean.TM.;
Hybaid-AGS, Ulm, Germany). Reverse transcriptase reaction is
performed on 1 .mu.g of RNA using random hexamers reverse
transcriptase (Gibco BRL, Life Technologies, Vienna, Austria). 10
.mu.L of the reverse transcriptase reaction mixture is then
subjected to 35 cycles of PCR in a 50 .mu.L reaction mixture
containing 1 pmol of sense and anti-sense primer pairs in a
Perkin-Elmer thermocycler: 95.degree. C.--30 sec (denaturation),
53.degree. C.--60 sec (annealing), 72.degree. C.--30 sec
(extension). Hot Start Taq polymerase is from Qiagen Inc.
(Valencia, Calif., USA). Primers (MWG Biotech, Ebersdorf, Germany)
are designed to amplify about 400 bp coding sequences of the
receptors. Primers are designed as follows: Sphingosine-1-phosphate
receptor (S1PR) 1 sense: CTG TGA ACA ATG CAC TGG, anti-sense: CCT
ACG TAC TCA ACA TAG CC. S1PR 3 sense: ATC TGC AGC TTC ATC GTC,
anti-sense: AGA TTG AGG CAG TTC. S1PR 2 sense: ACC ACG CAC AGC ACA
TAA TG, anti-sense: AAA CAG CAA GTT CCA CTC GG. S1PR 4 sense: TGA
ACA TCA CGC TGA GTG, anti-sense: ATC ATC AGC ACC GTC TTC. S1PR 5
sense: GAA ATG CAG CCA AAG GTG, anti-sense: TT ATC ACC CAC AAG GTC
CTT C. The PCR products are subjected to agarose gel analysis.
Results
A.beta.- and A.beta. Precursor Protein-Induced Chemotaxis.
[0072] To confirm that A.beta. induces monocyte chemotaxis and to
investigate whether A.beta. precursor protein (A.beta.-PP) is able
to act comparably, monocytes are allowed to migrate toward
different concentrations of A.beta. [10 nmol/L to 1 .mu.mol/L] or
A.beta.-PP [10 nmol/L to 1 .mu.mol/L] for 90 min. Directed
migration of monocytes is measured using a modified 48-blindwell
microchemotaxis chamber equipped with 5 .mu.m pore-sized
nitrocellulose filters for monocyte chemotaxis. Migration depth is
quantified by microscopy, measuring the distance from the surface
of the filter to the leading front of three cells. Data are
expressed as "chemotaxis index", which is the ratio between the
distance of directed and undirected migration. Mean distance of
undirected migration was 57.+-.4.5 .mu.m. Results confirm that
A.beta. induces chemotaxis in human monocytes with a maximum
response at 1 pmol/L. A.beta.-PP induces chemotaxis in a
concentration-dependent manner, with the maximal response also at 1
pM.
Inhibition of A.beta. and A.beta.-Precursor Protein-Induced
Monocyte Migration by Neuropeptides.
[0073] To delineate whether monocyte attracting neuropeptides
influence A.beta.- and A.beta.-PP-induced monocyte locomotion,
cells are exposed to neuropeptides, e.g. bombesin, CGRP, SP, SN or
VIP and chemotaxis toward A.beta. and A.beta.-PP is tested as
described above. All neuropeptides inhibit chemotaxis
concentration-dependently.
Signaling Enzyme Inhibitors Affect A.beta.-Induced Migration
[0074] Monocytes are incubated with several enzyme blockers. The
protein kinase C inhibitor GFX, the tyrosine kinase inhibitor
tyrphostin-23, and the phospholipase-3 inhibitor WTN are used first
for blocking signaling enzymes; involvement of G proteins is then
tested with PTX which is known to induce Gi proteins, and CTX which
induces Gs proteins. After washing, chemotaxis experiments toward
A.beta.(1 pmol/l) and A.beta.-PP (1 pmol/l) are performed. Data are
expressed as chemotaxis index, which is the ratio between directed
and random migration. Mean distance of random migration is
54.+-.3.2 .mu.m.
