U.S. patent application number 13/959084 was filed with the patent office on 2014-04-17 for therapeutic methods for type i diabetes.
This patent application is currently assigned to University of Massachusetts. The applicant listed for this patent is University of Massachusetts. Invention is credited to Roger J. Davis, Anja Jaeschke.
Application Number | 20140107123 13/959084 |
Document ID | / |
Family ID | 37053698 |
Filed Date | 2014-04-17 |
United States Patent
Application |
20140107123 |
Kind Code |
A1 |
Davis; Roger J. ; et
al. |
April 17, 2014 |
Therapeutic Methods For Type I Diabetes
Abstract
The invention relates to the treatment and prevention of type I
diabetes. More specifically, the invention relates to compounds
that treat or prevent the body's immune system from destroying
.beta.-cells (i.e., insulin-producing cells in the pancreatic
islets of Langerhans) by inhibition of JNK2, selective inhibition
of JNK2, or inhibition of the expression of the MAPK9 gene or gene
product. In one embodiment, the present invention contemplates the
diagnosis, identification, production, and use of compounds which
modulate MAPK9 gene expression or the activity of the MAPK9 gene
product including but not limited to, JNK2, the nucleic acid
encoding MAPK9 and homologues, analogues, and deletions thereof, as
well as antisense, ribozyme, triple helix, antibody, and
polypeptide molecules as well as small inorganic molecules. The
present invention contemplates a variety of pharmaceutical
formulations and routes of administration for such compounds.
Inventors: |
Davis; Roger J.; (Princeton,
MA) ; Jaeschke; Anja; (Worcester, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
University of Massachusetts |
Boston |
MA |
US |
|
|
Assignee: |
University of Massachusetts
Boston
MA
|
Family ID: |
37053698 |
Appl. No.: |
13/959084 |
Filed: |
August 5, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13038127 |
Mar 1, 2011 |
8501812 |
|
|
13959084 |
|
|
|
|
11643480 |
Dec 21, 2006 |
7897572 |
|
|
13038127 |
|
|
|
|
11092099 |
Mar 29, 2005 |
|
|
|
11643480 |
|
|
|
|
Current U.S.
Class: |
514/235.8 ;
514/212.06; 514/234.5; 514/252.14; 514/275; 514/300; 514/309;
514/326; 514/406; 514/422; 514/445 |
Current CPC
Class: |
A61K 31/4725 20130101;
A61K 31/50 20130101; A61K 31/428 20130101; A61K 31/5377 20130101;
A61K 31/445 20130101; A61K 31/4535 20130101; A61K 31/416 20130101;
A61K 31/506 20130101; A61P 3/10 20180101; A61K 31/54 20130101; A61K
31/4025 20130101; A61K 31/415 20130101; A61K 31/42 20130101; Y10S
514/866 20130101; A61K 31/497 20130101; A61K 31/425 20130101; A61K
31/70 20130101; A61K 31/55 20130101; A61K 31/381 20130101; A61K
31/18 20130101; A61K 31/437 20130101; A61K 31/40 20130101 |
Class at
Publication: |
514/235.8 ;
514/326; 514/445; 514/422; 514/212.06; 514/406; 514/234.5; 514/275;
514/252.14; 514/300; 514/309 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 31/381 20060101 A61K031/381; A61K 31/4025
20060101 A61K031/4025; A61K 31/4725 20060101 A61K031/4725; A61K
31/416 20060101 A61K031/416; A61K 31/5377 20060101 A61K031/5377;
A61K 31/437 20060101 A61K031/437; A61K 31/4535 20060101
A61K031/4535; A61K 31/55 20060101 A61K031/55 |
Claims
1. A method for treating type I diabetes in a subject, comprising
administering a compound that inhibits activity of JNK2 in the
subject.
2. The method of claim 1, wherein the compound inhibits enzymatic
activity of JNK2, and has minimal effect on inhibiting enzymatic
activity of JNK1.
3. The method of claim 1 in which the activity of JNK1 is not
inhibited.
4. The method in claim 1, wherein the activity of the compound does
not result in an adverse drug reaction to the subject.
5-7. (canceled)
8. A method of claim 1, wherein the compound has the following
formula: ##STR00096## wherein Ar.sup.1 and Ar.sup.2 are
independently from each other substituted or unsubstituted aryl or
heteroaryl groups; X is O or S; R.sup.1 is hydrogen or a
C.sub.1-C.sub.6 alkyl group, or R.sup.1 forms a substituted or
unsubstituted 5-6 membered saturated or unsaturated ring with
Ar.sup.1; n is an integer from 0 to 5, preferably between 1-3 and
most preferred 1; Y is an unsubstituted or a substituted 4-12
membered saturated cyclic or bicyclic alkyl containing at least one
nitrogen atom, whereby one nitrogen atom within said ring is
forming a bond with the sulfonyl group thus providing a
sulfamide.
9. The method of claim 1, wherein the compounds has the following
formula: ##STR00097## wherein Ar.sup.1 and Ar.sup.2 are
independently from each other substituted or unsubstituted aryl or
heteroaryl; X is O or S; R.sup.1 is hydrogen or an unsubstituted or
substituted C.sub.1-C.sub.6-alkyl group, or R.sup.1 could form a
substituted or unsubstituted 5-6-membered saturated or unsaturated
fused ring with Ar.sup.1, or R.sup.2 and R.sup.4 form a substituted
or unsubstituted 5-6-membered saturated or non-saturated ring;
R.sup.2 is hydrogen or a substituted or unsubstituted
C.sub.1-C.sub.6-alkyl group; n is an integer from 0 to 5; R.sup.3
and R.sup.4 are independently from each other selected from the
group comprising or consisting of natural amino acid residues or
synthetic amino acid residues, hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6-alkyl, like trihalomethyl,
substituted or unsubstituted C.sub.1-C.sub.6-alkoxy, NH.sub.2, SH,
thioalkyl, aminoacyl, aminocarbonyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkoxycarbonyl, aryl, heteroaryl, substituted or
unsubstituted 4-8-membered cyclic alkyl, optionally containing 1-3
heteroatoms, carboxyl, cyano, halogen, hydroxy, nitro, acetoxy,
aminoacyl, sulfoxy, sulfonyl, C.sub.1-C.sub.6-thioalkoxy, whereby
at least one of R.sup.3 and/or R.sup.4 must be an amino acid
residue; R.sup.5 is H or substituted or unsubstituted
C.sub.1-C.sub.6-alkyl; R.sup.6 is selected from the group
comprising or consisting of H, substituted or unsubstituted
C.sub.1-C.sub.6-aliphatic alkyl, substituted or unsubstituted
saturated cyclic C.sub.4-C.sub.8-alkyl optionally containing 1-3
heteroatoms and optionally fused with an aryl or an heteroaryl; or
R.sup.6 is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, whereby said aryl or heteroaryl groups
are optionally substituted with substituted or unsubstituted
C.sub.1-C.sub.6-alkyl, like trihalomethyl, substituted or
unsubstituted C.sub.1-C.sub.6-alkoxy, substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl, substituted or unsubstituted
C.sub.2-C.sub.6-alkynyl, amino, aminoacyl, aminocarbonyl,
substituted or unsubstituted C.sub.1-C.sub.6-alkoxycarbonyl, aryl,
carboxyl, cyano, halogen, hydroxy, nitro, acetoxy, aminoacyl,
sulfoxy, sulfonyl, C.sub.1-C.sub.6-thioalkoxy; or R.sup.5 and
R.sup.6 taken together could form a substituted or unsubstituted
4-8-membered saturated cyclic alkyl or heteroalkyl group.
10. The method of claim 1, wherein the compound has the following
formula: ##STR00098## wherein Ar.sup.1 and Ar.sup.2 are
independently from each other substituted or unsubstituted aryl or
heteroaryl groups; X.sup.1 and X.sup.2 are independently from each
other O or S; R.sup.1, R.sup.2, and R.sup.3 are independently from
each other hydrogen or a C.sub.1-C.sub.6 alkyl substituent or
R.sup.1 forms a substituted or unsubstituted 5-6-membered saturated
or unsaturated ring with Ar.sup.1; or R.sup.2 and R.sup.3 form a
substituted or unsubstituted 5-6-membered saturated or unsaturated
ring; n is an integer from 0 to 5; G is selected from a group
comprising or consisting of an unsubstituted or substituted
4-8-membered heterocycle containing at least one heteroatom, or G
is a substituted or unsubstituted C.sub.1-C.sub.6 alkyl group.
11. The method of claim 1, wherein the compound has the following
formula: ##STR00099## wherein Z.sup.11 and Z.sup.12 each
independently represent a carbonyl group, an oxygen atom, a sulfur
atom, a methine group which may be substituted, a methylene group
which may be substituted or a nitrogen atom which may be
substituted; represents a double bond or a single bond; R.sup.1a
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group, a phenyl
group or a benzyl group; R.sup.2a, R.sup.2b and R.sup.2c each
independently represent a group selected from the following
Substituent Group (a); the ring A represents a benzene ring which
may have one to three groups selected from the following
Substituent Group (a), a naphthalene ring which may have one to
three groups selected from the following Substituent Group (a) or a
5- to 10-membered aromatic heterocyclic ring which may have one to
three groups selected from the following Substituent Group (a);
Substituent Group (a) (1) a hydrogen atom, (2) halogen atoms, (3) a
nitro group, (4) a hydroxyl group, (5) a cyano group, (6) a
carboxyl group, (7) an amino group, (8) a formyl group or (9) a
group represented by the formula: ##STR00100## wherein X.sup.1 and
X.sup.2 each independently represent a single bond, --CO--,
--SO.sub.2-- or C.sub.1-C.sub.6-methylene group; X.sup.3 represents
a single bond, --CO--, --SO.sub.2, --O--, --CO--O-- or --O--CO--;
R.sup.3b represents a C.sub.1-C.sub.6 alkylene group or a single
bond; R.sup.3a and R.sup.3c represent a hydrogen atom, a
C.sub.1-C.sub.6 alkyl group which may be substituted, a
C.sub.2-C.sub.6 alkenyl group which may be substituted, a
C.sub.2-C.sub.6 alkynyl group which may be substituted, a
C.sub.3-C.sub.8 cycloalkyl group which may be substituted, a
C.sub.6-C.sub.14 aromatic cyclic hydrocarbon group which may be
substituted, a 5- to 14-membered aromatic heterocyclic group which
may be substituted or a hydrogen atom.
12. The method of claim 1, wherein the compound has the following
formula: ##STR00101## wherein A is a direct bond,
--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.bCH.dbd.CH(CH.sub.2).sub.c--, or
--(CH.sub.2).sub.bC.ident.C(CH.sub.2).sub.c--; R.sup.1 is aryl,
heteroaryl or heterocycle fused to phenyl, each being optionally
substituted with one to four substituents independently selected
from R.sup.3; R.sup.2 is --R.sup.3, --R.sup.4,
--(CH.sub.2).sub.bC(.dbd.O)R.sup.5,
--(CH.sub.2).sub.bC(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.bC(.dbd.O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.bC(.dbd.O)NR.sub.5(CH.sub.2)CC(.dbd.O)R.sup.6,
--(CH.sub.2).sub.bNR.sup.5C(.dbd.O)R.sup.6,
--(CH.sub.2).sub.bNR.sup.5C(.dbd.O)NR.sup.6R.sup.7,
--(CH.sub.2).sub.bNR.sup.5R.sup.6, --(CH.sub.2).sub.bOR.sup.5,
--(CH.sub.2).sub.bSO.sub.dR.sup.5 or
--(CH.sub.2).sub.bSO.sub.2NR.sup.5R.sup.6; a is 1, 2, 3, 4, 5 or 6;
b and c are the same or different and at each occurrence
independently selected from 0, 1, 2, 3 or 4; d is at each
occurrence 0, 1 or 2; R.sup.3 is at each occurrence independently
halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy,
thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,
arylalkyl, heterocycle, heterocycloalkyl, --C(.dbd.O)OR.sup.8,
--OC(.dbd.O)R.sup.8, --C(.dbd.O)NR.sup.8R.sup.9,
--C(.dbd.O)NR.sup.8OR.sup.9, --SO.sub.2NR.sup.8R.sup.9,
--NR.sup.8SO.sub.2R.sup.9, --CN, --NO.sub.2, --NR.sup.8R.sup.9,
--NR.sup.8C(.dbd.O)R.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2).sub.bOR.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2).sub.bR.sup.9,
--O(CH.sub.2).sub.bNR.sup.8R.sup.9, or heterocycle fused to phenyl;
R.sup.4 is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl,
each being optionally substituted with one to four substituents
independently selected from R.sup.3, or R.sup.4 is halogen or
hydroxy; R.sup.5, R.sup.6 and R.sup.7 are the same or different and
at each occurrence independently hydrogen, alkyl, aryl, arylalkyl,
heterocycle or heterocycloalkyl, wherein each of R.sup.5, R.sup.6
and R.sup.7 are optionally substituted with one to four
substituents independently selected from R.sup.3; and R.sup.8 and
R.sup.9 are the same or different and at each occurrence
independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or
heterocycloalkyl, or R.sup.8 and R.sup.9 taken together with the
atom or atoms to which they are bonded form a heterocycle, wherein
each of R.sup.8, R.sup.9, and R.sup.8 and R.sup.9 taken together to
form a heterocycle are optionally substituted with one to four
substituents independently selected from R.sup.3.
13. The method of claim 1, wherein the compound has the following
formula: ##STR00102## wherein R.sup.1 is aryl or heteroaryl
optionally substituted with one to four substituents independently
selected from R.sup.7; R.sup.2 is hydrogen; R.sup.3 is hydrogen or
lower alkyl; R.sup.4 represents one to four optional substituents,
wherein each substituent is the same or different and independently
selected from halogen, hydroxy, lower alkyl and lower alkoxy;
R.sup.5 and R.sup.6 are the same or different and independently
--R.sup.8, --(CH.sub.2).sub.aC(.dbd.O)R.sup.9,
--(CH2).sub.aC(.dbd.O)OR.sup.9,
--(CH2).sub.aC(.dbd.O)NR.sup.9R.sup.10,
--(CH2).sub.aC(.dbd.O)NR.sup.9(CH2).sub.bC(.dbd.O)R.sup.10,
--(CH2).sub.aNR.sup.9C(.dbd.O)R.sup.10,
(CH2).sub.aNR.sup.11C(.dbd.O)NR.sup.9R.sup.10,
--(CH2).sub.aNR.sup.9R.sup.10, --(CH2).sub.aOR.sup.9,
--(CH2).sub.aSO.sub.cR.sup.9 or --(CH2).sub.nSO2NR.sup.9R.sup.10;
or R.sup.5 and R.sup.6 taken together with the nitrogen atom to
which they are attached to form a heterocycle or substituted
heterocycle; R.sup.7 is at each occurrence independently halogen,
hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl, acyloxy,
thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,
arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl,
--C(.dbd.O)OR.sup.8, --OC(.dbd.O)R.sup.8,
--C(.dbd.O)NR.sup.8R.sup.9, --C(.dbd.O)NR.sup.8OR.sup.9,
--SO.sub.cR.sup.8, --SO.sub.cNR.sup.8R.sup.9, --NR.sup.8SOR.sup.9,
--NR.sup.8R.sup.9, --NR.sup.8C(.dbd.O)R.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2)bOR.sup.9,
--NR.sup.8C(.dbd.O)(CH2).sub.bR.sup.9,
--O(CH2).sub.bNR.sup.8R.sup.9, or heterocycle fused to phenyl;
R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are the same or different
and at each occurrence independently hydrogen, alkyl, aryl,
arylalkyl, heterocycle, heterocycloalkyl; or R.sup.8 and R.sup.9
taken together with the atom or atoms to which they are attached to
form a heterocycle; a and b are the same or different and at each
occurrence independently selected from 0, 1, 2, 3 or 4; and c is at
each occurrence 0, 1 or 2.
14. A method of claim 1, wherein the compound has the following
formula: ##STR00103## wherein R.sup.0 is --O--, --S--, --S(O)--,
--S(O).sub.2--, NH or --CH.sub.2--; being: (i) unsubstituted, (ii)
monosubstituted and having a first substituent, or (iii)
disubstituted and having a first substituent and a second
substituent; the first or second substituent, when present, is at
the 3, 4, 5, 7, 8, 9, or 10 position, wherein the first and second
substituent, when present, are independently alkyl, hydroxy,
halogen, nitro, trifluoromethyl, sulfonyl, carboxyl,
alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl,
cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy,
aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy,
--NHR.sup.3R.sup.4, --NH(CH.sub.2).sub.nNR.sup.3R.sup.4,
--NH(.dbd.O)R.sup.5, --NHSO.sub.2R.sup.5,
--C(.dbd.O)NR.sup.3R.sup.4, or --SO.sub.2NR.sup.3R.sup.4; wherein n
is 0-6, R.sup.3 and R.sup.4 are taken together and represent
alkylidene or a heteroatom-containing cyclic alkylidene or R.sup.3
and R.sup.4 are independently hydrogen, alkyl, cycloalkyl, aryl,
arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl,
mono-alkylaminoalkyl, or di-alkylaminoalkyl; and R.sup.5 is
hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,
alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,
di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,
cycloalkylalkylamino, aminoalkyl, mono-alkylaminoalkyl, or
di-alkylaminoalkyl.
15. The method of claim 1, wherein the compound has the following
formula: ##STR00104## wherein N.sup.1 is a nitrogen atom optionally
having a substituent or a hydrogen atom, X.sup.1 is (i) a carbon
atom optionally having substituent(s) or hydrogen atom(s), (ii) an
oxygen atom, (iii) a sulfur atom or (iv) a nitrogen atom optionally
having a substituent or a hydrogen atom, X.sup.2 is (i) a carbon
atom optionally having substituent(s) or hydrogen atom(s), (ii) an
oxygen atom, (iii) a sulfur atom or (iv) a nitrogen atom optionally
having a substituent or a hydrogen atom, X.sup.3 is (i) a carbon
atom or (ii) a nitrogen atom, wherein (1) when X.sup.1 is an oxygen
atom or a sulfur atom, X.sup.2 is a carbon atom optionally having
substituent(s) or hydrogen atom(s), X.sup.3 is a carbon atom and
N.sup.1 is a nitrogen atom, (2) when X.sup.1is a nitrogen atom
having a substituent or a hydrogen atom and X.sup.3 is a carbon
atom, X2 is a carbon atom optionally having substituent(s) or
hydrogen atom(s) and N.sup.1 is a nitrogen atom, (3) when X.sup.1
and X.sup.3 are each a nitrogen atom, X.sup.2 is a carbon atom
optionally having substituent(s) or hydrogen atom(s), and N.sup.1
is a nitrogen atom, (4) when X.sup.1 is a carbon atom optionally
having substituent(s) or hydrogen atom(s) and X.sup.2 is an oxygen
atom or a sulfur atom, X.sup.3 is a carbon atom and N.sup.1 is a
nitrogen atom, (5) when X.sup.1 is a carbon atom optionally having
substituent(s) or hydrogen atom(s) and X.sup.3 is a carbon atom,
one of N.sup.1 and X.sup.2 is a nitrogen atom, and the other is a
nitrogen atom having a substituent or a hydrogen atom, (6) when
X.sup.1 and X.sup.2 are each a carbon atom optionally having
substituent(s) or hydrogen atom(s) and X.sup.3 is a carbon atom,
N.sup.1 is a nitrogen atom having a substituent or a hydrogen atom,
and (7) when X.sup.1 and X.sup.2 are each a carbon atom optionally
having substituent(s) or hydrogen atom(s) and X.sup.3 is a nitrogen
atom, N.sup.1 is a nitrogen atom, ring A optionally further has
substituent(s), ring B is an aromatic ring, Y is (i) a carbon atom
optionally having substituent(s) or hydrogen atom(s) or (ii) a
nitrogen atom, Z is a bond, --NR.sup.4-- (R.sup.4 is a hydrogen
atom or a hydrocarbon group optionally having substituent(s)), an
oxygen atom or an optionally oxidized sulfur atom, W is a bond or a
divalent hydrocarbon group optionally having substituent(s),
R.sup.2 is an aromatic group optionally having substituent(s), and
R.sup.3 is a hydrocarbon group optionally having substituent(s) or
a heterocyclic group optionally having substituent(s).
16. The method of claim 1, wherein the compound has the following
formula: ##STR00105## wherein: W is nitrogen or CH; G is hydrogen
or C.sub.1-3 aliphatic wherein one methylene unit of G is
optionally replaced by --C(O)--, --C(O)O--, --C(O)NH--,
--SO.sub.2--, or --SO.sub.2NH--; A is --N-T.sub.(n)-R, oxygen, or
sulfur; R.sup.1 is selected from -T.sub.(n)-R or
-T.sub.(1)-Ar.sup.1; each n is independently 0 or 1; T is a
C.sub.1-4 alkylidene chain wherein one methylene unit of T is
optionally replaced by --C(O)--, --C(O)O--, --C(O)NH--,
--SO.sub.2--, or --SO.sub.2NH--; Ar.sup.1 is a 3-7 membered
monocyclic saturated, partially saturated or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 8-10 membered bicyclic saturated, partially saturated
or aromatic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein each member of Ar.sup.1 is
optionally substituted with one --Z--R.sup.3 and one to three
additional groups independently selected from --R, halogen, oxo,
--NO.sub.2, --CN, --OR, --SR, --N(R).sub.2, --NRC(O)R,
--NRC(O)N(R).sub.2, --NRCO.sub.2R, --C(O)R, --CO.sub.2R, --OC(O)R,
--C(O)N(R).sub.2, --OC(O)N(R).sub.2, --S(O)R, --SO.sub.2R,
--SO.sub.2N(R).sub.2, --NRSO.sub.2R, --NRSO.sub.2N(R).sub.2,
--C(O)C(O)R, or --C(O)CH.sub.2C(O)R; each R is independently
selected from hydrogen or a C.sub.1-6 aliphatic, wherein said
aliphatic is optionally substituted with one to three groups
independently selected from oxo, --CO.sub.2R', --OR',
--N(R').sub.2, --SR', --NO.sub.2, --NR'C(O)R',
--NR'C(O)N(R').sub.2, --NR'CO.sub.2R', --C(O)R', --OC(O)R',
--C(O)N(R').sub.2, --OC(O)N(R').sub.2, --S(O)R', --SO.sub.2R',
--SO.sub.2N(R').sub.2, --NR'SO.sub.2R', --NR'SO.sub.2N(R').sub.2,
--C(O)C(O)R', --C(O)CH.sub.2C(O)R', halogen, or --CN, or two R
bound to the same nitrogen atom are taken together with that
nitrogen atom to form a five or six membered heterocyclic or
heteroaryl ring having one to two additional heteroatoms
independently selected from oxygen, nitrogen, or sulfur; each R' is
independently selected from hydrogen or C.sub.1-6 aliphatic,
wherein said aliphatic is optionally substituted with one to three
groups independently selected from oxo, --CO.sub.2H, --OH,
--NH.sub.2, --SH, --NO.sub.2, --NHC(O)H, --NHC(O)NH.sub.2,
--NHCO.sub.2H, --C(O)H, --OC(O)H, --C(O)NH.sub.2, --OC(O)NH.sub.2,
--S(O)H, --SO.sub.2H, --SO.sub.2NH.sub.2, --NHSO.sub.2H,
--NHSO.sub.2NH.sub.2, --C(O)C(O)H, --C(O)CH.sub.2C(O)H, halogen, or
--CN, or two R' bound to the same nitrogen atom are taken together
with that nitrogen atom to form a five or six membered heterocyclic
or heteroaryl ring optionally having one or two additional
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; Z is a C.sub.1-C.sub.6 alkylidene chain wherein up to two
nonadjacent methylene units of Z are optionally replaced by
--C(O)--, --C(O)O--, --C(O)C(O)--, --C(O)N(R)--, --OC(O)N(R)--,
--N(R)N(R)--, --N(R)N(R)C(O)--, --N(R)C(O)--, --N(R)C(O)O--,
--N(R)C(O)N(R)--, --S(O)--, --SO.sub.2--, --N(R)SO.sub.2--,
--SO.sub.2N(R)--, --N(R)SO.sub.2N(R)--, --O--, --S--, or --N(R)--;
R.sup.2 is -Q.sub.(n)-Ar.sup.2; Ar.sup.2 is selected from a 3-7
membered monocyclic saturated, saturated or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 8-10 membered bicyclic saturated, saturated or
aromatic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein each member of Ar.sup.2 is
optionally substituted with 1-5 groups independently selected from
--Z--R.sup.3, --R, halogen, oxo, --NO2, --CN, --OR, --SR,
--N(R).sub.2, NRC(O)R, --NRC(O)N(R).sub.2, --NRCO.sub.2R, --C(O)R,
--CO.sub.2R, OC(O)R, --C(O)N(R).sub.2, --OC(O)N(R).sub.2, --S(O)R,
--SO.sub.2R, SO.sub.2N(R).sub.2, --N(R)SO.sub.2R,
--N(R)SO.sub.2N(R).sub.2, --C(O)C(O)R, or --C(O)CH.sub.2C(O)R; Q is
a C.sub.1-3 alkylidene chain wherein up to two nonadjacent
methylene units of Q are optionally replaced by --C(O)--,
--C(O)O--, --C(O)C(O)--, --C(O)N(R)--, --OC(O)N(R)--, --N(R)N(R)--,
--N(R)N(R)C(O)--, --N(R)C(O)--, --N(R)C(O)O--, --N(R)C(O)N(R)--,
--S(O)--, --SO.sub.2--, --N(R)SO.sub.2--, --SO.sub.2N(R)--,
--N(R)SO.sub.2N(R)--, --O--, --S--, or --N(R)--; R.sup.3 is
selected from --Ar.sup.3, --R, halogen, --NO.sub.2, --CN, --OR,
--SR, --N(R).sub.2, --NRC(O)R, --NRC(O)N(R).sub.2, --NRCO.sub.2R,
--C(O)R, --CO.sub.2R, --OC(O)R, --C(O)N(R).sub.2,
--OC(O)N(R).sub.2, --SOR, --SO.sub.2R, --SO.sub.2N(R).sub.2,
--NRSO.sub.2R, --NRSO.sub.2N(R).sub.2, --C(O)C(O)R, or
--C(O)CH2C(O)R; and Ar.sup.3 is a 5-6 membered saturated, partially
saturated, or aromatic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, wherein each member of
Ar.sup.3 is optionally substituted with halogen, oxo, --CN,
--NO.sub.2, --R', --OR', --N(R').sub.2, --N(R')C(O)R',
N(R')C(O)N(R').sub.2, --N(R')CO.sub.2R', --C(O)R', --CO.sub.2R',
OC(O)R', --C(O)N(R').sub.2, --OC(O)N(R').sub.2, or --SO.sub.2R';
provided that when W is nitrogen and: (i) A is --N-T.sub.(n)-R and
R2 is a saturated ring or (ii) A is sulfur, then R.sup.1 is other
than an optionally substituted phenyl.
17. The method of claim 1, wherein the compound has the following
formula: ##STR00106## wherein R.sup.1 is optionally substituted
carbocyclyl or heterocyclyl group, R.sup.2 is an optionally
substituted five or six membered heterocyclyl group or an
optionally substituted six membered carbocyclyl group, E is
hydrogen, halogen cyano, C.sub.1-6 alkoxyl or C.sub.1-6 alkyl, G is
hydrogen, halogen, cyano, C.sub.1-6 alkoxy or C.sub.1-6 alkyl, and
L is hydrogen, halogen, cyano, C.sub.1-6 alkoxy or C.sub.1-6
alkyl.
18. The method of claim 1, wherein the compound has the following
formula: ##STR00107## wherein R.sup.1 is an optionally substituted
C.sub.3-16 carbocyclyl or C.sub.3-12 heterocyclyl group, Y is N or
C and Z is lone electron pair, hydrogen, C.sub.1-12 alkyl,
C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.1-12 haloalkyl,
C.sub.3-12 carbocyclyl, C.sub.3-12 heterocyclyl,
--(CH.sub.2).sub.nOR.sup.2, --(CH.sub.2)NR.sup.2.sub.2,
--CO.sub.2R.sup.2, --COR.sup.2, --CONR.sup.2.sub.2, wherein the
C.sub.1-12 alkyl group optionally contains one or more insertions
selected from --O--, --N(R.sup.2)--, --S--, --SO--, --SO.sub.2--;
and each substitutable nitrogen atom in Z is optionally substituted
by --R.sup.3, --COR.sup.3, --SO.sub.2R.sup.3 or --CO.sub.2R.sup.3;
wherein n is 1 to 6, preferably n is 1, 2, or 3; wherein R.sup.2 is
hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, C.sub.1-12 alkylC.sub.3-16 carbocyclyl, or C.sub.1-12
alkylC.sub.3-12 heterocyclyl optionally substituted by one or more
of C.sub.1-6 alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.4,
--SR.sup.4, --NO.sub.2, CN, --NR.sup.4R.sup.4, --NR.sup.4COR.sup.4,
--NR.sup.4CONR.sup.4R.sup.4, --NR.sup.4CO.sub.2R.sup.4,
--CO.sub.2R.sup.4, --COR.sup.4, --CONR.sup.4.sub.2,
--SO.sub.2R.sup.4, --SONR.sup.4.sub.2, --SOR.sup.4,
--SO.sub.2NR.sup.4R.sup.4, --NR.sup.4SO.sub.2R.sup.4, wherein the
C.sub.1-12 alkyl group optionally incorporates on or two insertions
selected for the group consisting of --O--, --N(R.sup.4)--, --S--,
--SO--, --SO.sub.2--, wherein each R.sup.4 may be the same or
different and is defined below; wherein two R.sup.2 and
NR.sup.2.sub.2 may form a partially saturated, unsaturated or fully
saturated five to seven membered ring containing one to three
heteroatoms, optionally and independently substituted with one or
more halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12
alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl, C.sub.3-12
heterocyclyl, --OR.sup.5, --SR.sup.5, --NO.sub.2, CN,
--NR.sup.5R.sup.5, --NR.sup.5COR.sup.5,
--NR.sup.5CONR.sup.5R.sup.5, --NRCO.sub.2R.sup.5,
--CO.sub.2R.sup.5, --COR.sup.5, --CONR.sup.5.sub.2,
--SO.sub.2R.sup.5, --SONR.sup.5.sub.2, --SOR.sup.5,
--SO.sub.2NR.sup.5R.sup.5, --NR.sup.5SO.sub.2R.sup.5; and each
saturated carbon in the optional ring is further optionally and
independently substituted by .dbd.O, .dbd.S, NNR.sup.6.sub.2,
.dbd.N--OR.sup.6, .dbd.NNR.sup.6COR.sup.6,
.dbd.NNR.sup.6CO.sub.2R.sup.6, .dbd.NNSO.sub.2R.sup.6, or
.dbd.NR.sup.6; wherein R.sup.3 is hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, or C.sub.6-12 aryl; wherein R.sup.4 is
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or C.sub.6-12 aryl;
wherein R.sup.5 is hydrogen, C.sub.1-12 alkyl, C.sub.3-16
carbocyclyl or C.sub.3-12 heterocyclyl, optionally substituted by
one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6 haloalkyl,
--OR.sup.7, --SR.sup.7, --NO.sub.2, CN, --NR.sup.7R.sup.7,
--NR.sup.7COR.sup.7, --NR.sup.7CONR.sup.7R.sup.7,
--NR.sup.7CO.sub.2R.sup.7, --CO.sub.2R.sup.7, --COR.sup.7,
--CONR.sup.7.sub.2, --SO.sub.2R.sup.7, --SONR.sup.7.sub.2,
--SOR.sup.7, --SO.sub.2NR.sup.7R.sup.7, --NR.sup.7SO.sub.2R.sup.7;
wherein the C.sub.1-12 alkyl group optionally incorporates one or
two insertions selected from the group consisting of --O--,
--N(R.sup.7)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein R.sup.6
is hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.7, --SR.sup.7,
--NO.sub.2, CN, --NR.sup.7R.sup.7, --NR.sup.7COR.sup.7,
--NR.sup.7CONR.sup.7R.sup.7, --NR.sup.7CO.sub.2R.sup.7,
--CO.sub.2R.sup.7, --COR.sup.7, --CONR.sup.7.sub.2,
--SO.sub.2R.sup.7, --SONR.sup.7.sub.2, --SOR.sup.7,
--SO.sub.2NR.sup.7R.sup.7, --NR.sup.7SO.sub.2R.sup.7; wherein the
C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.7)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein R.sup.7
is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; wherein the
optionally substituted carbocyclyl or heterocyclyl group in R.sup.1
and Z is optionally and independently fused to a partially
saturated, unsaturated or fully saturated five to seven membered
ring containing zero to three heteroatoms, and each substitutable
carbon atom in R.sup.1 or Z, including the optional fused ring, is
optionally and independently substituted by one or more of halogen,
C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl,
C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl, C.sub.3-12
heterocyclyl, --(CH.sub.2).sub.nOR.sup.12,
--(CH.sub.2).sub.nNR.sup.12.sub.2, --OR.sup.12, --SR.sup.12,
--NO.sub.2, CN, --NR.sup.12R.sup.12, --NR.sup.12COR.sup.12,
--NR.sup.12CONR.sup.12R.sup.12, --NR.sup.12CO.sub.2R.sup.12,
--CO.sub.2R.sup.12, --COR.sup.12, --CONR.sup.12.sub.2,
--SO.sub.2R.sup.12, --SONR.sup.12.sub.2, --SOR.sup.12,
--SO.sub.2NR.sup.12R.sup.12, --NR.sup.2SO.sub.2R.sup.12; wherein
the C.sub.1-12 alkyl group optionally contains one or more
insertions selected from --O--, --N(R.sup.12)--, --S--, --SO--,
--SO.sub.2--, and each saturated carbon in the optionally fused
ring is further optionally and independently substituted by .dbd.O,
.dbd.S, NNR.sup.13.sub.2, .dbd.N--OR.sup.13,
.dbd.NNR.sup.13COR.sup.13, .dbd.NNR.sup.13CO.sub.2R.sup.13,
.dbd.NNSO.sub.2R.sup.13, or .dbd.NR.sup.13; and each substitutable
nitrogen atom in R.sup.1 is optionally substituted by --R.sup.14,
--COR.sup.14, --SO.sub.2R.sup.14, or --CO.sub.2R.sup.14; wherein n
is 1 to 6, preferably n is 1, 2, or 3; wherein R.sup.12 is
hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.15, --SR.sup.15,
--NO.sub.2, CN, --NR.sup.15R.sup.15, --NR.sup.15COR.sup.15,
--NR.sup.15CONR.sup.15R.sup.11, --NR.sup.15CO.sub.2R.sup.15,
--CO.sub.2R.sup.15, --COR.sup.15, --CONR.sup.15.sub.2,
--SO.sub.2R.sup.15, --SONR.sup.15.sub.2, --SOR.sup.15,
--SO.sub.2NR.sup.15R.sup.15, --NR.sup.15SO.sub.2R.sup.15; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.15)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein two
R.sup.12 and NR.sup.12.sub.2 may form a partially saturated,
unsaturated or fully saturated five to seven membered ring
containing one to three heteroatoms, optionally and independently
substituted with one or more halogen, C.sub.1-12 alkyl, C.sub.2-12
alkenyl, C.sub.2-12 alkynyl, C.sub.1-12 haloalkyl,
C.sub.3-12-carbocyclyl, C.sub.3-12 heterocyclyl, --OR.sup.16,
--SR.sup.16, --NO.sub.2, CN, --NR.sup.16R.sup.16,
--NR.sup.16COR.sup.16, --NR.sup.16CONR.sup.6R.sup.6,
--NR.sup.16CO.sub.2R.sup.16, --CO.sub.2R.sup.16, --COR.sup.16,
--CONR.sup.16.sub.2, --SO.sub.2R.sup.16, --SONR.sup.16.sub.2,
--SOR.sup.16, --SO.sub.2NR.sup.16R.sup.16,
--NR.sup.16SO.sub.2R.sup.16; and each saturated carbon in the
optional ring is further optionally and independently substituted
by .dbd.O, .dbd.S, NNR.sup.17.sub.2, .dbd.N--OR.sup.7,
.dbd.NNR.sup.17COR.sup.17, .dbd.NNR.sup.17CO.sub.2R.sup.17,
.dbd.NNSO.sub.2R.sup.17, or .dbd.NR.sup.17; wherein R.sup.13 is
hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.15, --SR.sup.15,
--NO.sub.2, CN, --NR.sup.15R.sup.15, --NR.sup.15COR.sup.15,
--NR.sup.15CONR.sup.15R.sup.15, --NR.sup.15CO.sub.2R.sup.15,
--CO.sub.2R.sup.15, --COR.sup.15, --CONR.sup.15.sub.2,
--SO.sub.2R.sup.15, --SONR.sup.15.sub.2, --SOR.sup.15,
--SO.sub.2NR.sup.15R.sup.15, --NR.sup.15SO.sub.2R.sup.15; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.15)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.15
may be the same or different and is defined below; wherein R.sup.14
is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or C.sub.6-12
aryl; wherein R.sup.15 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl; wherein R.sup.16 is hydrogen, C.sub.1-12 alkyl,
C.sub.3-16 carbocyclyl or C.sub.3-12 heterocyclyl, optionally
substituted by one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6
haloalkyl, --OR.sup.18, --SR.sup.18, --NO.sub.2, CN,
--NR.sup.18R.sup.18, --NR.sup.18COR.sup.18,
--NR.sup.18CONR.sup.18CONR.sup.18, --NR.sup.18CO.sub.2R.sup.18,
--CO.sub.2R.sup.18, --COR.sup.18, --CONR.sup.18.sub.2,
--SO.sub.2R.sup.18, --SONR.sup.18.sub.2, --SOR.sup.18,
--SO.sub.2NR.sup.18R.sup.18, --NR.sup.18SO.sub.2R.sup.18; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.18)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.18
may be the same or different and is defined below; wherein R.sup.17
is hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.18, --SR.sup.18,
--NO.sub.2, CN, --NR.sup.18R.sup.18, --NR.sup.18COR.sup.18,
--NR.sup.18CONR.sup.18R.sup.18, --NR.sup.18CO.sub.2R.sup.18,
--CO.sub.2R.sup.18, --COR.sup.18, --CONR.sup.18.sub.2,
--SO.sub.2R.sup.18, --SONR.sup.18.sub.2, --SOR.sup.18,
--SO.sub.2NR.sup.18R.sup.18, --NR.sup.18SO.sub.2R.sup.18; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.18)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.8
may be the same or different and is defined below; wherein R.sup.18
is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl.
