U.S. patent application number 09/946214 was filed with the patent office on 2002-03-21 for method for treating allergies.
Invention is credited to Gu, Yin, Karlsson, Lars, Sun, Siquan, Thurmond, Robin L..
Application Number | 20020035108 09/946214 |
Document ID | / |
Family ID | 22865099 |
Filed Date | 2002-03-21 |
United States Patent
Application |
20020035108 |
Kind Code |
A1 |
Gu, Yin ; et al. |
March 21, 2002 |
Method for treating allergies
Abstract
Use of cathepsin S inhibitors for the treatment of an allergic
condition, in particular an atopic allergic condition, more
specifically for the treatment of hay fever, asthma, atopic
dermatitis or a food allergy.
Inventors: |
Gu, Yin; (San Diego, CA)
; Karlsson, Lars; (La Jolla, CA) ; Sun,
Siquan; (San Diego, CA) ; Thurmond, Robin L.;
(San Diego, CA) |
Correspondence
Address: |
AUDLEY A. CIAMPORCERO JR.
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
22865099 |
Appl. No.: |
09/946214 |
Filed: |
September 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60230407 |
Sep 6, 2000 |
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Current U.S.
Class: |
514/237.2 ;
514/255.01; 514/519 |
Current CPC
Class: |
A61P 37/00 20180101;
A61K 31/519 20130101; A61K 31/495 20130101; A61K 31/454 20130101;
A61K 31/4745 20130101; A61K 31/5377 20130101; A61K 31/55 20130101;
A61P 1/00 20180101; A61P 11/02 20180101; A61K 31/541 20130101; A61K
31/4155 20130101; A61K 31/496 20130101; A61K 31/13 20130101; A61P
43/00 20180101; A61P 17/04 20180101; A61P 27/14 20180101; A61K
31/4439 20130101; A61P 37/08 20180101; A61K 31/00 20130101; A61P
11/06 20180101; A61K 31/53 20130101; A61K 31/275 20130101 |
Class at
Publication: |
514/237.2 ;
514/255.01; 514/519 |
International
Class: |
A61K 031/275; A61K
031/535; A61K 031/495 |
Claims
What is claimed is:
1. A method of treating a subject suffering from an allergic
condition, said method comprising administering to said subject a
therapeutically effective amount of a pharmaceutical composition
comprising a cathepsin S inhibitor.
2. A method according to claim 1, wherein the allergic condition is
an atopic IgE-mediated allergic condition.
3. A method according to claim 1, wherein the allergic condition is
selected from hay fever, asthma, atopic dermatitis, and a food
allergy.
4. A method of claim 1, wherein said cathepsin S inhibitor is a
compound of formula: 1in which: n is 0 to 13; A-B represents a
linkage selected from --C(O)NR.sup.3--, --CH.sub.2NR.sup.3--,
--C(O)CH.sub.2-- and --NR.sup.3C(O)--, wherein R.sup.3 is hydrogen
or as defined below; X represents a bond, methylene or the linkage
--CH.sub.2CH(R.sup.4)--, wherein R.sup.4 is hydrogen, alkyl or
arylalkyl; Y is --CH(R.sup.5)-- or --N(R.sup.5)--, wherein R.sup.5
is hydrogen or as defined below; Z is --(CH.sub.2).sub.2--,
--C(R.sup.6)(R.sup.7)-- or --N(R.sup.7)--, wherein R.sup.6 is
hydrogen or methyl and R.sup.7 is as defined below; Z.sup.1 is
--(CH.sub.2).sub.2--, --C(R.sup.6)(R.sup.8)-- or --N(R.sup.8)--,
wherein R.sup.6 is hydrogen or methyl and R.sup.8 is as defined
below; R.sup.1 is hydrogen, alkyloxycarbonylalkanoyl,
alkyloxycarbonyl, alkanoyl (optionally substituted with a radical
selected from carboxy, alkyloxycarbonyl and
heterocycloalkylalkanoylamino), cycloalkylcarbonyl,
heterocycloalkylcarbonyl (optionally substituted with a radical
selected from hydroxy, alkyl, alkanoyl, alkyloxycarbonyl,
arylalkyloxycarbonyl and heterocycloalkylcarbonyl),
arylalkyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
arylcarbamoyl, arylalkylcarbamoyl, arylalkanoyl, aroyl,
alkylsulfonyl, dialkylaminosulfonyl, arylsulfonyl or
heteroarylsulfonyl; R.sup.7 and R.sup.8 are independently hydrogen,
alkyl (optionally substituted with a radical selected from hydroxy,
amino, alkylamino, dialkylamino, uriedo, mercapto, alkylthio,
carboxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylsulfonyl
and guanidino, or a protected derivative thereof, cycloalkyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, a group selected from
aryl and arylalkyl (which group is optionally substituted at its
aryl ring with one to three radicals selected from hydroxy, amino,
guanidino, halo, optionally halo-substituted alkyl, alkyloxy and
aryl, or a protected derivative thereof) or together with an
adjacent R.sup.3 or R.sup.5 forms a divalent radical selected from
(C.sub.3-4)methylene and 1,2-phenylenedimethylene (which radical is
optionally substituted with hydroxy, or a protected derivative
thereof, or oxo); and R.sup.2 is hydrogen, alkyl (optionally
substituted with one or more radicals selected from amino, halo,
hydroxy, alkyloxy, nitro, alkylsulfonyl and arylsulfonyl, or a
protected derivative thereof, cycloalkyl, cycloalkylalkyl or a
group selected from aryl and arylalkyl (which group is optionally
substituted at its aryl ring with one to two radicals selected from
amino, guanidino, halo, hydroxy, optionally halo-substituted alkyl,
alkyloxy, nitro, alkylsulfonyl and arylsulfonyl, or a protected
derivative thereof; or a pharmaceutically acceptable salt, isomer
or mixture of isomers thereof.
5. The method of claim 4, wherein said cathepsin S inhibitor is a
compound wherein Z is --C(R.sup.6)(R.sup.7)--; n is 0; R.sup.3,
R.sup.5 and R.sup.8 are each hydrogen; R.sup.1 is hydrogen,
tert-butxoycarbonyl, benzyloxycarbonyl, biotinylaminohexanoyl,
benzoyl, 1-piperiziny-carbonyl, 4-methyl-1-piperazinylcarbonyl or
4-morpholinylcarbonyl; R.sup.8 is butyl, 2-phenylethyl or
2-methylsulfonylethyl; R.sup.2 is phenyl, 1-naphthyl or
2-phenylethyl; and R.sup.7 is (C.sub.1-5)alkyl,
2-methylsulfonylethyl, optionally substituted benzyl,
1-naphthylmethyl, 2-naphthylmethyl, 3-pyridinylmethyl or
2-methylsulfonylethyl.
6. The method of claim 5, wherein said cathepsin S inhibitor is a
compound wherein R.sup.1 is 1-piperizinylcarbonyl,
4-methyl-1-piperazincarbonyl or 4-morpholinylcarbonyl; R.sup.8 is
2-phenylethyl; R.sup.2 is phenyl or naphth-2-yl; and R.sup.7 is
optionally substituted benzyl, 1-naphthylmethyl or
2-naphthylmethyl.
7. A method of claim 1, wherein said cathepsin S inhibitor is a
compound of formula: 2in which: n is 0 to 13; A-B represents a
linkage selected from --C(O)NR.sup.3--, --CH.sub.2NR.sup.3--,
--C(O)CH.sub.2-- and --NR.sup.3C(O)--, wherein R.sup.3 is hydrogen
or as defined below; Y is --CH(R.sup.5)-- or --N(R.sup.5)--,
wherein R.sup.5 is hydrogen or as defined below; Z is
--(CH.sub.2).sub.2--, --C(R.sup.6)(R.sup.7)-- or --N(R.sup.7)--,
wherein R.sup.6 is hydrogen or methyl and R.sup.7 is as defined
below; Z.sup.1 is --(CH.sub.2).sub.2--, --C(R.sup.6)(R.sup.8)-- or
--N(R.sup.8)--, wherein R.sup.6 is hydrogen or methyl and R.sup.8
is as defined below; R.sup.1 is hydrogen, alkyloxycarbonylalkanoyl,
alkyloxycarbonyl, alkanoyl (optionally substituted with a radical
selected from carboxy, alkyloxycarbonyl and
heterocycloalkylalkanoylamino- ), cycloalkylcarbonyl,
heterocycloalkylcarbonyl (optionally substituted with a radical
selected from hydroxy, alkyl, alkanoyl, alkyloxycarbonyl,
arylalkyloxycarbonyl and heterocycloalkylcarbonyl),
arylalkyloxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
arylcarbamoyl, arylalkylcarbamoyl, arylalkanoyl, aroyl,
alkylsulfonyl, dialkylaminosulfonyl, arylsulfonyl or
heteroarylsulfonyl; R.sup.7 and R.sup.8 are independently hydrogen,
alkyl (optionally substituted with a radical selected from hydroxy,
amino, alkylamino, dialkylamino, uriedo, mercapto, alkylthio,
carboxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylsulfonyl
and guanidino, or a protected derivative thereof), cycloalkyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, a group selected from
aryl and arylalkyl (which group is optionally substituted at its
aryl ring with one to three radicals selected from hydroxy, amino,
guanidino, halo, optionally halo-substituted alkyl, alkyloxy and
aryl, or a protected derivative thereof) or together with an
adjacent R.sup.3 or R.sup.5 forms a divalent radical selected from
a divalent radical selected from (C.sub.3-4)methylene and
1,2-phenylenedimethylene (which radical is optionally substituted
with hydroxy, or a protected derivative thereof, or oxo); and
R.sup.9 is cyano, --C(O)OR.sup.10, --P(O)(OR.sup.10).sub.2,
--S(O)(NR.sup.10)R.sup.1- 0, C(O)R.sup.11, --S(O)R.sup.11,
--C(O)NR.sup.12R.sup.13, --S(O).sub.2NR.sup.12R.sup.13,
--C(O)NHR.sup.14 or --S(O).sub.2NHR.sup.14, wherein each R.sup.10
is independently hydrogen, alkyl (optionally substituted with one
or more radicals selected from amino, halo, hydroxy, alkyloxy,
nitro, alkylsulfonyl and arylsulfonyl, or a protected derivative
thereof), cycloalkyl, cycloalkylalkyl or a group selected from aryl
and arylalkyl (which group is optionally substituted at its aryl
ring with one to two radicals selected from amino, halo, hydroxy,
optionally halo-substituted alkyl, alkyloxy, nitro, alkylsulfonyl
and arylsulfonyl, or a protected derivative thereof), R.sup.11 is
hydrogen, alkyl, perfluoroalkyl, cycloalkyl, cycloalkylalkyl,
perfluoroaryl, perfluoroarylakyl or a group selected from aryl and
arylalkyl (which group is optionally substituted at its aryl ring
with one to two radicals selected from amino, halo, hydroxy,
optionally halo-substituted alkyl, alkyloxy, nitro, alkylsulfonyl
and arylsulfonyl, or a protected derivative thereof), R.sup.12 and
R.sup.13 are independently hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, aryl or aralkyl and R.sup.14 is --C(O)OR.sup.10,
in which R.sup.10 is as defined above, or a group selected from
Formula (a) and (b): 3wherein each n, A, B, Y, Z, R.sup.1 and
R.sup.10 are as defined above in claim 4; or a pharmaceutically
acceptable salt, isomer or mixtureof isomers thereof.