TABLE-US-00001 TABLE 1 Chemotaxis Index Treatment A.beta. Mean (+/-
SEM) A.beta.-PP Mean (+/- SEM) Medium 1.786 (0.078) 1.639 (0.076)
GFX (500 nmol/l) 1.143 (0.08) 1.098 (0.10) IBMX (10 ng/ml) 1.234
(0.06) 1.208 (0.09) Tyrphostin-23 1.435 (0.04) 1.398 (0.07) (10
ng/ml) WTN (10 nmol/l) 1.023 (0.05) 1.115 (0.08) CTX (1 nmol/l)
1.768 (0.10) 1.790 (0.13) PTX (1 nmol/l) 1.098 (0.08) 1.123
(0.06)
N,N-dimethylsphingosine Inhibits A.beta.- and A.beta.-PP-Induced
Monocyte Migration
[0075] Human monocytes are pre-treated with the selective
sphingosine kinase inhibitor, DMS, at different concentrations
(e.g. 100 fmol/l to 100 nmol/l). fMLP is used as a control
attractant. Treatment with DMS inhibits A.beta.- and
A.beta.-PP-induced chemotaxis, whereas fMLP-induced chemotaxis is
not affected.
S1P Receptor Agonist Deactivates Migration of Human Monocytes
Toward A.beta. and Chemokines
[0076] Monocytes are incubated with DMS, Compound A or medium for
20 min. After washing, chemotaxis experiments toward A.beta. [1
pmol/L] are performed. Data are expressed as chemotaxis index,
which is the ratio between directed and random migration. Mean
distance of random migration is 56.+-.5.6 .mu.m. DMS and a S1P
receptor agonist alone inhibit the migration of the cells, whereas
co-treatment with both restores the chemotactic effect of A.beta.
and A.beta.-PP. Results with Compound A are as follows:
TABLE-US-00002 TABLE 2 Chemotaxis Treatment Mean (+/- SEM) Medium
1.825 (0.14) DMS (2 ng/ml) 1.423 (0.18) Compound A (2 ng/ml) 1.077
(0.18)
S1P Receptor mRNA Expression is Regulated by A.beta.
[0077] After pretreatment with Compound A at various concentrations
[20 pg/mL to 20 .mu.g/mL] for 20 min, cells are washed and
chemotaxis toward A.beta. and A.beta.-PP [1 pM] is tested as
described above. Data are expressed as chemotaxis index, which is
the ratio between directed and undirected migration of cells. After
the incubation period, RT-PCR is performed and equal amounts of
cDNA are subjected to agarose gel electrophoresis. Induction of
S1PR 2 and S1PR 5 mRNA in A.beta.-treated cells is observed.
B. Clinical Trial
[0078] The trial is carried out employing groups comprising 6 to 10
subjects identified as exhibiting mild to moderate Alzheimer
dementia in accordance with parameters defined in DSM-III
(Diagnostic and Statistical Manual of Mental Disorders, 3rd
edition) and excluding subjects exhibiting severe cardiovascular
disease, hypotension, severe endocrine disease, severe liver
disease, renal insufficiency. The trial commences with an EEG and
psychometric test at time 0. Subjects then receive placebo, or test
medication administered as described below, and the EEG and
psychometric tests are repeated 60, 120 and 180 minutes subsequent
to administration. Psychometric tests employed include:
(i) The Selective Reminding Test/Buschke: "Selective Reminding for
Analysis of Memory and Learning", J. Verbal Learning and Verbal
Behaviour 12, 543-550 (1973);
[0079] (ii) Measurement of Constructional Ability (Muratomo et al.:
"Effect of Physiostigmin on Constructional and Memory Tasks in
Alzheimer's disease", Arch. Neurol. 36, 501-503 (1973); and (iii)
Memory of Geometric Figures (Benton revised visual retention
test).
[0080] During the course of the trial, subjects receive either a
placebo or a S1P receptor agonist, e.g. Compound A, at dosages of
from ca. 0.25 to ca. 10 mg/p.o. administered once or in divided
dosages 2 or 3.times..