19. A method of claim 1, wherein the compound has the following
formula: ##STR00108## wherein ring A is an optionally substituted
benzene ring, X is --O--, --N.dbd., --NR.sup.3-- or --CHR.sup.3--,
R.sup.2 is an acyl group, an optionally esterified or
thioesterified carboxyl group, and optionally substituted carbamoyl
group or an optionally substituted amino group and the line, a
broken line shows a single bond or a double bond, and R.sup.1 is a
hydrogen atom, optionally substituted hydrocarbon group, and
optionally substituted heterocyclic group and the like.
20. A method of claim 1, wherein the compound has the following
formula: ##STR00109## wherein each of Ar.sup.a and Ar.sup.b is an
aromatic group optionally having substituents, Ar.sup.a and
Ar.sup.b optionally form a condensed cyclic group together with the
adjacent carbon atom; ring B.sup.a is a nitrogen-containing
heterocycle optionally having substituents; X.sup.a and Y.sup.a are
the same or different and each is (1) a bond, (2) an oxygen atom,
(3) S(O).sub.p (wherein p is an integer of 0 to 2), (4) NR.sup.d
(wherein R.sup.d is a hydrogen atom or a lower alkyl group) or (5)
a divalent linear lower hydrocarbon group optionally having
substituents and containing 1 to 3 hetero atom(s); ring A.sup.a is
a 5-membered ring optionally having substituents; R.sup.a and
R.sup.b are the same or different and each is (1) a hydrogen atom,
(2) a halogen atom, (3) a hydrocarbon group optionally having
substituents, (4) an acyl group or (5) a hydroxy group optionally
having a substituent; R.sup.c is (1) a hydrogen atom, (2) a hydroxy
group optionally substituted by a lower alkyl group or (3) a
carboxyl group.
Description
BACKGROUND
[0001] Insulin made in the pancreas is necessary for the body to be
able to use sugar as fuel. Insulin signals the intake of sugar
(i.e., glucose) from the blood into cells of the body (e.g.,
muscles). In type I diabetes, the pancreas no longer produces
insulin; so, patients with type I diabetes need to take insulin
shots in order to compensate for the pancreas' inability to produce
insulin. Conditions associated with type I diabetes include
hypoglycemia, ketoacidosis and celiac disease. Having type I
diabetes increases your risk for many serious complications
including: heart disease (cardiovascular disease), blindness
(retinopathy), nerve damage (neuropathy), and kidney damage
(nephropathy). The insulin shortage in type I diabetes is believed
to be caused by an autoimmune process in which the body's immune
system destroys the .beta.-cells in the pancreas. Thus, there is a
need to identify methods of treating and preventing type I diabetes
by preventing the body's immune system from destroying .beta.-cells
in the pancreas.
SUMMARY OF THE INVENTION
[0002] The invention relates to the treatment and prevention of
type I diabetes. More specifically, the invention relates to
compounds that treat or prevent the body's immune system from
destroying .beta.-cells (i.e., insulin-producing cells in the
pancreatic islets of Langerhans) by inhibition of JNK2, selective
inhibition of JNK2, or inhibition of the expression of the MAPK9
gene or gene product. In one embodiment, the present invention
contemplates the diagnosis, identification, production, and use of
compounds which modulate MAPK9 gene expression or the activity of
the MAPK9 gene product including but not limited to, JNK2, the
nucleic acid encoding MAPK9 and homologues, analogues, and
deletions thereof, as well as antisense, ribozyme, triple helix,
antibody, and polypeptide molecules as well as small inorganic
molecules. The present invention contemplates a variety of
pharmaceutical formulations and routes of administration for such
compounds.
[0003] In one embodiment, the invention is a method for treating
type I diabetes in a subject, comprising administering a compound
that inhibits activity of JNK2 in the subject. In further
embodiments, the compound inhibits the enzymatic activity of JNK2,
and has minimal effect on enzymatic activity of JNK1. In further
embodiments, the activity of JNK1 is not inhibited.
[0004] It is not intended that the present invention be limited to
complete inhibition of JNK2. For example, it is sufficient that the
inhibitor has an IC.sub.50 of less than 10 mM in a c-jun
phosphorylation assay described below. Inhibition can be measured
in vitro or in vivo. In vitro inhibition is readily measured in a
variety of assays (an example of which is provided below).
Inhibition in vivo is established by the observation of reduced
insulitis (e.g. a reduction in non-diabetic obese mice islets
showing invasive, destructive, or peri-insulitis of 10% or more as
measured by a histological analysis of the pancreas).
[0005] In another embodiment, the invention is a method for
treating type I diabetes in a subject, comprising administering a
compound that selectively inhibits activity of JNK2 compared to
JNK1 in a subject, wherein the activity of the compound does not
result in adverse drug reactions to the subject. It is not intended
that the present invention be limited to complete absence of
adverse drug reactions in the subject.
[0006] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering an antisense
oligonucleotides of MAPK9 that inhibits the expression of JNK2. In
further embodiments, the antisense oligonucleotide of JNK2 inhibits
the expression of JNK2, and has minimal effect on the expression of
JNK1.
[0007] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering an amino
acid sequence within JIP-1 or JIP-2 that inhibits the activity of
JNK2 in the subject (i.e. a portion preferably comprising at least
10 amino acids and more preferably at least 18). In further
embodiments, the amino acid sequence has a minimal effect on the
enzymatic activity of JNK1.
[0008] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00001##
wherein: Ar.sup.1 is a substituted or unsubstituted aryl or
heteroaryl group; X is O or S; Ar.sup.2 a substituted or
unsubstituted aryl or heteroaryl group; R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen and a
C.sub.1-C.sub.6-alkyl group; R.sup.a, R.sup.a', R.sup.b, R.sup.b'
are independently selected from the group consisting of hydrogen
and C.sub.1-C.sub.6-alkyl; or R.sup.a' and R.sup.a or R.sup.b'
together with the carbon atoms they are linked, form a substituted
or unsubstituted 5-8-membered saturated, partially unsaturated or
aromatic ring containing optionally one or more heteroatoms
selected from O, N, S; R.sup.3 is selected from the group
consisting of H, C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl
optionally containing 1-3 heteroatoms selected from the group
consisting of N, O, and S; aryl C.sub.1-C.sub.10-alkyl and
heteroaryl C.sub.1-C.sub.10-alkyl; or R.sup.3 and R.sup.a or
R.sup.a' form, together with the N atom linked to R.sup.3, a
5-8-membered saturated ring, containing optionally at least one
further heteroatom selected from O, N, S; R.sup.4 is selected from
the group consisting of H and --C(H)R.sup.5R.sup.6; R.sup.5 and
R.sup.6 are independently selected from the group consisting of H,
C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl
optionally containing 1-3 heteroatoms selected from the group
consisting of N, O, and S; aryl C.sub.1-C.sub.10-alkyl and
heteroaryl C.sub.1-C.sub.10-alkyl; m is an integer from 1 to 5; n
is an integer from 0 to 2; and p is an integer from 1 to 10; that
inhibits the activity of JNK2 in the subject. In further
embodiments, the compound has a minimal effect on the enzymatic
activity of JNK1.
[0009] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00002##
wherein Ar.sup.1 and Ar.sup.2 are independently from each other
substituted or unsubstituted aryl or heteroaryl groups; X is O or
S; R.sup.1 is hydrogen or a C.sub.1-C.sub.6 alkyl group, or R.sup.1
forms a substituted or unsubstituted 5-6 membered saturated or
unsaturated ring with Ar.sup.1; n is an integer from 0 to 5,
preferably between 1-3 and most preferred 1; Y is an unsubstituted
or a substituted 4-12 membered saturated cyclic or bicyclic alkyl
containing at least one nitrogen atom, whereby one nitrogen atom
within said ring is forming a bond with the sulfonyl group thus
providing a sulfamide: that inhibits the activity of JNK2 in the
subject. In further embodiments, the compound has a minimal effect
on the enzymatic activity of JNK1.
[0010] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00003##
wherein Ar.sup.1 and Ar.sup.2 are independently from each other
substituted or unsubstituted aryl or heteroaryl; X is O or S;
R.sup.1 is hydrogen or an unsubstituted or substituted
C.sub.1-C.sub.6-alkyl group, or R.sup.1 could form a substituted or
unsubstituted 5-6-membered saturated or unsaturated fused ring with
Ar.sup.1, or R.sup.2 and R.sup.4 form a substituted or
unsubstituted 5-6-membered saturated or non-saturated ring; R.sup.2
is hydrogen or a substituted or unsubstituted C.sub.1-C.sub.6-alkyl
group; n is an integer from 0 to 5; R.sup.3 and R.sup.4 are
independently from each other selected from the group comprising or
consisting of natural amino acid residues or synthetic amino acid
residues, hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl, like trihalomethyl, substituted or
unsubstituted C.sub.1-C.sub.6-alkoxy, NH.sub.2, SH, thioalkyl,
aminoacyl, aminocarbonyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkoxycarbonyl, aryl, heteroaryl, substituted or
unsubstituted 4-8-membered cyclic alkyl, optionally containing 1-3
heteroatoms, carboxyl, cyano, halogen, hydroxy, nitro, acetoxy,
aminoacyl, sulfoxy, sulfonyl, C.sub.1-C.sub.6-thioalkoxy, whereby
at least one of R.sup.3 and/or R.sup.4 must be an amino acid
residue; R.sup.s is H or substituted or unsubstituted
C.sub.1-C.sub.6-alkyl; R.sup.6 is selected from the group
comprising or consisting of H, substituted or unsubstituted
C.sub.1-C.sub.6-aliphatic alkyl, substituted or unsubstituted
saturated cyclic C.sub.4-C.sub.8-alkyl optionally containing 1-3
heteroatoms and optionally fused with an aryl or an heteroaryl; or
R.sup.6 is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, whereby said aryl or heteroaryl groups
are optionally substituted with substituted or unsubstituted
C.sub.1-C.sub.6-alkyl, like trihalomethyl, substituted or
unsubstituted C.sub.1-C.sub.6-alkoxy, substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl, substituted or unsubstituted
C.sub.2-C.sub.6-alkynyl, amino, aminoacyl, aminocarbonyl,
substituted or unsubstituted C.sub.1-C.sub.6-alkoxycarbonyl, aryl,
carboxyl, cyano, halogen, hydroxy, nitro, acetoxy, aminoacyl,
sulfoxy, sulfonyl, C.sub.1-C.sub.6-thioalkoxy; or R.sup.5 and
R.sup.6 taken together could form a substituted or unsubstituted
4-8-membered saturated cyclic alkyl or heteroalkyl group; that
inhibits the activity of JNK2 in the subject. In further
embodiments, the compound has a minimal effect on the enzymatic
activity of JNK1.
[0011] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00004##
wherein Ar.sup.1 and Ar.sup.2 are independently from each other
substituted or unsubstituted aryl or heteroaryl groups; X.sup.1 and
X.sup.2 are independently from each other O or S; R.sup.1, R.sup.2,
and R.sup.3 are independently from each other hydrogen or a
C.sub.1-C.sub.6 alkyl substituent or R.sup.1 forms a substituted or
unsubstituted 5-6-membered saturated or unsaturated ring with
Ar.sup.1; or R.sup.2 and R.sup.3 form a substituted or
unsubstituted 5-6-membered saturated or unsaturated ring; n is an
integer from 0 to 5; G is selected from a group comprising or
consisting of an unsubstituted or substituted 4-8-membered
heterocycle containing at least one heteroatom, or G is a
substituted or unsubstituted C.sub.1-C.sub.6 alkyl group; that
inhibits the activity of JNK2 in the subject. In further
embodiments, the compound has a minimal effect on the enzymatic
activity of JNK1.
[0012] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00005##
wherein Z.sup.11 and Z.sup.12 each independently represent a
carbonyl group, an oxygen atom, a sulfur atom, a methine group
which may be substituted, a methylene group which may be
substituted or a nitrogen atom which may be substituted; represents
a double bond or a single bond; R.sup.a represents a hydrogen atom,
a C.sub.1-C.sub.6 alkyl group, a phenyl group or a benzyl group;
R.sup.2a, R.sup.2b and R.sup.2c each independently represent a
group selected from the following Substituent Group (a); the ring A
represents a benzene ring which may have one to three groups
selected from the following Substituent Group (a), a naphthalene
ring which may have one to three groups selected from the following
Substituent Group (a) or a 5- to 10-membered aromatic heterocyclic
ring which may have one to three groups selected from the following
Substituent Group (a); Substituent Group (a) (1) a hydrogen atom,
(2) halogen atoms, (3) a nitro group, (4) a hydroxyl group, (5) a
cyano group, (6) a carboxyl group, (7) an amino group, (8) a formyl
group or (9) a group represented by the formula:
##STR00006##
wherein X.sup.1 and X.sup.2 each independently represent a single
bond, --CO--, --SO.sub.2-- or C.sub.1-C.sub.6-methylene group;
X.sup.3 represents a single bond, --CO--, --SO.sub.2, --O--,
--CO--O-- or --O--CO--; R.sup.3b represents a C.sub.1-C.sub.6
alkylene group or a single bond; R.sup.3a and R.sup.3c represent a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may be
substituted, a C.sub.2-C.sub.6 alkenyl group which may be
substituted, a C.sub.2-C.sub.6 alkynyl group which may be
substituted, a C.sub.3-C.sub.8 cycloalkyl group which may be
substituted, a C.sub.6-C.sub.14 aromatic cyclic hydrocarbon group
which may be substituted, a 5- to 14-membered aromatic heterocyclic
group which may be substituted or a hydrogen atom; that inhibits
the activity of JNK2 in the subject. In further embodiments, the
compound has a minimal effect on the enzymatic activity of
JNK1.
[0013] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00007##
wherein A is a direct bond, --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.bCH.dbd.CH(CH.sub.2).sub.c--, or
--(CH.sub.2).sub.bC.ident.C(CH.sub.2).sub.c--; R.sup.1 is aryl,
heteroaryl or heterocycle fused to phenyl, each being optionally
substituted with one to four substituents independently selected
from R.sup.3; R.sup.2 is --R.sup.3, --R.sup.4,
--(CH.sub.2).sub.bC(.dbd.O)R.sup.5,
--(CH.sub.2).sub.bC(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.bC(.dbd.O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.bC(.dbd.O)NR.sub.5(CH.sub.2)CC(.dbd.O)R.sup.6,
--(CH.sub.2).sub.bNR.sup.5C(.dbd.O)R.sup.6,
--(CH.sub.2).sub.bNR.sup.5C(.dbd.O)NR.sup.6R.sup.7,
--(CH.sub.2).sub.bNR.sup.5R.sup.6, --(CH.sub.2).sub.bOR.sup.5,
--(CH.sub.2).sub.bSO.sub.dR.sup.5 or
--(CH.sub.2).sub.bSO.sub.2NR.sup.5R.sup.6; a is 1, 2, 3, 4, 5 or 6;
b and c are the same or different and at each occurrence
independently selected from 0, 1, 2, 3 or 4; d is at each
occurrence 0, 1 or 2; R.sup.3 is at each occurrence independently
halogen, hydroxy, carboxyl, alkyl, alkoxy, haloalkyl, acyloxy,
thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,
arylalkyl, heterocycle, heterocycloalkyl, --C(.dbd.O)OR.sup.8,
--OC(.dbd.O)R.sup.8, --C(.dbd.O)NR.sup.8R.sup.9,
--C(.dbd.O)NR.sup.8OR.sup.9, --SO.sub.2NR.sup.8R.sup.9,
--NR.sup.8SO.sub.2R.sup.9, --CN, --NO.sub.2, --NR.sup.8R.sup.9,
--NR.sup.8C(.dbd.O)R.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2).sub.bOR.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2).sub.bR.sup.9,
--O(CH.sub.2).sub.bNR.sup.8R.sup.9, or heterocycle fused to phenyl;
R.sup.4 is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl,
each being optionally substituted with one to four substituents
independently selected from R.sup.3, or R.sup.4 is halogen or
hydroxy; R.sup.5, R.sup.6 and R.sup.7 are the same or different and
at each occurrence independently hydrogen, alkyl, aryl, arylalkyl,
heterocycle or heterocycloalkyl, wherein each of R.sup.5, R.sup.6
and R.sup.7 are optionally substituted with one to four
substituents independently selected from R.sup.3; and R.sup.8 and
R.sup.9 are the same or different and at each occurrence
independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or
heterocycloalkyl, or R.sup.8 and R.sup.9 taken together with the
atom or atoms to which they are bonded form a heterocycle, wherein
each of R.sup.8, R.sup.9, and R.sup.8 and R.sup.9 taken together to
form a heterocycle are optionally substituted with one to four
substituents independently selected from R.sup.3; that inhibits the
activity of JNK2 in the subject. In further embodiments, the
compound has a minimal effect on the enzymatic activity of
JNK1.
[0014] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00008##
wherein R.sup.1 is aryl or heteroaryl optionally substituted with
one to four substituents independently selected from R.sup.7;
R.sup.2 is hydrogen; R.sup.3 is hydrogen or lower alkyl; R.sup.4
represents one to four optional substituents, wherein each
substituent is the same or different and independently selected
from halogen, hydroxy, lower alkyl and lower alkoxy; R.sup.5 and
R.sup.6 are the same or different and independently --R.sup.8,
--(CH.sub.2).sub.aC(.dbd.O)R.sup.9, --(CH2).sub.aC(.dbd.O)OR.sup.9,
--(CH2).sub.aC(.dbd.O)NR.sup.9R.sup.10,
--(CH2).sub.aC(.dbd.O)NR.sup.9(CH2).sub.bC(.dbd.O)R.sup.10,
--(CH2).sub.aNR.sup.9C(.dbd.O)R.sup.10,
(CH2).sub.aNR.sup.11C(.dbd.O)NR.sup.9R.sup.10,
--(CH2).sub.aNR.sup.9R.sup.10, --(CH2).sub.aOR.sup.9,
--(CH2).sub.aSO.sub.cR.sup.9 or --(CH2).sub.nSO2NR.sup.9R.sup.10;
or R.sup.5 and R.sup.6 taken together with the nitrogen atom to
which they are attached to form a heterocycle or substituted
heterocycle; R.sup.7 is at each occurrence independently halogen,
hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl, acyloxy,
thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,
arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl,
--C(.dbd.O)OR.sup.8, --OC(.dbd.O)R.sup.8,
--C(.dbd.O)NR.sup.8R.sup.9, --C(.dbd.O)NR.sup.8OR.sup.9,
--SO.sub.cR.sup.8, --SO.sub.cNR.sup.8R.sup.9, --NR.sup.8SOR.sup.9,
--NR.sup.8R.sup.9, --NR.sup.8C(.dbd.O)R.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2)bOR.sup.9,
--NR.sup.8C(.dbd.O)(CH2).sub.bR.sup.9,
--O(CH2).sub.bNR.sup.8R.sup.9, or heterocycle fused to phenyl;
R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are the same or different
and at each occurrence independently hydrogen, alkyl, aryl,
arylalkyl, heterocycle, heterocycloalkyl; or R.sup.8 and R.sup.9
taken together with the atom or atoms to which they are attached to
form a heterocycle; a and b are the same or different and at each
occurrence independently selected from 0, 1, 2, 3 or 4; and c is at
each occurrence 0, 1 or 2; that inhibits the activity of JNK2 in
the subject. In further embodiments, the compound has a minimal
effect on the enzymatic activity of JNK1.
[0015] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00009##
wherein R.sup.0 is --O--, --S--, --S(O)--, --S(O).sub.2--, NH or
--CH.sub.2--; being: (i) unsubstituted, (ii) monosubstituted and
having a first substituent, or (iii) disubstituted and having a
first substituent and a second substituent; the first or second
substituent, when present, is at the 3, 4, 5, 7, 8, 9, or 10
position, wherein the first and second substituent, when present,
are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl,
sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy,
arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,
alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,
di-alkylaminoalkoxy, --NHR.sup.3R.sup.4,
--NH(CH.sub.2).sub.nNR.sup.3R.sup.4, --NH(.dbd.O)R.sup.5,
--NHSO.sub.2R.sup.5, --C(.dbd.O)NR.sup.3R.sup.4, or
--SO.sub.2NR.sup.3R.sup.4; wherein n is 0-6, R.sup.3 and R.sup.4
are taken together and represent alkylidene or a
heteroatom-containing cyclic alkylidene or R.sup.3 and R.sup.4 are
independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl,
cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl,
mono-alkylaminoalkyl, or di-alkylaminoalkyl; and R.sup.5 is
hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,
alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,
di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,
cycloalkylalkylamino, aminoalkyl, mono-alkylaminoalkyl, or
di-alkylaminoalkyl; that inhibits the activity of JNK2 in the
subject.
[0016] In further embodiments, the compound has a minimal effect on
the enzymatic activity of JNK1.
[0017] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00010##
wherein N.sup.1 is a nitrogen atom optionally having a substituent
or a hydrogen atom, X.sup.1 is (i) a carbon atom optionally having
substituent(s) or hydrogen atom(s), (ii) an oxygen atom, (iii) a
sulfur atom or (iv) a nitrogen atom optionally having a substituent
or a hydrogen atom, X.sup.2 is (i) a carbon atom optionally having
substituent(s) or hydrogen atom(s), (ii) an oxygen atom, (iii) a
sulfur atom or (iv) a nitrogen atom optionally having a substituent
or a hydrogen atom, X.sup.3 is (i) a carbon atom or (ii) a nitrogen
atom, wherein (1) when X.sup.1 is an oxygen atom or a sulfur atom,
X.sup.2 is a carbon atom optionally having substituent(s) or
hydrogen atom(s), X.sup.3 is a carbon atom and N.sup.1 is a
nitrogen atom, (2) when X.sup.1 is a nitrogen atom having a
substituent or a hydrogen atom and X.sup.3 is a carbon atom, X2 is
a carbon atom optionally having substituent(s) or hydrogen atom(s)
and N.sup.1 is a nitrogen atom, (3) when. X.sup.1 and X.sup.3 are
each a nitrogen atom, X.sup.2 is a carbon atom optionally having
substituent(s) or hydrogen atom(s), and N.sup.1 is a nitrogen atom,
(4) when X.sup.1 is a carbon atom optionally having substituent(s)
or hydrogen atom(s) and X.sup.2 is an oxygen atom or a sulfur atom,
X.sup.3 is a carbon atom and N.sup.1 is a nitrogen atom, (5) when
X.sup.1 is a carbon atom optionally having substituent(s) or
hydrogen atom(s) and X.sup.3 is a carbon atom, one of N.sup.1 and
X.sup.2 is a nitrogen atom, and the other is a nitrogen atom having
a substituent or a hydrogen atom, (6) when X.sup.1 and X.sup.2 are
each a carbon atom optionally having substituent(s) or hydrogen
atom(s) and X.sup.3 is a carbon atom, N.sup.1 is a nitrogen atom
having a substituent or a hydrogen atom, and (7) when X.sup.1 and
X.sup.2 are each a carbon atom optionally having substituent(s) or
hydrogen atom(s) and X.sup.3 is a nitrogen atom, N.sup.1 is a
nitrogen atom, ring A optionally further has substituent(s), ring B
is an aromatic ring, Y is (i) a carbon atom optionally having
substituent(s) or hydrogen atom(s) or (ii) a nitrogen atom, Z is a
bond, --NR.sup.4--(R.sup.4 is a hydrogen atom or a hydrocarbon
group optionally having substituent(s)), an oxygen atom or an
optionally oxidized sulfur atom, W is a bond or a divalent
hydrocarbon group optionally having substituent(s), R.sup.2 is an
aromatic group optionally having substituent(s), and R.sup.3 is a
hydrocarbon group optionally having substituent(s) or a
heterocyclic group optionally having substituent(s); that inhibits
the activity of JNK2 in the subject. In further embodiments, the
compound has a minimal effect on the enzymatic activity of
JNK1.
[0018] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00011##
wherein: W is nitrogen or CH; G is hydrogen or C.sub.1-3 aliphatic
wherein one methylene unit of G is optionally replaced by --C(O)--,
--C(O)O--, --C(O)NH--, --SO.sub.2--, or --SO.sub.2NH--; A is
--N-T.sub.(n)-R, oxygen, or sulfur; R.sup.1 is selected from
-T.sub.(n)-R or -T.sub.(n)-Ar.sup.1; each n is independently 0 or
1; T is a C.sub.1-4 alkylidene chain wherein one methylene unit of
T is optionally replaced by --C(O)--, --C(O)O--, --C(O)NH--,
--SO.sub.2--, or --SO.sub.2NH--; Ar.sup.1 is a 3-7 membered
monocyclic saturated, partially saturated or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 8-10 membered bicyclic saturated, partially saturated
or aromatic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein each member of Ar.sup.1 is
optionally substituted with one --Z--R.sup.3 and one to three
additional groups independently selected from --R, halogen, oxo,
--NO.sub.2, --CN, --OR, --SR, --N(R).sub.2, --NRC(O)R,
--NRC(O)N(R).sub.2, --NRCO.sub.2R, --C(O)R, --CO.sub.2R, --OC(O)R,
--C(O)N(R).sub.2, --OC(O)N(R).sub.2, --S(O)R, --SO.sub.2R,
--SO.sub.2N(R).sub.2, --NRSO.sub.2R, --NRSO.sub.2N(R).sub.2,
--C(O)C(O)R, or --C(O)CH.sub.2C(O)R; each R is independently
selected from hydrogen or a C.sub.1-6 aliphatic, wherein said
aliphatic is optionally substituted with one to three groups
independently selected from oxo, --CO.sub.2R', --OR',
--N(R').sub.2, --SR', --NO.sub.2, --NR'C(O)R',
--NR'C(O)N(R').sub.2, --NR'CO.sub.2R', --C(O)R', --OC(O)R',
--C(O)N(R').sub.2, --OC(O)N(R').sub.2, --S(O)R', --SO.sub.2R',
--SO.sub.2N(R').sub.2, --NR'SO.sub.2R', --NR'SO.sub.2N(R').sub.2,
--C(O)C(O)R', --C(O)CH.sub.2C(O)R', halogen, or --CN, or two R
bound to the same nitrogen atom are taken together with that
nitrogen atom to form a five or six membered heterocyclic or
heteroaryl ring having one to two additional heteroatoms
independently selected from oxygen, nitrogen, or sulfur; each R' is
independently selected from hydrogen or C.sub.1-6 aliphatic,
wherein said aliphatic is optionally substituted with one to three
groups independently selected from oxo, --CO.sub.2H, --OH,
--NH.sub.2, --SH, --NO.sub.2, --NHC(O)H, --NHC(O)NH.sub.2,
--NHCO.sub.2H, --C(O)H, --OC(O)H, --C(O)NH.sub.2, --OC(O)NH.sub.2,
--S(O)H, --SO.sub.2H, --SO.sub.2NH.sub.2, --NHSO.sub.2H,
--NHSO.sub.2NH.sub.2, --C(O)C(O)H, --C(O)CH.sub.2C(O)H, halogen, or
--CN, or two R' bound to the same nitrogen atom are taken together
with that nitrogen atom to form a five or six membered heterocyclic
or heteroaryl ring optionally having one or two additional
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; Z is a C.sub.1-C.sub.6 alkylidene chain wherein up to two
nonadjacent methylene units of Z are optionally replaced by
--C(O)--, --C(O)O--, --C(O)C(O)--, --C(O)N(R)--, --OC(O)N(R)--,
--N(R)N(R)--, --N(R)N(R)C(O)--, --N(R)C(O)--, --N(R)C(O)O--,
--N(R)C(O)N(R)--, --S(O)--, --SO.sub.2--, --N(R)SO.sub.2--,
--SO.sub.2N(R)--, --N(R)SO.sub.2N(R)--, --O--, --S--, or --N(R)--;
R.sup.2 is -Q.sub.(n)-Ar.sup.2; Ar.sup.2 is selected from a 3-7
membered monocyclic saturated, saturated or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 8-10 membered bicyclic saturated, saturated or
aromatic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein each member of Ar.sup.2 is
optionally substituted with 1-5 groups independently selected from
--Z--R.sup.3, --R, halogen, oxo, --NO2, --CN, --OR, --SR,
--N(R).sub.2, NRC(O)R, --NRC(O)N(R).sub.2, --NRCO.sub.2R, --C(O)R,
--CO.sub.2R, OC(O)R, --C(O)N(R).sub.2, --OC(O)N(R).sub.2, --S(O)R,
--SO.sub.2R, SO.sub.2N(R).sub.2, --N(R)SO.sub.2R,
--N(R)SO.sub.2N(R).sub.2, --C(O)C(O)R, or --C(O)CH.sub.2C(O)R; Q is
a C.sub.1-3 alkylidene chain wherein up to two nonadjacent
methylene units of Q are optionally replaced by --C(O)--,
--C(O)O--, --C(O)C(O)--, --C(O)N(R)--, --OC(O)N(R)--, --N(R)N(R)--,
--N(R)N(R)C(O)--, --N(R)C(O)--, --N(R)C(O)O--, --N(R)C(O)N(R)--,
--S(O)--, --SO.sub.2--, --N(R)SO.sub.2--, --SO.sub.2N(R)--,
--N(R)SO.sub.2N(R)--, --O--, --S--, or --N(R)--; R.sup.3 is
selected from --Ar.sup.3, --R, halogen, --NO.sub.2, --CN, --OR,
--SR, --N(R).sub.2, --NRC(O)R, --NRC(O)N(R).sub.2, --NRCO.sub.2R,
--C(O)R, --CO.sub.2R, --OC(O)R, --C(O)N(R).sub.2,
--OC(O)N(R).sub.2, --SOR, --SO.sub.2R, --SO.sub.2N(R).sub.2,
--NRSO.sub.2R, --NRSO.sub.2N(R).sub.2, --C(O)C(O)R, or
--C(O)CH2C(O)R; and Ar.sup.3 is a 5-6 membered saturated, partially
saturated, or aromatic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, wherein each member of
Ar.sup.3 is optionally substituted with halogen, oxo, --CN,
--NO.sub.2, --R', --OR', --N(R').sub.2, --N(R')C(O)R',
N(R')C(O)N(R').sub.2, --N(R')CO.sub.2R', --C(O)R', --CO.sub.2R',
OC(O)R', --C(O)N(R').sub.2, --OC(O)N(R').sub.2, or --SO.sub.2R';
provided that when W is nitrogen and: (i) A is --N-T.sub.(n)-R and
R2 is a saturated ring or (ii) A is sulfur, then R.sup.1 is other
than an optionally substituted phenyl; that inhibits the activity
of JNK2 in the subject. In further embodiments, the compound has a
minimal effect on the enzymatic activity of JNK1.