8. The method of claim 7, wherein said cathepsin S inhibitor is a
compound, wherein each R.sup.1 is 1-piperizinylcarbonyl,
4-methyl-1-piperazinylcarbonyl or 4-morpholinylcarbonyl; R.sup.8 is
2-phenylethyl; and R.sup.7 is optionally substituted benzyl,
1-naphthylmethyl or 2-naphthylmethyl.
9. The method of claim 8, wherein said cathepsin S inhibitor is a
compound, wherein R.sup.1 is 4-morpholinylcarbonyl, R.sup.1 is
2-phenylethyl, R.sup.7 is benzyl and R.sup.1 is benzylcarbamoyl
namely
N.sup.2-4-(morpholinylcarbonyl)-N.sup.1-)3-phenyl-1S-(2-benzylcarbamoylet-
hyl)propyl-L-phenylalaninamide.
10. A method of claim 1, wherein said cathepsin S inhibitor is a
compound of formula: 4wherein A and X are N-substituents selected
from the group consisting of acyl, acyl peptidyl, alkyloxycarbonyl,
alkyloxycarbonyl peptidyl, sulfonyl, peptidyl, sulfamoyl, sulfamoyl
peptidyl, sulfinyl, sulfinyl peptidyl, carbamoyl, and carbamoyl
peptidyl; R.sub.1 is (a) an amino acid side chain or (b) hydrogen;
R.sub.2 is (a) an amino acid side chain or (b) hydrogen, wherein
either (1) both R.sub.1 and R.sub.2 are hydrogen, or (2) one of
R.sub.1 or R.sub.2 is an amino acid side chain and the other one of
R.sub.1 and R.sub.2 is hydrogen; and R.sub.3 and R.sub.4 are
hydrogen, or are bonded together to form ethylene or substituted
ethylene; wherein said ethylene substituent is an amino acid side
chain.
11. A method of claim 1, wherein said cathepsin S inhibitor is a
compound of formula: 5wherein A is a N-substituent selected from
the group consisting of acyl peptidyl, alkyloxycarbonyl peptidyl,
peptidyl, sulfamoyl peptidyl, sulfinyl peptidyl, and carbamoyl
peptidyl; X is a N-substituent selected from the group consisting
of acyl, acyl peptidyl, alkyloxycarbonyl, alkyloxycarbonyl
peptidyl, sulfonyl, sulfonyl peptidyl, peptidyl, sulfamoyl,
sulfamoyl peptidyl, sulfinyl, sulfinyl peptidyl, carbamoyl, and
carbamoyl peptidyl; R.sub.1 is hydrogen; and R.sub.2 is an amino
acid side chain.
12. A method of claim 1, wherein said cathepsin S inhibitor is a
compound of formula: 6wherein A and X are N-substituents selected
from the group consisting of C(O)R.sub.7 (acyl), acyl peptidyl,
C(O)OR.sub.8 (alkyloxycarbonyl), alkyloxycarbonyl peptidyl,
S(O)2R.sub.9 (sulfonyl), peptidyl, S(O).sub.2NR.sub.10R.sub.11,
(sulfamoyl), sulfamoyl peptidyl, S(O)R.sub.9 (sulfinyl), sulfinyl
peptidyl, C(O)NR.sub.10R.sub.11 (carbamoyl), and carbamoyl
peptidyl; R.sub.7 is selected from the group consisting of
(C.sub.1-5)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-5)alkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-5)al- kenyl,
hetero(C.sub.3-7)cycoalkyl, (C.sub.5-14)aryl,
substituted(C.sub.5-14)aryl, (C.sub.7-12)aralkyl, and
substituted(C.sub.7-12)aralkyl; wherein said hetero group is
selected from the group consisting of hydroxy, (C.sub.1-5)alkyl,
hetero(C.sub.3-7)cycloalkyl, (C.sub.1-5)alkanoyl,
(C.sub.1-5)alkoxycarbon- yl,
(C.sub.5-14)aryl(C.sub.1-5)alkoxycarbonyl, and
hetero(C.sub.3-7)cycloa- lkylcarbonyl; R.sub.8 is selected from the
group consisting of (C.sub.1-5)alkyl (optionally substituted with a
member of the group consisting of hydroxy, (C.sub.1-5)alkoxy,
amino, and halogens of atomic number 9-35), (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-5)alky- l,
(C.sub.3-7)cycloalkyl(C.sub.1-5)alkenyl, (C.sub.5-14)aryl,
substituted(C.sub.5-14)aryl, (C.sub.7-12)aralkyl, and
substituted(C.sub.7-12)aralkyl; R.sub.9 is selected from the group
consisting of (C.sub.1-5)alkyl (optionally substituted with a
member of the group consisting of hydroxy, (C.sub.1-5)alkoxy,
amino, and halogens of atomic number 9-35), (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.su- b.1-5)alkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-5)alkenyl, (C.sub.5-14)aryl,
substituted(C.sub.5-14)aryl, (C.sub.7-12)aralkyl, and
substituted(C.sub.7-.sub.12)aralkyl; R.sub.10 and R.sub.11 are
independently selected from the group consisting of hydrogen,
(C.sub.1-5)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-5)- alkyl, (C.sub.5-14)aryl,
substituted(C.sub.5-14)aryl, (C.sub.7-12)aralkyl,
substituted(C.sub.7-12)aralkyl; di(C.sub.1-5)alkyl,
(C.sub.1-5)alkyl(C.sub.7-12)aralkyl; or R.sub.10 and R.sub.11 are
bonded to form a 5 or 6 membered alicyclic or heteroalicylic ring
moieties; Peptidyl is 1-10 amino acids; said substituents of said
substituted aryl and substituted aralkyl are 1 or 2 members of the
group consisting of (C.sub.1-5)alkyl, (C.sub.1-5)alkoxy, halogens
of atomic number 9-35, hydroxy, and amino; R.sub.1 is (a) an amino
acid side chain or (b) hydrogen; R.sub.2 is (a) an amino acid side
chain or (b) hydrogen, wherein either (1) both R, and R.sub.2 are
hydrogen, or (2) one of R.sub.1 or R.sub.2 is an amino acid side
chain and the other one of R.sub.1 and R.sub.2 is hydrogen; and
R.sub.3 and R.sub.4 are hydrogen, or are bonded together to form
ethylene or substituted ethylene wherein said ethylene substituent
is an amino acid side chain.