[0081] The following additional parameters are monitored: [0082]
Haematology: R.B.C., HB, HCT, W.B.C, differential counts,
sedimentation rate, blood glucose. [0083] Urine: Albumin, glucose.
[0084] Serum: Alkaline phosphatase, ALT, AST, S-GT, S-bilirubin,
S-T4, S-T3, S-TSH, creatinin.
[0085] Subjects receiving a S1P receptor agonist, e.g. Compound A,
in the above indicated dosages exhibit improved condition as
evidenced by EEG results and the results of psychometric tests as
compared with subjects receiving placebo.
[0086] Daily dosages required in practicing the method of the
present invention when S1P receptor agonist is used will vary
depending upon, for example, the compound used, the host, the mode
of administration and the severity of the condition to be treated.
A preferred daily dosage range is about from 0.1 to 100 mg as a
single dose or in divided doses. Suitable daily dosages for
patients are on the order of from e.g. 0.1 to 50 mg p.o. The S1P
receptor agonist may be administered by any conventional route, in
particular enterally, e.g. orally, e.g. in the form of tablets,
capsules, drink solutions, nasally, pulmonary (by inhalation) or
parenterally, e.g. in the form of injectable solutions or
suspensions. Suitable unit dosage forms for oral administration
comprise from ca. 0.1 to 30 mg, usually 0.25 to 30 mg S1P receptor
agonist, e.g. Compound A, together with one or more
pharmaceutically acceptable diluents or carriers therefor.
[0087] The S1P 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, or topically. Pharmaceutical compositions comprising a
S1P 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.
[0088] The S1P receptor agonists may be administered as the sole
ingredient or together with other drugs useful in the alleviation
or treatment of brain degenerative diseases or progressive
dementia, e.g. an AMPA receptor agonist, a noortropic agent, a
painkiller or an anti-inflammatory agent.
[0089] The term "AMPA receptor antagonist" as used herein includes,
but is not limited to an quinoxaline-dione aminoalkylphosphonate,
e.g. as disclosed in WO 98/17672, or to further compounds such as
EGIS 8332
(7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,-
3]benzodiazepine-8-carbonitrile), GYKI 47261
4-(7-chloro-2-methyl-4H-3,10,10a-triaza-benzo[f]azulen-9-yl)-phenylamine)-
, irampanel (BIIR 561;
N,N-dimethyl-2-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy]ethanamine),
KRP 199
(7-[4-[[[[(4-carboxyphenyl)-amino]carbonyl]oxy]methyl]-1H-imidazol-1--
yl]-3,4-dihydro-3-oxo-6-(trifluoromethyl)-2-quinoxalinecarboxylic
acid), NS 1209
(2-[[[5-[4-[(dimethylamino)-sulfonyl]phenyl]-1,2,6,7,8,9-hexahydr-
o-8-methyl-2-oxo-3H-pyrrolo[3,2-h]isoquinolin-3-ylidene]amino]oxy]-4-hydro-
xybutanoic acid monosodium salt, e.g. prepared as described in WO
98/14447), topiramate (TOPAMAX,
2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate,
preparation, e.g. as described in U.S. Pat. No. 535,475) and
talampanel (LY-300164,
(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h]-
[2,3]benzo-diazepine, preparation, e.g. as described in EP 492485),
YM90K (6-imidazol-1-yl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione),
S-34730 (7-chloro-6-sulfamoyl-2-(1H)-quinolinone-3-phosphonic
acid), Zonampanel (YM-872;
(7-imidazol-1-yl-6-nitro-2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-y-
l)-acetic acid), GYKI-52466
(4-(8-methyl-9H-1,3-dioxa-6,7-diaza-cyclohepta[f]inden-5-yl)-phenylamine)-
, ZK-200775 (MPQX,
(7-morpholin-4-yl-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H-quinoxalin-1-
-ylmethyl)-phosphonic acid), CP-465022
(3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fl-
uoro-3H-quinazolin-4-one), SYM-2189
(4-(4-amino-phenyl)-6-methoxy-1-methyl-1H-phthalazine-2-carboxylic
acid propylamide), SYM-2206
(8-(4-amino-phenyl)-5-methyl-5H-[1,3]dioxolo[4,5-g]phthalazine-6-carboxyl-
ic acid propylamide, RPR-117824
((4-oxo-2-phosphono-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9--
yl)-acetic acid), LY-293558
(6-[2-(1H-tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic
acid).