[0019] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00012##
wherein R.sup.1 is optionally substituted carbocyclyl or
heterocyclyl group, R.sup.2 is an optionally substituted five or
six membered heterocyclyl group or an optionally substituted six
membered carbocyclyl group, E is hydrogen, halogen cyano, C.sub.1-6
alkoxy or C.sub.1-6 alkyl, G is hydrogen, halogen, cyano, C.sub.1-6
alkoxy or C.sub.1-6 alkyl, and L is hydrogen, halogen, cyano,
C.sub.1-6 alkoxy or C.sub.1-6 alkyl; that inhibits the activity of
JNK2 in the subject. In further embodiments, the compound has a
minimal effect on the enzymatic activity of JNK1.
[0020] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00013##
wherein R.sup.1 is an optionally substituted C.sub.3-16 carbocyclyl
or C.sub.3-12 heterocyclyl group, Y is N or C and Z is lone
electron pair, hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl,
C.sub.2-12 alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl,
C.sub.3-12 heterocyclyl, --(CH.sub.2).sub.nOR.sup.2,
--(CH.sub.2)NR.sup.2.sub.2, --CO.sub.2R.sup.2, --COR.sup.2,
--CONR.sup.2.sub.2, wherein the C.sub.1-12 alkyl group optionally
contains one or more insertions selected from --O--,
--N(R.sup.2)--, --S--, --SO--, --SO.sub.2--; and each substitutable
nitrogen atom in Z is optionally substituted by --R.sup.3,
--COR.sup.3, --SO.sub.2R.sup.3 or --CO.sub.2R.sup.3; wherein n is 1
to 6, preferably n is 1, 2, or 3; wherein R.sup.2 is hydrogen,
C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, C.sub.1-12 alkylC.sub.3-16 carbocyclyl, or C.sub.1-12
alkylC.sub.3-12 heterocyclyl optionally substituted by one or more
of C.sub.1-6 alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.4,
--SR.sup.4, --NO.sub.2, CN, --NR.sup.4R.sup.4, --NR.sup.4COR.sup.4,
--NR.sup.4CONR.sup.4R.sup.4, --NR.sup.4CO.sub.2R.sup.4,
--CO.sub.2R.sup.4, --COR.sup.4, --CONR.sup.4.sub.2,
--SO.sub.2R.sup.4, --SONR.sup.4.sub.2, --SOR.sup.4,
--SO.sub.2NR.sup.4R.sup.4, --NR.sup.4SO.sub.2R.sup.4, wherein the
C.sub.1-12 alkyl group optionally incorporates on or two insertions
selected for the group consisting of --O--, --N(R.sup.4)--, --S--,
--SO--, --SO.sub.2--, wherein each R.sup.4 may be the same or
different and is defined below; wherein two R.sup.2 and
NR.sup.2.sub.2 may form a partially saturated, unsaturated or fully
saturated five to seven membered ring containing one to three
heteroatoms, optionally and independently substituted with one or
more halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12
alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl, C.sub.3-12
heterocyclyl, --OR.sup.5, --SR.sup.5, --NO.sub.2, CN,
--NR.sup.5R.sup.5, --NR.sup.5COR.sup.5,
--NR.sup.5CONR.sup.5R.sup.5, --NR.sup.5CO.sub.2R.sup.5,
--CO.sub.2R.sup.5, --COR.sup.5, --CONR.sup.5.sub.2,
--SO.sub.2R.sup.5, --SONR.sup.5.sub.2, --SOR.sup.5,
--SO.sub.2NR.sup.5R.sup.5, --NR.sup.5SO.sub.2R.sup.5; and each
saturated carbon in the optional ring is further optionally and
independently substituted by .dbd.O, .dbd.S, NNR.sup.6.sub.2,
.dbd.N--OR.sup.6, .dbd.NNR.sup.6COR.sup.6,
.dbd.NNR.sup.6CO.sub.2R.sup.6, .dbd.NNSO.sub.2R.sup.6, or
.dbd.NR.sup.6; wherein R.sup.3 is hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, or C.sub.6-12 aryl; wherein R.sup.4 is
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or C.sub.6-12 aryl;
wherein R.sup.5 is hydrogen, C.sub.1-12 alkyl, C.sub.3-16
carbocyclyl or C.sub.3-12 heterocyclyl, optionally substituted by
one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6 haloalkyl,
--OR.sup.7, --SR.sup.7, --NO.sub.2, CN, --NR.sup.7R.sup.7,
--NR.sup.7COR.sup.7, --NR.sup.7CONR.sup.7R.sup.7,
--NR.sup.7CO.sub.2R.sup.7, --CO.sub.2R.sup.7, --COR.sup.7,
--CONR.sup.7.sub.2, --SO.sub.2R.sup.7, --SONR.sup.7.sub.2,
--SOR.sup.7, --SO.sub.2NR.sup.7R.sup.7, --NR.sup.7SO.sub.2R.sup.7;
wherein the C.sub.1-12 alkyl group optionally incorporates one or
two insertions selected from the group consisting of --O--,
--N(R.sup.7)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein R.sup.6
is hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.7, --SR.sup.7,
--NO.sub.2, CN, --NR.sup.7R.sup.7, --NR.sup.7COR.sup.7,
--NR.sup.7CONR.sup.7R.sup.7, --NR.sup.7CO.sub.2R.sup.7,
--CO.sub.2R.sup.7, --COR.sup.7, --CONR.sup.7.sub.2,
--SO.sub.2R.sup.7, --SONR.sup.7.sub.2, --SOR.sup.7,
--SO.sub.2NR.sup.7R.sup.7, --NR.sup.7SO.sub.2R.sup.7; wherein the
C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.7)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein R.sup.7
is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl; wherein the
optionally substituted carbocyclyl or heterocyclyl group in R.sup.1
and Z is optionally and independently fused to a partially
saturated, unsaturated or fully saturated five to seven membered
ring containing zero to three heteroatoms, and each substitutable
carbon atom in R.sup.1 or Z, including the optional fused ring, is
optionally and independently substituted by one or more of halogen,
C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl,
C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl, C.sub.3-12
heterocyclyl, --(CH.sub.2).sub.nOR.sup.12,
--(CH.sub.2).sub.nNR.sup.12.sub.2, --OR.sup.2, --SR.sup.12,
--NO.sub.2, CN, --NR.sup.12R.sup.12, --NR.sup.12COR.sup.12,
--NR.sup.12CONR.sup.12R.sup.12, --NR.sup.12CO.sub.2R.sup.12,
--CO.sub.2R.sup.12, --COR.sup.12, --CONR.sup.12.sub.2,
--SO.sub.2R.sup.12, --SONR.sup.12.sub.2, --SOR.sup.12,
--SO.sub.2NR.sup.12R.sup.12, --NR.sup.12SO.sub.2R.sup.12; wherein
the C.sub.1-12 alkyl group optionally contains one or more
insertions selected from --O--, --N(R.sup.12)--, --S--, --SO--,
--SO.sub.2--, and each saturated carbon in the optionally fused
ring is further optionally and independently substituted by .dbd.O,
.dbd.S, NNR.sup.13.sub.2, .dbd.N--OR.sup.13,
.dbd.NNR.sup.13COR.sup.13, .dbd.NNR.sup.13CO.sub.2R.sup.13,
.dbd.NNSO.sub.2R.sup.13, or .dbd.NR.sup.13; and each substitutable
nitrogen atom in R.sup.1 is optionally substituted by --R.sup.14,
--COR.sup.14, --SO.sub.2R.sup.14, or --CO.sub.2R.sup.4; wherein n
is 1 to 6, preferably n is 1, 2, or 3; wherein R.sup.12 is
hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.15, --SR.sup.15,
--NO.sub.2, CN, --NR.sup.15R.sup.15, --NR.sup.15COR.sup.15,
--NR.sup.15CONR.sup.15R.sup.15, --NR.sup.15CO.sub.2R.sup.15,
--CO.sub.2R.sup.15, --COR.sup.15, --CONR.sup.15.sub.2,
--SO.sub.2R.sup.15, --SONR.sup.15.sub.2, --SOR.sup.15,
--SO.sub.2NR.sup.15R.sup.15, --NR.sup.15SO.sub.2R.sup.15; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.15)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein two
R.sup.12 and NR.sup.12.sub.2 may form a partially saturated,
unsaturated or fully saturated five to seven membered ring
containing one to three heteroatoms, optionally and independently
substituted with one or more halogen, C.sub.1-12 alkyl, C.sub.2-12
alkenyl, C.sub.2-12 alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12
carbocyclyl, C.sub.3-12 heterocyclyl, --OR.sup.16, --SR.sup.16,
--NO.sub.2, CN, --NR.sup.16R.sup.16, --NR.sup.16COR.sup.16,
--NR.sup.16CONR.sup.16R.sup.16, --NR.sup.16CO.sub.2R.sup.16,
--CO.sub.2R.sup.16, --COR.sup.16, --CONR.sup.16.sub.2,
--SO.sub.2R.sup.16, --SONR.sup.16.sub.2, --SOR.sup.16,
--SO.sub.2NR.sup.16R.sup.16, --NR.sup.16SO.sub.2R.sup.16; and each
saturated carbon in the optional ring is further optionally and
independently substituted by .dbd.O, .dbd.S, NNR.sup.17.sub.2,
.dbd.N--OR.sup.17, .dbd.NNR.sup.17COR.sup.17,
.dbd.NNR.sup.17CO.sub.2R.sup.17, .dbd.NNSO.sub.2R.sup.17, or
.dbd.NR.sup.17; wherein R.sup.13 is hydrogen, C.sub.1-12 alkyl,
C.sub.3-16 carbocyclyl or C.sub.3-12 heterocyclyl, optionally
substituted by one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6
haloalkyl, --OR.sup.15, --SR.sup.15, --NO.sub.2, CN,
--NR.sup.15R.sup.15, --NR.sup.15COR.sup.15,
--NR.sup.15CONR.sup.15R.sup.15, --NR.sup.15CO.sub.2R.sup.15,
--CO.sub.2R.sup.15, --COR.sup.15, --CONR.sup.15.sub.2,
--SO.sub.2R.sup.15, --SONR.sup.15.sub.2, --SOR.sup.15,
--SO.sub.2NR.sup.15R.sup.15, --NR.sup.15SO.sub.2R.sup.15; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.15)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.15
may be the same or different and is defined below; wherein R.sup.14
is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or C.sub.6-12
aryl; wherein R.sup.15 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl; wherein R.sup.16 is hydrogen, C.sub.1-12 alkyl,
C.sub.3-16 carbocyclyl or C.sub.3-12 heterocyclyl, optionally
substituted by one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6
haloalkyl, --OR.sup.18, --SR.sup.18, --NO.sub.2, CN,
--NR.sup.18R.sup.18, --NR.sup.18COR.sup.18,
--NR.sup.18CONR.sup.18R.sup.18, --NR.sup.18CO.sub.2R.sup.18,
--CO.sub.2R.sup.18, --COR.sup.8, --CONR.sup.18.sub.2,
--SO.sub.2R.sup.18, --SONR.sup.18.sub.2, --SOR.sup.18,
--SO.sub.2NR.sup.18R.sup.18, --NR.sup.18SO.sub.2R.sup.18; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.18)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.18
may be the same or different and is defined below; wherein R.sup.17
is hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.18, --SR.sup.18,
--NO.sub.2, CN, --NR.sup.18R.sup.18, --NR.sup.18COR.sup.18,
--NR.sup.18CONR.sup.18R.sup.18, --NR.sup.18CO.sub.2R.sup.18,
--CO.sub.2R.sup.18, --COR.sup.18, --CONR.sup.18.sub.2,
--SO.sub.2R.sup.18, --SONR.sup.18.sub.2, --SOR.sup.18,
--SO.sub.2NR.sup.18R.sup.18, --NR.sup.18SO.sub.2R.sup.18; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.18)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.18
may be the same or different and is defined below; wherein R.sup.18
is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl; that inhibits
the activity of JNK2 in the subject. In further embodiments, the
compound has a minimal effect on the enzymatic activity of
JNK1.
[0021] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00014##
wherein ring A is an optionally substituted benzene ring, X is
--O--, --N.dbd., --NR.sup.3-- or --CHR.sup.3--, R.sup.2 is an acyl
group, an optionally esterified or thioesterified carboxyl group,
and optionally substituted carbamoyl group or an optionally
substituted amino group and the line, a broken line shows a single
bond or a double bond, and R.sup.1 is a hydrogen atom, optionally
substituted hydrocarbon group, and optionally substituted
heterocyclic group and the like; that inhibits the activity of JNK2
in the subject. In further embodiments, the compound has a minimal
effect on the enzymatic activity of JNK1.
[0022] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00015##
wherein each of Ar.sup.a and Ar.sup.b is an aromatic group
optionally having substituents, Ar.sup.a and Ar.sup.b optionally
form a condensed cyclic group together with the adjacent carbon
atom; ring B.sup.a is a nitrogen-containing heterocycle optionally
having substituents; X.sup.a and Y.sup.a are the same or different
and each is (1) a bond, (2) an oxygen atom, (3) S(O).sub.p (wherein
p is an integer of 0 to 2), (4) NR.sup.d (wherein R.sup.d is a
hydrogen atom or a lower alkyl group) or (5) a divalent linear
lower hydrocarbon group optionally having substituents and
containing 1 to 3 hetero atom(s); ring A.sup.a is a 5-membered ring
optionally having substituents; R.sup.a and R.sup.b are the same or
different and each is (1) a hydrogen atom, (2) a halogen atom, (3)
a hydrocarbon group optionally having substituents, (4) an acyl
group or (5) a hydroxy group optionally having a substituent;
R.sub.c is (1) a hydrogen atom, (2) a hydroxy group optionally
substituted by a lower alkyl group or (3) a carboxyl group; that
inhibits the activity of JNK2 in the subject. In further
embodiments, the compound has a minimal effect on the enzymatic
activity of JNK1.
[0023] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00016## ##STR00017## ##STR00018## ##STR00019##
that inhibits the activity of JNK2 in the subject. In further
embodiments, the compound has a minimal effect on the enzymatic
activity of JNK1.
[0024] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00020##
wherein Y is selected from O, NH, N(R), S, S(O) or S(O).sub.2; X is
selected from O, NH or N(R); R.sup.1 and R.sup.2 are each
independently selected from H, a C.sub.1-C.sub.6 straight chain or
branched alkyl or alkenyl group, optionally substituted with one to
four substituents, each of which is independently selected from
NH.sub.2, NHR, N(R).sub.2, NO.sub.2, OH, OR, CF.sub.3, halo, CN,
CO.sub.2H, CONH.sub.2, CONHR, CON(R).sub.2, COR, SR, S(O)R,
S(O).sub.2R, S(O)2NH.sub.2, S(O).sub.2NHR or R; a 5-7 membered
aromatic or non-aromatic carbocyclic or heterocyclic ring,
optionally substituted with one to four substituents, each of which
is independently selected from NH.sub.2, NHR, N(R).sub.2, NO.sub.2,
OH, OR, CF.sub.3, halo, CN, CO.sub.2H, CONH.sub.2, CONHR,
CON(R).sub.2, COR, SR, S(O)R, S(O).sub.2R, S(O).sub.2NH.sub.2,
S(O).sub.2NHR or R; or a 9-10 membered bicyclic aromatic or
non-aromatic carbocyclic or heterocyclic ring optionally
substituted with one to four substituents, each of which is
independently selected from NH.sub.2, NHR, N(R).sub.2, NO.sub.2,
OH, OR, CF.sub.3, halo, CN, CO.sub.2H, CONH.sub.2, CONHR,
CON(R).sub.2, COR, SR, S(O)R, S(O).sub.2R, S(O).sub.2NH.sub.2,
S(O).sub.2NHR or R; wherein said heterocyclic ring contains 1 to 4
heteroatoms, each of which heteroatoms are independently selected
from N, O, S, SO or SO.sub.2; and R is selected from a
C.sub.1-C.sub.6 straight chain or branched alkyl or alkenyl group,
a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic
ring, or a 9-10 membered bicyclic aromatic or non-aromatic
carbocyclic or heterocyclic ring system; that inhibits the activity
of JNK2 in the subject. In further embodiments, the compound has a
minimal effect on the enzymatic activity of JNK1.
[0025] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00021##
wherein ring A and ring B are each an optionally substituted
benzene ring, X is --O--, --N.dbd., --NR.sup.3-- or --CHR.sup.3--,
R.sup.2 is an acyl group, an optionally esterified or
thioesterified carboxyl group, and optionally substituted carbamoyl
group or an optionally substituted amino group and the line, a
broken line shows a single bond or a double bond, and R.sup.1 is a
hydrogen atom, optionally substituted hydrocarbon group, and
optionally substituted heterocyclic group and the like; that
inhibits the activity of JNK2 in the subject. In further
embodiments, the compound has a minimal effect on the enzymatic
activity of JNK1.
[0026] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00022##
wherein X is O, S or NR.sup.0, with R.sup.0 being H or an
unsubstituted or substituted C.sub.1-C.sub.6 alkyl; G is an
unsubstituted or substituted pyrimidinyl group; R.sup.1 is selected
from the group comprising or consisting of hydrogen, unsubstituted
or substituted C.sub.1-C.sub.6-alkoxy, unsubstituted or substituted
C.sub.1-C.sub.6-thioalkoxy, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl, primary, secondary or tertiary amino
groups, aminoacyl, aminocarbonyl, unsubstituted or substituted
C.sub.1-C.sub.6 alkoxycarbonyl unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen,
hydroxy, nitro, sulfoxy, sulfonyl sulfonamide, unsubstituted or
substituted hydrazides; R.sup.2 is selected from the group
comprising or consisting of hydrogen, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl-aryl, unsubstituted or substituted aryl or
heteroaryl unsubstituted or substituted
C.sub.1-C.sub.6-alkyl-heteroaryl, --C(O)--OR.sup.3,
--C(O)--R.sup.3, --C(O)--NR.sup.3R.sup.3', --(SO.sub.2)R.sup.3,
with R.sup.3 and R.sup.3' being independently selected from the
group comprising or consisting of hydrogen, unsubstituted or
substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alknyl, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl aryl, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl heteroaryl; that inhibits the
activity of JNK2 in the subject. In further embodiments; the
compound has a minimal effect on the enzymatic activity of
JNK1.
[0027] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00023##
[0028] wherein Y is selected from --(CH.sub.2)-Q.sup.1;
--(CO)-Q.sup.1; --(CO)NH-Q.sup.1; --(CO)--O-Q.sup.1;
--(SO.sub.2)-Q.sup.1 or --(SO.sub.2)NH-Q.sup.1; Q.sup.1 is a
C.sub.1-C.sub.6 straight chain or branched alkyl or alkenyl group;
a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic
ring; or a 9-14 membered bicyclic or tricyclic aromatic or
non-aromatic carbocyclic or heterocyclic ring system, wherein said
alkyl, alkenyl, ring or ring system is optionally substituted with
one to four substituents, each of which is independently selected
from NH.sub.2, NH--R, N(R).sub.2, NO.sub.2, OH, OR, CF.sub.3, halo,
CN, CO.sub.2H, C(O)--NH.sub.2, C(O)--NH--R, C(O)--N(R).sub.2,
C(O)--R, SR, S(O)--R, S(O).sub.2--R, S(O).sub.2--NH--R or --R; W is
N or C; wherein when W is N, R.sup.8 is a lone pair of electrons;
and wherein when W is C, R.sup.8 is R.sup.7. A.sup.1 is N or
CR.sup.1; A.sup.2 is N or CR.sup.2; A.sup.3 is N or CR.sup.3;
A.sup.4 is N or CR.sup.4; provided that at least one of A.sup.1,
A.sup.2, A.sup.3 and A.sup.4 must not be N; R.sup.1 is --NHR.sup.5,
--OR.sup.5, --SR.sup.5, or --R.sup.5; R.sup.2, R.sup.3, and R.sup.4
are independently selected from --(CO)NH.sub.2, --(CO)NHR,
--(CO)N(R).sub.2, --NHR.sup.5, --NHCH.sub.2R.sup.5, --OR.sup.5,
--SR.sup.5, --R.sup.5, --NH(CO)--R.sup.6, --NH(CO)--NHR.sup.6,
--NH(CO)--NH(CO)R.sup.6, --NH(CO)--OR.sup.6,
--NH(SO.sub.2)--R.sup.6, --NH(SO.sub.2)--NHR.sup.6, --C(O)OH,
--C(O)OR, --(CO)-Q.sup.1, --(CO)NH-Q.sup.1, --(CO)NR-Q.sup.1,
--(CO)--O-Q.sup.1, --(SO.sub.2)-Q.sup.1 or --(SO.sub.2)NH-Q.sup.1;
R.sup.5 and R.sup.6 are each independently selected from H;
N(R).sub.2, NHOH, NO.sub.2, C(O)OR or halo; a C.sub.1-C.sub.6
straight chain or branched alkyl, alkenyl or alkynyl group; a 5-7
membered aromatic or non-aromatic carbocyclic or heterocyclic ring;
or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic
carbocyclic or heterocyclic ring; wherein said alkyl, alkenyl, ring
or ring system is optionally substituted with one to four
substituents, each of which is independently selected from
NH.sub.2, NHR, NHC(O)OR, N(R).sub.2, NO.sub.2, OH, OR, CF.sub.3,
halo, CN, Si(R).sub.3, CO2H, COOR, CONH.sub.2, CONHR, CON(R).sub.2,
COR, SR, S(O)R, S(O).sub.2R, S(O).sub.2NHR or R; R.sup.7 is H; a
C.sub.1-C.sub.6 straight chain or branched alkyl or alkenyl group;
a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic
ring; or a 9-14 membered bicyclic or tricyclic aromatic or
non-aromatic carbocyclic or heterocyclic ring; wherein said alkyl,
alkenyl, ring or ring system is optionally substituted with one to
four substituents, each of which is independently selected from
NH.sub.2, NHR, N(R).sub.2, NO.sub.2, OH, OR, CF.sub.3, halo, CN,
CO.sub.2H, CONH.sub.2, CONHR, CON(R).sub.2, COR, SR, S(O)R,
S(O).sub.2R, S(O).sub.2NHR or R; R is a C.sub.1-C.sub.6 straight
chain or branched alkyl or alkenyl group, a 5-7 membered aromatic
or non-aromatic carbocyclic or heterocyclic ring, or a 9-10
membered bicyclic aromatic or non-aromatic carbocyclic or
heterocyclic ring system; and Z is CH or N; that inhibits the
activity of JNK2 in the subject. In further embodiments, the
compound has a minimal effect on the enzymatic activity of
JNK1.
[0029] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00024##
wherein: R.sup.1 is aryl or heteroaryl, each of which is optionally
substituted with one or more of R.sup.3, OR.sup.3, OCOR.sup.3,
COOR.sup.3, COR.sup.3, CON.sup.4R.sup.3R.sup.4, NHCOR.sup.3,
NR.sup.3R.sup.4, NHSO.sub.2R.sup.3, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, SR.sup.3, CN, halogen, and NO.sub.2;
R.sup.2 is R.sup.5, R.sup.6, COR.sup.s, COR.sup.S, CONHR.sup.5,
CONHR.sup.6, CON(R.sup.6).sub.2, COOR.sup.5, COOR.sup.6,
SO.sub.2R.sup.5 or SO.sub.2R.sup.6; R3 and R4 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)
C.sub.1-4 alkyl, heterocycle, heterocycle C.sub.1-6 alkyl,
C.sub.1-6 fluoroalkyl, C.sub.1-6 trifluoroalkoxy; R.sup.5 is aryl
or heteroaryl, each of which is optionally substituted with one or
more of R.sup.7, OR.sup.7, OCOR.sup.7, COOR.sup.7, COR.sup.7,
CONR.sup.7R.sup.8, CONHOR.sup.7, NHCOR.sup.7, NR.sup.7R.sup.8,
NHSO.sub.2R.sup.7, SO.sub.2R.sup.7, SO.sub.2NHR.sup.7R.sup.8,
SR.sup.7, R.sup.7SR.sup.8, CN, halogen, oxygen and NO.sub.2;
R.sup.6 is hydrogen, C.sub.4-6 alkyl, C.sub.3-8 cycloalkyl,
(C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, heterocycle, heterocycle
C.sub.1-6 alkyl, heteroaryl C.sub.1-6 alkyl, aryl C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or C.sub.2-6 alkenyl, wherein any of C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-6
alkyl, heterocycle, heterocycle C.sub.1-6 alkyl, heteroaryl
C.sub.1-6 alkyl, aryl C.sub.1-6 alkyl, C.sub.1-6 alkoxy and
C.sub.2-6 alkenyl is optionally substituted with one or more A;
R.sup.7 and R.sup.8 are each independently hydrogen, C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heteroaryl, heteroaryl C.sub.1-6
alkyl, heterocycle, heterocycle C.sub.1-6 alkyl, aryl, C.sub.1-6
fluoroalkyl and C.sub.1-6 chloroalkyl, wherein any of C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, heteroaryl, heteroaryl C.sub.1-6 alkyl,
heterocycle and heterocycle C.sub.1-6 alkyl is optionally
substituted with one or more B; R.sup.9 and R.sup.10 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl,
(C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
heterocycle, heterocycle C.sub.1-6 alkyl, heteroaryl, heteroaryl
C.sub.1-6 alkyl, aryl or aryl C.sub.1-6 alkyl, wherein any of
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, heterocycle, heterocycle
C.sub.1-6 alkyl, heteroaryl, heteroaryl C.sub.1-6 alkyl, aryl or
aryl C.sub.1-6 alkyl is optionally substituted with one or more B;
A is R.sup.9, OR.sup.9, OCOR.sup.9, COOR.sup.9, COR.sup.9,
CONR.sup.9R.sup.10, CONHOR.sup.9, NHCOR.sup.9, NR.sup.9R.sup.10,
NR.sup.9SO.sub.2R.sup.10, SO.sub.2R.sup.9,
SO.sub.2NR.sup.9R.sup.10, SR.sup.9, R.sup.9SR.sup.10, CN or
halogen; B is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylamino, di (C.sub.1-6 alkyl)amino or halogen; that inhibits the
activity of JNK2 in the subject. In further embodiments, the
compound has a minimal effect on the enzymatic activity of
JNK1.
[0030] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00025##
wherein: R.sup.1 is selected from hydrogen, CONH.sub.2,
T.sub.(n)-R, or T.sub.(n)-Ar.sup.1; R is an aliphatic or
substituted aliphatic group; n is zero or one; T is C(.dbd.O),
CO.sub.2, CONH, S(O).sub.2, S(O).sub.2NH, COCH.sub.2 or CH.sub.2;
R.sub.2 is selected from hydrogen, --R, --CH.sub.2OR, --CH.sub.2OH,
--CH.dbd.O, --CH.sub.2SR, --CH.sub.2S(O).sub.2R,
--CH.sub.2(C.dbd.O)R, --CH.sub.2CO.sub.2R, --CH.sub.2CO.sub.2H,
--CH.sub.2CN, --CH.sub.2NHR, --CH.sub.2N(R).sub.2, --CH.dbd.N--OR,
--CH.dbd.NNHR, --CH.dbd.NN(R).sub.2, --CH.dbd.NNHCOR,
--CH.dbd.NNHCO.sub.2R, --CH.dbd.NNHSO.sub.2R, -aryl,
--CH.sub.2(aryl), --CH.sub.2NH.sub.2, --CH.sub.2NHCOR,
--CH.sub.2NHCONHR, --CH.sub.2NHCON(R).sub.2, --CH.sub.2NRCOR,
--CH.sub.2NHCO.sub.2R, --CH.sub.2CONHR, --CH.sub.2CON(R).sub.2,
--CH.sub.2SO.sub.2NH.sub.2, --CH.sub.2(heterocyclyl), or
-(heterocyclyl); R.sup.3 is selected from hydrogen, --R,
hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, or aryloxyalkyl; G is hydrogen
or C.sub.1-3 alkyl; Q-NH is
##STR00026##
wherein the H of Q-NH is optionally replaced by R, COR,
S(O).sub.2R, or CO.sub.2R; A is N or CH; Ar.sup.1 is aryl,
substituted aryl, heterocyclyl or substituted heterocyclyl, wherein
Ar.sup.1 is optionally fused to a partially unsaturated or fully
unsaturated five to seven membered ring containing zero to three
heteroatoms; wherein each substitutable carbon atom in Ar.sup.1,
including the fused ring when present, is optionally and
independently substituted by halo, R, OR, SR, OH, NO.sub.2, CN,
NH.sub.2, NHR, N(R).sub.2, NHCOR, NHCONHR, NHCON(R).sub.2, NRCOR,
NHCO.sub.2R, CO.sub.2R, CO.sub.2H, COR, CONHR, CON(R).sub.2,
S(O).sub.2R, SONH.sub.2, S(O)R, SO.sub.2NHR, or NHS(O).sub.2R, and
wherein each saturated carbon in the fused ring is further
optionally and independently substituted by .dbd.O, .dbd.S,
.dbd.NNHR, .dbd.NNR.sub.2, .dbd.N--OR, .dbd.NNHCOR,
.dbd.NNHCO.sub.2R, .dbd.NNHSO.sub.2R, or .dbd.NR; and wherein each
substitutable nitrogen atom in Ar.sup.1 is optionally substituted
by R, COR, S(O).sub.2R, or CO.sub.2R; that inhibits the activity of
JNK2 in the subject. In further embodiments, the compound has a
minimal effect on the enzymatic activity of JNK1.