13. A method of claim 1, wherein said cathepsin S inhibitor is a
compound of formula: 7wherein A and X are independently
R.sub.13--X.sub.1--; R.sub.13 is selected from the group consisting
of hydrogen, alkyloxycarbonylalkanoyl of overall 3-10 carbon atoms,
(C.sub.1-9)alkyloxycarbonyl, (C.sub.2-10)alkanoyl (optionally
substituted with a radical selected from carboxy,
(C.sub.1-9)alkyloxycarbonyl and
hetero(C.sub.4-8)cycloalkyl(C.sub.2-10)alkanoylamino),
(C.sub.4-8)cycloalkylcarbonyl, hetero(C.sub.4-8)cycloalkylcarbonyl
(optionally substituted with a radical selected from hydroxy,
(C.sub.1-5)alkyl, hetero(C.sub.4-8)cycloalkyl, (C.sub.1-5)alkanoyl,
(C.sub.1-5)alkyloxycarbonyl,
(C.sub.6-10)aryl(C.sub.1-5)alkyloxycarbonyl and
hetero(C.sub.4-8)cycloalkylcarbonyl),
(C.sub.6-10)aryl(C.sub.1-5)alky- loxycarbonyl, carbamoyl,
(C.sub.1-5)alkylcarbamoyl, di(C.sub.1-5)alkylcarbamoyl,
(C.sub.6-10)arylcarbamoyl,
(C.sub.6-10)aryl(C.sub.1-5)alkylcarbamoyl,
(C.sub.6-10)aryl(C.sub.1-5)alk- anoyl, (C.sub.7-11)aroyl,
(C.sub.1-10)alkylsulfonyl, (C.sub.6-10)arylsulfonyl,
(C.sub.6-10)aryl(C.sub.1-5)alkylsulfonyl,
(C.sub.1-5)alkylsulfamoyl, di(C.sub.1-5)alkylsulfamoyl,
(C.sub.6-10)arylsulfamoyl, (C.sub.1-5)alkylsulfinyl,
di(C.sub.1-5)alkylaminosulfinyl, and (C.sub.6-10)arylsulfinyl;
X.sub.1 is a bond or a divalent radical of formula (a) or (b): 8n
is 0 to 9; X.sub.3-X.sub.4 represents a linkage selected from
--C(O)NR.sub.14--, --CH.sub.2NR.sub.14--, --C(O)CH.sub.2-- and
--NR.sub.14C(O)--; Y is --CH(R.sub.14)-- or --NR.sub.14--; Z is
--(CH.sub.2).sub.2', --C(R.sub.15)(R.sub.16)-- or --N(R.sub.16)--;
R.sub.14 is hydrogen or as defined below; R.sub.15 is hydrogen or
methyl; each R.sub.16 is independently hydrogen, (C.sub.1-5)alkyl
(optionally substituted with a radical selected from hydroxy,
(C.sub.1-5)alkyloxy, amino, (C.sub.1-5)alkylamino,
di(C.sub.1-5)alkylamino, uriedo, (C.sub.1-5) alkyluriedo, mercapto,
(C.sub.1-5)alkylthio, carboxy, carbamoyl,
(C.sub.1-5)alkylcarbamoyl, di(C.sub.1-5)alkylcarbamoyl,
(C.sub.1-5)alkylsulfinyl, (C.sub.1-5)alkylsulfonyl, guanidino,
--P(O)(OR.sub.12).sub.2, --OP(O)(OR.sub.12).sub.2 or
--OP(O)(R.sub.12).sub.2, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.s- ub.1-5)alkyl, (C.sub.5-14)aryl,
(C.sub.5-14)aryl(C.sub.1-5)alkyl (which group is optionally
substituted at its aryl ring with one to three radicals selected
from hydroxy, amino, guanidino, a halogen, optionally halogen
substituted (C.sub.1-5)alkyl, (C.sub.1-5)alkyloxy and
(C.sub.5-14)aryl, or a protected derivative thereof) or together
with an adjacent R.sub.14 forms a divalent radical selected from
(C.sub.3-4)methylene and 1,2-phenylenedimethylene (which radical is
optionally substituted with hydroxy, or a protected derivative
thereof, or oxo), with the proviso X and A are not both hydrogen;
each R.sub.12 is independently hydrogen or (C.sub.1-5)alkyl or a
protected derivative thereof; R.sub.1 and R.sub.2 are both hydrogen
or one of R.sub.1 or R.sub.2 is cyano, carboxy,
(C.sub.1-5)alkyloxycarbonyl, (C.sub.1-5)alkanoyl, carbamoyl,
(C.sub.1-5)alkylcarbamoyl, di(C.sub.1-5)alkylcarbamoyl,
(C.sub.1-5)alkyloxy((C.sub.1-5)alkyl)carbamo- yl,
amino(C.sub.1-5)alkylcarbamoyl, R.sub.16, as defined above, or
R.sub.13--X.sub.2--, wherein R.sub.13 is as defined above and
X.sub.2 is a divalent radical of formulae (a) or (b), as defined
above; R.sub.3 and R.sub.4 are hydrogen or together form optionally
substituted ethylene, wherein said ethylene substituent is an amino
acid side chain or are independently R.sub.14, as defined above; or
a pharmaceutically acceptable salt, isomer or mixture of isomers
thereof.
14. A method of claim 1, wherein said CatS inhibitor is a compound
of formula: 9wherein: R is optionally substituted (aryl, lower
alkyl, lower alkenyl, lower alkynyl, or heterocyclyl); R.sub.2 and
R.sub.3 are independently hydrogen, or optionally substituted
[lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl,
cycloalkyl or bicycloalkyl)lower alkyl]; or R.sub.2 and R.sub.3
together represent lower alkylene, optionally interrupted by O, S
or NR.sub.6, so as to form a ring with the carbon atom to which
they are attached wherein R.sub.6 is hydrogen, lower alkyl or
aryl-lower alkyl; or either R.sub.2or R.sub.3 are linked by lower
alkylene to the adjacent nitrogent to form a ring; R.sub.4 and
R.sub.5 are independently H, or optionally substituted (lower
alkyl, aryl-lower alkyl), C(O) OR.sub.7, or --C(O)NR.sub.7R.sub.8,
wherein R.sub.7 is optionally substituted (lower alkyl, aryl,
aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and
R.sub.8 is H, or optionalloy substituted (lower alkyl, aryl,
aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), or
R.sub.4 and R.sub.5 together represent lower alkylene, optionally
interrupted by O, S or NR.sub.6 so as to form a ring with the
carbon atom to which they are attached wherein R.sub.6 is hydrogen,
lower alkyl or aryl-lower alkyl, or R.sub.4 is H or optionally
substituted lower alkyl and R.sub.5 is a substituent of
formula-X.sub.2--(Y.sub.1).sub.n--(Ar)P--Q--Z wherein Y.sub.1 is O,
S, SO, SO.sub.2, N(R.sub.6)SO.sub.2, N--R.sub.6, SO.sub.2NR.sub.6,
CONR.sub.6 or NR.sub.6CO; n is zero or one; p is zero or one;
X.sub.2 is lower alkylene; or when n is zero, X.sub.2 is also
C.sub.2-C.sub.7-alkylene interrupted by O, S, SO, SO.sub.2,
NR.sub.6, SO.sub.2NR.sub.6, CONR.sub.6 or NR.sub.6CO; wherein
R.sub.6 is hydrogen, lower alkyl or aryl-lower alkyl; Ar is
arylene; Z is hydroxy, acyloxy, carboxyl, esterified carboxyl,
amidated carboxyl, aminosulfonyl, (lower alkyl or aryl-lower
alkyl)aminosulfonyl, or (lower alkyl or aryl-lower
alkyl)sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or
imidazolyl; Q is direct bond, lower alkylene, Y.sub.1-lower
alkylene or C.sub.2-C.sub.7-alkylene interrupted by Y.sub.1;
X.sub.1 is --C(O)--, --C(S)--, --S(O)--, --S(O).sub.2--, or
--P(O)(OR.sub.6)--, wherein R.sub.6 is as defined above; Y is
oxygen or sulfur; L is optionally substituted -Het-,
-Het-CH.sub.2-- or --CH.sub.2-Het-, wherein Het is a hetero atom
selected from O, N or S, and x is zero or one; and aryl in the
above definitions represents carboxyclic or heterocyclic aryl; or a
physiologically-acceptable and -cleavable ester or a salt
thereof.
15. A method of claim 14, provided that when R is lower alkyl not
substituted by aryl, one of R.sub.4 or R.sub.5 is a substituent of
formula --X.sub.2--(Y.sub.1).sub.n--(Ar)P--Q--Z; provided that when
x is one, L is --O--, or --CH.sub.2--O-- and X.sub.1 is --C(O)--,
either one of R.sub.4 or R.sub.5 is a substituent of formula
--X.sub.2--(Y.sub.1).su- b.n--(Ar).sub.p--Q--Z, or R is not
unsubstituted phenyl; provided that when R.sub.2=R.sub.4=R.sub.5=H,
x is zero and X.sub.1 is --C(O)--, R.sub.3 is not H, --CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2--CH--(CH.sub.3).sub.2,
--CH.sub.2--COOH, or --CH.sub.2--COO--CH.sub.2--CH.sub.3, when R is
unsubstituted phenyl, R.sub.3 is not H, --CH(CH.sub.3).sub.2, or
--CH.sub.2--CH--(CH.sub.3).sub- .2, when R is 4-aminophenyl or
4-nitrophenyl, R.sub.3 is not H when R is 3-aminophenyl,
3-nitrophenyl 2-chloropyridin-4-yl, or vinyl or R.sub.3 is not
--CH.sub.2--CH.sub.2--S--CH.sub.3 when R is pyridin-3-yl or
2-chloropyridin-4-yl, provided that when R.sub.2=R.sub.3=R.sub.4=H,
x is zero and X.sub.1 is --C(O)-- and R is phenyl, R.sub.5 is not
--CH(CH.sub.3).sub.2, provided that when R.sub.3=R.sub.4=H, R.sub.5
is --CH.sub.2--CH.sub.2--COOH, x is zero and X.sub.1 is --C(O)--,
R.sub.2 does not form a heterocyclic ring with the adjacent
nitrogen atom, and provided that when
R.sub.2=R.sub.3=R.sub.4=R.sub.5=H, x is zero and X.sub.1 is
--SO.sub.2--, R is not 4-methylphenyl.
16. A method of claim 1, wherein said CatS inhibitor is a compound
of formula III 10wherein R.sub.30 is an acyl group derived from an
organic carboxylic, carbonic, carbamic or sulfonic acid; R.sub.32
and R.sub.33 are independently hydrogen, lower alkyl, cycloalkyl,
bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower
alkyl; or R.sub.32 and R.sub.33 together represent lower alkylene
so as to form a ring together with the carbon to which they are
attached; R.sub.34 is hydrogen or lower alkyl; X.sub.2, Y.sub.1,
Ar, Q, Z, n and p are as defined in claim 14; or a pharmaceutically
acceptable salt or ester thereof.