[0090] The term "nootropics" as used herein includes, but is not
limited to nootropical plant extracts, calcium antagonists,
cholinesterase inhibitors, dihydroergotoxin, nicergoline,
piracetame, purine derivates, pyritinol, vincamine and vinpocetine.
The term "nootropical plant extracts" as used herein includes, but
is not limited to extracts from Ginkgo leafs. The term "calcium
antagonists" as used herein includes, but is not limited to
cinnarizine and nimodipine. The term "cholinesterase inhibitors" as
used herein includes, but is not limited to donepezil
hydrochloride, rivastigmine and galantamine hydrobromide. The term
"purine derivates" as used herein includes, but is not limited, to
pentifyllin. A painkiller as used herein includes, but is not
limited, to ibuprofen. A suitable anti-inflammatory agent is e.g. a
NSAIDs, e.g. naproxen.
[0091] Extracts from Ginkgo leafs can be administered, e.g., in the
form as marketed, e.g. under the trademark Ginkodilat.TM. according
to the information provided by the package insert. Cinnarizine can
be administered, e.g., in the form as marketed, e.g. under the
trademark Cinnarizin Forte-Ratiopharm.TM.. Nimodipine can be
administered, e.g., in the form as marketed, e.g. under the
trademark Nimotop.TM.. Donepezil hydrochloride can be administered,
e.g., in the form as marketed, e.g. under the trademark
Aricept.TM.. Rivastigmine can be prepared as disclosed in U.S. Pat.
No. 5,602,176. It can be administered, e.g., in the form as
marketed, e.g. under the trademark Exelon.TM.. Galantamine
hydrobromide can be administered, e.g., in the form as marketed,
e.g. under the trademark Reminyl.TM.. Dihydroergotoxin can be
administered, e.g., in the form as marketed, e.g. under the
trademark Hydergin.TM.. Nicergoline can be administered, e.g., in
the form as marketed, e.g. under the trademark Sermion.TM..
Piracetam can be administered, e.g., in the form as marketed, e.g.
under the trademark Cerebrofortem. Pentifyllin can be administered,
e.g., in the form as marketed, e.g. under the trademark
Cosaldon.TM.. Pyritinol can be administered, e.g., in the form as
marketed, e.g. under the trademark Encephabol.TM.. Vinpocetin can
be administered, e.g., in the form as marketed, e.g. under the
trademark Cavinton.TM..
[0092] The structure of the active ingredients identified by code
nos., generic or trade names mentioned herein may be taken from the
actual edition of the standard compendium "The Merck Index" or from
databases, e.g. Patents International (e.g. IMS World
Publications). The corresponding content thereof is hereby
incorporated by reference. Any person skilled in the art is fully
enabled to identify the active ingredients and, based on these
references, likewise enabled to manufacture.
[0093] Where the S1P 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.
[0094] In accordance with the foregoing the present invention
provides in a yet further aspect: [0095] 5. A pharmaceutical
combination comprising a) a first agent which is a S1P receptor
agonist, e.g. a compound of formula I, e.g. Compound A, or a
pharmaceutically acceptable salt thereof, and b) a co-agent, e.g. a
second drug agent as defined above. [0096] 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. Compound A, or a
pharmaceutically acceptable salt thereof, and a second drug
substance, e.g. as indicated above.
[0097] S1P receptor agonists are well tolerated at dosages required
for use in accordance with the present invention. For example,
Compound A has an acute LD.sub.50>10 mg/kg p.o. in rats and
monkeys.
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