[0031] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00027##
wherein: X--Y--Z is selected from one of the following:
##STR00028##
R.sup.1 is H, CONH.sub.2, T.sub.(n)-R, or T.sub.(n)-Ar.sup.2; R is
an aliphatic or substituted aliphatic group; n is zero or one; T is
C(.dbd.O), CO.sub.2, CONH, S(O).sub.2, S(O).sub.2NH, COCH.sub.2 or
CH.sub.2; each R.sup.2 is independently selected from hydrogen,
--R, --CH.sub.2OR, --CH.sub.2OH, --CH.dbd.O, --CH.sub.2SR,
--CH.sub.2S(O).sub.2 R, --CH.sub.2(C.dbd.O)R,
--CH.sub.2CH.sub.2CO.sub.2R, --CH.sub.2CO.sub.2H, --CH.sub.2CN,
--CH.sub.2NHR, --CH.sub.2N(R).sub.2, --H.dbd.N--OR, --CH.dbd.NNHR,
--CH.dbd.NN(R).sub.2, --CH.dbd.NNHCOR, --CH.dbd.NNHCO.sub.2R,
--CH.dbd.NNHSO.sub.2R, -aryl, -substituted aryl, --CH.sub.2(aryl),
--CH.sub.2(substituted aryl), --CH.sub.2 NHz, --CH.sub.2NHCOR,
--CH.sub.2NHCONHR, --CH.sub.2NHCON(R).sub.2, --CH.sub.2NRCOR,
--CH.sub.2NHCO.sub.2R, --CH.sub.2CONHR, --CH.sub.2CON(R).sub.2,
--CH.sub.2SO.sub.2NH.sub.2, --CH.sub.2 (heterocyclyl), --CH.sub.2
(substituted heterocyclyl), --(heterocyclyl), or --(substituted
heterocyclyl); each R.sup.3 is independently selected from
hydrogen, R, COR, CO.sup.2R or S(O).sup.2R; C is R or Ar.sup.1;
Ar.sup.1 is aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heterocyclyl, or substituted heterocyclyl, wherein
Ar.sup.1 is optionally fused to a partially unsaturated or fully
unsaturated five to seven membered ring containing zero to three
heteroatoms; Q-NH is
##STR00029##
wherein the H of Q-NH is optionally replaced by R.sup.3; Ar.sup.2
is aryl, substituted aryl, heterocyclyl or substituted
heterocyclyl, wherein Ar.sup.2 is optionally fused to a partially
unsaturated or fully unsaturated five to seven membered ring
containing zero to three heteroatoms; wherein each substitutable
carbon atom in Ar.sup.2, including the fused ring when present, is
optionally and independently substituted by halo, R, OR, SR, OH,
NO.sub.2, CN, NH.sub.2, NHR, N(R).sub.2, NHCOR, NHCONHR,
NHCON(R).sub.2, NRCOR, NHCO.sub.2R, CO.sub.2R, CO.sub.2H, COR,
CONHR, CON(R).sub.2, S(O)R, SONH.sub.2, S(O)R, SO.sub.2NHR, or
NHS(O).sub.2R, and wherein each saturated carbon in the fused ring
is further optionally and independently substituted by .dbd.O,
.dbd.S, .dbd.NNHR, .dbd.NNR.sub.2, .dbd.N--OR, .dbd.NNHCOR,
.dbd.NNHCO.sub.2R, .dbd.NNHSO.sub.2R, or .dbd.NR; and wherein each
substitutable nitrogen atom in Ar.sup.2 is optionally substituted
by R, COR, S(O).sub.2R, or CO.sub.2R; that inhibits the activity of
JNK2 in the subject. In further embodiments, the compound has a
minimal effect on the enzymatic activity of JNK1.
[0032] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00030##
wherein: A and B are each independently selected from N or CH;
R.sup.1 and R.sup.2 are each independently selected from halogen,
CN, NO.sub.2, N(R).sub.2, OR, SR, or (T).sub.n-R.sup.5; R.sup.3 is
selected from a 3-6 membered carbocyclic or heterocyclic ring
having one to two heteroatoms independently selected from nitrogen,
oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having
one to three heteroatoms independently selected from nitrogen,
oxygen, or sulfur, wherein said phenyl or heteroaryl ring is
optionally substituted with one (T).sub.n-Ar and one to two
R.sup.7; each n is independently selected from zero or one; T is a
C.sub.1-C.sub.6 alkylidene chain, wherein one methylene unit of T
is optionally replaced by CO, CO.sub.2, COCO, CONR, OCONR, NRNR,
NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO.sub.2, NRSO.sub.2, SO.sub.2NR,
NRSO.sub.2NR, O, S, or NR; each R is independently selected from
hydrogen or an optionally substituted C.sub.1-C.sub.6 aliphatic
group; or two R on the same nitrogen atom may be taken together
with the nitrogen to form a four to eight membered, saturated or
unsaturated heterocyclic ring containing one to three heteroatoms
independently selected from nitrogen, oxygen, or sulfur; R.sup.4 is
(T).sub.n-R, (T).sub.n-Ar, or (T).sub.n-Ar.sup.1; R.sup.a is
selected from R.sup.b, halogen, NO.sub.2, OR.sup.b, SR.sup.b, or
N(R.sup.b).sub.2; R.sup.b is selected from hydrogen or a
C.sub.1-C.sub.4 aliphatic group optionally substituted with oxo,
OH, SH, NH.sub.2, halogen, NO.sub.2, or CN; R.sup.5 is an
optionally substituted C.sub.1-C.sub.6 aliphatic or Ar; Ar is a 5-6
membered saturated, partially unsaturated, or aryl monocyclic ring
having zero to three heteroatoms independently selected from
nitrogen, sulfur, or oxygen, or an 8-10-membered saturated,
partially unsaturated, or aryl bicyclic ring having zero to four
heteroatoms independently selected from nitrogen, sulfur, or
oxygen, wherein Ar is optionally substituted with one to three
R.sup.7; Ar.sup.1 is a 6-membered aryl ring having zero to two
nitrogens, wherein said ring is substituted with one Z--R.sup.6
group and optionally substituted with one to three R.sup.7; Z is a
C.sub.1-C.sub.6 alkylidene chain wherein up to two nonadjacent
methylene units of Z are optionally replaced by CO, CO.sub.2, COCO,
CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO, SO.sub.2,
NRSO.sub.2, SO.sub.2NR, NRSO.sub.2NR, O, S, or NR; provided that
said optionally replaced methylene unit of Z is a methylene unit
non-adjacent to R.sup.6; R.sup.6 is selected from Ar, R, halogen,
NO.sub.2, CN, OR, SR, N(R).sub.2, NRC(O)R, NRC(O)N(R).sub.2,
NRCO.sub.2R, C(O)R, CO.sub.2R, OC(O)R, C(O)N(R).sub.2,
OC(O)N(R).sub.2, SOR, SO.sub.2R, SO.sub.2N(R).sub.2, NRSO.sub.2R,
NRSO.sub.2N(R).sub.2, C(O)C(O)R, or C(O)CH.sub.2C(O)R; and each
R.sup.7 is independently selected from R, halogen, NO.sub.2, CN,
OR, SR, N(R).sub.2, NRC(O)R, NRC(O)N(R).sub.2, NRCO.sub.2R, C(O)R,
CO.sub.2R, C(O)N(R).sub.2, OC(O)N(R).sub.2, SOR, SO.sub.2R,
SO.sub.2N(R).sub.2, NRSO.sub.2R, NRSO.sub.2N(R).sub.2, C(O)C(O)R,
or C(O)CH.sub.2C(O)R; or two R.sup.7 on adjacent positions of
Ar.sup.1 may be taken together to form a saturated, partially
unsaturated, or fully unsaturated five to seven membered ring
containing zero to three heteroatoms selected from O, S, or N; that
inhibits the activity of JNK2 in the subject. In further
embodiments, the compound has a minimal effect on the enzymatic
activity of JNK1.
[0033] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00031##
wherein: each W is independently selected from nitrogen or CH; each
R.sup.1, R.sup.2, and R.sup.3 is independently selected from
halogen, QR, Q.sub.(n)CN, Q.sub.(n)NO.sub.2, or Q.sub.(n)Ar;
wherein: R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 are optionally
taken together to form a 4-8 membered saturated, partially
unsaturated, or fully unsaturated ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; n is zero
or one; Q is a C.sub.1-4 alkylidene chain wherein one methylene
unit of Q is optionally replaced by O, S, NR, NRCO, NRCONR,
NRCO.sub.2, CO, CO.sub.2, CONR, OC(O)NR, SO.sub.2, SO.sub.2NR,
NRSO.sub.2, NRSO.sub.2NR, C(O)C(O), or C(O)CH.sub.2C(O); each R is
independently selected from hydrogen or an optionally substituted
C.sub.1-C.sub.4 aliphatic, wherein: two R bound to the same
nitrogen atom are optionally taken together with the nitrogen atom
to form a 3-7 membered saturated, partially unsaturated, or fully
unsaturated ring having 1-2 additional heteroatoms independently
selected from nitrogen, oxygen, or sulfur; R.sup.4 is Ar.sup.1,
T-Ar.sup.2, or T.sub.(n)-Ar.sup.3; T is a C.sub.1-2 alkylidene
chain wherein one methylene unit of T is optionally replaced by O,
NR, NRCO, NRCONR, NRCO.sub.2, CO, CO2, CONR, OC(O)NR, SO.sub.2,
SO.sub.2NR, NRSO.sub.2, NRSO.sub.2NR, C(O)C(O), or
C(O)CH.sub.2C(O); Ar.sup.1 is a 5-6 membered monocyclic or 8-10
membered bicyclic saturated, partially unsaturated, or fully
unsaturated ring system; wherein: Ar1 is optionally substituted
with up to five substituents, wherein the first substituent is
selected from R.sup.x or R.sup.5 and wherein any additional
substituents are independently selected from R.sup.5; each R.sup.x
is independently selected from a 5-6 membered aryl ring having 0-3
heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
R.sup.x is optionally substituted with 1-3 R.sup.5; each R.sup.5 is
independently selected from R, halogen, NO.sub.2, CN, OR, SR,
N(R).sub.2, NRC(O)R, NRC(O)N(R).sub.2, NRCO.sub.2R, C(O)R,
CO.sub.2R, C(O)N(R).sub.2, OC(O)N(R).sub.2, SOR, SO.sub.2R,
SO.sub.2N(R).sub.2, NRSO.sub.2R, NRSO.sub.2N(R).sub.2, C(O)C(O)R,
or C(O)CH.sub.2C(O)R; Ar.sup.2 is a 5-6 membered saturated,
partially unsaturated, or fully unsaturated monocyclic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an 8-10 membered saturated, partially unsaturated, or
fully unsaturated bicyclic ring system having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; wherein:
Ar.sup.2 is optionally substituted with up to five substituents,
wherein the first substituent is selected from R.sup.x or R.sup.5
and wherein any additional substituents are independently selected
from R.sup.5; Ar.sup.3 is a 6-membered aryl ring having 0-2
nitrogens, wherein: Ar.sup.3 is substituted with one Z--R group and
optionally substituted with 1-3 R.sup.5; Z is a C.sub.1-C.sub.6
alkylidene chain wherein up to two non adjacent methylene units of
Z are optionally replaced by CO, CO.sub.2, COCO, CONR, OCONR, NRNR,
NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO, SO.sub.2, NRSO.sub.2,
SO.sub.2NR, NRSO.sub.2NR, O, S, or NR; and R.sup.6 is selected from
Ar.sup.2, R, halogen, NO.sub.2, CN, OR, SR, N(R).sub.2, NRC(O)R,
NRC(O)N(R).sub.2, NRCO.sub.2R, C(O)R, CO.sub.2R, OC(O)R,
C(O)N(R).sub.2, OC(O)N(R).sub.2, SOR, SO.sub.2R,
SO.sub.2N(R).sub.2, NRSO.sub.2R, NRSO.sub.2N(R).sub.2, C(O)C(O)R,
or C(O)CH.sub.2C(O)R; that inhibits the activity of JNK2 in the
subject. In further embodiments, the compound has a minimal effect
on the enzymatic activity of JNK1.
[0034] In another embodiment, the invention is a method of treating
type I diabetes in a subject, comprising administering a compound
of the following formula:
##STR00032##
wherein R.sup.1 is --F, --Cl, --Br, --OH, --SH, --NH.sub.2, or
--CH.sub.3; R.sup.2 is --F, --Cl, --Br --OH, --SH, --NH.sub.2, or
--CH.sub.3; R.sup.3 is --H, --F, --Cl, --Br, --OH, --SH,
--NH.sub.2, --CH.sub.3, --OCH.sub.3, or --CH.sub.2CH.sub.3; R.sup.4
is --C.sub.1-4 alkyl optionally substituted with a --C.sub.3-7
cycloalkyl; R.sup.5 is --C.sub.1-4 alkyl or --C.sub.3-7 cycloalkyl,
wherein the --C.sub.1-4 alkyl is optionally substituted with a
phenyl; X is a bond or an alkyl bridge having 1-3 carbons; Y is
--NH-- or --NH.sub.2+--; and HETCy is a 4 to 10 membered
non-aromatic heterocycle containing at least one N atom, optionally
containing 1-2 additional N atoms and 0-10 or S atom, and
optionally substituted with --C.sub.1-4 alkyl or
--C(O)--O--CH.sub.2-phenyl; that inhibits the activity of JNK2 in
the subject. In further embodiments, the compound has a minimal
effect on the enzymatic activity of JNK1.
DESCRIPTION OF THE FIGURES
[0035] FIG. 1. Spontaneous diabetes is decreased in JNK2-deficient
mice. The presence of hyperglycemia (blood glucose>200 mg/dl)
was examined in a cohort of 32 NOD mice and 28 female NOD/Mapk9-/-
mice. The data are presented as the % of mice with
hyperglycemia.
[0036] FIG. 2A. JNK2-defiency causes reduced insulitis in NOD mice.
Representative islets from 13-week-old mice stained with
hematoxylin and eosin are shown.
[0037] FIG. 2B. The extent of insulitis was quantitated (6 mice per
genotype; 10 to 20 islets per mouse). The percentage of islets with
normal morphology and with inflammatory infiltration that was
restricted to the periphery of the islet (peri-insulitis) or
throughout the islet (insulitis) is shown. 0=normal islet,
1=peri-insulitis, 2=insulitis.
[0038] FIG. 3A. JNK2-deficiency causes reduced diabetes in adoptive
transfer studies. Splenocytes isolated from pre-diabetic 13 week
old NOD or NOD/Mapk9-/- mice were adoptively transferred to
immune-deficient NOD/Scid mice. The incidence of diabetes was
monitored post-transplantation.
[0039] FIG. 3B. Splenocytes isolated from diabetic NOD mice were
adoptively transferred irradiated NOD or NOD/Mapk9-/- male mice.
The incidence of diabetes was monitored post-transplantation.
[0040] FIG. 4A. T cell defects in JNK2-deficient NOD mice.
Pancreatic sections of NOD and NOD/Mapk9-/- mice were stained with
either anti-CD4 or anti-CD8 antibodies (green) and counterstained
with DAPI (blue). Stained sections of representative infiltrated
islets are illustrated.
[0041] FIG. 4B. CD4+ T cells isolated from 8-week-old female mice
were differentiated in the absence (Th0) or the presence of
exogenously added polarizing cytokine to Th1 (IL-12) or Th2 (IL-4)
effector cells for 4 days. The cells were washed prior to
re-stimulation with an immobilized antibody to CD3 for 24 h.
Cytokine secretion into the culture supernatant was measured by
ELISA. The data presented are the mean.+-.SD of triplicate
determinations.
[0042] FIG. 4C. Cytokine amounts in the medium of Th0 cultures
after differentiation for 4 days and prior to washing and
re-stimulation. The data presented are the mean.+-.SD of triplicate
determinations.
DEFINITIONS
[0043] "Acylamino" or "aminoacyl" refers to a group --NR(CO)R'
where each R, R' is independently hydrogen or
"C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl".
[0044] "Acyloxy" means an --OC(O)alkyl group.
[0045] "Adverse drug reaction" means any response to a drug that is
noxious and unintended and occurs in doses for prophylaxis,
diagnosis, or therapy including side effects, toxicity,
hypersensitivity, drug interactions, complications, or other
idiosyncrasy. Side effects are often adverse symptom produced by a
therapeutic serum level of drug produced by its pharmacological
effect on unintended organ systems (e.g., blurred vision from
anticholinergic antihistamine). A toxic side effect is an adverse
symptom or other effect produced by an excessive or prolonged
chemical exposure to a drug (e.g., digitalis toxicity, liver
toxicity). Hypersensitivities are immune-mediated adverse reactions
(e.g., anaphylaxis, allergy). Drug interactions are adverse effects
arising from interactions with other drugs, foods or disease states
(e.g., warfarin and erythromycin, cisapride and grapefruit,
loperamide and Clostridium difficile colitis). Complications are
diseases caused by a drug (e.g., NSAID-induced gastric ulcer,
estrogen-induced thrombosis). The adverse drug reaction may be
mediated by known or unknown mechanisms (e.g., Agranulocytosis
associated with chloramphenicol or clozapine). Such adverse drug
reaction can be determined by an subject observation, assay or
animal model well-known in the art.
[0046] "Alkyl" means a straight chain or branched, saturated or
unsaturated alkyl, cyclic or non-cyclic hydrocarbon having from 1
to 10 carbon atoms. Representative saturated straight chain alkyls
include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and
the like; while saturated branched alkyls include isopropyl,
sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
Unsaturated alkyls contain at least one double or triple bond
between adjacent carbon atoms (also referred to as an "alkenyl" or
"alkynyl", respectively). Representative straight chain and
branched alkenyls include ethylenyl, propylenyl, 1-butenyl,
2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl,
3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butynyl and
the like; while representative straight chain and branched alkynyls
include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,
2-pentynyl, 3-methyl-1-butynyl, and the like. Representative
saturated cyclic alkyls include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic
alkyls include cyclopentenyl and cyclohexenyl, and the like.
Cycloalkyls are also referred to herein as "carbocyclic" rings
systems, and include bi- and tri-cyclic ring systems having from 8
to 14 carbon atoms such as a cycloalkyl (such as cyclopentane or
cyclohexane) fused to one or more aromatic (such as phenyl) or
non-aromatic (such as cyclohexane) carbocyclic rings.
[0047] "Alkylamino" means --NH(alkyl).
[0048] An "alkenyl group" or "alkylene group" means a monovalent
unbranched or branched hydrocarbon chain having one or more double
bonds therein. The double bond of an alkenyl group can be
unconjugated or conjugated to another unsaturated group. Suitable
alkenyl groups include, but are not limited to, (C.sub.2-C.sub.6)
alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl,
butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,
2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl
group can be unsubstituted or substituted.
[0049] "Alkylidene" means the divalent radical --C.sub.nH.sub.2n--,
wherein n is an integer from 1 to 8, such as --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the like, unsubstituted
or substituted with one or more alkyl groups.
[0050] "Alkoxy" refers to a group --O--R where R includes
"C.sub.1-C.sub.6-alyl" or "aryl" or "hetero-aryl" or "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl".
Preferred alkoxy groups include by way of example, methoxy, ethoxy,
phenoxy and the like.
[0051] "Alkoxycarbonyl" refers to a group --C(O)OR where R includes
H, "C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl".
[0052] "Alkynyl" refers to alkynyl groups preferably having from 2
to 6 carbon atoms and having at least 1-2 sites of alkynyl
unsaturation. Examples include ethynyl (--C.ident.CH), propargyl
(--CH.sub.2C.ident.CH), and the like.
[0053] "Aminoalkyl" means -(alkyl)-NH.sub.2.
[0054] "Aminoalkoxy" means --O-(alkyl)-NH.sub.2.
[0055] "Aminocarbonyl" and the like refers to a group --C(O)NRR'
where each R, R' is independently hydrogen or
"C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl".
[0056] "Aryl" means a carbocyclic or heterocyclic aromatic group
containing from 5 to 10 ring atoms. The ring atoms of a carbocyclic
aromatic group are all carbon atoms, and include, but are not
limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl,
azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties
such as 5,6,7,8-tetrahydronaphthyl. A carbocyclic aromatic group
can be unsubstituted or substituted. Preferably, the carbocyclic
aromatic group is a phenyl group. The ring atoms of a heterocyclic
aromatic group contains at least one heteroatom, preferably 1 to 3
heteroatoms, independently selected from nitrogen, oxygen, and
sulfur. Illustrative examples of heterocyclic aromatic groups
include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl,
pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and
(1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, indolyl,
oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl
and oxazolyl. A heterocyclic aromatic group can be unsubstituted or
substituted. Preferably, a heterocyclic aromatic is a monocyclic
ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3
heteroatoms.
[0057] "Arylamino" means --NH(aryl).
[0058] "Arylalkylamino" means --NH-(alkyl)-(aryl), wherein alkyl
and aryl are defined above. Preferably, arylalkylamino is
--NH-benzyl or --NHCH.sub.2-pyridinyl.
[0059] "Aryloxy" means --O-aryl group, wherein aryl is as defined
above. An aryloxy group can be unsubstituted or substituted.
Preferably, the aryl ring of an aryloxy group is a phenyl group
"Aryl C.sub.1-C.sub.6-alkyl" or "Arylalkyl" and the like, refers to
C.sub.1-C.sub.6-alkyl groups, as defined above, having an aryl
substituent, including benzyl, phenethyl and the like.
[0060] "C.sub.1-C.sub.6-alkyl" or "C.sub.1-6-alkyl" and the like
refer to monovalent branched or unbranched alkyl groups having 1 to
6 carbon atoms. This term is exemplified by groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl
and the like.
[0061] "C.sub.2-C.sub.6 Alkenyl" refers to alkenyl groups
preferably having from 2 to 6 carbon atoms and having at least 1 or
2 sites of alkenyl unsaturation. Examples include ethenyl
(--CH.dbd.CH.sub.2), n-2-propenyl (allyl,
--CH.sub.2CH.dbd.CH.sub.2) and the like.
[0062] "C.sub.3-C.sub.6-cycloalkyl" refers to saturated or
partially unsaturated carbocyclic rings having 3 to 6 carbon atoms.
Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexenyl and the like.
[0063] "C.sub.3-C.sub.6-heterocycloalkyl" refers to saturated or
partially unsaturated rings having 3 to 6 atoms and containing at
least one heteroatom selected from N, S and O. Examples include
pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl
and the like.
[0064] "Carboxyl" means (--CO.sub.2H).
[0065] "Carbocyclyl" means a saturated, partly saturated or
unsaturated 3-12 membered hydrocarbon ring, preferably a 6-12
membered hydrocarbon ring, including cycloalkyl and aryl.
[0066] "Cycloalkylamino" means --NH-(cycloalkyl).
[0067] "Cycloalkylalkylamino" means --NH-(alkyl)-(cycloalkyl),
wherein alkyl and cycloalkyl are defined above. Preferably,
cycloalkylalkylamino is --NHCH.sub.2-cyclohexyl.
[0068] "Cycloalkyl" means a monocyclic or polycyclic saturated ring
comprising carbon and hydrogen atoms and having no carbon-carbon
multiple bonds. Examples of cycloalkyl groups include, but are not
limited to, (C.sub.3-C.sub.7) cycloalkyl groups, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl,
and saturated cyclic and bicyclic terpenes. A cycloalkyl group can
be unsubstituted or substituted. Preferably, the cycloalkyl group
is a monocyclic ring or bicyclic ring.
[0069] "Di-alkylamino" means --N(alkyl)(alkyl), wherein each
"alkyl" is independently an alkyl group "Di-alkylaminoalkyl" means
-(alkyl)-N(alkyl)(alkyl), wherein each "alkyl" is independently an
alkyl group.
[0070] "Di-alkylaminoalkoxy" means --O-(alkyl)N(alkyl)(alkyl),
wherein each "alkyl" is independently an alkyl group "Enantiomeric
excess" (ee) refers to the products that are obtained by a
synthesis comprising an enantioselective step, whereby a surplus of
one enantiomer in the order of at least about 52% ee is
yielded.
[0071] As used herein the phrase "an effective amount" when used in
connection with a JNK2 inhibitor means an amount of the JNK2
inhibitor, that produces a measurable change of invasive,
destructive, or peri-insulitis by a histological analysis of the
pancreas.
[0072] "Expression" means the translation or transcription in
expressing a gene.
[0073] "Halogen" refers to fluoro, chloro, bromo and iodo
atoms.
[0074] "Heteroaryl" refers to a monocyclic heteroaromatic, or a
bicyclic or a tricyclic fused-ring heteroaromatic group. Particular
examples of heteroaromatic groups include optionally substituted
pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl,
1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,
isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl,
indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,
imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,
quinazolinyl, quinoxalinyl, cinnolinyl, pyrido[3,4-b]pyridyl,
pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,
tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl or benzoquinolyl.
[0075] "Heteroaryl C.sub.1-C.sub.6-alkyl" and the like refers to
C.sub.1-C.sub.6-alkyl groups having a heteroaryl substituent,
including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl
and the like.
[0076] "Heteroatom-containing alkylidene" means an alkylidene
wherein at least one carbon atom is replaced by a heteroatom
selected from nitrogen, oxygen, or sulfur, such as
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, and the like, unsubstituted
or substituted with one or more alkyl groups.
[0077] "Heterocycle" means a 5- to 7-membered monocyclic, or 7- to
10-membered bicyclic, heterocyclic ring which is either saturated,
unsaturated, or aromatic, and which contains from 1 to 4
heteroatoms independently selected from nitrogen, oxygen and
sulfur, and wherein the nitrogen and sulfur heteroatoms may be
optionally oxidized, and the nitrogen heteroatom may be optionally
quaternized, including bicyclic rings in which any of the above
heterocycles are fused to a benzene ring. The heterocycle may be
attached via any heteroatom or carbon atom. Heterocycles include
heteroaryls as defined above. Thus, in addition to the heteroaryls
listed above, heterocycles also include morpholinyl,
pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl,
valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
[0078] "Heterocycloalkyl" means an alkyl having at least one alkyl
hydrogen atom replaced with a heterocycle, such as --CH.sub.2
morpholinyl, and the like.
[0079] "Keto" means a carbonyl group.
[0080] "Inhibiting the activity of JNK2" means interacting with a
JNK2 protein or natural substrate (e.g. c-jun and JIP-1) to prevent
an ordinary biological process (e.g., c-jun phosphorylation) in
vitro or in vivo. However, completely preventing the biological
process from occurring is not necessary.
[0081] The term "JNK2 inhibitor" and the like mean a compound
capable of inhibiting the activity of JNK2 in vitro or in vivo.
However, complete inhibition is not required. For example, it is
sufficient that the inhibitor has an IC.sub.50 of less than 10 mM
in a c-jun phosphorylation assay. The JNK2 inhibitor can be in the
form of a pharmaceutically acceptable salt, free-base, solvate,
hydrate, stereoisomer, clathrate or prodrug thereof. Such
inhibitory activity can be determined by an assay or animal model
well known in the art including those set forth in the "detailed
description of the invention."
[0082] "JNK2" means a protein or an isoform thereof expressed by a
JNK2 gene.
[0083] As used herein, the term "manage" when used in connection
with a disease or condition means to provide beneficial effects to
a patient being administered with a prophylactic or therapeutic
agent, which does not result in a cure of the disease. In certain
embodiments, a patient is administered with one or more
prophylactic or therapeutic agents to manage a disease so as to
prevent the progression or worsening of the disease.
[0084] "Minimal effect" on activity of a protein means a compound
has less than half of the same effect on activity compared to
another protein. For example, if a compound has an IC.sub.50 of 1
.mu.M for JNK2 using c-Jun phosphorylation assay as described
below, then the compound has minimal effect on the inhibition of
JNK1 as long as the IC.sub.50 for JNK1 in the same assay is greater
than 2 .mu.M. Such minimal effect can be determined by an assay or
animal model well known in the art including those set forth in the
"detailed description of the invention."
[0085] "Mono-alkylamino" means --NH(alkyl).
[0086] "Mono-alkylaminoalkoxy" means --O-(alkyl)-NH(alkyl), wherein
each "alkyl" is independently an alkyl group.
[0087] "Mono-alkylaminoalkyl" means -(alkyl)-NH(alkyl), wherein
each "alkyl" is independently an alkyl group.
[0088] As used herein and unless otherwise indicated, the term
"prodrug" means a JNK2 inhibitor derivative that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide an active compound, particularly a JNK2
inhibitor. Examples of prodrugs include, but are not limited to,
derivatives and metabolites of a JNK2 inhibitor that include
biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues. Preferably, prodrugs of compounds with carboxyl
functional groups are the lower alkyl esters of the carboxylic
acid. The carboxylate esters are conveniently formed by esterifying
any of the carboxylic acid moieties present on the molecule.
[0089] "Pharmaceutically active derivative" refers to any compound
that upon administration to the recipient, is capable of providing
directly or indirectly, the activity disclosed herein.
[0090] "Pharmaceutically acceptable salts or "complexes" refers to
salts or complexes of the below-identified compounds of formula I
that retain the desired biological activity. Examples of such salts
include, but are not restricted to acid addition salts formed with
inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric acid, nitric acid, and the like), and salts formed
with organic acids such as acetic acid, oxalic acid, tartaric acid,
succinic acid, malic acid, fumaric acid, maleic acid, ascorbic
acid, benzoic acid, tannic acid, pamoic acid, alginic acid, poly
glutamic, acid, naphthalene sulfonic acid, naphthalene disulfonic
acid, and poly galacturonic acid. Said compounds can also be
administered as pharmaceutically acceptable quaternary salts known
by a person skilled in the art, which specifically include the
quaternary ammonium salts of the formula --NR,R',R''.sup.+Z.sup.-,
wherein R, R', R'' is independently hydrogen, alkyl, or benzyl, and
Z is a counter ion, including chloride, bromide, iodide, alkoxide,
toluenesulfonate, methylsulfonate, sulfonate, phosphate, or
carboxylate (such as benzoate, succinate, acetate, glycolate,
maleate, malate, fumarate, citrate, tartrate, ascorbate,
cinnamoate, mandeloate, and diphenylacetate).
[0091] As used herein, the terms "prevent" and "preventing" include
the prevention of the recurrence, spread or onset of type I
diabetes. It is not intended that the present invention be limited
to complete prevention. In some embodiments, the onset is delayed,
or the severity of the disease is reduced.
[0092] As used herein, the term "prophylactic agent" includes any
agent that can be used in the prevention of a disease.
[0093] "Sulfonyl" refers to a group "--SO.sub.2--R" wherein R is
selected from H, "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl",
"C.sub.1-C.sub.6-alkyl" which may be substituted with halogens e.g.
an --SO.sub.2--CF.sub.3 group, "aryl C.sub.1-C.sub.6-alkyl" or
"heteroaryl C.sub.1-C.sub.6-alkyl".
[0094] "Sulfoxy" refers to a group "--S(O)--R" wherein R is
selected from H, "C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl"
which may be substituted with halogens e.g. an --SO--CF.sub.3
group, "aryl", "heteroaryl", "aryl C.sub.1-C.sub.6-alkyl" or
"heteroaryl C.sub.1-C.sub.6-alkyl".
[0095] "Substituted or unsubstituted" unless otherwise constrained
by the definition of the individual substituent, the above set out
groups, like "alkyl", "Alkenyl", "alkynyl", "aryl" and "heteroaryl"
etc. groups can optionally be substituted with from 1 to 5
substituents selected from the group consisting of
"C.sub.1-C.sub.6-alkyl", "aryl C.sub.1-C.sub.6-alkyl", "heteroaryl
C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkenyl",
"C.sub.1-C.sub.6-alkynyl", primary, secondary or tertiary amino
groups or quaternary ammonium moieties, "acyl", "acyloxy",
"acylamino", "aminocarbonyl", "alkoxycarbonyl", "aryl",
"heteroaryl", carboxyl, cyano, halogen, hydroxy, mercapto, nitro,
sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like.
Alternatively said substitution could also comprise situations
where neighboring substituents have undergone ring closure, notably
when viccinal functional substituents are involved, thus forming
e.g. lactams, lactons, cyclic anhydrides, but also acetals,
thioacetals, aminals formed by ring closure for instance in an
effort to obtain a protective group.