17. A method of claim 16, wherein said CatS inhibitor is compound
wherein (a) p is one; (b) Y.sub.1 is O, S, SO, SO.sub.2,
N(R.sub.6)SO.sub.2 or N--R.sub.6; and (c) X.sub.2 is lower
alkylene; or when n is zero, X.sub.2 is also
C.sub.2-C.sub.7-alkylene interrupted by O, S, SO, SO.sub.2 or
NR.sub.6, (d) R.sub.30 is an acyl group derived from an organic
carboxylic, carbamic, or sulfonic acid, (e) and pharmaceutically
acceptable salts and esters thereof.
18. A method of claim 14, wherein said CatS inhibitor is a compound
of the formula: 11wherein R.sub.40 is substituted phenyl or
heterocyclic aryl, (mono- or di-carbocyclic or heterocyclic
aryl)-lower alkyl or lower alkenyl, or heterocyclyl; R.sub.42 is
hydrogen or lower alkyl; R.sub.43 is carbocyclic or heterocyclic
aryl or lower alkyl; R.sub.44 and R.sub.45 are independently
hydrogen or lower alkyl; or R.sub.44 and R.sub.45 combined
represent lower alkylene; Or a pharmaceutically acceptable salt or
ester thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the use of cathepsin S
inhibitors for the treatment of an allergic condition, in
particular an atopic allergic condition.
BACKGROUND OF THE INVENTION
[0002] Atopic allergies afflict at least 20% of populations in
developed countries and comprise a wide range of IgE-mediated
diseases such as hay fever, asthma, atopic dermatitis, and food
allergies. Exposure of an allergic subject to relevant allergens
cross-links allergen specific IgE bound to mast cells, triggering
degranulation and release of proinflammatory mediators, such as
histamine and eicosanoids, which cause the weal-and-flare response
on a skin test. Characteristically, this early response is followed
by a prolonged late reaction in which inflammatory cells,
particularly eosinophils and activated TH-2 CD4 T cells, are
recruited to the site of allergen exposure. Inflammatory cytokines
such as IL-4 and IL-5, both produced by TH-2 cells, are important
for IgE production by B cells and for eosinophilia, respectively.
Immunotherapies targeting CD4 T cells have been shown to be
effective in reducing the production of IgE, the activation of
proinflammatory cells, and the release of inflammatory
mediators.
[0003] Current allergy therapies targeting CD4 T cells have met
with mixed success. Desensitization with allergen extracts or
vaccines is effective for many allergens, such as the Hymenoptera
insect sting which can induce life-threatening allergic reactions.
The mechanism may be either induction of T cell tolerance or the
conversion of TH-2 to TH-1. However, such treatment requires a
long-term treatment regime, frequent doctor visits and prior
stabilization by other medications, and is associated with a
certain morbidity rate and rare deaths. Alternatively,
immunosuppressive drugs such as steroids which effectively
stabilize ongoing allergy responses, are often associated with
severe side effects.
[0004] The activation of CD4 T cells is a major factor in the
initiation and maintenance of the allergic response. Allergens are
taken up by specialized antigen presenting cells (APCs) such as
dendritic cells and B cells. Protein allergens pass through the
endosomal or lysosomal system where they are degraded by different
proteases. These peptide fragments are bound by the MHC class II
molecules which, at the cell surface, are heterotrimeric complexes
consisting of two transmembrane glycoprotein chains (.alpha. and
.beta.) that form a binding scaffold for the third component, a
peptide of 11-20 amino acids. The antigen-MHC class II molecule
complex is recognized by CD4 T cells and leads to the activation of
the T cell. Activated T cells in turn activate several other
components of the immune system, such as B cells and macrophages,
that are crucial for the body's response to pathogens, but also
lead to the symptoms of allergies.
[0005] Class II molecules, like other transmembrane proteins, are
translocated into the endoplasmic reticulum (ER) after synthesis,
where they associate with a third protein, the invariant chain
(Ii). The invariant chain molecule is a type II transmembrane
protein that serves as a class II-specific chaperone, promoting the
exit of class II-Ii complexes from the ER and preventing class II
molecules from binding to peptides and unfolded proteins in the ER
and in the secretory pathway. A targeting motif in the cytoplasmic
tail of Ii directs the class II-Ii complexes from the secretory
pathway into the endosomal system.
[0006] Before the MHC class II molecules can present antigen the Ii
must be removed by a series of proteases that break down Ii. The
resultant Ii peptide fragments, called class II-associated
invariant chain peptides (CLIP), occupy the peptide binding groove
of the class II molecule, and in most cases are not spontaneously
released. The CLIP protects the class II binding pocket from
collapsing both during intracellular transport and after Ii
degradation in the endosomal system. Binding of antigenic peptides
generated from endocytosed proteins requires an empty, and yet open
binding site. The CLIP therefore must be released while the open
binding site is stabilized to allow the binding of other peptides.
Human Leukocyte Antigen-DM (`HLA-DM`) mediates both of these
functions, thus promoting the binding of antigenic peptides. After
acquiring peptides, the class II molecules are transported to the
cell surface via routes that are largely unknown.
[0007] In view of the above, inhibition of invariant chain
proteolysis will prevent removal of Ii from the class II binding
pocket, which in turn will specifically block antigen binding to
the MHC class II molecule.
[0008] Cathepsin S (`CatS`) is a cysteine protease expressed in
lymphatic tissues. CatS mediates invariant chain proteolysis, which
is a prerequisite for peptide loading of MHC class II molecules
(Riese et al. (1996) Immunity 4:357). CatS has 50-60% homology with
cathepsins L and K, but differs from them in that it has a broad pH
optimum that extends to alkaline pH. CatS modulates antigen
presentation in animal models, and inhibitors are effective in an
asthma model (Riese et al. (1998) J. Clin. Invest. 101:2351). Mice
deficient in cathepsin S have an impaired ability to present
exogenous proteins by professional antigen presenting cells
(Nakagawa et al. (1999) Immunity 10:207; Shi et al. (1999) Immunity
10:197).
[0009] Compounds that inhibit the proteolytic activity of human
cathepsin S are expected to find utility in the treatment of
chronic autoimmune diseases including, but not limited to, lupus
and rheumatoid arthritis; and have potential utility in modulating
the immune response to tissue transplantation. Methods of
modulating autoimmunity with an agent that modulates cathepsin S
activity, e.g., proteolysis of the Ii chain, as well as methods of
treating a subject having an autoimmune disorder, methods of
evaluating a treatment for its ability to modulate an immune
response are described in WO 99/58153.
SUMMARY OF THE INVENTION
[0010] The present invention features the use of cathepsin S
inhibitors to treat allergic conditions, including but not limited
to atopic allergies. Examples of an allergic condition include hay
fever, asthma, atopic dermatitis and food allergies. Allergens
include dust, pollen, mold, and pet dander or pet hair.
[0011] In one aspect, the invention provides a method for treating
a subject suffering from an allergic condition, in particular an
atopic allergic condition, said method comprising administering to
said subject a therapeutically effective amount of a pharmaceutical
composition comprising a cathepsin S inhibitor.
[0012] In another aspect, the invention provides a method for
treating a subject suffering from an IgE-mediated allergic
condition, in particular an atopic allergic condition, said method
comprising administering to said subject a therapeutically
effective amount of a pharmaceutical composition comprising a
cathepsin S inhibitor.
[0013] A third aspect of the invention provides the use, or the use
for the manufacture of a medicament, of a cathepsin S inhibitor for
treating an allergic condition, more in particular for treating
IgE-mediated allergic conditions, still more in particular treating
hay fever, asthma, atopic dermatitis or food allergies. The
invention also features anti-allergic pharmaceutical compositions
comprising as active ingredient an effective amount of a cathepsin
S inhibitor, and a pharmaceutically acceptable carrier. The active
ingredient can be formulated in any manner suitable for the
particular allergic condition, including aerosol, oral and topical
formulations and time-release formulations.
[0014] Cathepsin S inhibitors are known in the art; alternatively,
they can be identified using methods known in the art, such as the
Cathepsin S inhibition assay described in Example 1 below.
[0015] Additional features and advantages of the invention will
become apparent from the detailed description and examples below,
and the appended claims.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1 shows the inhibition of human T cell proliferative
responses to two species of dust mites, Der p and Der f. Top panel,
FIG. 1A: Dilution curve for purified PBMC from an allergy donor
were cultured with titrated doses of allergen extracts prepared
from Derp and Der f for seven days. Proliferation of T cells was
scored by measuring .sup.3H-thymidine incorporation for 18 h at the
end of culture. Bottom panel, FIG. 1B: Effect of titrated doses of
LHVS on proliferative responses of T cells to dust mite
extracts.
[0017] FIG. 2 is shows the inhibition of human T cell proliferative
responses to ragweeds but not ConA by LHVS. Top panel, FIG. 2A:
Dilution curve for Ipurified PBMC from an allergy donor were
cultured with titrated doses of allergen extracts prepared from
Ragweed short and Ragweed giant for seven days. Proliferation of T
cells was scored by measuring .sup.3H-thymidine incorporation for
18 h at the end of culture. Bottom panel, FIG. 2B: Effect of
titrated doses of LHVS on proliferative responses of T cells to
ragweed extracts.
DETAILED DESCRIPTION OF THE INVENTION
[0018] A target of the present invention was to determine whether
the presentation of particular antigens in a human system is
affected by the inhibition of cathepsin S. According to the
invention, it now has been found that inhibitors of cathepsin S
block the presentation of several crude allergen extracts in a
human ex vivo assay, thereby supporting the use of cathepsin S
inhibitors for the treatment of such allergic conditions.