[0096] "Substituent(s)" of the "hydrocarbon group optionally having
substituent(s)", or the like, means to have, oxo (.dbd.O), halogen
atom (e.g., fluorine, chlorine, bromine, iodine etc.),
C.sub.1-C.sub.3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy
etc.), nitro, cyano, optionally halogenated C.sub.1-C.sub.6 alkyl,
optionally halogenated C.sub.2-C.sub.6 alkenyl, carboxy
C.sub.2-C.sub.6 alkenyl (e.g., 2-carboxyethenyl,
2-carboxy-2-methylethenyl etc.), optionally halogenated
C.sub.2-C.sub.6 alkynyl, optionally halogenated C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.14 aryl (e.g., phenyl, 1-naphthyl,
2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl
etc.), optionally halogenated C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.6 alkoxy-carbonyl-C.sub.1-C.sub.6 alkoxy (e.g.,
ethoxycarbonylmethyloxy etc.), hydroxy, C.sub.6-C.sub.14 aryloxy
(e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy etc.),
C.sub.7-C.sub.16 aralkyloxy (e.g., benzyloxy, phenethyloxy etc.),
mercapto, optionally halogenated C.sub.1-C.sub.6 alkylthio,
C.sub.6-C.sub.14 arylthio (e.g., phenylthio, 1-naphthylthio,
2-naphthylthio etc.), C.sub.7-C.sub.16 aralkylthio (e.g.,
benzylthio, phenethylthio etc.), amino, mono-C.sub.1-C.sub.6
alkylamino (e.g., methylamino, ethylamino etc.),
mono-C.sub.6-C.sub.14 arylamino (e.g., phenylamino,
1-naphthylamino, 2-naphthylamino etc.), di-C.sub.1-C.sub.6
alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino
etc.), C.sub.3-C.sub.8 cycloalkylamino (e.g., cyclopentylamino,
cyclohexylamino etc.), di-C.sub.6-C.sub.14 arylamino (e.g.,
diphenylamino etc.), formyl, carboxy, carboxy-C.sub.1-C.sub.6 alkyl
(e.g., carboxymethyl, carboxyethyl etc.), C.sub.1-C.sub.6
alkyl-carbonyl (e.g., acetyl, propionyl, pivaloyl etc.),
C.sub.3-C.sub.8 cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl etc.), C.sub.1-C.sub.6
alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, tert-butoxycarbonyl etc.), C.sub.6-C.sub.14
aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.),
C.sub.7-C.sub.16 aralkyl-carbonyl (e.g., phenylacetyl,
3-phenylpropionyl etc.), C.sub.6-C.sub.14 aryloxy-carbonyl (e.g.,
phenoxycarbonyl etc.), C.sub.7-C.sub.16 aralkyloxy-carbonyl (e.g.,
benzyloxycarbonyl, phenethyloxycarbonyl etc.), 5- or 6-membered
heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl,
furoyl, morpholinocarbonyl, thiomorpholinocarbonyl,
piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl etc.), carbamoyl,
thiocarbamoyl, mono-C.sub.1-C.sub.6 alkyl-carbamoyl (e.g.,
methylcarbamoyl, ethylcarbamoyl etc.), di-C.sub.1-C.sub.6
alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,
ethylmethylcarbamoyl etc.), mono- or di-C.sub.6-C.sub.14
aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,
2-naphthylcarbamoyl etc.), mono- or di-5- or 6-membered
heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl,
3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl,
3-thienylcarbamoyl etc.), C.sub.1-C.sub.6 alkylsulfonyl (e.g.,
methylsulfonyl, ethylsulfonyl etc.), C.sub.1-C.sub.6 alkylsulfinyl
(e.g., methylsulfinyl, ethylsulfinyl etc.), C.sub.6-C.sub.14
arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,
2-naphthylsulfonyl etc.), C.sub.6-C.sub.14 arylsulfinyl (e.g.,
phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl etc.),
formylamino, C.sub.1-C.sub.6 alkyl-carbonylamino (e.g.,
acetylamino, propionylamino, pivaloylamino etc.), C.sub.3-C.sub.8
cycloalkyl-carbonylamino (e.g., cyclopentylcarbonylamino-,
cyclohexylcarbonylamino etc.), C.sub.6-C.sub.14 aryl-carbonylamino
(e.g., benzoylamino, naphthoylamino etc.), C.sub.1-C.sub.6
alkoxy-carbonylamino (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino
etc.), C.sub.1-C.sub.6 alkylsulfonylamino (e.g.,
methylsulfonylamino, ethylsulfonylamino etc.), C.sub.6-C.sub.14
arylsulfonylamino (e.g., phenylsulfonylamino,
2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.),
C.sub.1-C.sub.6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy
etc.), C.sub.6-C.sub.14 aryl-carbonyloxy (e.g., benzoyloxy,
naphthylcarbonyloxy etc.), C.sub.1-C.sub.6 alkoxy-carbonyloxy
(e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy etc.), mono-C.sub.1-C.sub.6 alkylcarbamoyloxy
(e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),
di-C.sub.1-C.sub.6 alkylcarbamoyloxy (e.g., dimethylcarbamoyloxy,
diethylcarbamoyloxy etc.), mono- or di-C.sub.6-C.sub.14
aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy
etc.), nicotinoyloxy, isonicotinoyloxy, 5- to 7-membered saturated
cyclic amino optionally having substituents, 5- to 10-membered
aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,
5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), sulfo, sulfamoyl,
sulfinamoyl, sulfenamoyl, a group wherein 2 or more (e.g., 2-3) of
these substituents are bonded and the like can be mentioned.
[0097] "Selective inhibition" means that the inhibition of protein
activity of a compound on one molecular entity has a minimal effect
on a second molecular entity.
[0098] As used herein in connection with the term "therapeutic
agent", "therapeutically effective amount" includes the amount of
the therapeutic agent sufficient to delay, reduce or minimize
symptoms associated with type I diabetes. A therapeutically
effective amount also includes the amount of the therapeutic agent
that provides a therapeutic benefit in the treatment or management
of type I diabetes.
[0099] "Thioalkoxy" refers to groups --S--R where R includes
"C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl".
Examples include thiomethoxy, thioethoxy, and the like.
[0100] As used herein, the term "therapeutic agent" includes any
agent(s) that can be used in the treatment of a disease.
[0101] As used herein, the terms "treat" and "treating" are not
limited to the case where the subject (e.g. patient) is cured and
the disease is eradicated. Rather, the present invention also
contemplates treatment that merely reduces symptoms, and/or delays
disease progression. Thus, in certain embodiments, treatment aids
in the management or control of type I diabetes.
DETAILED DESCRIPTION OF THE INVENTION
[0102] The invention relates to the treatment and prevention of
type I diabetes. More specifically, the invention relates to
compounds that treat or prevent the body's immune system from
destroying .beta.-cells (i.e., insulin-producing cells in the
pancreatic islets of Langerhans) by inhibition of JNK2, selective
inhibition of JNK2, or inhibition of the expression of the MAPK9
gene or gene product. In one embodiment, the present invention
contemplates the diagnosis, identification, production, and use of
compounds which modulate MAPK9 gene expression or the activity of
the MAPK9 gene product including but not limited to, JNK2, the
nucleic acid encoding MAPK9 and homologues, analogues, and
deletions thereof, as well as antisense, ribozyme, triple helix,
antibody, and polypeptide molecules as well as small inorganic
molecules.
[0103] The present invention contemplates a variety of
pharmaceutical formulations and routes of administration for such
compounds. The pancreas is an organ located behind the lower part
of the stomach. It makes insulin and enzymes that help the body
digest and use food. Spread all over the pancreas are clusters of
cells called the islets of Langerhans. Islets are made up of two
types of cells: alpha cells, which make glucagon, a hormone that
raises the level of glucose (sugar) in the blood, and beta (.beta.)
cells, which make insulin. Failure of the insulin-producing beta
cells in the pancreatic islets of Langerhans is a characteristic of
type I (insulin-dependent) diabetes.
[0104] JNK1, JNK2, and JNK3 c-jun N-terminal protein kinase
isoforms comprise a family of serine/threonine protein kinases of
the mitogen-activating protein kinase (MAPK) group. As regulators
of stress-signaling responses, JNKs play key roles in: tumor
suppression, aging, neurogenesis, and immune responses. JNK2 (c-Jun
N-terminal knase 2) is also called Stress-activated protein kinase
2 (SAPK2). The JNK2 gene (MAPK9) maps on chromosome 5q35 spanning
58494 base pairs (Accession No. U09759). It contains 17 confirmed
introns, 14 of which are alternative. By alternative splicing, JNK2
gene encodes 12 types of transcripts that translate into 12
distinct JNK2 isoforms. The molecular weight of JNK2 is about 55
kD.
[0105] JNK1 is a protein comprising the amino acid sequence of
GenBank Accession Number: L26318: Sequence Identification Number 1:
(M S R S K R D N N F Y S V E I G D S T F T V L K R Y Q N L K P I G
S G A Q G I V C A A Y D A I L E R N V A I K K L S R P F Q N Q T H A
K R A Y R E L V L M K C V N H K N I I G L L N V F T P Q K S L E E F
Q D V Y I V M E L M D A N L C Q V I Q M E L D H E R M S Y L L Y Q M
L C G I K H L H S A G I I H R D L K P S N I V V K S D C T L K I L D
F G L A R T A G T S F M M T P Y V V T R Y Y R A P E V I L G M G Y K
E N V D L W S V G C I M G E M V C H K I L F P G R D Y I D Q W N K V
I E Q L G T P C P E F M K K L Q P T V R T Y V E N R P K Y A G Y S F
E K L F P D V L F P A D S E H N K L K A S Q A R D L L S K M L V I D
A S K R I S V D E A L Q H P Y I N V W Y D P S E A E A P P P K I P D
K Q L D E R E H T I E E W K E L I Y K E V M D L E E R T K N G V I R
G Q P S P L A Q V Q Q)
[0106] In one embodiment, JNK2 is a protein comprising the amino
acid sequence of GenBank Accession No. L3195: Sequence
Identification Number 2: (M S D S K C D S Q F Y S V Q V A D S T F T
V L K R Y Q Q L K P I G S G A Q G I V C A A F D T V L G I S V A V K
K L S R P F Q N Q T H A K R A Y R E L V L L K C V N H K N I I S L L
N V F T P Q K T L E E F Q D V Y L V M E L M D A N L C Q V I H M E L
D H E R M S Y L L Y Q M L C G I K H L H S A G I I H R D L K P S N I
V V K S D C T L K I L D F G L A R T A C T N F M M T P Y V V T R Y Y
R A P E V I L G M G Y K E N V D I W S V G C I M G E L V K G C V I F
Q G T D H I D Q W N K V I E Q L G T P S A E F M K K L Q P T V R N Y
V E N R P K Y P G I K F E E L F P D W I F P S E S E R D K I K T S Q
A R D L L S K M L V I D P D K R I S V D E A L R H P Y I T V W Y D P
A E A E A P P P Q I Y D A Q L E E R E H A I E E W K E L I Y K E V M
D W E E R S K N G V V K D Q P S D A A V S S N A T P S Q S S S I N D
I S S M S T E Q T L A S D T D S S L D A S T G P L E G C R).
[0107] Daxx is a Fas-binding protein that activates JNK and
apoptosis as described in U.S. Pat. No. 6,159,731, which is hereby
incorporated by reference.
JNK2 and Type I Diabetes
[0108] Mitogen-activated protein kinases (MAPKs) form a large
family of serine-threonine protein kinases conserved through
evolution. In mammalian cells, four distinct MAPK cascades have
been identified: extracellular signal-regulated kinases (ERKs),
c-Jun amino-terminal kinases (JNKs) or stress-activated protein
kinases (SAPKs), p38 MAP kinase (p38) or cytokine suppressive
anti-inflammatory drug binding protein, and Erk5/BMK. JNK protein
kinases are activated by dual phosphorylation on Tyr and Thr. The
JNK family includes JNK1 (46 kDa isoform), JNK2 (55-kDa isoform),
and JNK3. JNK1 and JNK2 are ubiquitously expressed, while JNK3 is
largely restricted to brain, heart and testis. Ip and Davis, Curr
Opin Cell Biol. 1998 April; 10(2):205-19; Sluss et al., Mol Cell
Biol. 1994 December; 14(12):8376-84. In addition to stress such as
UV exposure, the JNK family is activated by cytokines and
TNF-.alpha..
[0109] Recently, it has been suggested that JNK1, but not JNK2, is
implicated in obesity and insulin resistance associated with type
II diabetes. International publication PCT (WO 02/085396), Lee et
al., c-Jun N-terminal kinase (JNK) mediates feedback inhibition of
the insulin signaling cascade. J Biol Chem 278, 2896-902 (2003),
and Aguirre et al., The c-Jun NH(2)-terminal kinase promotes
insulin resistance during association with insulin receptor
substrate-1 and phosphorylation of Ser(307). J Biol Chem 275,
9047-54 (2000).
[0110] JNKs take part in the regulation of CD4+ T cell
differentiation. Recently studies suggest the cooperation of CD4+
and CD8+ T cells for islet infiltration and destruction of
.beta.-cells. The cytokine environment enables the differentiation
of CD4+ T cells to two different phenotypes: 1) Th1 cells which
produce interleukin-2 (IL-2) and interferon-.gamma. (IFN-.gamma.)
inducing a cellular immune response or 2) Th2 cells that secrete
IL-4, IL-5, and IL-10 which support humoral immunity and
down-regulate the inflammatory actions of Th1 cells. Benign
insulitis is associated with differentiation of CD+ T cells in a
phenotype of Th2 cells, whereas destructive insulitis appears to be
associated with Th1 cells. Pro-inflammatory cytokines produced by
islet infiltrating immune cells act as effector molecules, and
IL-1.beta. in combination with IFN-.gamma. and TNF-.alpha. triggers
apoptosis of the .beta.-cells.
[0111] The applicant has discovered that JNK2 plays role in type I
(insulin-dependent) diabetes that is caused by autoimmune
destruction of .beta.-cells. Studies of non-obese diabetic (NOD)
mice demonstrated that disruption of the MAPK9 gene (which encodes
the JNK2 protein kinase) decreased destructive insulitis and
reduced disease progression to type I diabetes. CD4+ T cells from
JNK2-deficient NOD mice produced less IFN-.gamma., and
significantly increased amounts of IL-4 and IL-5, indicating
polarization towards the Th2 phenotype. This role of JNK2 to
control the Th1/Th2 balance of the immune response motivated the
applicant to use JNK2 inhibitors to protect against type I
autoimmune diabetes.
[0112] The applicants discovered reduced insulitis and reduced
progression to type I diabetes in NOD/Mapk9-/- mice. The transition
from non-pathogenic insulitis to type I diabetes correlates with
the change from a predominance of Th2 to Th1 cytokines in the
islets. A Th1 (IFN-.gamma.) environment accelerates the recruitment
of islet-specific CD4+ T cells and also accelerates the onset of
type I diabetes. In contrast, a Th2 pancreatic environment appears
to protect against autoimmune diabetes. Thus, administration of
IL-4 systemically or expression of IL-4 in NOD mice in vivo
interferes with the islet infiltration by T cells and prevents
Th1-mediated destructive insulitis and type I diabetes. The
observation that JNK2-deficiency causes selective polarization of
CD4+ T cells to the Th2 phenotype with increased IL-4 expression
can lead to creation of a Th2 pancreatic environment that protects
against autoimmune diabetes. Thus, one embodiment of the current
invention is the treatment and prevention of type I diabetes by
administering to a subject an inhibitor of JNK2. In further
embodiments, the JNK2 inhibitor selectively inhibits JNK2.
[0113] Inappropriate activation of T cells initiates many
autoimmune diseases. Although, the applicant does not desire the
invention to be limited to any particular mechanism, JNK2
inhibitors may play several roles in preventing type I diabetes.
JNK2 inhibitors may play a suppressive role in autoimmune disease
by causing a negative selection of autoreactive T cells in the
thymus. In type I diabetes, JNK2 inhibitors may prevent beta-cell
apoptosis caused by cytokines and oxidative stress caused by
reactive oxygen species and nitric oxide. Furthermore, JNK2
inhibitors may prevent the production of macrophage-derived
cytokines, including TNF-.alpha., contributing to the development
of destructive insulitis and diabetes. It is possible that JNK2
inhibitors act in multiple ways as those mentioned or those not
mentioned.
JNK2 Inhibitors
[0114] The present invention is direct to methods useful for
treating or preventing type I diabetes in a subject, comprising
administering an effective amount of a JNK2 inhibitor or selective
JNK2 inhibitor. Illustrative JNK2 inhibitors and JNK2 selective
inhibitors are set forth below.
[0115] Antisense oligonucleotides of JNK2 have been described in
U.S. Pat. Nos. 6,221,850 and 6,133,246, which are hereby
incorporated by reference. Oligonucleotides that are specifically
hybridizable with nucleic acids encoding JNK2 are JNK2 inhibitors.
Embodiments include oligonucleotides comprising up to 30
nucleotides (typically between 15 and 25 nucleotides) in length
wherein said oligonucleotides have a sequence that specifically
binds to nucleic acids encoding JNK2 (e.g. human MAPK9 gene,
GenBank Accession number NC 000005 and any corresponding mRNA).
Further illustrative embodiments can be found in the corresponding
patents provided above. JNK-interacting protein-1 (JIP-1) was first
identified as a direct binding partner for JNK1 in yeast two-hybrid
analysis. The specificity of interactions was underlined by JIP-1
interacting with JNK1, JNK2, and JNK3, but not ERK or p38 MAPKs,
and failing to alter the activity of these two closely related
MAPKs. Furthermore, JNKs bound to JIP-1 with greater affinity than
its transcription factor substrates, c-Jun and activating
transcription factor-2 (ATF2). A number of amino acid sequences
based on the binding domain of JIP-1, JIP-2, and c-Jun have been
disclosed as JNK inhibitors including those disclosed in WO
03/103698, U.S. Pat. No. 6,780,970, and U.S. Patent Application
Publication 2002/0119135, all of which or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Examples of JNK2 inhibitor peptides include a peptide
which includes (in whole or in part) the sequence
NH.sub.2-DTYRPKRPTTLNLFPQVPRSQDT-COOH [SEQ ID NO:3]. In another
embodiment, the peptide includes the sequence
NH.sub.2-EEPHKHRPTTLRLTTLGAQDS-COOH [SEQ ID NO:4]. In another
embodiment, the peptide includes the sequence NH2-FLNLTTPRKPR-COOH
[SEQ ID NO:5]. In another embodiment the peptide includes the
sequence NH.sub.2-FLNLTTPRKPRYTDGSGTGPG-COOH [SEQ ID NO:6]. Further
illustrative embodiments can be found in the identified
references.
[0116] The JNK2 inhibitor peptides can be polymers of L-amino
acids, D-amino acids, or a combination of both. For example, in
various embodiments, the peptides are D retro-inverso peptides. The
term "retro-inverso isomer" refers to an isomer of a linear peptide
in which the direction of the sequence is reversed and the
chirality of each amino acid residue is inverted. The net result of
combining D-enantiomers and reverse synthesis is that the positions
of carbonyl and amino groups in each amide bond are exchanged,
while the position of the side-chain groups at each alpha carbon is
preserved. Unless specifically stated otherwise, it is presumed
that any given L-amino acid sequence of the invention may be made
into a D retro-inverso peptide by synthesizing a reverse of the
sequence for the corresponding native L-amino acid sequence.
[0117] The following sulfonamide derivatives are contemplated for
use as therapeutics in treating type I diabetes:
##STR00033##
wherein: Ar.sup.1 is a substituted or unsubstituted aryl or
heteroaryl group; X is O or S; Ar.sup.2 a substituted or
unsubstituted aryl or heteroaryl group; R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen and a
C.sub.1-C.sub.6-alkyl group; R.sup.a, R.sup.a', R.sup.b, R.sup.b'
are independently selected from the group consisting of hydrogen
and C.sub.1-C.sub.6-alkyl; or R.sup.a' and R.sup.a or R.sup.b'
together with the carbon atoms they are linked, form a substituted
or unsubstituted 5-8-membered saturated, partially unsaturated or
aromatic ring containing optionally one or more heteroatoms
selected from O, N, S; R.sup.3 is selected from the group
consisting of H, C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl
optionally containing 1-3 heteroatoms selected from the group
consisting of N, O, and S; aryl C.sub.1-C.sub.10-alkyl and
heteroaryl C.sub.1-C.sub.10-alkyl; or R.sup.3 and R.sup.a or
R.sup.a' form, together with the N atom linked to R.sup.3, a
5-8-membered saturated ring, containing optionally at least one
further heteroatom selected from O, N, S; R.sup.4 is selected from
the group consisting of H and --C(H)R.sup.5R.sup.6; R.sup.5 and
R.sup.6 are independently selected from the group consisting of H,
C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl
optionally containing 1-3 heteroatoms selected from the group
consisting of N, O, and S; aryl C.sub.1-C.sub.10-alkyl and
heteroaryl C.sub.1-C.sub.10-alkyl; m is an integer from 1 to 5; n
is an integer from 0 to 2; and p is an integer from 1 to 10. These
compounds have been described in United States Patent Application
Publication US 2004/0248886 as particular efficient and selective
inhibitors of JNK2, and this publication or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference.
[0118] Preferred embodiments include compounds of the following
formula:
##STR00034## ##STR00035##
Further illustrative embodiments can be found in the identified
reference.
[0119] The following sulfonamide derivatives are contemplated for
use as therapeutics in treating type I diabetes:
##STR00036##
wherein Ar.sup.1 and Ar.sup.2 are independently from each other
substituted or unsubstituted aryl or heteroaryl groups; X is O or
S, preferably O; R.sup.1 is hydrogen or a C.sub.1-C.sub.6 alkyl
group, or R.sup.1 forms a substituted or unsubstituted 5-6 membered
saturated or unsaturated ring with Ar.sup.1; n is an integer from 0
to 5, preferably between 1-3 and most preferred 1; Y is an
unsubstituted or a substituted 4-12 membered saturated cyclic or
bicyclic alkyl containing at least one nitrogen atom, whereby one
nitrogen atom within said ring is forming a bond with the sulfonyl
group thus providing a sulfamide. These compounds have been
described in PCT International Publication Number WO 01/23378 as
particular efficient and selective inhibitors of JNK2, and this
publication or any present or future corresponding U.S. application
or patent are hereby incorporated by reference. Preferred
embodiments include: [0120]
4-chloro-N-[(5-{[4-(2,4-difluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-y-
l)methyl]benzamide; [0121]
4-chloro-N-[(5-{[4-(phenylacetyl)-1,4-diazepan-1-yl]sulfonyl}thien-2-yl)m-
ethyl]benzamide; [0122]
N-({5-[(4-anilinopiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-4-chlorobenza-
mide; [0123]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)-
methyl]-4-chlorobenzamide; [0124]
N-[(5-{[4-(1H-benzimidazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl-
]-4-chlorobenzamide; [0125]
4-chloro-N-{[5-({4-[3-propylanilino]piperidin-1-yl}sulfonyl)thien-2-yl]me-
thyl}benzamide; [0126]
4-chloro-N-[(5-{[4-(4-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide; [0127]
4-chloro-N-({5-[(4-{3-[(2-hydroxyethyl)sulfonyl]anilino}piperidin-1-yl)su-
lfonyl]thien-2-yl}methyl)benzamide; [0128]
N-{[5-({4-[3-(aminosulfonyl)anilino]piperidin-1-yl}sulfonyl)thein-2-yl]me-
thyl}-4-chlorobenzamide; [0129]
4-chloro-N-[(5-{[4-(1-naphtholyl)piperazin-1-yl]sulfonyl}thien-2-yl)methy-
l]benzamide; [0130]
4-nitro-N-[(5-{[4-(3-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)me-
thyl]benzamide; [0131] methyl
3-{[1-({5-[({4-nitrobenzoyl}amino)methyl]thien-2-yl}sulfonyl)piperidin-4--
yl]amino}benzoate; [0132]
N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thein-2-yl)-
methyl]-2-hydroxybenzamide; [0133]
N-({5-[(4-{2-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-me-
thoxybenzamide. Further illustrative embodiments can be found in
the identified reference.
[0134] The following sulfonyl derivatives are contemplated for use
as therapeutics in treating type I diabetes:
##STR00037##
wherein Ar.sup.1 and Ar.sup.2 are independently from each other
substituted or unsubstituted aryl or heteroaryl groups; X is O or
S, preferably O; R.sup.1 is hydrogen or a C.sub.1-C.sub.6 alkyl
group, preferably hydrogen; alternatively, R.sup.1 forms a
substituted or unsubstituted 5-6 membered saturated or unsaturated
fused ring with Ar.sup.1; According to a further alternative R2 and
R4 could form a substituted or unsubstituted 5-6-membered saturated
or unsaturated ring. R.sup.2 is hydrogen, or a substituted or
unsubstituted C.sub.1-C.sub.6-alkyl, preferably hydrogen; n is an
integer from 0 to 5, preferably between 1-3 and most preferred 1;
R.sub.3 and R.sub.4 are independently from each other selected form
the group comprising or consisting of natural or synthetic amino
acid residues, hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6-alkyl, like trihalomethyl, substituted or
unsubstituted C.sub.1-C.sub.6 alkoxy, NH.sub.2, SH,
C.sub.1-C.sub.6-thioalkyl, acylamino, aminocarbonyl, substituted or
unsubstituted C.sub.1-C.sub.6-alkoxycarbonyl, aryl, heteroaryl,
substituted or unsubstituted 4-8-membered cyclic alkyl, optionally
contain 1-3 heteroatoms, carboxyl, cyano, halogen, hydroxyl, nitro,
acyloxy, sulfoxy, sulfonyl C.sub.1-C.sub.6-thioalkoxy, whereby
though, at least one of R.sub.3 and/or R.sub.4 must be an amino
acid residue; R.sup.5 is H or substituted or unsubstituted
C.sub.1-C.sub.6-alkyl; R.sup.6 is selected from the group
comprising or consisting of substituted or unsubstituted
C.sub.1-C.sub.6 aliphatic alkyl, substituted or unsubstituted
saturated cyclic C.sub.4-C.sub.8-alkyl optionally containing 1-3
heteroatoms and optionally fused with an aryl or an heteroaryl; or
R.sup.6 is a substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl whereby said aryl or heteroaryl groups are
optionally substituted or unsubstituted C.sub.1-C.sub.6-alkoxy,
substituted or unsubstituted C.sub.2-C.sub.6 alkenyl, substituted
or unsubstituted C.sub.2-C.sub.6 alkynyl, amino acylamino
aminocarbonyl, substituted or unsubstituted
C.sub.1-C.sub.6-alkoxycarbonyl, aryl, carboxyl, cyano, halogen,
hydroxy, nitro, acyloxy, acylamino, sulfoxy, sulfonyl,
C.sub.1-C.sub.6-thioalkoxy or; or R.sup.5 and R.sup.6 taken
together form a substituted or unsubstituted 4-8-membered saturated
cyclic alkyl or heteroalkyl group. These compounds have been
described in PCT International Publication Number WO 01/23379 as
particular efficient and selective inhibitors of JNK2, and this
publication or any present or future corresponding U.S. application
or patent are hereby incorporated by reference. Preferred
embodiments include: [0135]
4-chloro-N-({5-[({2-[(2-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}-
ethyl)amino]-2-oxoethyl}amino)sulfonyl]thien-2-yl}methyl)benzamide
and [0136]
4-chloro-N-[(5-{[(2-oxo-2-{3-{(trifluoromethyl)sulfonyl]anilino}et-
hyl)amino]sulfonyl}thien-2-yl)methyl]benzamide. Further
illustrative embodiments can be found in the identified
reference.
[0137] The following sulfonyl hydrazine derivatives are
contemplated for use as therapeutics in treating type I
diabetes:
##STR00038##
wherein Ar.sup.1 and Ar.sup.2 are independently from each other
substituted or unsubstituted aryl or heteroaryl groups; X.sup.1 and
X.sup.2 are independently from each other O or S; R.sup.1, R.sup.2,
and R.sup.3 are independently from each other hydrogen or a
C.sub.1-C.sub.6 alkyl substituent or R.sup.1 forms a substituted or
unsubstituted 5-6-membered saturated or unsaturated ring with
Ar.sup.1; or R.sup.2 and R.sup.3 form a substituted or
unsubstituted 5-6-membered saturated or unsaturated ring; n is an
integer from 0 to 5; G is selected from a group comprising or
consisting of an unsubstituted or substituted 4-8-membered
heterocycle containing at least one heteroatom, or G is a
substituted or unsubstituted C.sub.1-C.sub.6 alkyl group. These
compounds have been described in PCT International Publication
Number WO 01/23382 as particular efficient and selective inhibitors
of JNK2, and this publication or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Preferred embodiments include: [0138]
4-chloro-N-(4-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}but-
anoyl)hydrazino]sulfonyl}benzyl)benzamide; [0139]
N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hy-
drazino]sulfonyl}thien-2-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamid-
e; [0140]
N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}bu-
tanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2-hydroxybenzamide;
[0141]
4-chloro-N-[(5-{[2-({2-[(2-chlorophenoxy)methyl]-1,3-thiazol-4-yl}carbony-
l)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide [0142]
4-chloro-N-[(5-{[2-({2-[4-(1,3-dithiolan-2-yl)phenyl]-1,3-thiazol-4-yl}ca-
rbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide. Further
illustrative embodiments can be found in the identified
reference.
[0143] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00039##
Wherein Z.sup.11 and Z.sup.12 each independently represent a
carbonyl group, an oxygen atom, a sulfur atom, a methine group
which may be substituted, a methylene group which may be
substituted or a nitrogen atom which may be substituted; represents
a double bond or a single bond; R.sup.1a represents a hydrogen
atom, a C.sub.1-C.sub.6 alkyl group, a phenyl group or a benzyl
group; R.sup.2a, R.sup.2b and R.sup.2c each independently represent
a group selected from the following Substituent Group (a); the ring
A represents a benzene ring which may have one to three groups
selected from the following Substituent Group (a), a naphthalene
ring which may have one to three groups selected from the following
Substituent Group (a) or a 5- to 10-membered aromatic heterocyclic
ring which may have one to three groups selected from the following
Substituent Group (a); Substituent Group (a) (1) a hydrogen atom,
(2) halogen atoms, (3) a nitro group, (4) a hydroxyl group, (5) a
cyano group, (6) a carboxyl group, (7) an amino group, (8) a formyl
group or (9) a group represented by the formula:
##STR00040##
wherein X.sup.1 and X.sup.2 each independently represent a single
bond, --CO--, --SO.sub.2-- or C.sub.1-C.sub.6-methylene group;
X.sup.3 represents a single bond, --CO--, --SO.sub.2, --O--,
--CO--O-- or --O--CO--; R.sup.3b represents a C.sub.1-C.sub.6
alkylene group or a single bond; R.sup.3a and R.sup.3c represent a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may be
substituted, a C.sub.2-C.sub.6 alkenyl group which may be
substituted, a C.sub.2-C.sub.6 alkynyl group which may be
substituted, a C.sub.3-C.sub.8 cycloalkyl group which may be
substituted, a C.sub.6-C.sub.14 aromatic cyclic hydrocarbon group
which may be substituted, a 5- to 14-membered aromatic heterocyclic
group which may be substituted or a hydrogen atom. These compounds
have been described in PCT International Publication Number WO
03/072550, and this publication or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Preferred embodiments include:
##STR00041##
Further illustrative embodiments can be found in the identified
references.
[0144] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00042##
wherein: A is a direct bond, --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.bCH.dbd.CH(CH.sub.2).sub.c--, or
--(CH.sub.2).sub.bC.ident.C(CH.sub.2).sub.c--; R.sup.1 is aryl,
heteroaryl or heterocycle fused to phenyl, each being optionally
substituted with one to four substituents independently selected
from R.sup.3; R.sup.2 is --R.sup.3, --R.sup.4,
--(CH.sub.2).sub.bC(.dbd.O)R.sup.5,
--(CH.sub.2).sub.bC(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.bC(.dbd.O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.bC(.dbd.O)NR.sub.5(CH.sub.2)CC(.dbd.O)R.sup.6,
--(CH.sub.2).sub.bNR.sup.5C(.dbd.O)R.sup.6,
--(CH.sub.2).sub.bNR.sup.5C(.dbd.O)NR.sup.6R.sup.7,
--(CH.sub.2).sub.bNR.sup.5R.sup.6, --(CH.sub.2).sub.bOR.sup.5,
--(CH.sub.2).sub.bSO.sub.dR.sup.5 or
--(CH.sub.2).sub.bSO.sub.2NR.sup.5R.sup.6; a is 1, 2, 3, 4, 5 or 6;
b and c are the same or different and at each occurrence
independently selected from 0, 1, 2, 3 or 4; d is at each
occurrence 0, 1 or 2; R.sup.3 is at each occurrence independently
halogen, hydroxy, carboxyl, alkyl, alkoxy, haloalkyl, acyloxy,
thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,
arylalkyl, heterocycle, heterocycloalkyl, --C(.dbd.O)OR.sup.8,
--OC(.dbd.O)R.sup.8, --C(.dbd.O)NR.sup.8R.sup.9,
--C(.dbd.O)NR.sup.8R.sup.9, --SO.sub.2NR.sup.8R.sup.9,
--NR.sup.8SO.sub.2R.sup.9, --CN, --NO.sub.2, --NR.sup.8R.sup.9,
--NR.sup.8C(.dbd.O)R.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2).sub.bOR.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2).sub.bR.sup.9,
--O(CH.sub.2).sub.bNR.sup.8R.sup.9, or heterocycle fused to phenyl;
R.sup.4 is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl,
each being optionally substituted with one to four substituents
independently selected from R.sup.3, or R.sup.4 is halogen or
hydroxy; R.sup.5, R.sup.6 and R.sup.7 are the same or different and
at each occurrence independently hydrogen, alkyl, aryl, arylalkyl,
heterocycle or heterocycloalkyl, wherein each of R.sup.5, R.sup.6
and R.sup.7 are optionally substituted with one to four
substituents independently selected from R.sup.3; and R.sup.8 and
R.sup.9 are the same or different and at each occurrence
independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or
heterocycloalkyl, or R.sup.8 and R.sup.9 taken together with the
atom or atoms to which they are bonded form a heterocycle, wherein
each of R.sup.8, R.sup.9, and R.sup.8 and R.sup.9 taken together to
form a heterocycle are optionally substituted with one to four
substituents independently selected from R.sup.3. These compounds
have been described in PCT International Publication Number WO
02/10137, as well as, U.S. Patent Application Publication
2004/0077877 and 2004/0127536 as particular efficient and selective
inhibitors of JNK2, all of which or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Preferred embodiments include:
##STR00043## ##STR00044##
Further illustrative embodiments can be found in the identified
reference(s).