[0019] Blocking Ii degradation should decrease antigen presentation
to CD4 T cells and disrupt the normal immune response. A cathepsin
S inhibitor should specifically affect the activation of CD4 T
cells, thus limiting the extent of concomitant immunosuppression,
an undesirable side effect of corticosteroid therapy.
[0020] By using cathepsin S inhibitors according to the methods of
the present invention, the immunological component of the allergic
reaction can be blocked to varying degrees, with the advantage over
current therapies of being more selective, having fewer or reduced
side effects, or both. The present invention is based, in part, on
the finding that cathepsin S inhibitors can block the presentation
of crude allergen extracts in a human ex vivo assay. This ex vivo
system closely mimics the process that occurs in the whole body
wherein antigens enter the blood stream, and are presented by
antigen presenting cells, which in turn activate CD4 T cells. In
the case of treating a subject, the inhibitor or a metabolite
thereof would also be present in the blood as in the ex vivo
assay.
[0021] A. Terms
[0022] The following terms are defined below and by their usage
throughout this disclosure.
[0023] "Alkyl" includes optionally substituted straight chain and
branched hydrocarbons with at least one hydrogen removed to form a
radical group. Alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl,
isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl
includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl.
[0024] "Alkenyl" includes optionally substituted straight chain and
branched hydrocarbon radicals as above with at least one
carbon-carbon double bond (sp.sup.2). Alkenyls include ethenyl (or
vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or
1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls,
hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture
of double bonds and triple bonds, such as 2-penten-4-ynyl, are
grouped as alkynyls herein. Alkenyl includes cycloalkenyl. Cis and
trans or (E) and (Z) forms are included within the invention.
[0025] "Alkynyl" includes optionally substituted straight chain and
branched hydrocarbon radicals as above with at least one
carbon-carbon triple bond (sp). Alkynyls include ethynyl,
propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a
mixture of double bonds and triple bonds, such as 2-penten-4-ynyl,
are grouped as alkynyls herein. Alkynyl does not include
cycloalkynyl.
[0026] "Alkoxy" includes an optionally substituted straight chain
or branched alkyl group with a terminal oxygen linking the alkyl
group to the rest of the molecule. Alkoxy includes methoxy, ethoxy,
propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
"Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are analogous to
alkoxy, replacing the terminal oxygen atom of alkoxy with,
respectively, NH (or NR), S, and SO.sub.2. Heteroalkyl includes
alkoxy, aminoalkyl, thioalkyl, and so on.
[0027] "Aryl" includes phenyl, naphthyl, biphenylyl,
tetrahydronaphthyl, and so on, any of which may be optionally
substituted. Aryl also includes arylalkyl groups such as benzyl,
phenethyl, and phenylpropyl. Aryl includes a ring system containing
an optionally substituted 6-membered carbocyclic aromatic ring,
said system may be bicyclic, bridge, and/or fused. The system may
include rings that are aromatic, or partially or completely
saturated. Examples of ring systems include indenyl, pentalenyl,
1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl,
indolyl, benzofuranyl, isoquinolinyl, and so on.
[0028] "Heterocyclyl" includes optionally substituted aromatic and
nonaromatic rings having carbon atoms and at least one heteroatom
(O, S, N) or heteroatom moiety (SO.sub.2, CO, CONH, COO) in the
ring. Unless otherwise indicated, a heterocyclic radical may have a
valence connecting it to the rest of the molecule through a carbon
atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom,
such as N-piperidyl or 1-pyrazolyl. Preferably a monocyclic
heterocyclyl has between 4 and 7 ring atoms, or between 5 and 6
ring atoms; there may be between 1 and 5 heteroatoms or heteroatom
moieties in the ring, and preferably between 1 and 3. A
heterocyclyl may be saturated, unsaturated, aromatic (e.g.,
heteroaryl), nonaromatic, or fused.
[0029] Heterocyclyl also includes fused, e.g., bicyclic, rings,
such as those optionally condensed with an optionally substituted
carbocyclic or heterocyclic five- or six-membered aromatic ring.
For example, "heteroaryl" includes an optionally substituted
six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen
atoms condensed with an optionally substituted five- or
six-membered carbocyclic or heterocyclic aromatic ring. Said
heterocyclic five- or six-membered aromatic ring condensed with the
said five- or six-membered aromatic ring may contain 1, 2 or 3
nitrogen atoms where it is a six-membered ring, or 1, 2 or 3
heteroatoms selected from oxygen, nitrogen and sulfur where it is a
five-membered ring.
[0030] Examples of heterocyclyls include thiazoylyl, furyl,
pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl,
isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,
quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
indolinyl, and morpholinyl. For example, preferred heterocyclyls or
heterocyclic radicals include morpholinyl, piperazinyl,
pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino,and more
preferably, piperidyl.
[0031] Examples illustrating heteroaryl are thienyl, furanyl,
pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl,
benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.
[0032] "Acyl" refers to a carbonyl moiety attached to either a
hydrogen atom (i.e., a formyl group) or to an optionally
substituted alkyl or alkenyl chain, or heterocyclyl.
[0033] "Halo" or "halogen" includes fluoro, chloro, bromo, and
iodo, and preferably chloro or bromo as a substituent.
[0034] "Alkanediyl" or "alkylene" represents straight or branched
chain optionally substituted bivalent alkane radicals such as, for
example, methylene, ethylene, propylene, butylene, pentylene or
hexylene.
[0035] "Alkenediyl" represents, analogous to the above, straight or
branched chain optionally substituted bivalent alkene radicals such
as, for example, propenylene, butenylene, pentenylene or
hexenylene. In such radicals, the carbon atom linking a nitrogen
preferably should not be unsaturated.
[0036] "Aroyl" refers to a carbonyl moiety attached to an
optionally substituted aryl or heteroaryl group, wherein aryl and
heteroaryl have the definitions provided above. In particular,
benzoyl is phenylcarbonyl.
[0037] As defined herein, two radicals, together with the atom(s)
to which they are attached may form an optionally substituted 4- to
7-, 5- to 7-, or a 5- to 6-membered ring carbocyclic or
heterocyclic ring, which ring may be saturated, unsaturated or
aromatic. Said rings may be as defined above in the Summary of the
Invention section. Particular examples of such rings are as follows
in the next section.
[0038] "Pharmaceutically acceptable salts, esters, and amides"
include carboxylate salts (e.g., C.sub.1-8 alkyl, cycloalkyl, aryl,
heteroaryl, or non-aromatic heterocyclic) amino acid addition
salts, esters, and amides which are within a reasonable
benefit/risk ratio, pharmacologically effective and suitable for
contact with the tissues of patients without undue toxicity,
irritation, or allergic response. Representative salts include
hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,
oxalate, valerate, oleate, palmitate, stearate, laurate, borate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate, and laurylsulfonate. These may include alkali metal
and alkali earth cations such as sodium, potassium, calcium, and
magnesium, as well as non-toxic ammonium, quaternary ammonium, and
amine cations such as tetramethyl ammonium, methylamine,
trimethylamine, and ethylamine. See example, S. M. Berge, et al.,
"Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 which is
incorporated herein by reference. Representative pharmaceutically
acceptable amides of the invention include those derived from
ammonia, primary C.sub.1-6 alkyl amines and secondary di(C.sub.1-6
alkyl) amines. Secondary amines include 5- or 6-membered
heterocyclic or heteroaromatic ring moieties containing at least
one nitrogen atom and optionally between 1 and 2 additional
heteroatoms. Preferred amides are derived from ammonia,
C.sub.1-3alkyl primary amines, and di(C.sub.1-2alkyl)amines.
Representative pharmaceutically acceptable esters of the invention
include C.sub.1-7alkyl, C.sub.5-7cycloalkyl, phenyl, and
phenyl(C.sub.1-6)alkyl esters. Preferred esters include methyl
esters.
[0039] "Patient" or "subject" includes mammals such as humans and
animals (dogs, cats, horses, rats, rabbits, mice, non-human
primates) in need of observation, experiment, treatment or
prevention in connection with the relevant disease or condition.
Preferably, the patient or subject is a human.
[0040] "Composition" includes a product comprising the specified
ingredients in the specified amounts as well as any product which
results directly or indirectly from combinations of the specified
ingredients in the specified amounts.
[0041] "Therapeutically effective amount" or "effective amount"
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the allergic disease or disorder being treated.
[0042] Concerning the various radicals in this disclosure and in
the claims, three general remarks are made. The first remark
concerns valency. As with all hydrocarbon radicals, whether
saturated, unsaturated or aromatic, and whether or not cyclic,
straight chain, or branched, and also similarly with all
heterocyclic radicals, each radical includes substituted radicals
of that type and monovalent, bivalent, and multivalent radicals as
indicated by the context of the claims. The context will indicate
that the substituent is an alkylene or hydrocarbon radical with at
least two hydrogen atoms removed (bivalent) or more hydrogen atoms
removed (multivalent). An example of a bivalent radical linking two
parts of the molecule is G in formula (I) which links two
rings.
[0043] Second, radicals or structure fragments as defined herein
are understood to include substituted radicals or structure
fragments. Hydrocarbyls include monovalent radicals containing
carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl,
and cycloalkenyl (whether aromatic or unsaturated), as well as
corresponding divalent radicals such as alkylene, alkenylene,
phenylene, and so on. Heterocarbyls include monovalent and divalent
radicals containing carbon, hydrogen, and at least one heteroatom.