[0145] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00045##
wherein R.sup.1 is aryl or heteroaryl optionally substituted with
one to four substituents independently selected from R.sup.7;
R.sup.2 is hydrogen; R.sup.3 is hydrogen or lower alkyl; R.sup.4
represents one to four optional substituents, wherein each
substituent is the same or different and independently selected
from halogen, hydroxy, lower alkyl and lower alkoxy; R.sup.5 and
R.sup.6 are the same or different and independently --R.sup.8,
--(CH.sub.2).sub.aC(.dbd.O)R.sup.9, --(CH2).sub.aC(.dbd.O)OR.sup.9,
--(CH2).sub.aC(.dbd.O)NR.sup.9R.sup.10,
--(CH2).sub.aC(.dbd.O)NR.sup.9(CH2).sub.bC(.dbd.O)R.sup.10,
--(CH2).sub.aNR.sup.9C(.dbd.O)R.sup.10,
(CH2).sub.aNR.sup.11C(.dbd.O)NR.sup.9R.sup.10,
--(CH2).sub.aNR.sup.9R.sup.10, --(CH2).sub.aOR.sup.9,
--(CH2).sub.aSO.sub.cR.sup.9 or --(CH2).sub.nSO2NR.sup.9R.sup.10;
or R.sup.5 and R.sup.6 taken together with the nitrogen atom to
which they are attached to form a heterocycle or substituted
heterocycle; R.sup.7 is at each occurrence independently halogen,
hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl, acyloxy,
thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,
arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl,
--C(.dbd.O)OR.sup.8, --OC(.dbd.O)R.sup.8,
--C(.dbd.O)NR.sup.8R.sup.9, --C(.dbd.O)NR.sup.8OR.sup.9,
--SO.sub.cR.sup.8, --SO.sub.cNR.sup.8R.sup.9, --NR.sup.8SOR.sup.9,
--NR.sup.8R.sup.9, --NR.sup.8C(.dbd.O)R.sup.9,
--NR.sup.8C(.dbd.O)(CH.sub.2)bOR.sup.9,
--NR.sup.8C(.dbd.O)(CH2).sub.bR.sup.9,
--O(CH2).sub.bNR.sup.8R.sup.9, or heterocycle fused to phenyl;
R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are the same or different
and at each occurrence independently hydrogen, alkyl, aryl,
arylalkyl, heterocycle, heterocycloalkyl; or R.sup.8 and R.sup.9
taken together with the atom or atoms to which they are attached to
form a heterocycle; a and b are the same or different and at each
occurrence independently selected from 0, 1, 2, 3 or 4; and c is at
each occurrence 0, 1 or 2. These compounds have been described in
PCT International Publication Number WO 02/46170, as well as U.S.
Patent Application Publication 2004/01066634 as particular
efficient and selective inhibitors of JNK2, and all of which or any
present or future corresponding U.S. application or patent are
hereby incorporated by reference. Preferred embodiments
include:
##STR00046## ##STR00047## ##STR00048##
Further illustrative embodiments can be found in the identified
reference.
[0146] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00049##
wherein R.sup.0 is --O--, --S--, --S(O)--, --S(O).sub.2--, NH or
--CH.sub.2--; being: (i) unsubstituted, (ii) monosubstituted and
having a first substituent, or (iii) disubstituted and having a
first substituent and a second substituent; the first or second
substituent, when present, is at the 3, 4, 5, 7, 8, 9, or 10
position, wherein the first and second substituent, when present,
are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl,
sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy,
arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,
alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,
di-alkylaminoalkoxy, --NHR.sup.3R.sup.4,
--NH(CH.sub.2).sub.nNR.sup.3R.sup.4, --NH(.dbd.O)R.sup.5,
--NHSO.sub.2R.sup.5, --C(.dbd.O)NR.sup.3R.sup.4, or
--SO.sub.2NR.sup.3R.sup.4; wherein n is 0-6, R.sup.3 and R.sup.4
are taken together and represent alkylidene or a
heteroatom-containing cyclic alkylidene or R.sup.3 and R.sup.4 are
independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl,
cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl,
mono-alkylaminoalkyl, or di-alkylaminoalkyl; and R.sup.5 is
hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl,
alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino,
di-alkylamino, arylamino, arylalkylamino, cycloalkylamino,
cycloalkylalkylamino, aminoalkyl, mono-alkylaminoalkyl, or
di-alkylaminoalkyl. These compounds have been described in PCT
International Publication Number WO 01/12609, as well as WO
02/066450, as well as U.S. Patent Application Publication
2004/0092562 and all of which or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Preferred embodiments include:
##STR00050##
Further illustrative embodiments can be found in the identified
reference(s).
[0147] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00051##
wherein N.sup.1 is a nitrogen atom optionally having a substituent
or a hydrogen atom, X.sup.1 is (i) a carbon atom optionally having
substituent(s) or hydrogen atom(s), (ii) an oxygen atom, (iii) a
sulfur atom or (iv) a nitrogen atom optionally having a substituent
or a hydrogen atom, X.sup.2 is (i) a carbon atom optionally having
substituent(s) or hydrogen atom(s), (ii) an oxygen atom, (iii) a
sulfur atom or (iv) a nitrogen atom optionally having a substituent
or a hydrogen atom, X.sup.3 is (i) a carbon atom or (ii) a nitrogen
atom, wherein (1) when X.sup.1 is an oxygen atom or a sulfur atom,
X.sup.2 is a carbon atom optionally having substituent(s) or
hydrogen atom(s), X.sup.3 is a carbon atom and N.sup.1 is a
nitrogen atom, (2) when X.sup.1 is a nitrogen atom having a
substituent or a hydrogen atom and X.sup.3 is a carbon atom, X2 is
a carbon atom optionally having substituent(s) or hydrogen atom(s)
and N.sup.1 is a nitrogen atom, (3) when X.sup.1 and X.sup.3 are
each a nitrogen atom, X.sup.2 is a carbon atom optionally having
substituent(s) or hydrogen atom(s), and N.sup.1 is a nitrogen atom,
(4) when X.sup.1 is a carbon atom optionally having substituent(s)
or hydrogen atom(s) and X.sup.2 is an oxygen atom or a sulfur atom,
X.sup.3 is a carbon atom and N.sup.1 is a nitrogen atom, (5) when
X.sup.1 is a carbon atom optionally having substituent(s) or
hydrogen atom(s) and X.sup.3 is a carbon atom, one of N.sup.1 and
X.sup.2 is a nitrogen atom, and the other is a nitrogen atom having
a substituent or a hydrogen atom, (6) when X.sup.1 and X.sup.2 are
each a carbon atom optionally having substituent(s) or hydrogen
atom(s) and X.sup.3 is a carbon atom, N.sup.1 is a nitrogen atom
having a substituent or a hydrogen atom, and (7) when X.sup.1 and
X.sup.2 are each a carbon atom optionally having substituent(s) or
hydrogen atom(s) and X.sup.3 is a nitrogen atom, N.sup.1 is a
nitrogen atom, ring A optionally further has substituent(s), ring B
is an aromatic ring, Y is (i) a carbon atom optionally having
substituent(s) or hydrogen atom(s) or (ii) a nitrogen atom, Z is a
bond, --NR.sup.4--(R.sup.4 is a hydrogen atom or a hydrocarbon
group optionally having substituent(s)), an oxygen atom or an
optionally oxidized sulfur atom, W is a bond or a divalent
hydrocarbon group optionally having substituent(s), R.sup.2 is an
aromatic group optionally having substituent(s), and R.sup.3 is a
hydrocarbon group optionally having substituent(s) or a
heterocyclic group optionally having substituent(s). These
compounds have been described in U.S. Patent Application
Publication 2004/0063946 and all of which or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Preferred embodiments include: [0148]
4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine;
[0149]
[5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amin-
e; [0150]
[5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-
-2-yl]amine; [0151]
4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-[(1S)-1-phenylethyl]-2--
Pyridylamine Hydrochloride; [0152]
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]Phenylacetam-
ide; [0153]
N-[4-[4-(4-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide;
[0154]
N-[4-[2-ethyl-4-(4-fluoro-3-methyl-phenyl)-1,3-thiazol-5-yl]-2-pyr-
idyl]benzamide. Further illustrative embodiments can be found in
the identified reference(s).
[0155] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00052##
wherein: W is nitrogen or CH; G is hydrogen or C.sub.1-3 aliphatic
wherein one methylene unit of G is optionally replaced by --C(O)--,
--C(O)O--, --C(O)NH--, --SO.sub.2--, or --SO.sub.2NH--; A is
--N-T.sub.(n)-R, oxygen, or sulfur; R.sup.1 is selected from
-T.sub.(n)-R or -T.sub.(n)-Ar.sup.1; each n is independently 0 or
1; T is a C.sub.1-4 alkylidene chain wherein one methylene unit of
T is optionally replaced by --C(O)--, --C(O)O--, --C(O)NH--,
--SO.sub.2--, or --SO.sub.2NH--; Ar.sup.1 is a 3-7 membered
monocyclic saturated, partially saturated or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 8-10 membered bicyclic saturated, partially saturated
or aromatic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein each member of Ar.sup.1 is
optionally substituted with one --Z--R.sup.3 and one to three
additional groups independently selected from --R, halogen, oxo,
--NO.sub.2, --CN, --OR, --SR, --N(R).sub.2, --NRC(O)R,
--NRC(O)N(R).sub.2, --NRCO.sub.2R, --C(O)R, --CO.sub.2R, --OC(O)R,
--C(O)N(R).sub.2, --OC(O)N(R).sub.2, --S(O)R, --SO.sub.2R,
--SO.sub.2N(R).sub.2, --NRSO.sub.2R, --NRSO.sub.2N(R).sub.2,
--C(O)C(O)R, or --C(O)CH.sub.2C(O)R; each R is independently
selected from hydrogen or a C.sub.1-6 aliphatic, wherein said
aliphatic is optionally substituted with one to three groups
independently selected from oxo, --CO.sub.2R', --OR',
--N(R').sub.2, --SR', --NO.sub.2, --NR'C(O)R',
--NR'C(O)N(R').sub.2, --NR'CO.sub.2R', --C(O)R', --OC(O)R',
--C(O)N(R').sub.2, --OC(O)N(R').sub.2, --S(O)R', --SO.sub.2R',
--SO.sub.2N(R').sub.2, --NR'SO.sub.2R', --NR'SO.sub.2N(R').sub.2,
--C(O)C(O)R', --C(O)CH.sub.2C(O)R', halogen, or --CN, or two R
bound to the same nitrogen atom are taken together with that
nitrogen atom to form a five or six membered heterocyclic or
heteroaryl ring having one to two additional heteroatoms
independently selected from oxygen, nitrogen, or sulfur; each R' is
independently selected from hydrogen or C.sub.1-6 aliphatic,
wherein said aliphatic is optionally substituted with one to three
groups independently selected from oxo, --CO.sub.2H, --OH,
--NH.sub.2, --SH, --NO.sub.2, --NHC(O)H, --NHC(O)NH.sub.2,
--NHCO.sub.2H, --C(O)H, --OC(O)H, --C(O)NH.sub.2, --OC(O)NH.sub.2,
--S(O)H, --SO.sub.2H, --SO.sub.2NH.sub.2, --NHSO.sub.2H,
--NHSO.sub.2NH.sub.2, --C(O)C(O)H, --C(O)CH.sub.2C(O)H, halogen, or
--CN, or two R' bound to the same nitrogen atom are taken together
with that nitrogen atom to form a five or six membered heterocyclic
or heteroaryl ring optionally having one or two additional
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; Z is a C.sub.1-C.sub.6 alkylidene chain wherein up to two
nonadjacent methylene units of Z are optionally replaced by
--C(O)--, --C(O)O--, --C(O)C(O)--, --C(O)N(R)--, --OC(O)N(R)--,
--N(R)N(R)--, --N(R)N(R)C(O)--, --N(R)C(O)--, --N(R)C(O)O--,
--N(R)C(O)N(R)--, --S(O)--, --SO.sub.2--, --N(R)SO.sub.2--,
--SO.sub.2N(R)--, --N(R)SO.sub.2N(R)--, --O--, --S--, or --N(R)--;
R.sup.2 is -Q.sub.(n)-Ar.sup.2; Ar.sup.2 is selected from a 3-7
membered monocyclic saturated, saturated or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 8-10 membered bicyclic saturated, saturated or
aromatic ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein each member of Ar.sup.2 is
optionally substituted with 1-5 groups independently selected from
--Z--R.sup.3, --R, halogen, oxo, --NO2, --CN, --OR, --SR,
--N(R).sub.2, NRC(O)R, --NRC(O)N(R).sub.2, --NRCO.sub.2R, --C(O)R,
--CO.sub.2R, OC(O)R, --C(O)N(R).sub.2, --OC(O)N(R).sub.2, --S(O)R,
--SO.sub.2R, SO.sub.2N(R).sub.2, --N(R)SO.sub.2R,
--N(R)SO.sub.2N(R).sub.2, --C(O)C(O)R, or --C(O)CH.sub.2C(O)R; Q is
a C.sub.1-3 alkylidene chain wherein up to two nonadjacent
methylene units of Q are optionally replaced by --C(O)--,
--C(O)O--, --C(O)C(O)--, --C(O)N(R)--, --OC(O)N(R)--, --N(R)N(R)--,
--N(R)N(R)C(O)--, --N(R)C(O)--, --N(R)C(O)O--, --N(R)C(O)N(R)--,
--S(O)--, --SO.sub.2--, --N(R)SO.sub.2--, --SO.sub.2N(R)--,
--N(R)SO.sub.2N(R)--, --O--, --S--, or --N(R)--; R.sup.3 is
selected from --Ar.sup.3, --R, halogen, --NO.sub.2, --CN, --OR,
--SR, --N(R).sub.2, --NRC(O)R, --NRC(O)N(R).sub.2, --NRCO.sub.2R,
--C(O)R, --CO.sub.2R, --OC(O)R, --C(O)N(R).sub.2,
--OC(O)N(R).sub.2, --SOR, --SO.sub.2R, --SO.sub.2N(R).sub.2,
--NRSO.sub.2R, --NRSO.sub.2N(R).sub.2, --C(O)C(O)R, or
--C(O)CH.sub.2C(O)R; and Ar.sup.3 is a 5-6 membered saturated,
partially saturated, or aromatic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, wherein
each member of Ar.sup.3 is optionally substituted with halogen,
oxo, --CN, --NO.sub.2, --R', --OR', --N(R').sub.2, --N(R')C(O)R',
N(R')C(O)N(R').sub.2, --N(R')CO.sub.2R', --C(O)R', --CO.sub.2R',
OC(O)R', --C(O)N(R').sub.2, --OC(O)N(R').sub.2, or --SO.sub.2R';
provided that when W is nitrogen and: (i) A is --N-T.sub.(n)-R and
R2 is a saturated ring or (ii) A is sulfur, then R.sup.1 is other
than an optionally substituted phenyl. These compounds have been
described in U.S. Patent Application Publication 2004/0097531 and
all of which or any present or future corresponding U.S.
application or patent are hereby incorporated by reference.
Preferred embodiments include:
##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057##
[0156] Further illustrative embodiments can be found in the
identified reference.
[0157] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00058##
[0158] wherein R.sup.1 is optionally substituted carbocyclyl or
heterocyclyl group, R.sup.2 is an optionally substituted five or
six membered heterocyclyl group or an optionally substituted six
membered carbocyclyl group, E is hydrogen, halogen cyano, C.sub.1-6
alkoxyl or C.sub.1-6 alkyl, G is hydrogen, halogen, cyano,
C.sub.1-6 alkoxy or C.sub.1-6 alkyl, and L is hydrogen, halogen,
cyano, C.sub.1-6 alkoxy or C.sub.1-6 alkyl. These compounds have
been described in International Publication Number WO 2004/078756
and all of which or any present or future corresponding U.S.
application or patent are hereby incorporated by reference.
Preferred embodiments include:
##STR00059##
Further illustrative embodiments can be found in the identified
reference.
[0159] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00060##
[0160] wherein R.sup.1 is an optionally substituted C.sub.3-16
carbocyclyl or C.sub.3-12 heterocyclyl group, Y is N or C and Z is
lone electron pair, hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl,
C.sub.2-12 alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl,
C.sub.3-12 heterocyclyl, --(CH.sub.2).sub.nOR.sup.2,
--(CH.sub.2).sub.nNR.sup.2.sub.2, --CO.sub.2R.sup.2, --COR.sup.2,
--CONR.sup.2.sub.2, wherein the C.sub.1-12 alkyl group optionally
contains one or more insertions selected from --O--,
--N(R.sup.2)--, --S--, --SO--, --SO.sub.2--; and each substitutable
nitrogen atom in Z is optionally substituted by --R.sup.3,
--COR.sup.3, --SO.sub.2R.sup.3 or --CO.sub.2R.sup.3; wherein n is 1
to 6, preferably n is 1, 2, or 3; wherein R.sup.2 is hydrogen,
C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, C.sub.1-12 alkylC.sub.3-12 carbocyclyl, or C.sub.1-12
alkylC.sub.3-12 heterocyclyl optionally substituted by one or more
of C.sub.1-6 alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.4,
--SR.sup.4, --NO.sub.2, CN, --NR.sup.4R.sup.4, --NR.sup.4COR.sup.4,
--NR.sup.4CONR.sup.4R.sup.4, --NR.sup.4CO.sub.2R.sup.4,
--CO.sub.2R.sup.4, --COR.sup.4, --CONR.sup.4.sub.2,
--SO.sub.2R.sup.4, --SONR.sup.4.sub.2, --SOR.sup.4,
--SO.sub.2NR.sup.4R.sup.4, --NR.sup.4SO.sub.2R.sup.4, wherein the
C.sub.1-12 alkyl group optionally incorporates on or two insertions
selected for the group consisting of --O--, --N(R.sup.4)--, --S--,
--SO--, --SO.sub.2--, wherein each R.sup.4 may be the same or
different and is defined below; wherein two R.sup.2 and
NR.sup.2.sub.2 may form a partially saturated, unsaturated or fully
saturated five to seven membered ring containing one to three
heteroatoms, optionally and independently substituted with one or
more halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12
alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl, C.sub.3-12
heterocyclyl, --OR.sup.5, --SR.sup.5, --NO.sub.2, CN,
--NR.sup.5R.sup.5, --NR.sup.5COR.sup.5,
--NR.sup.5CONR.sup.5R.sup.5, --NR.sup.5CO.sub.2R.sup.5,
--CO.sub.2R.sup.5, --COR.sup.5, --CONR.sup.5.sub.2,
--SO.sub.2R.sup.5, --SONR.sup.5.sub.2, --SOR.sup.5,
--SO.sub.2NR.sup.5R.sup.5, --NR.sup.5SO.sub.2R.sup.5; and each
saturated carbon in the optional ring is further optionally and
independently substituted by .dbd.O, .dbd.S, NNR.sup.6.sub.2,
.dbd.N--OR.sup.6, .dbd.NNR.sup.6COR.sup.6,
.dbd.NNR.sup.6CO.sub.2R.sup.6, .dbd.NNSO.sub.2R.sup.6, or
.dbd.NR.sup.6; wherein R.sup.3 is hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, or C.sub.6-12 aryl; wherein R.sup.4 is
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or C.sub.6-12 aryl;
wherein R.sup.5 is hydrogen, C.sub.1-12 alkyl, C.sub.3-16
carbocyclyl or C.sub.3-12 heterocyclyl, optionally substituted by
one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6 haloalkyl,
--OR.sup.7, --SR.sup.7, --NO.sub.2, CN, --NR.sup.7R.sup.7,
--NR.sup.7COR.sup.7, --NR.sup.7CONR.sup.7R.sup.7,
--NR.sup.7CO.sub.2R.sup.7, --CO.sub.2R.sup.7, --COR.sup.7,
--CONR.sup.7.sub.2, --SO.sub.2R.sup.7, --SONR.sup.7.sub.2,
--SOR.sup.7, --SO.sub.2NR.sup.7R.sup.7, --NR.sup.7SO.sub.2R.sup.7;
wherein the C.sub.1-12 alkyl group optionally incorporates one or
two insertions selected from the group consisting of --O--,
--N(R.sup.7)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein R.sup.6
is hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.7, --SR.sup.7,
--NO.sub.2, CN, --NR.sup.7R.sup.7, --NR.sup.7COR.sup.7,
--NR.sup.7CONR.sup.7R.sup.7, --NR.sup.7CO.sub.2R.sup.7,
--CO.sub.2R.sup.7, --COR.sup.7, --CONR.sup.7.sub.2, --SO.sub.2R,
--SONR.sup.7.sub.2, --SOR.sup.7, --SO.sub.2NR.sup.7R.sup.7,
--NR.sup.7SO.sub.2R.sup.7; wherein the C.sub.1-12 alkyl group
optionally incorporates one or two insertions selected from the
group consisting of --O--, --N(R.sup.7)--, --S--, --SO--,
--SO.sub.2--, wherein each R.sup.7 may be the same or different and
is defined below; wherein R.sup.7 is hydrogen, C.sub.1-6 alkyl, or
C.sub.1-6 haloalkyl; wherein the optionally substituted carbocyclyl
or heterocyclyl group in R1 and Z is optionally and independently
fused to a partially saturated, unsaturated or fully saturated five
to seven membered ring containing zero to three heteroatoms, and
each substitutable carbon atom in R1 or Z, including the optional
fused ring, is optionally and independently substituted by one or
more of halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12
alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12 carbocyclyl, C.sub.3-12
heterocyclyl, --(CH.sub.2).sub.nOR.sup.12,
--(CH.sub.2).sub.nNR.sup.12.sub.2, --OR.sup.12, --SR.sup.12,
--NO.sub.2, CN, --NR.sup.12R.sup.12, --NR.sup.12COR.sup.12,
--NR.sup.12CONR.sup.12R.sup.12, --NR.sup.12CO.sub.2R.sup.12,
--CO.sub.2R.sup.12, --COR.sup.12, --CONR.sup.12.sub.2,
--SO.sub.2R.sup.12, --SONR.sup.12.sub.2, --SOR.sup.12,
--SO.sub.2NR.sup.12R.sup.12, --NR.sup.12SO.sub.2R.sup.12; wherein
the C.sub.1-12 alkyl group optionally contains one or more
insertions selected from --O--, --N(R.sup.12)--, --S--, --SO--,
--SO.sub.2--, and each saturated carbon in the optionally fused
ring is further optionally and independently substituted by .dbd.O,
.dbd.S, NNR.sup.13.sub.2, .dbd.N--OR.sup.13,
.dbd.NNR.sup.13COR.sup.13, .dbd.NNR.sup.13CO.sub.2R.sup.13,
.dbd.NNSO.sub.2R.sup.13, or .dbd.NR.sup.13; and each substitutable
nitrogen atom in R.sup.1 is optionally substituted by --R.sup.14,
--COR.sup.14, --SO.sub.2R.sup.14, or --CO.sub.2R.sup.14; wherein n
is 1 to 6, preferably n is 1, 2, or 3; wherein R.sup.12 is
hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.15, --SR.sup.15,
--NO.sub.2, CN, --NR.sup.15R.sup.15, --NR.sup.15COR.sup.15,
--NR.sup.15CONR.sup.15R.sup.15, --NR.sup.15CO.sub.2R.sup.15,
--CO.sub.2R.sup.15, --COR.sup.15, --CONR.sup.15.sub.2,
--SO.sub.2R.sup.15, --SONR.sup.15.sub.2, --SOR.sup.15,
--SO.sub.2NR.sup.15R.sup.15, --NR.sup.15SO.sub.2R.sup.15; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.15)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.7
may be the same or different and is defined below; wherein two
R.sup.12 and NR.sup.12.sub.2 may form a partially saturated,
unsaturated or fully saturated five to seven membered ring
containing one to three heteroatoms, optionally and independently
substituted with one or more halogen, C.sub.1-12 alkyl, C.sub.2-12
alkenyl, C.sub.2-12 alkynyl, C.sub.1-12 haloalkyl, C.sub.3-12
carbocyclyl, C.sub.3-12 heterocyclyl, --OR.sup.16, --SR.sup.16,
--NO.sub.2, CN, --NR.sup.16R.sup.16, --NR.sup.16COR.sup.16,
--NR.sup.16CONR.sup.16R.sup.16, --NR.sup.16CO.sub.2R.sup.16,
--CO.sub.2R.sup.16, --COR.sup.16, --CONR.sup.16.sub.2,
--SO.sub.2R.sup.16, --SONR.sup.16.sub.2, --SOR.sup.16,
--SO.sub.2NR.sup.16R.sup.16, --NR.sup.16SO.sub.2R.sup.16; and each
saturated carbon in the optional ring is further optionally and
independently substituted by .dbd.O, .dbd.S, NNR.sup.17.sub.2,
.dbd.N--OR.sup.17, .dbd.NNR.sup.17COR.sup.17,
.dbd.NNR.sup.17CO.sub.2R.sup.17, .dbd.NNSO.sub.2R.sup.17, or
.dbd.NR.sup.17; wherein R.sup.13 is hydrogen, C.sub.1-12 alkyl,
C.sub.3-16 carbocyclyl or C.sub.3-12 heterocyclyl, optionally
substituted by one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6
haloalkyl, --OR.sup.15, --SR.sup.15, --NO.sub.2, CN,
--NR.sup.15R.sup.15, --NR.sup.15COR.sup.15,
--NR.sup.15CONR.sup.15R.sup.15, --NR.sup.15CO.sub.2R.sup.15,
--CO.sub.2R.sup.15, --COR.sup.15, --CONR.sup.15.sub.2,
--SO.sub.2R.sup.15, --SONR.sup.15.sub.2, --SOR.sup.15,
--SO.sub.2NR.sup.15R.sup.15, --NR.sup.15SO.sub.2R.sup.15; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.15)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.15
may be the same or different and is defined below; wherein R.sup.14
is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or C.sub.6-12
aryl; wherein R.sup.15 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl; wherein R.sup.16 is hydrogen, C.sub.1-12 alkyl,
C.sub.3-16 carbocyclyl or C.sub.3-12 heterocyclyl, optionally
substituted by one or more of C.sub.1-6 alkyl, halogen, C.sub.1-6
haloalkyl, --OR.sup.18, --SR.sup.18, --NO.sub.2, CN,
--NR.sup.18R.sup.18, --NR.sup.18COR.sup.18,
--NR.sup.18CONR.sup.18R.sup.18, --NR.sup.18CO.sub.2R.sup.18,
--CO.sub.2R.sup.18, --COR.sup.18, --CONR.sup.18.sub.2,
--SO.sub.2R.sup.18, --SONR.sup.18.sub.2, --SOR.sup.18,
--SO.sub.2NR.sup.18R.sup.18, --NR.sup.18SO.sub.2R.sup.18; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.18)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.18
may be the same or different and is defined below; wherein R.sup.17
is hydrogen, C.sub.1-12 alkyl, C.sub.3-16 carbocyclyl or C.sub.3-12
heterocyclyl, optionally substituted by one or more of C.sub.1-6
alkyl, halogen, C.sub.1-6 haloalkyl, --OR.sup.18, --SR.sup.18,
--NO.sub.2, CN, --NR.sup.18R.sup.18, --NR.sup.18COR.sup.18,
--NR.sup.18CONR.sup.18R.sup.18, --NR.sup.18CO.sub.2R.sup.18,
--CO.sub.2R.sup.18, --COR.sup.18, --CONR.sup.18.sub.2,
--SO.sub.2R.sup.18, --SONR.sup.18.sub.2, --SOR.sup.18,
--SO.sub.2NR.sup.18R.sup.18, --NR.sup.18SO.sub.2R.sup.18; wherein
the C.sub.1-12 alkyl group optionally incorporates one or two
insertions selected from the group consisting of --O--,
--N(R.sup.18)--, --S--, --SO--, --SO.sub.2--, wherein each R.sup.18
may be the same or different and is defined below; wherein R.sup.18
is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl. These compounds
have been described in International Publication Number WO
2004/101565 and all of which or any present or future corresponding
U.S. application or patent are hereby incorporated by reference.
Preferred embodiments include:
##STR00061## ##STR00062## ##STR00063##
[0161] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00064##
[0162] wherein ring A is an optionally substituted benzene ring, X
is --O--, --N.dbd., --NR.sup.3-- or --CHR.sup.3--, R.sup.2 is an
acyl group, an optionally esterified or thioesterified carboxyl
group, and optionally substituted carbamoyl group or an optionally
substituted amino group and the line, a broken line shows a single
bond or a double bond, and R.sup.1 is a hydrogen atom, optionally
substituted hydrocarbon group, and optionally substituted
heterocyclic group and the like. These compounds have been
described in Japanese Publication JP2004210772 and all of which or
any present or future corresponding U.S. application or patent are
hereby incorporated by reference. Preferred embodiments
include:
##STR00065## ##STR00066##
[0163] Further illustrative examples can be found in the identified
reference.
[0164] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00067##
[0165] wherein each of Ar.sup.a and Ar.sup.b is an aromatic group
optionally having substituents, Ar.sup.a and Ar.sup.b optionally
form a condensed cyclic group together with the adjacent carbon
atom; ring B.sup.a is a nitrogen-containing heterocycle optionally
having substituents; X.sup.a and Y.sup.a are the same or different
and each is (1) a bond, (2) an oxygen atom, (3) S(O).sub.p (wherein
p is an integer of 0 to 2), (4) NR.sup.d (wherein R.sup.d is a
hydrogen atom or a lower alkyl group) or (5) a divalent linear
lower hydrocarbon group optionally having substituents and
containing 1 to 3 hetero atom(s); ring A.sup.a is a 5-membered ring
optionally having substituents; R.sup.a and R.sup.b are the same or
different and each is (1) a hydrogen atom, (2) a halogen atom, (3)
a hydrocarbon group optionally having substituents, (4) an acyl
group or (5) a hydroxy group optionally having a substituent;
R.sup.c is (1) a hydrogen atom, (2) a hydroxy group optionally
substituted by a lower alkyl group or (3) a carboxyl group. These
compounds have been described in U.S. Patent Application
Publication 2004/0254189 and Japanese Publication JP2004161716, all
of which or any present or future corresponding U.S. application or
patent are hereby incorporated by reference. Preferred embodiments
include:
##STR00068## ##STR00069##
[0166] Further illustrative embodiments can be found in the
corresponding identified references.
[0167] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00070## ##STR00071## ##STR00072## ##STR00073##
[0168] These compounds have been described in Japanese Publication
JP2003015481 and all of which or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference.
[0169] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00074##
wherein Y is selected from O, NH, N(R), S, S(O) or S(O).sub.2; X is
selected from O, NH or N(R); R.sup.1 and R.sup.2 are each
independently selected from H, a C.sub.1-C.sub.6 straight chain or
branched alkyl or alkenyl group, optionally substituted with one to
four substituents, each of which is independently selected from
NH.sub.2, NHR, N(R).sub.2, NO.sub.2, OH, OR, CF.sub.3, halo, CN,
CO.sub.2H, CONH.sub.2, CONHR, CON(R).sub.2, COR, SR, S(O)R,
S(O).sub.2R, S(O)2NH.sub.2, S(O).sub.2NHR or R; a 5-7 membered
aromatic or non-aromatic carbocyclic or heterocyclic ring,
optionally substituted with one to four substituents, each of which
is independently selected from NH.sub.2, NHR, N(R).sub.2, NO.sub.2,
OH, OR, CF.sub.3, halo, CN, CO.sub.2H, CONH.sub.2, CONHR,
CON(R).sub.2, COR, SR, S(O)R, S(O).sub.2R, S(O).sub.2NH.sub.2,
S(O).sub.2NHR or R; or a 9-10 membered bicyclic aromatic or
non-aromatic carbocyclic or heterocyclic ring optionally
substituted with one to four substituents, each of which is
independently selected from NH.sub.2, NHR, N(R).sub.2, NO.sub.2,
OH, OR, CF.sub.3, halo, CN, CO.sub.2H, CONH.sub.2, CONHR,
CON(R).sub.2, COR, SR, S(O)R, S(O).sub.2R, S(O).sub.2NH.sub.2,
S(O).sub.2NHR or R; wherein said heterocyclic ring contains 1 to 4
heteroatoms, each of which heteroatoms are independently selected
from N, O, S, SO or SO.sub.2; and R is selected from a
C.sub.1-C.sub.6 straight chain or branched alkyl or alkenyl group,
a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic
ring, or a 9-10 membered bicyclic aromatic or non-aromatic
carbocyclic or heterocyclic ring system. These compounds have been
described in U.S. Patent Application Publication 2003/100549 and
all of which or any present or future corresponding U.S.
application or patent are hereby incorporated by reference.
Preferred embodiments include:
##STR00075##
Further illustrative embodiment can be found in the corresponding
identified reference.