Examples of monovalent heterocarbyls include acyl, acyloxy,
alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino,
hydroxyalkyl, and so on. Using "alkyl" as an example, "alkyl"
should be understood to include substituted alkyl having one or
more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4
substituents. The substituents may be the same (dihydroxy,
dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or
aminomethyl-substituted). Examples of substituted alkyl include
haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl,
perchloromethyl, 2-bromoethyl, perfluoromethyl, and
3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl,
hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl,
2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl,
alkylalkyl, and so on. A di(C.sub.1-6alkyl)amino group includes
independently selected alkyl groups, to form, for example,
methylpropylamino and isopropylmethylamino, in addition
dialkylamino groups having two of the same alkyl group such as
dimethyl amino or diethylamino.
[0044] Third, only stable compounds are intended. For example,
where there is an NR'R" group, and R can be an alkenyl group, the
double bond is at least one carbon removed from the nitrogen to
avoid enamine formation. Similarly, where a dashed line is an
optional sp.sup.2 bond, if it is absent, the appropriate hydrogen
atom(s) is(are) included.
[0045] Compounds of the invention are further described in the next
section.
[0046] B. Compounds
[0047] The invention features the treatment of an allergic
condition using one or more cathepsin S inhibitors as described in
the Summary section.
[0048] Suitable cathepsin S inhibiting compounds for use in the
methods according to the present invention are those disclosed in
the art or found to be CatS inhibitors by methods known in the art
(see Example 1 below). Examples of suitable compounds for use in
the methods of the invention include (a) the group of dipeptidyl
nitriles disclosed in WO-99/24460 by Altmann, et al. (Novartis);
(b) the group of dipeptidyl vinyl sulfones disclosed by Palmer, et
al. in U.S. Pat. No. 5,976,858, assigned to Arris (now Axys), as
cysteine protease inhibitors, including cathepsin S inhibitors, and
in particular, morpholinurea-leucine-homo-phe-
nylalanine-vinylsulfonephenyl (`LHVS`), also referred to as
4-morpholinecarboxamide,
N-[(1S)-3-methyl-1-[[[(1S,2E)-1-(2-phenylethyl)--
3-(phenylsulfonyl)-2-propenyl]amino]carbonyl]butyl]-; (c) the group
of peptidyl sulfonamides disclosed by Palmer, et al. in U.S. Pat.
No. 5,776,718, also assigned to Arris/Axys, (d) the compounds
disclosed by Klaus, et al. in U.S. Pat. No. 6,030,946 as cysteine
protease inhibitors, including cathepsin S, inhibitors. The former
is assigned to Arris, now Axys, the latter to Axys; and (e) the
group of cathepsin S inhibitors described in WO 99/58153. All five
above-cited patents or patent applications provide how to make the
disclosed compounds and how to test them for protease and/or CatS
inhibitory activity. These patents or patent applications are
incorporated entirely herein by reference.
[0049] Related Compounds
[0050] The invention provides the disclosed compounds and closely
related, pharmaceutically acceptable forms of the disclosed
compounds, such as salts, esters, amides, acids, hydrates or
solvated forms thereof; masked or protected forms; and racemic
mixtures, or enantiomerically or optically pure forms. Related
compounds also include compounds of the invention that have been
modified to be detectable, e.g., isotopically labelled with
.sup.18F for use as a probe in positron emission tomography (PET)
or single-photon emission computed tomography (SPECT).
[0051] The invention also includes disclosed compounds having one
or more functional groups (e.g., hydroxyl, amino, or carboxyl)
masked by a protecting group. See, e.g., Greene and Wuts,
Protective Groups in Organic Synthesis, 3.sup.rd ed., (1999) John
Wiley & Sons, NY. Some of these masked or protected compounds
are pharmaceutically acceptable; others will be useful as
intermediates. Synthetic intermediates and processes disclosed
herein, and minor modifications thereof, are also within the scope
of the invention.
[0052] Hydroxyl Protecting Groups
[0053] Protection for the hydroxyl group includes methyl ethers,
substituted methyl ethers, substituted ethyl ethers, substitute
benzyl ethers, and silyl ethers.
Substituted Methyl Ethers
[0054] Examples of substituted methyl ethers include
methyoxymethyl, methylthiomethyl, t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,
p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,
t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,
2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,
tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,
4-methoxytetrahydrothiop- yranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and
2,3,3a,4,5,6,7,7a-octahydro--
7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
Substituted Ethyl Ethers
[0055] Examples of substituted ethyl ethers include 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyeth- yl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
[0056] Examples of substituted benzyl ethers include
p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-
and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,
p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyidiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxy)phenyldiphenylmethyl,
4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4'-tris(levulinoyloxyphenyl)methyl,
4,4',4"-tris(benzoyloxyphenyl)me- thyl,
3-(Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
[0057] Examples of silyl ethers include trimethylsilyl,
triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl, and
t-butylmethoxyphenylsilyl.
Esters
[0058] In addition to ethers, a hydroxyl group may be protected as
an ester. Examples of esters include formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate,
3-phenylpropionate, 4-oxopentanoate(levulinate),
4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate(mesitoate)
Carbonates
[0059] Examples of carbonate protecting groups include methyl,
9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl,
2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,
2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl,
p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,
o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate,
4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
[0060] Assisted Cleavage
[0061] Examples of assisted cleavage include 2-iodobenzoate,
4-azidobutyrate, 4-nitro-4-methylpentanoate,
o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethyl carbonate,
4-(methylthiomethoxy)butyrate, and
2-(methylthiomethoxymethyl)benzoate.
[0062] Miscellaneous Esters
[0063] Examples of miscellaneous esters include
2,6-dichloro-4-methylpheno- xyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),
o-(methoxycarbonyl)benzoate, p-P-benzoate, (.alpha.-naphthoate,
nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate,
N-phenylcarbamate, borate, dimethylphosphinothioyl, and
2,4-dinitrophenylsulfenate.
[0064] Sulfonates
[0065] Examples of sulfonates include sulfate,
methanesulfonate(mesylate), benzylsulfonate, and tosylate.
[0066] Amino Protecting Groups
[0067] Protection for the amino group includes carbamates, amides,
and special --NH protective groups.
[0068] Examples of carbamates include methyl and ethyl carbamates,
substituted ethyl carbamates, assisted cleavage carbamates,
photolytic cleavage carbamates, urea-type derivatives, and
miscellaneous carbamates.
[0069] Carbamates
[0070] Examples of methyl and ethyl carbamates include methyl and
ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,
9-(2,7-dibromo)fluorenylme- thyl,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]me-
thyl, and 4-methoxyphenacyl.
[0071] Substituted Ethyl
[0072] Examples of substituted ethyl carbamates include
2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,
1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,
1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,
1-methyl-1-(4-biphenylyl)ethyl,
1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and
4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,
1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,
4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,
benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,
p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,
9-anthrylmethyl and diphenylmethyl.
Assisted Cleavage
[0073] Examples of assisted cleavage include 2-methylthioethyl,
2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,
[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,
2,4-dimethylthiophenyl, 2-phosphonioethyl,
2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,
m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,
5-benzisoxazolylmethyl, and
2-(trifluoromethyl)-6-chromonylmethyl.
[0074] Photolytic Cleavage
[0075] Examples of photolytic cleavage include m-nitrophenyl,
3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,
and phenyl(o-nitrophenyl)methyl.
[0076] Urea-Type Derivatives
[0077] Examples of urea-type derivatives include
phenothiazinyl-(10)-carbo- nyl derivative,
N'-p-toluenesulfonylaminocarbonyl, and
N'-phenylaminothiocarbonyl.
[0078] Miscellaneous Carbamates
[0079] Examples of miscellaneous carbamates include t-amyl,
S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl,
diisopropylmethyl, 2,2-dimethoxycarbonylvinyl,
o-(N,N-dimethylcarboxamido)benzyl,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,
2-iodoethyl, isobornyl, isobutyl, isonicotinyl,
p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutyl,
1-methylcyclohexyl, 1-methyl-1-cyclopropyl methyl,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl,
1-methyl-1-(p-phenylazophenyl)ethy- l, 1-methyl-1-phenylethyl,
1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,
2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl- , and
2,4,6-trimethylbenzyl.
[0080] Examples of Amides Include
[0081] Amides
[0082] N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,
N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,
N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, N-benzoyl, N-p-phenylbenzoyl.
[0083] Assisted Cleavage
[0084] N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl,
N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl,
N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,
N-2-methyl-2-(o-nitrophenoxy)propionyl,
N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,
N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine
derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and
4,5-diphenyl-3-oxazolin-2-one.
[0085] Cyclic Imide Derivatives
[0086] N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,
N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyidisilylazacyclopentane
adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,
5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and
1-substituted 3,5-dinitro-4-pyridonyl.
[0087] Special--NH Protective Groups
[0088] Examples of special NH protective groups include
[0089] N-Alkyl and N-Aryl Amines
[0090] N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,
N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),
quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,
N-5-dibenzosuberyl, N-triphenylmethyl,
N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,
N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and
N-2-picolylamine N'-oxide.
[0091] Imine Derivatives
[0092] N-1,1-dimethylthiomethylene, N-benzylidene,
N-p-methoxybenzylidene, N-diphenylmethylene,
N-[(2-pyridyl)mesityl]methylene, and
N-(N',N'-dimethylaminomethylene).
[0093] Protection for the Carbonyl Group
[0094] Acyclic Acetals and Ketals
[0095] Examples of acyclic acetals and ketals include dimethyl,
bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and
diacetyl.
[0096] Cyclic Acetals and Ketals
[0097] Examples of cyclic acetals and ketals include 1,3-dioxanes,
5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,
5-(2-pyridyl)-1,3-dioxa- ne, 1,3-dioxolanes,
4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxola- ne,
4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane,
4,5-dimethoxymethyl-1,3-dioxolane, O,O'-phenylenedioxy and
1,5-dihydro-3H-2,4-benzodioxepin.
[0098] Acyclic Dithio Acetals and Ketals
[0099] Examples of acyclic dithio acetals and ketals include
S,S'-dimethyl, S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl,
S,S'-dipentyl, S,S'-diphenyl, S,S'-dibenzyl and S,S'-diacetyl.
[0100] Cyclic Dithio Acetals and Ketals
[0101] Examples of cyclic dithio acetals and ketals include
1,3-dithiane, 1,3-dithiolane and
1,5-dihydro-3H-2,4-benzodithiepin.
[0102] Acyclic Monothio Acetals and Ketals
[0103] Examples of acyclic monothio acetals and ketals include
O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl and
O-methyl-S-2-(methylthio)ethyl.
[0104] Cyclic Monothio Acetals and Ketals
[0105] Examples of cyclic monothio acetals and ketals include
1,3-oxathiolanes.
[0106] Miscellaneous Derivatives
[0107] O-Substituted Cyanohydrins
[0108] Examples of O-substituted cyanohydrins include O-acetyl,
O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
[0109] Substituted Hydrazones
[0110] Examples of substituted hydrazones include N,N-dimethyl and
2,4-dinitrophenyl.
[0111] Oxime Derivatives
[0112] Examples of oxime derivatives include O-methyl, O-benzyl and
O-phenylthiomethyl.
[0113] Imines
[0114] Substituted Methylene Derivatives, Cyclic Derivatives
[0115] Examples of substituted methylene and cyclic derivatives
include oxazolidines, 1-methyl-2-(1'-hydroxyalkyl)imidazoles,
N,N'-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,
diethylamine adducts, and methylaluminum
bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)com- plex.
[0116] Protection for the Carboxyl Group
[0117] Esters
[0118] Substituted Methyl Esters
[0119] Examples of substituted methyl esters include
9-fluorenylmethyl, methoxymethyl, methylthiomethyl,
tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl,
p-bromophenacyl, .alpha.-methylphenacyl, p-methoxyphenacyl,
carboxamidomethyl, and N-phthalimidomethyl.
[0120] 2-Substituted Ethyl Esters
[0121] Examples of 2-substituted ethyl esters include
2,2,2-trichloroethyl, 2-haloethyl, .omega.-chloroalkyl,
2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,
2-(2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyl,
1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl,
3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl,
.alpha.-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and
benzyl.
[0122] Substituted Benzyl Esters
[0123] Examples of substituted benzyl esters include
triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl,
9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl,
1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl,
2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl,
4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
[0124] Silyl Esters
[0125] Examples of silyl esters include trimethylsilyl,
triethylsilyl, t-butyldimethylsilyl, i-propyidimethylsilyl, phenyld
imethylsilyl and di-t-butylmethylsilyl.
[0126] Activated Esters
[0127] Examples of activated esters include thiols.
[0128] Miscellaneous Derivatives
[0129] Examples of miscellaneous derivatives include oxazoles,
2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,
5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and
pentaaminocobalt(III) complex.
[0130] Stannyl Esters
[0131] Examples of stannyl esters include triethylstannyl and
tri-n-butylstannyl.
[0132] Amides and Hydrazides
[0133] Amides
[0134] Examples of amides include N,N-dimethyl, pyrrolidinyl,
piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides,
N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and
p-P-benzenesulfonamides.
[0135] Hydrazides
[0136] Examples of hydrazides include N-phenyl and N,N'-diisopropyl
hydrazides.
[0137] C. Formulation and Administration
[0138] The present compounds inhibit the proteolytic activity of
human cathepsin S and therefore are useful as a medicine especially
in methods for treating patients suffering from allergic disorders
or conditions which are modulated or regulated by the inhibition of
cathepsin S activity.
[0139] The invention features a method for treating a subject with
an allergic condition mediated by cathepsin S, said method
comprising administering to the subject a therapeutically effective
amount of a pharmaceutical composition comprising a compound of the
invention. The invention also provides a method for inhibiting
cathepsin S activity in a subject, wherein the method comprises
administering to the subject a therapeutically effective amount of
a pharmaceutical composition comprising a compound of the
invention
[0140] In view of their inhibitory effect on the proteolytic
activity of human cathepsin S the compounds of the present
invention may be formulated into various pharmaceutical forms for
administration purposes. To prepare these pharmaceutical
compositions, an effective amount of a particular compound, in base
or acid addition salt form, as the active ingredient is intimately
mixed with a pharmaceutically acceptable carrier.
[0141] A carrier may take a wide variety of forms depending on the
form of preparation desired for administration. These
pharmaceutical compositions are desirably in unitary dosage form
suitable, preferably, for oral administration or parenteral
injection. For example, in preparing the compositions in oral
dosage form, any of the usual pharmaceutical media may be employed.
These include water, glycols, oils, alcohols and the like in the
case of oral liquid preparations such as suspensions, syrups,
elixirs and solutions; or solid carriers such as starches, sugars,
kaolin, lubricants, binders, disintegrating agents and the like in
the case of powders, pills, capsules and tablets. In view of their
ease in administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are generally employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, which additives do not cause a
significant deleterious effect to the skin. Such additives may
facilitate the administration to the skin and/or may be helpful for
preparing the desired compositions. These compositions may be
administered in various ways, e.g., as a transdermal patch, as a
spot-on, as an ointment. Acid addition salts of the compounds of
formula I, due to their increased water solubility over the
corresponding base form, are more suitable in the preparation of
aqueous compositions.
[0142] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in dosage unit form for
ease of administration and uniformity of dosage. Dosage unit form
as used in the specification herein refers to physically discrete
units suitable as unitary dosages, each unit containing a
predetermined quantity of active ingredient calculated to produce
the desired therapeutic effect in association with the required
pharmaceutical carrier. Examples of such dosage unit forms are
tablets (including scored or coated tablets), capsules, pills,
powder packets, wafers, injectable solutions or suspensions,
teaspoonfuls, tablespoonfuls and the like, and segregated multiples
thereof.
[0143] Pharmaceutically acceptable acid addition salts include the
therapeutically active non-toxic acid addition salt forms which the
disclosed compounds are able to form. The latter can conveniently
be obtained by treating the base form with an appropriate acid.
Appropriate acids comprise, for example, inorganic acids such as
hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric;
nitric; phosphoric and the like acids; or organic acids such as,
for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic,
oxalic, malonic, succinic, maleic, fumaric, malic, tartaric,
citric, methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic
and the like acids. The term addition salt also comprises the
solvates which the disclosed componds, as well as the salts
thereof, are able to form. Such solvates are for example hydrates,
alcoholates and the like. Conversely the salt form can be converted
by treatment with alkali into the free base form.
[0144] Stereoisomeric forms defines all the possible isomeric forms
which the compounds of formula (I) may possess. Unless otherwise
mentioned or indicated, the chemical designation of compounds
denotes the mixture of all possible stereochemically isomeric
forms, said mixtures containing all diastereomers and enantiomers
of the basic molecular structure. More in particular, stereogenic
centers may have the (R)- or (S)-configuration; substituents on
bivalent cyclic saturated radicals may have either the cis- or
trans-configuration. The invention encompasses stereochemically
isomeric forms including diastereoisomers, as well as mixtures
thereof in any proportion of the disclosed compounds. The disclosed
compounds may also exist in their tautomeric forms. Such forms
although not explicitly indicated in the above and following
formulae are intended to be included within the scope of the
present invention.
[0145] Those of skill in the treatment of disorders or conditions
mediated by the cathepsin S enzyme could easily determine the
effective daily amount from the test results presented hereinafter
and other information. In general it is contemplated that a
therapeutically effective dose would be from 0.001 mg/kg to 5 mg/kg
body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg body
weight. It may be appropriate to administer the therapeutically
effective dose as two, three, four or more sub-doses at appropriate
intervals throughout the day. Said sub-doses may be formulated as
unit dosage forms, for example, containing 0.05 mg to 250 mg, and
in particular 0.5 to 50 mg of active ingredient per unit dosage
form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and
35 mg dosage forms. Compounds of the invention may also be prepared
in time-release or subcutaneous or transdermal patch formulations.
Disclosed compound may also be formulated as a spray or other
topical or inhalable formulations.
[0146] The exact dosage and frequency of administration depends on
the particular compound of formula (I) used, the particular
condition being treated, the severity of the condition being
treated, the age, weight and general physical condition of the
particular patient as well as other medication the patient may be
taking, as is well known to those skilled in the art. Furthermore,
it is evident that said effective daily amount may be lowered or
increased depending on the response of the treated patient and/or
depending on the evaluation of the physician prescribing the
compounds of the instant invention. The effective daily amount
ranges mentioned herein are therefore only guidelines.
[0147] The next section includes detailed information relating to
the use of the disclosed compounds.
[0148] D. Examples
EXAMPLE 1
[0149] Cathepsin S Inhibition Assay
[0150] Recombinant human cathepsin S (CatS) is expressed in the
baculovirus system and purified in one step with a
thiopropyl-sepharose column. 10-L yielded .about.700 mg of CatS and
N-terminal sequencing confirmed identity. The assay is run in 100
mM sodium acetate pH 5.0 containing 1 mM DTT and 100 mM NaCl. The
substrate for the assay is
(Aedens)EKARVLAEAA(Dabcyl)K-amide
[0151] The K.sub.m for the substrate is around 5 .mu.M but the
presence of substrate inhibition makes kinetic analysis difficult.