[0170] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00076##
[0171] wherein ring A and ring B are each an optionally substituted
benzene ring, X is --O--, --N.dbd., --NR.sup.3-- or --CHR.sup.3--,
R.sup.2 is an acyl group, an optionally esterified or
thioesterified carboxyl group, and optionally substituted carbamoyl
group or an optionally substituted amino group and the line, a
broken line shows a single bond or a double bond, and R.sup.1 is a
hydrogen atom, optionally substituted hydrocarbon group, and
optionally substituted heterocyclic group and the like. These
compounds have been described in International Publication Number
WO 2003/068750 and all of which or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Preferred embodiments include: [0172]
2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquin-
oline-3-carboxylic acid methyl ester; [0173]
6-bromo-1-oxo-4-phenyl-2-(4-sulfamoylbenzyl)-1,2-dihydroisoquinoline-3-ca-
rboxylic acid methyl ester; [0174]
6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinolin-
e-3-carboxylic acid methyl ester; [0175]
6-bromo-2-(4-carboxylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-car-
boxylic acid methyl ester; [0176]
2-(2-acetylpiperidin-4-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoqui-
noline-3-carboxylic acid methyl ester; [0177]
6-bromo-2-[4-(3-carboxylpropionylamino)benzyl]-1-oxo-4-phenyl-1,2-dihydro-
isoquinoline-3-carboxylic acid methyl ester; [0178]
6-bromo-1-oxo-4-phenyl-2-[4-(2-(pyrrolidini-1-yl)ethylcarbamoyl)benzyl]-1-
,2-dihydroisoquinoline-3-carboxylic acid methyl ester; [0179]
6-amino-2-(benzo[1,3]dioxol-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquin-
oline-3-carboxylic acid methyl ester; [0180]
6-bromo-2-(4-methanesulfonylbenzyl)-4-phenyl-3-propionyl-2H-isoquinolin-1-
-one; [0181]
6-bromo-2-[4-(N',N'-diethylhydrazinocarbonyl)benzyl]-1-oxo-4-phenyl-1,2-d-
ihydroisoquinoline-3-carboxylic acid methyl ester; [0182]
3-acetyl-6-bromo-4-phenyl-2-(4-sulfamoylbenzyl)-2H-isoquinolin-1-one;
[0183]
4-(6-chloro-3-butyryl-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)ben-
zenesulfonamide; [0184]
4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzoic
acid; [0185]
4-(6-chloro-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzoic
acid; [0186]
6-bromo-4-phenyl-3-propionyl-2-[4-(1H-tetrazol-5-yl)benzyl]-2H-isoquinoli-
n-1-one; and [0187]
3-[(2Z)-3-aminobut-2-enoyl]-6-bromo-2-(4-methanesulfonylbenzyl)-4-phenyl--
2H-isoquinolin-1-one. Further illustrative embodiments can be found
in the identified reference(s).
[0188] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00077##
wherein X is O, S or NR.sup.0, with R.sup.0 being H or an
unsubstituted or substituted C.sub.1-C.sub.6 alkyl; G is an
unsubstituted or substituted pyrimidinyl group; R.sup.1 is selected
from the group comprising or consisting of hydrogen, unsubstituted
or substituted C.sub.1-C.sub.6-alkoxy, unsubstituted or substituted
C.sub.1-C.sub.6-thioalkoxy, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl, primary, secondary or tertiary amino
groups, aminoacyl, aminocarbonyl, unsubstituted or substituted
C.sub.1-C.sub.6 alkoxycarbonyl unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen,
hydroxy, nitro, sulfoxy, sulfonyl sulfonamide, unsubstituted or
substituted hydrazides; R.sup.2 is selected from the group
comprising or consisting of hydrogen, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6-alkynyl, unsubstituted or substituted
C.sub.1-C.sub.6-alkyl-aryl, unsubstituted or substituted aryl or
heteroaryl unsubstituted or substituted
C.sub.1-C.sub.6-alkyl-heteroaryl, --C(O)--OR.sup.3,
--C(O)--R.sup.3, --C(O)--NR.sup.3R.sup.3', --(SO.sub.2)R.sup.3,
with R.sup.3 and R.sup.3' being independently selected from the
group comprising or consisting of hydrogen, unsubstituted or
substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
C.sub.2-C.sub.6 alkenyl, unsubstituted or substituted
C.sub.2-C.sub.6 alknyl, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl aryl, unsubstituted or
substituted C.sub.1-C.sub.6-alkyl heteroaryl. These compounds have
been described in U.S. Patent Application Publication 2003/0162794
and all of which or any present or future corresponding U.S.
application or patent are hereby incorporated by reference.
Preferred embodiments include: [0189]
1,3-benzothiazol-2-yl(2-chloro-4-pyrimidinyl)-acetonitrile; [0190]
1,3-benzothiazol-2-yl[2-methylsulfanyl)-4-pyrimidinyl]acetonitrile;
[0191]
1,3-benzothiazol-2-yl(2-{[2-(1H-imidazolyl-4-yl)ethyl-1]amino}-4-p-
yrimidinyl)acetonitrile; [0192]
1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidinyl]acetonitrile;
[0193] 1,3-benzothiazol-2-yl
{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}acetonitrile; [0194]
1,3-benzothiazol-2-yl[2-(benzyloxy)pyrimidin-4-yl]acetonitrile;
[0195]
1,3-benzothiazol-2-yl[2-(4-methoxyphenoxy)pyrimidin-4-yl]acetonitrile;
and [0196]
1,3-benzothiazol-2-yl(2-methoxy-4-pyrimidinyl)-acetonitrile.
Further illustrative embodiments can be found in the identified
reference.
[0197] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00078##
wherein Y is selected from --(CH.sub.2)-Q.sup.1; --(CO)-Q.sup.1;
--(CO)NH-Q.sup.1; --(CO)--O-Q.sup.1; --(SO.sub.2)-Q.sup.1 or
--(SO.sub.2)NH-Q.sup.1; Q.sup.1 is a C.sub.1-C.sub.6 straight chain
or branched alkyl or alkenyl group; a 5-7 membered aromatic or
non-aromatic carbocyclic or heterocyclic ring; or a 9-14 membered
bicyclic or tricyclic aromatic or non-aromatic carbocyclic or
heterocyclic ring system, wherein said alkyl, alkenyl, ring or ring
system is optionally substituted with one to four substituents,
each of which is independently selected from NH.sub.2, NH--R,
N(R).sub.2, NO.sub.2, OH, OR, CF.sub.3, halo, CN, CO.sub.2H,
C(O)--NH.sub.2, C(O)--NH--R, C(O)--N(R).sub.2, C(O)--R, SR,
S(O)--R, S(O).sub.2--R, S(O).sub.2--NH--R or --R; W is N or C;
wherein when W is N, R.sup.8 is a lone pair of electrons; and
wherein when W is C, R.sup.8 is R.sup.7. A.sup.1 is N or CR.sup.1;
A.sup.2 is N or CR.sup.2; A.sup.3 is N or CR.sup.3; A.sup.4 is N or
CR.sup.4; provided that at least one of A.sup.1, A.sup.2, A.sup.3
and A.sup.4 must not be N; R.sup.1 is --NHR.sup.5, --OR.sup.5,
--SR.sup.5, or --R.sup.5; R.sup.2, R.sup.3, and R.sup.4 are
independently selected from --(CO)NH.sub.2, --(CO)NHR,
--(CO)N(R).sub.2, --NHR.sup.5, --NHCH.sub.2R.sup.5, --OR.sup.5,
--SR.sup.5, --R.sup.5, --NH(CO)--R.sup.6, --NH(CO)--NHR.sup.6,
--NH(CO)--NH(CO)R.sup.6, --NH(CO)--OR.sup.6,
--NH(SO.sub.2)--R.sup.6, --NH(SO.sub.2)--NHR.sup.6, --C(O)OH,
--C(O)OR, --(CO)-Q.sup.1, --(CO)NH-Q.sup.1, --(CO)NR-Q.sup.1,
--(CO)--O-Q.sup.1, --(SO.sub.2)-Q.sup.1 or --(SO.sub.2)NH-Q.sup.1;
R.sup.5 and R.sup.6 are each independently selected from H;
N(R).sub.2, NHOH, NO.sub.2, C(O)OR or halo; a C.sub.1-C.sub.6
straight chain or branched alkyl, alkenyl or alkynyl group; a 5-7
membered aromatic or non-aromatic carbocyclic or heterocyclic ring;
or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic
carbocyclic or heterocyclic ring; wherein said alkyl, alkenyl, ring
or ring system is optionally substituted with one to four
substituents, each of which is independently selected from
NH.sub.2, NHR, NHC(O)OR, N(R).sub.2, NO.sub.2, OH, OR, CF.sub.3,
halo, CN, Si(R).sub.3, CO.sub.2H, COOR, CONH.sub.2, CONHR,
CON(R).sub.2, COR, SR, S(O)R, S(O).sub.2R, S(O).sub.2NHR or R;
R.sup.7 is H; a C.sub.1-C.sub.6 straight chain or branched alkyl or
alkenyl group; a 5-7 membered aromatic or non-aromatic carbocyclic
or heterocyclic ring; or a 9-14 membered bicyclic or tricyclic
aromatic or non-aromatic carbocyclic or heterocyclic ring; wherein
said alkyl, alkenyl, ring or ring system is optionally substituted
with one to four substituents, each of which is independently
selected from NH.sub.2, NHR, N(R).sub.2, NO.sub.2, OH, OR,
CF.sub.3, halo, CN, CO.sub.2H, CONH.sub.2, CONHR, CON(R).sub.2,
COR, SR, S(O)R, S(O).sub.2R, S(O).sub.2NHR or R; R is a
C.sub.1-C.sub.6 straight chain or branched alkyl or alkenyl group,
a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic
ring, or a 9-10 membered bicyclic aromatic or non-aromatic
carbocyclic or heterocyclic ring system; and Z is CH or N. These
compounds have been described in U.S. Patent Application
Publication 2003/0162794 and all of which or any present or future
corresponding U.S. application or patent are hereby incorporated by
reference. Preferred embodiments include:
##STR00079##
Further illustrative embodiments can be located in the identified
reference.
[0198] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00080##
wherein: R.sup.1 is aryl or heteroaryl, each of which is optionally
substituted with one or more of R.sup.3, OR.sup.3, OCOR.sup.3,
COOR.sup.3, COR.sup.3, CON.sup.4R.sup.3R.sup.4, NHCOR.sup.3,
NR.sup.3R.sup.4, NHSO.sub.2R.sup.3, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, SR.sup.3, CN, halogeno and NO.sub.2;
R.sup.2 is R.sup.5, R.sup.6, COR.sup.5, COR.sup.5, CONHR.sup.5,
CONHR.sup.6, CON(R.sup.6).sub.2, COOR.sup.5, COOR.sup.6,
SO.sub.2R.sup.5 or SO.sub.2R.sup.6; R3 and R4 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)
C.sub.1-6 alkyl, heterocycle, heterocycle C.sub.1-6 alkyl,
C.sub.1-6 fluoroalkyl, C.sub.1-6 trifluoroalkoxyl; R.sup.5 is aryl
or heteroaryl, each of which is optionally substituted with one or
more of R.sup.7, OR.sup.7, OCOR.sup.7, COOR.sup.7, COR.sup.7,
CONR.sup.7R.sup.8, CONHOR.sup.7, NHCOR.sup.7, NR.sup.7R.sup.8,
NHSO.sub.2R.sup.7, SO.sub.2R.sup.7, SO.sub.2NHR.sup.7R.sup.8,
SR.sup.7, R.sup.7SR.sup.8, CN, halogeno, oxygen and NO.sub.2;
R.sup.6 is hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl,
(C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, heterocycle, heterocycle
C.sub.1-6 alkyl, heteroaryl C.sub.1-6 alkyl; aryl C.sub.1-6 alkyl,
C.sub.1-6 alkoxyl, or C.sub.2-6 alkenyl, wherein any of C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cyclolakyl) C.sub.1-6
alkyl, heterocycle, heerocycle C.sub.1-6 alkyl, heteronaryl
C.sub.1-6 alkyl, aryl C.sub.1-6 alkyl, C.sub.1-6 alkoxyl and
C.sub.2-6 alkenyl is optionally substituted with one or more A;
R.sup.7 and R.sup.8 are each independently hydrogen, C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heteroaryl, heteroaryl C.sub.1-6
alkyl, heterocycle, heterocycle C.sub.1-6 alkyl, aryl, C.sub.1-6
fluoroalkyl and Cl.sub.6 chloroalkyl, wherein any of C.sub.1-6
alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, heteroaryl, heteroaryl C.sub.1-6 alkyl,
heterocycle and heterocycle C.sub.1-6 alkyl is optionally
substituted with one or more B; R.sup.9 and R.sup.10 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl,
(C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
heterocycle, heterocycle C.sub.1-6 alkyl, heteroaryl, heteroaryl
C.sub.1-6 alkyl, aryl or aryl C.sub.1-6 alkyl, wherein any of
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, heterocycle, heterocycle
C.sub.1-6 alkyl, heteroaryl, heteroaryl C.sub.1-6 alkyl, aryl or
aryl C.sub.1-6 alkyl is optionally substituted with one or more B;
A is R.sup.9, OR.sup.9, OCOR.sup.9, COOR.sup.9, COR.sup.9,
CONR.sup.9R.sup.10, CONHOR.sup.9, NHCOR.sup.9, NR.sup.9R.sup.10,
NR.sup.9SO.sub.2R.sup.10, SO.sub.2R.sup.9,
SO.sub.2NR.sup.9R.sup.10, SR.sup.9, R.sup.9SR.sup.10, CN or
halogen; B is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylamino, di (C.sub.1-6 alkyl)amino or halogen. These compounds
have been described in International Publication Number WO
2004/101565 and all of which or any present or future corresponding
U.S. application or patent are hereby incorporated by reference.
Preferred embodiments include: [0199]
N,N'-Bis[4-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-diamine;
[0200] N,N'-Bis(4-fluorophenyl)-4,4'-bipyridine-2,2'-diamine;
[0201] N,N'-Bis(3,4-difluorophenyl)-4,4'-bipyridine-2,2'-diamine;
[0202]
N,N'-Bis[3-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-diamine;
[0203]
N,N'-Bis[3-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-diamine;
[0204]
N,N'-Bis(2-fluorophenyl)-4,4'-bipyridine-2,2'-diamine;N,N'-Bis(2-methylph-
enyl)-4,4'-bipyridine-2,2'-diamine;N,N'-Bis(2-aminophenyl)-4,4'-bipyridine-
-2,2'-diamine;N,N'-Bis(2-methoxyphenyl)-4,4'-bipyridine-2,2'-diamine;
[0205] N,N'-Bis(2-ethoxyphenyl)-4,4'-bipyridine-2,2'-diamine;
[0206]
N-(2'-anilino-4,4-bipyridin-2-yl)trans-4-methoxycyclohexanecarboxamide;
[0207] N
(2'-anilino-4,4'-bipyridin-2-yl)-cis-4-methoxycyclohexanecarboxa-
mide; [0208]
N-12'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}-trans-4-methoxycyclohe-
xanecarboxamide; [0209]
N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}-cis-4-methoxycyclohexa-
necarboxamide; [0210]
N-(6-methylpyridin-2-yl)-N-phenyl-4,4'-bipyridine-2,2'-diamine;
N-phenyl-N-pyridin-2-yl-4,4'-bipyridine-2,2'-diamine; [0211]
{4-[(4-methylpiperazin-1-yl)
sulfonyl]phenyl}-N-phenyl-4,4'-bipyridine-2,2'-diamine; [0212]
N-phenyl-N'-pyridin-3-yl-4,4'-bipyridine-2,2'-diamine; [0213]
N-phenyl-N'-pyrimidin-2-yl-4,4'-bipyridine-2,2'-diamine; [0214]
N-phenyl-N'-pyrimidin-5-yl-4,4'-bipyridine-2,2'-diamine; [0215]
(2E)-1-{4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]phenyl}-3-(dimethylamino-
) prop-2-en-1-one; [0216]
4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-N-(2-pyrrolidin-1-ylethyl)benze-
nesulfonamide; [0217]
4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-N-(2-morpholin-4-ylethyl)benzen-
esulfonamide; [0218] N-{4-[(4-ethylpiperazin-1-yl)
sulfonyl]phenyl}-N'-phenyl-4,4'-bipyridine-2,2'-diamine; [0219]
N-phenyl-N'-pyridin-4-yl-4,4'-bipyridine-2,2'-diamine; [0220]
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;
[0221]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-piperidin-1-ylpropanamide;
[0222]
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;
[0223] N-(2'-anilino-4,4'-bipyridin-2-yl)nicotinamide; [0224]
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-(dimethylamino)benzamide;
[0225]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2,6-dimethoxynicotinamide;
[0226] N-(2'-anilino-4,4'-bipyridin-2-yl)-1H-indole-2-carboxamide;
[0227] N-(2'-anilino-4,4'-bipyridin-2-yl)pyridine-2-carboxamide;
[0228] N-(2'-anilino-4,4'-bipyridin-2-yl)-3-furamide; [0229]
N-(2'-anilino-4,4'-bipyridin-2-yl)-1,2,3-thiadiazole-4-carboxamide;
[0230] N-(2'-anilino-4,4'-bipyridin-2-yl) isoxazole-5-carboxamide;
[0231]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methylisoxazole-3-carboxamide;
[0232] N-(2'-anilino-4,4'-bipyridin-2-yl)pyrazine-2-carboxamide;
[0233]
N-(2'-anilino-4,4'-bipyridin-2-yl)-1-methyl-1H-imidazole-4-carboxamide;
[0234] N-(2'-anilino-4,4'-bipyridin-2-yl)-2-furamide; [0235]
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-methoxybenzamide; [0236]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-bromo-2-furamide; [0237]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-(methylthio) nicotinamide;
[0238]
Methyl-4-{[(2'-anilino-4,4'-bipyridin-2-yl)amino]carbonyl}benzoate;
[0239] 3-(acetylamino)-N-(2'-anilino-4,4'-bipyridin-2-yl)benzamide;
[0240]
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1-benz-
ofuran-3-carboxamide; [0241]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-[(pyridin-2-ylthio)
methyl]-2-furamide; [0242]
N-(2'-anilino-4,4'-bipyridin-2-yl)nicotinamide 1-oxide; [0243]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-hydroxypyridine-2-carboxamide;
[0244]
N-(2'-anilino-4,4'-bipyridin-2-yl)-6-bromopyridine-2-carboxamide;
[0245] N-(2'-anilino-4,4'-bipyridin-2-yl)isonicotinamide 1-oxide;
[0246] N-(2'-anilino-4,4'-bipyridin-2-yl)-2-hydroxynicotinamide;
[0247]
N-(2'-anilino-4,4'-bipyridin-2-yl)-6-hydroxypyridine-2-carboxamide;
[0248]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-benzoylpyridine-2-carboxamide-
; [0249]
N-(2'-anilino-4,4'-bipyridin-2-yl)-6-methylpyridine-2-carboxamide-
; [0250]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3,5-dimethylisoxazole-4-carbox-
amide; [0251]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-methoxynicotinamide; [0252]
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-methyl-1,2,3-thiadiazole-5-ca-
rboxamide; [0253]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-chloroisonicotinamide; [0254]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methylisoxazole-4-carboxamide;
[0255]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-methylisoxazole-4-carboxamide-
; [0256]
N-(2'-anilino-4,4'-bipyridin-2-yl)-1-methyl-1H-pyrrole-2-carboxam-
ide; [0257]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-chloronicotinamide; [0258]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-chloro-1H-indole-2-carboxamid-
e; [0259]
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-chloro-1H-pyrazole-3-carbox-
amide; [0260]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;
[0261]
(2E)-N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(3-furyl)acrylamide;
[0262]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(2-oxo-1,3-benzoxazol-3(2H)-y-
l) propanamide; [0263]
N'-(2'-anilino-4,4'-bipyridin-2-yl)-N,N-dimethylsuccinamide; [0264]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-[(4-chlorophenyl)
sulfonyl]acetamide; [0265]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-oxoprolinamide; [0266]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-methoxypropanamide; [0267]
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-methoxycyclohexanecarboxamide;
[0268] N-(2'-anilino-4,4'-bipyridin-2-yl)-3-methoxypropanamide;
[0269]
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;
[0270] N-(2'-anilino-4,4'-bipyridin-2-yl)-4-(dimethylamino)
butanamide; [0271] N-(2'-anilino-4,4'-bipyridin-2-yl)nicotinamide;
[0272]
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-(dimethylamino)benzamide;
[0273]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2,6-dimethoxynicotinamide;
[0274] N-(2'-anilino-4,4'-bipyridin-2-yl)-1H-indole-2-carboxamide;
[0275]
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methylpyrazine-2-carboxamide;
[0276] N-(2'-anilino-4,4'-bipyridin-2-yl)pyridine-2-carboxamide;
[0277] N-(2'-anilino-4,4'-bipyridin-2-yl)-3-furamide;N
(2'-anilino-4,4'-bipyridin-2-yl)-N-phenylurea; [0278]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-phenylurea; [0279]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[1-(4-bromophenyl)ethyl]urea;
[0280]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-thien-3-ylurea;N-(2'-anilino-
-4,4'-bipyridin-2-yl)-N'-(2-methylphenyl)urea; [0281]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methylphenyl)urea;N-(2'-anilino--
4,4'-bipyridin-2-yl)-N'-(3-fluorophenyl)urea; [0282]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-fluorophenyl)urea; [0283]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-fluorophenyl)urea; [0284]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(chloromethyl)phenyl]urea;
[0285] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-cyanophenyl)urea;
[0286] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-cyanophenyl)urea;
[0287] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-cyanophenyl)urea;
[0288]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,3-dimethylphenyl)urea;
[0289]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,5-dimethylphenyl)urea;
[0290] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-ethylphenyl)urea;
[0291] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-ethylphenyl)urea;
[0292] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methoxyphenyl)urea;
[0293] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-methoxyphenyl)urea;
[0294] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methoxyphenyl)urea;
[0295]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-fluoro-2-methylphenyl)urea;
[0296] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-fluorobenzyl)urea;
[0297]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-fluoro-5-methylphenyl)urea;
[0298] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-fluorobenzyl)urea;
[0299] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorophenyl)urea;
[0300] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-chlorophenyl)urea;
[0301] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorobenzyl)urea;
[0302]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,5-difluorophenyl)urea;
[0303]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,4-difluorophenyl)urea;
[0304]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,4-dichlorobenzyl)urea;
[0305] N-(4-acetylphenyl)-N'-(2'-anilino-4,4'-bipyridin-2-yl)urea;
[0306] N-(3-acetylphenyl)-N'-(2'-anilino-4,4'-bipyridin-2-yl)urea;
[0307]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-isopropylphenyl)urea;
[0308]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-isopropylphenyl)urea;
[0309]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-ethyl-6-methylphenyl)urea;
[0310] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-mesitylurea; [0311]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-propylphenyl)urea; [0312]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(dimethylamino)
phenyl]urea; [0313]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-1,3-benzodioxol-5-ylurea;
[0314]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methoxy-2-methylphenyl)ur-
ea; [0315]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methoxy-5-methylphenyl-
)urea; [0316]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-ethoxyphenyl)urea; [0317]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methoxybenzyl)urea; [0318]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-nitrophenyl)urea; [0319]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-nitrophenyl)urea; [0320]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[3-(methylthio) phenyl]urea;
[0321] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(methylthio)
phenyl]urea; [0322]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methylbenzyl)urea; [0323]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-chloro-2-methylphenyl)urea;
[0324]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chloro-5-methylphenyl)ure-
a; [0325]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorobenzyl)urea; [0326]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-chloro-4-fluorophenyl)ure-
a; [0327]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,3,4-trifluorophenyl)ure-
a; [0328]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-butylphenyl)urea; [0329]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-isopropyl-6-methylphenyl)-
urea; [0330]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-tert-butylphenyl)urea;
[0331] methyl
4-({[(2'-anilino-4,4'-bipyridin-2-yl)amino]carbonyl}amino)benzoate-
; [0332]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,4-dimethoxyphenyl)urea;
[0333]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,5-dimethoxyphenyl)urea;
[0334]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-chloro-4-methoxyphenyl)ur-
ea; [0335]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(difluoromethoxy)pheny-
l]urea; [0336]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[2-(trifluoromethyl)phenyl]urea;
[0337]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[3-(trifluoromethyl)phenyl]u-
rea; [0338]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(trifluoromethyl)phenyl]urea;
[0339]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,5-dichlorophenyl)urea;
[0340]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,5-dichlorophenyl)urea;
[0341]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,4-dichlorophenyl)urea;
[0342]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,3-dichlorophenyl)urea;
[0343]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,4-dichlorophenyl)urea;
[0344]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-bromo-3-methylphenyl)urea-
; [0345]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,6-dichloropyridin-4-yl)u-
rea; [0346]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-butyl-2-methylphenyl)urea;
[0347]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[5-methyl-2-(trifluoromethyl-
)-3-furyl]urea; [0348]
ethyl3-({[(2'-anilino-4,4'-bipyridin-2-yl)amino]carbonyl}amino)benzoate;
[0349] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-butoxyphenyl)urea;
[0350]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,6-diisopropylphenyl)urea;
[0351] N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methylbenzyl)urea;
[0352]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-chloro-2,4-dimethoxyphenyl)urea;
[0353]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-{4-[(trifluoromethyl)thio]ph-
enyl}urea; [0354]
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[3,5-bis(trifluoromethyl)phenyl]ure-
a; [0355]
1-acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-4-carboxam-
ide; [0356] N-(2'-anilino-4,4'-bipyridin-2-yl)-5-oxoprolinamide;
[0357] N3-acetyl-N1-(2'-anilino-4,4'-bipyridin-2-yl)-1-alaninamide;
[0358] N-(2
'-anilino-4,4'-bipyridin-2-yl)piperidine-4-carboxamide; [0359]
3-amino-N-(2'-anilino-4,4'-bipyridin-2-yl) butanamide; [0360]
N-(2'-anilino-4,4'-bipyridin-2-yl)-L-prolinamide; [0361]
N-(2'-anilino-4,4'-bipyridin-2-yl)acetamide; [0362] Methyl
2'-anilino-4,4'-bipyridin-2-ylcarbamate; [0363]
N-(2'-anilino-4,4'-bipyridin-2-yl)methanesulfonamide; [0364]
N-(2'-anilino-4,4'-bipyridin-2-yl)cyclohexanecarboxamide; [0365]
1-Acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-2-carboxamide;
[0366]
1-Acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-3-carboxamid-
e; [0367]
Ethyl-4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-4-oxobutanoate;
[0368]
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-2-carboxamide;
[0369] (S)-3
N2-acetyl-N1-(2'-anilino-4,4'-bipyridin-2-yl)methioninamide; [0370]
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydro-2H-pyran-4-carboxamid-
e; [0371] Ethyl
3-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-3-oxopropanoate; [0372]
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(methylthio) propanamide;
[0373]
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-pyrrolidin-2-ylacetamide;
[0374] (3S)-3-amino-N
(2'-anilino-4,4'-bipyridin-2-yl)-4-cyanobutanamide; [0375]
N1-(2'-anilino-4,4'-bipyridin-2-yl)cyclopropane-1,1-dicarboxamide;
[0376]
(3S)-1-acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-3-carbo-
xamide; [0377]
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide (+)
and (-); [0378]
N{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}tetrahydrofuran-3-carbox-
amide; [0379]
N{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}tetrahydro-2H-pyran-4-ca-
rboxamide; [0380]
Ethyl4-({2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}amino)-4-oxobutan-
oate;
4-({2'-(4-Fluorophenyl)amino]-4,4'-bipyridin-2-yl}amino)-4-oxobutano-
ic acid; [0381]
N-2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}-3-(methylthio)
propanamide; [0382] (f)-1-Acetyl-N
{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3-carboxamide;
[0383]
(3R)-1-Acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}pi-
peridine-3-carboxamide; [0384]
(3R)-1-acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidin-
e-3-carboxamide; [0385] 1-Acetyl-N
{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}pyrrolidine-3-carboxamide-
; [0386] 3-(Aminosulfonyl)-N
{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}benzamide; [0387]
Ethyl2-{[(2'-anilino-4,4'-bipyridin-2-yl)amino]methyl}cyclopropanecarboxy-
late; [0388]
2-{[(2'-Anilino-4,4'-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylic
acid; [0389]
N-phenyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-4,4'-bipyridine-2,2'-diamine;
[0390]
N-phenyl-N-(tetrahydrofuran-3-ylmethyl)-4,4'-bipyridine-2,2'-diami-
ne.
[0391] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00081##
wherein: R.sup.1 is selected from hydrogen, CONH.sub.2,
T.sub.(n)-R, or T.sub.(n)-Ar.sup.1; R is an aliphatic or
substituted aliphatic group; n is zero or one; T is C(.dbd.O),
CO.sub.2, CONH, S(O).sub.2, S(O).sub.2NH, COCH.sub.2 or CH.sub.2;
R.sub.2 is selected from hydrogen, --R, --CH.sub.2OR, --CH.sub.2OH,
--CH.dbd.O, --CH.sub.2SR, --CH.sub.2S(O).sub.2R,
--CH.sub.2(C.dbd.O)R, --CH.sub.2CO.sub.2R, --CH.sub.2CO.sub.2H,
--CH.sub.2CN, --CH.sub.2NHR, --CH.sub.2N(R).sub.2, --CH.dbd.N--OR,
--CH.dbd.NNHR, --CH.dbd.NN(R).sub.2, --CH.dbd.NNHCOR,
--CH.dbd.NNHCO.sub.2R, --CH.dbd.NNHSO.sub.2R, -aryl,
--CH.sub.2(aryl), --CH.sub.2NH.sub.2, --CH.sub.2NHCOR,
--CH.sub.2NHCONHR, --CH.sub.2NHCON(R).sub.2, --CH.sub.2NRCOR,
--CH.sub.2NHCO.sub.2R, --CH.sub.2CONHR, --CH.sub.2CON(R).sub.2,
--CH.sub.2SO.sub.2NH.sub.2, --CH.sub.2(heterocyclyl), or
--(heterocyclyl); R.sup.3 is selected from hydrogen, --R,
hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, or aryloxyalkyl; G is hydrogen
or C.sub.1-3 alkyl; Q-NH is
##STR00082##
wherein the H of Q-NH is optionally replaced by R, COR,
S(O).sub.2R, or CO.sub.2R; A is N or CH; Ar.sup.1 is aryl,
substituted aryl, heterocyclyl or substituted heterocyclyl, wherein
Ar.sup.1 is optionally fused to a partially unsaturated or fully
unsaturated five to seven membered ring containing zero to three
heteroatoms; wherein each substitutable carbon atom in Ar.sup.1,
including the fused ring when present, is optionally and
independently substituted by halo, R, OR, SR, OH, NO.sub.2, CN,
NH.sub.2, NHR, N(R).sub.2, NHCOR, NHCONHR, NHCON(R).sub.2, NRCOR,
NHCO.sub.2R, CO.sub.2R, CO.sub.2H, COR, CONHR, CON(R).sub.2,
S(O).sub.2R, SONH.sub.2, S(O)R, SO.sub.2NHR, or NHS(O).sub.2R, and
wherein each saturated carbon in the fused ring is further
optionally and independently substituted by .dbd.O, .dbd.S,
.dbd.NNHR, .dbd.NNR.sub.2, .dbd.N--OR, .dbd.NNHCOR,
.dbd.NNHCO.sub.2R, .dbd.NNHSO.sub.2R, or .dbd.NR; and wherein each
substitutable nitrogen atom in Ar.sup.1 is optionally substituted
by R, COR, S(O).sub.2R, or CO.sub.2R. These compounds have been
described in U.S. Patent Application Publication 2002/0111353 and
all of which or any present or future corresponding U.S.
application or patent are hereby incorporated by reference.
Preferred embodiments include:
##STR00083##
Further illustrative embodiments can be found in the corresponding
identified reference.