With 20 .mu.M substrate the assay rate is linear over the range of
1-8 ng CatS in 100 .mu.l reaction. Using 2 ng/well of CatS, the
production of product is linear and yields .about.7-fold signal
after 20 min with only 20% loss of substrate. Primary assays are
run by quenching the reaction after 20 min with 0.1% SDS and then
measuring the fluorescence. Forother assays, measurements are taken
every min for 20 min. The rate is calculated from the slope of the
increase and the percent inhibition is calculated from this.
EXAMPLE 2
[0152] Ex vivo inhibition by cathepsin S inhibitors of the
allergenic response The following assay demonstrates that cathepsin
S inhibitors block the response of human T cells to crude allergen
extracts.
[0153] Materials and Methods
[0154] Reagents. Glycerinated crude allergen extracts of house dust
mites (Dermataphagoides pteronyssinus, Dermataphagoides farinae)
and ragweed [Ambrosia trifida (giant), Ambrosia artemisilfolia
(short)] were purchased from Hollister-Stier Laboratories
(Minneapolis, Minn.). Concanavalin A (ConA) was purchased from
Calbiochem (La Jolla, Calif.).
[0155] Donors. All allergic donors were prescreened for their
specific allergies using RAST tests. The HLA class II haplotypes of
these donors were determined using PCR.
[0156] Cell culture. Human peripheral blood mononuclear cells
(PBMC) were purified from blood of allergic donors using
Ficoll-Hypaque gradient followed by washes with phosphate buffered
saline (PBS). PBMC were cultured in triplicate or duplicate at
0.5-1.0.times.10.sup.6 cells/well with titrated doses of allergen
extracts, in the presence or absence of a known cathepsin S
inhibitor, LHVS (morpholinurea-leucine-homo-phenylalani-
ne-vinylsulfonephenyl) (Palmer et al. (1995), J. Med. Chem. 38:3193
and Riese et al. (1996), Immunity 4:357). Serial diluted stock
solutions of LHVS were first made in 100% DMSO and then diluted
1:15 in 40% Hydroxypropynyl cyclodextrin (HPCD). Three microliters
of LHVS in HPCD was added into PBMC cultures (200 .mu.L/well).
After 6 days of culture, 1 .mu.Ci/well of .sup.3H-thymidine (TdR)
was added. Eighteen hours later, cells were harvested using a
Filtermate Harvester (Packard) and counted for .sup.3H-TdR
incorporation on Topcount (Packard).
[0157] Inhibition of T cell Proliferative Responses to House Dust
Mites
[0158] About 10% of most populations are allergic to house dust
mites (HDM) of the genus Dermatophagoides with Dermatophagoides
pteronyssinus (Der p) and D. farinae (Der f) being the two major
species present in varying proportions in most countries. The major
clinical manifestations are asthma and perennial rhinitis.
[0159] Effect of cathepsin S inhibition on activation of HDM
allergen-specific CD4 T cells was tested in an ex vivo human T
cell-proliferation assay. Culturing PBMC with crude extracts from
either Der p or Der f, resulted in strong proliferation (FIG. 1A).
This proliferation consisted primarily of allergen-specific CD4 T
cells. When cathepsin S activity was blocked by a specific
cathepsin S inhibitor, LHVS (cf. Riese et al. (1996) Immunity
4:357) the proliferation was strongly inhibited (FIG. 1B).
Inhibition by LHVS was specific for responses induced by HDM
extracts since T cell proliferative responses induced by ConA, a
pan-T cell mitogen, were not affected. Furthermore, this inhibition
was observed for all four HDM-allergic donors tested regardless of
the different HLA class II haplotypes (DR4; DR7, 15; DR11, 15; and
DR4, 11).
[0160] This system is very similar to an in vivo situation. The
allergic subject would be exposed to a crude mixture of allergens
that would lead to the proliferation of T cells and an allergic
response. The observation of inhibition of CD4 T cell activation by
a cathepsin S inhibitor shows that such inhibitors can be effective
in treating a generalized population of patients allergic to house
dust mites.
[0161] Inhibition of T Cell Proliferative Responses to Ragweed
[0162] About 10% of population in US are allergic to ragweed
pollen, making it one of the most important allergens in terms of
clinical diseases. Allergens from pollens are a common precipitant
of rhinitis and asthma in this population.
[0163] The effect of cathepsin S inhibition on activation of
ragweed allergen-specific CD4 T cells was tested in an ex vivo
human T cell-proliferation assay. Culturing PBMC with crude
extracts from both short and giant ragweed resulted in strong
proliferation (FIG. 2A). This proliferation consisted mainly of
allergen-specific CD4 T cells. When cathepsin S activity was
blocked by a specific cathepsin S inhibitor, LHVS (cf. Riese et al.
(1996) Immunity 4:357) the proliferation was strongly inhibited
(FIG. 2B). Inhibition by LHVS was specific for responses induced by
ragweed since T cell proliferative responses induced by ConA, a
pan-T cell mitogen, were not affected. Furthermore, this inhibition
was observed for the two ragweed-allergic donors tested regardless
of the different HLA class II haplotypes (DR7, 15 and DR4, 11).
[0164] This system is very similar to an in vivo situation. The
allergic subject would be exposed to a crude mixture of allergens
that would lead to the proliferation of T cells and an allergic
response. The observation of inhibition of CD4 T cell activation by
a cathepsin S inhibitor shows that such inhibitors can be effective
in treating a generalized population of patients allergic to
ragweed.
EXAMPLE 3
[0165] Monitoring Cathepsin S Inhibition in Human Blood
[0166] The effect of in vivo administration of cathepsin S
inhibitors, in a clinical trial setting, can be monitored by
measuring accumulation of an intermediate degradation product of
invariant chain (Ii), i.e. the p10Ii fragment, in blood of dosed
subjects. After administration of a cathepsin inhibitor for a
certain period of time, for example, 0.01 to 50 mg/kg/day to result
in a blood concentration of preferably 1 nM-10 .mu.M for 16-30 h,
blood is drawn and white blood cells are purified, e.g. either by
lysis of red blood cells or by a Ficoll-Hypaque gradient
centrifugation. Whole cell lysates of WBC are then made and
analyzed by either a Western blot assay or an ELISA assay. For the
Western blot assay, cell lysates are first resolved on SDS-PAGE
gels. After transferring to nitrocellulose membranes, Ii and its
intermediate degradation products, including the p10Ii, can be
detected using a mouse mAb against Ii, e.g. Pin1.1, or rabbit
polyclonal antibodies or a mouse monoclonal antibody specific for
the p10Ii fragment or against the entire p10Ii fragment. For ELISA
assay, a pair of antibodies against Ii, including Pin1.1, and a
rabbit polyclonal antibody against C-terminal of p10Ii, can be
used. The same assay can also be applied to monitor the effect of
cathepsin S inhibitors in vivo in animal studies, for example in
monkeys, dogs, pigs, rabbits, guinea pigs, and rodents.
[0167] In the present example PBMC from human blood were incubated
with the cathepsin S inhibitor, LHVS
(morpholinurea-leucine-homo-phenylalanine- -vinylsulfonephenyl,
also referred to as 4-morpholinecarboxamide,
N-[(1S)-3-methyl-1-[[[(1S,2E)-1-(2-phenylethyl)-3-(phenylsulfonyl)-2-prop-
enyl]amino]carbonyl]butyl]-. This compound has been described in
U.S. Pat. No. 5,976,858 and in Palmer et al. (1995) J. Med. Chem.
38:3193 and Riese et al. (1996) Immunity 4:357. After incubation
for 24 h the samples were run using standard SDS-PAGE protocols,
transferred to nitrocellulose membranes and probed with an antibody
that recognizes the invariant chain including the p10Ii fragment.
In the presence of LHVS the p10i fragment was seen, representing a
block in the degradation of Ii due to inhibition of cathepsin
S.
EXAMPLE 4
[0168] Monitoring in vivo Inhibition of Allergenic Response by
Cathepsin S Inhibitors
[0169] To demonstrate the efficacy of cathepsin S inhibitors for
suppressing allergic responses in vivo, allergic volunteers are
dosed with cathepsin S inhibitors to levels where invariant chain
degradation is inhibited. Allergens are deposited subcutaneously,
and the size of the cutaneous reactions are determined at 15 min, 6
h and 24 h. Skin biopsies are performed at 24 h. The immediate weal
and flare response is not mediated by a T cell response and is not
expected to be influenced by cathepsin S inhibitors, while the late
phase induration (noticeable at 6 hours, more pronounced at 24
hours) is characterized by activation and infiltration of CD4 T
cells (as well as of eosinophils) and should be inhibited by
administration of inhibitors of cathepsin S. The skin biopsies are
used to determine the cellular composition in the induration, and
cathepsin S treated subjects are expected to have fewer activated
CD4 T cells present than placebo-treated subjects.
[0170] References for these procedures are provided in
Eberlein-Konig et al. (1999) Clin. Exp. Allergy 29:1641-1647 and in
Gaga et al. (1991) J. Immunol. 147:816-822.
[0171] As controls for the experiment, prednisone and cyclosporine
A will be used. Prednisone will inhibit both the immediate and the
late phase responses, while cyclosporin A will inhibit only the
late phase response.
[0172] E. Other Embodiments
[0173] The features and advantages of the invention are apparent to
one of ordinary skill in the art. Based on this disclosure,
including the summary, detailed description, background, examples,
and claims, one of ordinary skill in the art will be able to make
modifications and adaptations to various conditions and usages.
These other embodiments are also within the scope of the
invention.
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