[0392] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00084##
wherein: X--Y--Z is selected from one of the following:
##STR00085##
[0393] R.sup.1 is H, CONH.sub.2, T.sub.(n)-R, or
T.sub.(n)-Ar.sup.2; R is an aliphatic or substituted aliphatic
group; n is zero or one; T is C(.dbd.O), CO.sub.2, CONH,
S(O).sub.2, S(O).sub.2NH, COCH.sub.2 or CH.sub.2; each R.sup.2 is
independently selected from hydrogen, --R, --CH.sub.2OR,
--CH.sub.2OH, --CH.dbd.O, --CH.sub.2SR, --CH.sub.2S(O).sub.2 R,
--CH.sub.2(C.dbd.O)R, --CH.sub.2CH.sub.2CO.sub.2R,
--CH.sub.2CO.sub.2H, --CH.sub.2CN, --CH.sub.2NHR,
--CH.sub.2N(R).sub.2, --H.dbd.N--OR, --CH.dbd.NNHR,
--CH.dbd.NN(R).sub.2, --CH.dbd.NNHCOR, --CH.dbd.NNHCO.sub.2R,
--CH.dbd.NNHSO.sub.2R, -aryl, -substituted aryl, --CH.sub.2(aryl),
--CH.sub.2(substituted aryl), --CH.sub.2 NHz, --CH.sub.2NHCOR,
--CH.sub.2NHCONHR, --CH.sub.2NHCON(R).sub.2, --CH.sub.2NRCOR,
--CH.sub.2 NHCO.sub.2R, --CH.sub.2CONHR, --CH.sub.2CON(R).sub.2,
--CH.sub.2SO.sub.2NH.sub.2, --CH.sub.2 (heterocyclyl), --CH.sub.2
(substituted heterocyclyl), -(heterocyclyl), or -(substituted
heterocyclyl); each R.sup.3 is independently selected from
hydrogen, R, COR, CO.sup.2R or S(O).sup.2R; C is R or Ar.sup.1;
Ar.sup.1 is aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heterocyclyl, or substituted heterocyclyl, wherein
Ar.sup.1 is optionally fused to a partially unsaturated or fully
unsaturated five to seven membered ring containing zero to three
heteroatoms; Q-NH is
##STR00086##
wherein the H of Q-NH is optionally replaced by R.sup.3; Ar.sup.2
is aryl, substituted aryl, heterocyclyl or substituted
heterocyclyl, wherein Ar.sup.2 is optionally fused to a partially
unsaturated or fully unsaturated five to seven membered ring
containing zero to three heteroatoms; wherein each substitutable
carbon atom in Ar.sup.2, including the fused ring when present, is
optionally and independently substituted by halo, R, OR, SR, OH,
NO.sub.2, CN, NH.sub.2, NHR, N(R).sub.2, NHCOR, NHCONHR,
NHCON(R).sub.2, NRCOR, NHCO.sub.2R, CO.sub.2R, CO.sub.2H, COR,
CONHR, CON(R).sub.2, S(O)R, SONH.sub.2, S(O)R, SO.sub.2NHR, or
NHS(O).sub.2R, and wherein each saturated carbon in the fused ring
is further optionally and independently substituted by .dbd.O,
.dbd.S, .dbd.NNHR, .dbd.NNR.sub.2, .dbd.N--OR, .dbd.NNHCOR,
.dbd.NNHCO.sub.2R, .dbd.NNHSO.sub.2R, or .dbd.NR; and wherein each
substitutable nitrogen atom in Ar.sup.2 is optionally substituted
by R, COR, S(O).sub.2R, or CO.sub.2R. These compounds have been
described in U.S. Pat. No. 6,693,108, and all of which or any
present or future corresponding U.S. application or patent are
hereby incorporated by reference. Preferred embodiments
include:
##STR00087##
Further illustrative embodiments can be found in the identified
reference.
[0394] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00088##
wherein: A and B are each independently selected from N or CH;
R.sup.1 and R.sup.2 are each independently selected from halogen,
CN, NO.sub.2, N(R).sub.2, OR, SR, or (T).sub.n-R.sup.5; R.sup.3 is
selected from a 3-6 membered carbocyclic or heterocyclic ring
having one to two heteroatoms independently selected from nitrogen,
oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having
one to three heteroatoms independently selected from nitrogen,
oxygen, or sulfur, wherein said phenyl or heteroaryl ring is
optionally substituted with one (T).sub.n-Ar and one to two
R.sup.7; each n is independently selected from zero or one; T is a
C.sub.1-C.sub.6 alkylidene chain, wherein one methylene unit of T
is optionally replaced by CO, CO.sub.2, COCO, CONR, OCONR, NRNR,
NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO.sub.2, NRSO.sub.2, SO.sub.2NR,
NRSO.sub.2NR, O, S, or NR; each R is independently selected from
hydrogen or an optionally substituted C.sub.1-C.sub.6 aliphatic
group; or two R on the same nitrogen atom may be taken together
with the nitrogen to form a four to eight membered, saturated or
unsaturated heterocyclic ring containing one to three heteroatoms
independently selected from nitrogen, oxygen, or sulfur; R.sup.4 is
(T).sub.n-R, (T).sub.n-Ar, or (T).sub.n-Ar.sup.1; R.sup.a is
selected from R.sup.b, halogen, NO.sub.2, OR.sup.b, SR.sup.b, or
N(R.sup.b).sub.2; R.sup.b is selected from hydrogen or a
C.sub.1-C.sub.4 aliphatic group optionally substituted with oxo,
OH, SH, NH.sub.2, halogen, NO.sub.2, or CN; R.sup.5 is an
optionally substituted C.sub.1-C.sub.6 aliphatic or Ar; Ar is a 5-6
membered saturated, partially unsaturated, or aryl monocyclic ring
having zero to three heteroatoms independently selected from
nitrogen, sulfur, or oxygen, or an 8-10-membered saturated,
partially unsaturated, or aryl bicyclic ring having zero to four
heteroatoms independently selected from nitrogen, sulfur, or
oxygen, wherein Ar is optionally substituted with one to three
R.sup.7; Ar.sup.1 is a 6-membered aryl ring having zero to two
nitrogens, wherein said ring is substituted with one Z--R.sup.6
group and optionally substituted with one to three R.sup.7; Z is a
C.sub.1-C.sub.6 alkylidene chain wherein up to two nonadjacent
methylene units of Z are optionally replaced by CO, CO.sub.2, COCO,
CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO, SO.sub.2,
NRSO.sub.2, SO.sub.2NR, NRSO.sub.2NR, O, S, or NR; provided that
said optionally replaced methylene unit of Z is a methylene unit
non-adjacent to R.sup.6; R.sup.6 is selected from Ar, R, halogen,
NO.sub.2, CN, OR, SR, N(R).sub.2, NRC(O)R, NRC(O)N(R).sub.2,
NRCO.sub.2R, C(O)R, CO.sub.2R, OC(O)R, C(O)N(R).sub.2,
OC(O)N(R).sub.2, SOR, SO.sub.2R, SO.sub.2N(R).sub.2, NRSO.sub.2R,
NRSO.sub.2N(R).sub.2, C(O)C(O)R, or C(O)CH.sub.2C(O)R; and each
R.sup.7 is independently selected from R, halogen, NO.sub.2, CN,
OR, SR, N(R).sub.2, NRC(O)R, NRC(O)N(R).sub.2, NRCO.sub.2R, C(O)R,
CO.sub.2R, C(O)N(R).sub.2, OC(O)N(R).sub.2, SOR, SO.sub.2R,
SO.sub.2N(R).sub.2, NRSO.sub.2R, NRSO.sub.2N(R).sub.2, C(O)C(O)R,
or C(O)CH.sub.2C(O)R; or two R.sup.7 on adjacent positions of
Ar.sup.1 may be taken together to form a saturated, partially
unsaturated, or fully unsaturated five to seven membered ring
containing zero to three heteroatoms selected from O, S, or N.
These compounds have been described in U.S. Patent Application
Publication Number 2004/0023963 and all of which or any present or
future corresponding U.S. application or patent are hereby
incorporated by reference. Preferred embodiments include:
##STR00089##
Further illustrative embodiments can be found in the identified
reference.
[0395] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00090##
wherein: each W is independently selected from nitrogen or CH; each
R.sup.1, R.sup.2, and R.sup.3 is independently selected from
halogen, QR, Q.sub.(n)CN, Q.sub.(n)NO.sub.2, or Q.sub.(n)Ar;
wherein: R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 are optionally
taken together to form a 4-8 membered saturated, partially
unsaturated, or fully unsaturated ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; n is zero
or one; Q is a C.sub.1-4 alkylidene chain wherein one methylene
unit of Q is optionally replaced by O, S, NR, NRCO, NRCONR,
NRCO.sub.2, CO, CO.sub.2, CONR, OC(O)NR, SO.sub.2, SO.sub.2NR,
NRSO.sub.2, NRSO.sub.2NR, C(O)C(O), or C(O)CH.sub.2C(O); each R is
independently selected from hydrogen or an optionally substituted
C.sub.1-C.sub.4 aliphatic, wherein: two R bound to the same
nitrogen atom are optionally taken together with the nitrogen atom
to form a 3-7 membered saturated, partially unsaturated, or fully
unsaturated ring having 1-2 additional heteroatoms independently
selected from nitrogen, oxygen, or sulfur; R.sup.4 is Ar.sup.1,
T-Ar.sup.2, or T.sub.(n)-Ar.sup.3; T is a C.sub.1-2 alkylidene
chain wherein one methylene unit of T is optionally replaced by O,
NR, NRCO, NRCONR, NRCO.sub.2, CO, CO2, CONR, OC(O)NR, SO.sub.2,
SO.sub.2NR, NRSO.sub.2, NRSO.sub.2NR, C(O)C(O), or
C(O)CH.sub.2C(O); Ar.sup.1 is a 5-6 membered monocyclic or 8-10
membered bicyclic saturated, partially unsaturated, or fully
unsaturated ring system; wherein: Ar1 is optionally substituted
with up to five substituents, wherein the first substituent is
selected from R.sup.x or R.sup.5 and wherein any additional
substituents are independently selected from R.sup.5; each R.sup.x
is independently selected from a 5-6 membered aryl ring having 0-3
heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:
R.sup.x is optionally substituted with 1-3 R.sup.5; each R.sup.5 is
independently selected from R, halogen, NO.sub.2, CN, OR, SR,
N(R).sub.2, NRC(O)R, NRC(O)N(R).sub.2, NRCO.sub.2R, C(O)R,
CO.sub.2R, C(O)N(R).sub.2, OC(O)N(R).sub.2, SOR, SO.sub.2R,
SO.sub.2N(R).sub.2, NRSO.sub.2R, NRSO2N(R).sub.2, C(O)C(O)R, or
C(O)CH.sub.2C(O)R; Ar.sup.2 is a 5-6 membered saturated, partially
unsaturated, or fully unsaturated monocyclic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an 8-10 membered saturated, partially unsaturated, or
fully unsaturated bicyclic ring system having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; wherein:
Ar2 is optionally substituted with up to five substituents, wherein
the first substituent is selected from R.sup.x or R.sup.5 and
wherein any additional substituents are independently selected from
R.sup.5; Ar.sup.3 is a 6-membered aryl ring having 0-2 nitrogens,
wherein: Ar.sup.3 is substituted with one Z--R group and optionally
substituted with 1-3 R.sup.5; Z is a C.sub.1-C.sub.6 alkylidene
chain wherein up to two non adjacent methylene units of Z are
optionally replaced by CO, CO.sub.2, COCO, CONR, OCONR, NRNR,
NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO, SO.sub.2, NRSO.sub.2,
SO.sub.2NR, NRSO.sub.2NR, O, S, or NR; and R.sup.6 is selected from
Ar.sup.2, R, halogen, NO.sub.2, CN, OR, SR, N(R).sub.2, NRC(O)R,
NRC(O)N(R).sub.2, NRCO.sub.2R, C(O)R, CO.sub.2R, OC(O)R,
C(O)N(R).sub.2, OC(O)N(R).sub.2, SOR, SO.sub.2R,
SO.sub.2N(R).sub.2, NRSO.sub.2R, NRSO.sub.2N(R).sub.2, C(O)C(O)R,
or C(O)CH.sub.2C(O)R. These compounds have been described in
International Publication Number WO 2002/079197 and all of which or
any present or future corresponding U.S. application or patent are
hereby incorporated by reference. Preferred embodiments
include:
##STR00091## ##STR00092##
[0396] Further illustrative embodiments can be found in the
identified reference.
[0397] The following derivatives are contemplated for use as
therapeutics in treating type I diabetes:
##STR00093##
wherein R.sup.1 is --F, --Cl, --Br, --OH, --SH, --NH.sub.2, or
--CH.sub.3; R.sup.2 is --F, --Cl, --Br --OH, --SH, --NH.sub.2, or
--CH.sub.3; R.sup.3 is --H, --F, --Cl, --Br, --OH, --SH,
--NH.sub.2, --CH.sub.3, --OCH.sub.3, or --CH.sub.2CH.sub.3; R.sup.4
is --C.sub.1-4 alkyl optionally substituted with a --C.sub.3-7
cycloalkyl; R.sup.5 is --C.sub.1-4 alkyl or --C.sub.3-7 cycloalkyl,
wherein the --C.sub.1-4 alkyl is optionally substituted with a
phenyl; X is a bond or an alkyl bridge having 1-3 carbons; Y is
--NH-- or --NH.sub.2+--; and HETCy is a 4 to 10 membered
non-aromatic heterocycle containing at least one N atom, optionally
containing 1-2 additional N atoms and 0-10 or S atom, and
optionally substituted with --C.sub.1-4 alkyl or
--C(O)--O--CH.sub.2-phenyl. These compounds have been described in
International Publication Number WO 2001/091749 and all of which or
any present or future corresponding U.S. application or patent are
hereby incorporated by reference. Preferred embodiments
include:
##STR00094## ##STR00095##
[0398] Further illustrative embodiments can be found in the
corresponding identified reference.
[0399] The embodiments of the current invention are not limited to
compounds with the structures provide. JNK2 inhibitors and
selective JNK2 inhibitors can be made using organic synthesis
techniques known to those skilled in the art, as well as by the
methods described in the respective identified references.
JNK2 Assays
[0400] Proteins can be purified by expressing the amino acid
sequence (i.e., JNK2) in a host, such as E. coli. The protein may
be expressed in combination with a second amino acid sequence
(fusion-proteins) that has properties preferential for
purification. For example, The Glutathione S-transferase (GST) gene
fusion system is an integrated system for the expression,
purification and detection of fusion proteins produced in
bacterial, yeast, mammalian and insect cells.
[0401] The sequence encoding the GST protein is incorporated into
an expression vector, generally upstream of the multi-cloning site.
The sequence encoding the protein of interest is then cloned into
this vector. Induction of the vector results in expression of a
fusion protein--the protein of interest fused to the GST protein.
The fusion protein can then be released from the cells and
purified.
[0402] Purification of the fusion protein is facilitated by the
affinity of the GST protein for glutathione residues. Glutathione
residues are coupled to a resin and the expressed protein product
is brought into contact with the resin. The fusion protein will
bind to the glutathione-resin complex and all other non-specific
proteins can be washed off. The fusion protein can then be released
from the resin using a mild elution buffer that is of low pH.
Similarly, poly-histidine sequences (his-tags) can be used.
[0403] It is possible to remove the GST or his-tag from the protein
of interest by using a number of different enzymes (thrombin,
factor X), which cleave specific sites between the GST or his-tag
and the protein of interest. Fusion proteins can also be detected
easily, with a number of antibodies now available on the
market.
[0404] There are many well-known methods to one skilled in the art
for determining the binding of one protein to another. One or more
of the following methods and other methods well-known to those
skilled in the art can be used to determine whether a compound is
an inhibitor JNK2 or selective inhibitor of JNK2.
[0405] For example, to 10 .mu.L of
5-amino-anthra(9,1-cd)isothiazol-6-one in 20% DMSO/80% dilution
buffer containing of 20 mM HEPES (pH 7.6), 0.1 mM EDTA, 2.5 mM
magnesium chloride, 0.004% Triton.times.100, 2 .mu.g/mL leupeptin,
20 mM .beta.-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM
DTT in water is added 30 .mu.L of 50-200 ng His6-JNK2 in the same
dilution buffer. The mixture is pre-incubated for 30 minutes at
room temperature. Sixty .mu.L of 10 .mu.g GST-c-Jun(1-79) in assay
buffer consisting of 20 mM HEPES (pH 7.6), 50 mM sodium chloride,
0.1 mM EDTA, 24 mM magnesium chloride, 1 mM DTT, 25 mM PNPP, 0.05%
Triton.times.100, 11 .mu.M ATP, and 0.5 .mu.Ci .gamma.-32P ATP in
water is added and the reaction is allowed to proceed for 1 hour at
room temperature. The c-Jun phosphorylation is terminated by
addition of 150 .mu.L of 12.5% trichloroacetic acid. After 30
minutes, the precipitate is harvested onto a filter plate, diluted
with 50 .mu.L of the scintillation fluid and quantified by a
counter. The IC.sub.50 values are calculated as the concentration
of 5-amino-anthra(9,1-cd)isothiazol-6-one at which the c-Jun
phosphorylation is reduced to 50% of the control value. Compounds
that inhibit JNK2 preferably have an IC.sub.50 value ranging
0.01-10 .mu.M in this assay. 5-Amino-anthra(9,1-cd)isothiazol-6-one
has an IC.sub.50 according to this assay of 1 .mu.M for JNK2 and
400 nM for JNK3. The measured IC.sub.50 value for
5-amino-anthra(9,1-cd)isothiazol-6-one, as measured by the above
assay, however, shows some variability due to the limited
solubility of 5-amino-anthra(9,1-cd)isothiazol-6-one in aqueous
media. Despite the variability, however, the assay consistently
does show that 5-amino-anthra(9,1-cd)isothiazol-6-one selectively
inhibits JNK2. This assay demonstrates that
5-amino-anthra(9,1-cd)isothiazol-6-one, an illustrative JNK2
inhibitor, inhibits JNK2 selectively and, accordingly, is useful
for treating or preventing type I diabetes.
[0406] In other examples, following pretreatment with JNK2
inhibitor (63-1700 nM in Buffer B (20 mM HEPES, 20 mM MgCl.sub.2,
20 mM .beta.-glycerophosphate, pH 7.6, containing 500 .mu.M
dithiothreitol, 100 .mu.M sodium orthovanadate), JNK activity is
assayed by incubation in Buffer B supplemented with 20 .mu.M ATP,
1.mu.Ci of [.gamma.-.sup.32P]ATP, and a protein substrate (10 .mu.g
of either GST-c-Jun, GST-Elk, or GST-ATF2). The reaction is
performed for 30 min at 30.degree. C., and then the phosphorylated
substrate was separated by SDS-PAGE, visualized by autoradiography,
and quantitated by Cerenkov counting.
C-Jun Reporter Assays
[0407] Detection of JNK2 inhibition is also described in United
States Patent Application Publication US 2004/0248886 A1, hereby
incorporated by reference. The phosphorylation of c-jun by JNK2 is
followed by monitoring the incorporation of .sup.33P into c-jun
following the protocol below. The inhibitory activity of the JNK2
inhibitors, towards c-jun phosphorylation through JNK2, is
determined by calculating phosphorylation activity in the presence
or absence of JNK2 inhibitor.
[0408] JNK2 assays can be performed in 96 well MTT plates:
incubation of 0.5 .mu.m of recombinant, pre-activated GST-JNK2 with
1 .mu.g of recombinant, biotinylated GST-c-Jun and 2 .mu.M
.sup.33.gamma.-ATP (2 nCi/.mu.L), in the presence or absence of
JNK2 inhibitor and in a reaction volume of 50 .mu.L containing 50
mM Tris-HCl, pH 8.0; 10 mM MgCl.sub.2; 1 mM Dithiothreitol, and 100
.mu.M Na.sub.3VO.sub.4. The incubation is performed for 120 min. at
R.T and stopped upon addition of 200 .mu.L of a solution containing
250 .mu.g of Streptavidine-coated SPA beads (Amershain, Inc.), 5 mM
EDTA, 0.1% TritonX-100 and 50 .mu.M ATP, in phosphate saline
buffer.
[0409] After incubation for 60 minutes at RT, beads are sedimented
by centrifugation, resuspended in 200 .mu.L of PBS containing 5 mM
EDTA, 0.1% Triton X-100 and 50 .mu.M ATP and the radioactivity
measured in a scintillation beta counter, following sedimentation
of the beads as described above. By replacing biotinylated GST-c
Jun with biotinylated GST-.sub.1ATF.sub.2 or biotinylated myelin
basic protein, this assay can be used to measure inhibition of
preactivated p38 and ERK MAP Kinases, respectively. The JNK2
inhibitors display an inhibition (IC.sub.50) with regard to JNK2 of
less than 10 .mu.M, preferably less than 1 .mu.M and more preferred
less than 0.25 .mu.M.
[0410] The phosphorylation of the transcriptional factor, c-jun, by
JNK2 in the MAP kinase signal transduction pathway can be followed
via a trans-reporting system such as the commercially available
PathDetect as provided in Xu, L. et al., Assess the in-vivo
activation of signal transduction pathways with Pathdetect
reporting systems, Strategies 2001, 14 (1): 17-19.
[0411] A trans-reporting system allows one to follow, via
Luciferase activity, the activation status of a fusion
trans-activator protein. The trans-activator protein consists of
the activation domain of the transcriptional factor of interest
(c-jun) fused with a yeast transcriptional activator, GALA DNA
binding domain (dbd). The GAL4 dbd has the advantage that no known
mammalian transcriptional factors bind to it and therefore the
background noise of the assay is very low.
[0412] In the present case, Hela luciferase reporter-c-Jun
(HLR-c-Jun) cell lines that constitutively express GAL4-cJun may be
used. Recombinant JNK2 and substrates (c-Jun-(1-135),
Elk-(307-428), or ATF2-(19-96)) may be produced in Escherichia coli
as GST fusion proteins. For JNK2, the GST portion of the fusion
protein may be removed by overnight cleavage with thrombin (3
units) in Thrombin Cleavage buffer (50 mM Tris, pH 8.0, 150 mM
NaCl, 5 mM MgCl.sub.2, 2.5 mM CaCl.sub.2, and 1 mM
dithiothreitol)
[0413] Once, JNK is activated it can induce the phosphorylation of
the c-jun domain of the fusion trans-activator protein (GAL4
dbd-cjun) which forms a dimer. The dimer is then is able to bind to
a GAL4 upstream activating sequence (GAL4 UAS) of the reporter that
activates Luciferase expression. Luciferase expression is detected
by luminescence using a simple assay such as Dual-Luciferase
Reporter Assay System in which Renilla is used as a "control
reporter". Inhibition of JNK is observed as a decrease in
Luciferase expression and detected by a decrease in luminescence.
U.S. Pat. No. 5,744,320, hereby incorporated by reference,
describes a Dual-Luciferase Reporter Assay System.
LPS Induced Endotoxin Shock in Mice
[0414] Endotoxins are the lipopolysaccharides (LPS) constituents of
the outer membrane of Gram-negative bacteria. Response to LPS has
been shown to involve the activation of different cell populations
and to lead to the expression of various inflammatory cytokines
that include tumor necrosis factor-alpha (TNF-.alpha.) and
interferon .gamma. (IFN-.gamma.). As LPS is known to stimulate the
activation of various MAP kinase pathways, including JNK, the
ability of JNK inhibitors can be tested after the JNK signaling
pathway has been switched on by a LPS challenge.
[0415] The activity as JNK inhibitors of compounds of formula may
be assessed after a LPS challenge using the following protocol: LPS
(S. abortus-Galanos Lab-) is injected (200 .mu.g/kg, i.v.) to Male
C57BL/6 mice to induce endotoxin shock. Compounds (0.1, 1, 10
mg/kg) or NaCl (200 uM) are injected intravenously (10 mL/kg) 15
min before the LPS challenge. Heparinized blood was obtained from
the orbital sinus at different time points after the LPS challenge,
and the blood was centrifuged at 9'000 rpm for 10 min at 4.degree.
C. to collect supernatant. Measurement of cytokines production such
as TNF-.alpha. and IFN-.gamma. by mouse is performed with an ELISA
kit such as Duoset DY410 for TNF-.alpha. and DY 485 for
IFN-.gamma.. Other ELISA assays can be used.
Surface Plasmon Resonance
[0416] Real time kinetic studies of the interactions between
recombinant JNK proteins (JNK2, JNK3, and kinase-inactive JNK3) and
peptide may be performed on a BIAcore 2000 biosensor. The running
and sample dilution buffer is 10 mM HEPES, pH 7.4, 150 mM NaCl, 3.4
mM EDTA, 0.005% (v/v) Tween 20. The biotinylated peptide may
immobilized onto 3 flow cells of each 4-flow cell SA-biosensor chip
to achieve .about.20, 40, and 80 resonance units (RU). The
remaining blank flow cell on each chip measured background
interactions.
[0417] The binding of proteins to the immobilized peptides is
recorded as RU in real time to provide a sensorgram. Binding
profiles are created by injecting 10 .mu.M JNK2, JNK3, and
kinase-inactive JNK3 (JNK3 (kin.sup.-)) at a flow rate of 20
.mu.l/min. GST-c-Jun-(1-135), GST-Elk-(307-428), and
GST-ATF2-(19-96) are injected at 5 .mu.M concentration to
approximate concentrations present during standard in vitro kinase
assays.
Pharmaceutical Compositions
[0418] The compositions comprising a JNK2 inhibitor include
bulk-drug compositions useful in the manufacture of pharmaceutical
compositions (e.g., impure or non-sterile compositions) and
pharmaceutical compositions (i.e., compositions that are suitable
for administration to a patient) that can be used in the
preparation of unit dosage forms. Such compositions optionally
comprise a prophylactically or therapeutically effective amount of
a prophylactic and/or therapeutic agent disclosed herein or a
combination of those agents and a pharmaceutically acceptable
carrier. Preferably, compositions of the invention comprise a
prophylactically or therapeutically effective amount of JNK2
inhibitor and another therapeutic or prophylactic agent, and a
pharmaceutically acceptable carrier.
[0419] In a specific embodiment, the term "pharmaceutically
acceptable" means approved by a regulatory agency of the Federal or
a state government or listed in the U.S. Pharmacopeia or other
generally recognized pharmacopeia for use in animals, and more
particularly in humans. The term "carrier" refers to a diluent,
adjuvant, excipient, or vehicle with which a JNK2 inhibitor is
administered. Such pharmaceutical vehicles can be liquids, such as
water and oils, including those of petroleum, animal, vegetable or
synthetic origin, such as peanut oil, soybean oil, mineral oil,
sesame oil and the like. The pharmaceutical vehicles can be saline,
gum acacia, gelatin, starch paste, talc, keratin, colloidal silica,
urea, and the like. In addition, auxiliary, stabilizing,
thickening, lubricating and coloring agents can be used. When
administered to a patient, the pharmaceutically acceptable vehicles
are preferably sterile. Water can be the vehicle when the JNK2
inhibitor is administered intravenously. Saline solutions and
aqueous dextrose and glycerol solutions can also be employed as
liquid vehicles, particularly for injectable solutions. Suitable
pharmaceutical vehicles also include excipients such as starch,
glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, sodium stearate, glycerol monostearate, talc, sodium
chloride, dried skim milk, glycerol, propyleneglycol, water,
ethanol and the like. The present compositions, if desired, can
also contain minor amounts of wetting or emulsifying agents, or pH
buffering agents.
[0420] The present compositions can take the form of solutions,
suspensions, emulsion, tablets, pills, pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions, aerosols, sprays, suspensions, or any
other form suitable for use. In one embodiment, the
pharmaceutically acceptable vehicle is a capsule (see e.g., U.S.
Pat. No. 5,698,155).
[0421] In a preferred embodiment, the JNK2 inhibitor and optionally
a therapeutic or prophylactic agent are formulated in accordance
with routine procedures as pharmaceutical compositions adapted for
intravenous administration to human beings. Typically, JNK2
inhibitors for intravenous administration are solutions in sterile
isotonic aqueous buffer. Where necessary, the compositions can also
include a solubilizing agent. Compositions for intravenous
administration can optionally include a local anesthetic such as
lignocaine to ease pain at the site of the injection. Generally,
the ingredients are supplied either separately or mixed together in
unit dosage form, for example, as a dry lyophilized powder or water
free concentrate in a hermetically sealed container such as an
ampoule or sachette indicating the quantity of active agent. Where
the JNK2 inhibitor is to be administered by infusion, it can be
dispensed, for example, with an infusion bottle containing sterile
pharmaceutical grade water or saline. Where the JNK2 inhibitor is
administered by injection, an ampoule of sterile water for
injection or saline can be provided so that the ingredients can be
mixed prior to administration.
[0422] Compositions for oral delivery can be in the form of
tablets, lozenges, aqueous or oily suspensions, granules, powders,
emulsions, capsules, syrups, or elixirs, for example. Orally
administered compositions can contain one or more optional agents,
for example, sweetening agents such as fructose, aspartame or
saccharin; flavoring agents such as peppermint, oil of wintergreen,
or cherry; coloring agents; and preserving agents, to provide a
pharmaceutically palatable preparation. Moreover, where in tablet
or pill form, the compositions can be coated to delay
disintegration and absorption in the gastrointestinal tract thereby
providing a sustained action over an extended period of time.
Selectively permeable membranes surrounding an osmotically active
driving compound are also suitable for an orally administered JNK2
inhibitor. In these later platforms, fluid from the environment
surrounding the capsule is imbibed by the driving compound, which
swells to displace the agent or agent composition through an
aperture. These delivery platforms can provide an essentially zero
order delivery profile as opposed to the spiked profiles of
immediate release formulations. A time delay material such as
glycerol monostearate or glycerol stearate can also be used. Oral
compositions can include standard vehicles such as mannitol,
lactose, starch, magnesium stearate, sodium saccharine, cellulose,
magnesium carbonate, and the like. Such vehicles are preferably of
pharmaceutical grade.
[0423] Further, the effect of the JNK2 inhibitor can be delayed or
prolonged by proper formulation. For example, a slowly soluble
pellet of the JNK2 inhibitor can be prepared and incorporated in a
tablet or capsule. The technique can be improved by making pellets
of several different dissolution rates and filling capsules with a
mixture of the pellets. Tablets or capsules can be coated with a
film that resists dissolution for a predictable period of time.
Even the parenteral preparations can be made long-acting, by
dissolving or suspending the compound in oily or emulsified
vehicles which allow it to disperse only slowly in the serum.
Formulations
[0424] Pharmaceutical compositions for use in accordance with the
present invention can be formulated in conventional manner using
one or more physiologically acceptable carriers or excipients.
[0425] Thus, the JNK2 inhibitor and optionally the therapeutic or
prophylactic agent and their physiologically acceptable salts and
solvates can be formulated into pharmaceutical compositions for
administration by inhalation or insufflation (either through the
mouth or the nose) or oral, parenteral or mucosol (such as buccal,
vaginal, rectal, sublingual) administration. In one embodiment,
local or systemic parenteral administration is used.
[0426] For oral administration, the pharmaceutical compositions can
take the form of, for example, tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients such
as binding agents (e.g., pregelatinised maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers
(e.g., lactose, microcrystalline cellulose or calcium hydrogen
phosphate); lubricants (e.g., magnesium stearate, talc or silica);
disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulphate). The tablets can be
coated by methods well known in the art. Liquid preparations for
oral administration can take the form of, for example, solutions,
syrups or suspensions, or they can be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations can be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible
fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous
vehicles (e.g., almond oil, oily esters, ethyl alcohol or
fractionated vegetable oils); and preservatives (e.g., methyl or
propyl-p-hydroxybenzoates or sorbic acid). The preparations can
also contain buffer salts, flavoring, coloring and sweetening
agents as appropriate.
[0427] Preparations for oral administration can be suitably
formulated to give controlled release of the active compound.
[0428] For buccal administration the pharmaceutical compositions
can take the form of tablets or lozenges formulated in conventional
manner.
[0429] For administration by inhalation, the pharmaceutical
compositions for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebulizer, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit can be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of e.g., gelatin for use in an inhaler or insufflator
can be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0430] The pharmaceutical compositions can be formulated for
parenteral administration by injection, e.g., by bolus injection or
continuous infusion. Formulations for injection can be presented in
unit dosage form, e.g., in ampoules or in multi-dose containers,
with an added preservative. The pharmaceutical compositions can
take such forms as suspensions, solutions or emulsions in oily or
aqueous vehicles, and can contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. Alternatively,
the active ingredient can be in powder form for constitution with a
suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0431] The pharmaceutical compositions can also be formulated in
rectal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0432] In addition to the formulations described previously, the
pharmaceutical compositions can also be formulated as a depot
preparation. Such long acting formulations can be administered by
implantation (for example subcutaneously or intramuscularly) or by
intramuscular injection. Thus, for example, the pharmaceutical
compositions can be formulated with suitable polymeric or
hydrophobic materials (for example as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0433] The invention also provides that a pharmaceutical
composition is packaged in a hermetically sealed container such as
an ampoule or sachette indicating the quantity. In one embodiment,
the pharmaceutical composition is supplied as a dry sterilized
lyophilized powder or water free concentrate in a hermetically
sealed container and can be reconstituted, e.g., with water or
saline to the appropriate concentration for administration to a
patient.
[0434] In other embodiments of the invention, radiation therapy
agents such as radioactive isotopes can be given orally as liquids
in capsules or as a drink. Radioactive isotopes can also be
formulated for intravenous injection. The skilled oncologist can
determine the preferred formulation and route of
administration.
[0435] The pharmaceutical compositions can, if desired, be
presented in a pack or dispenser device that can contain one or
more unit dosage forms containing the active ingredient. The pack
can for example comprise metal or plastic foil, such as a blister
pack. The pack or dispenser device can be accompanied by
instructions for administration.
[0436] In certain preferred embodiments, the pack or dispenser
contains one or more unit dosage forms containing no more than the
recommended dosage formulation as determined in the Physician's
Desk Reference (56.sup.th ed. 2002, herein incorporated by
reference in its entirety).
Routes of Administration
[0437] Methods of administering a JNK2 inhibitor and optionally a
therapeutic or prophylactic agent include, but are not limited to,
parenteral administration (e.g., intradermal, intramuscular,
intraperitoneal, intravenous and subcutaneous), epidural, and
mucosal (e.g., intranasal, rectal, vaginal, sublingual, buccal or
oral routes). In a specific embodiment, the JNK2 inhibitor and
optionally the prophylactic or therapeutic agents are administered
intramuscularly, intravenously, or subcutaneously. The JNK2
inhibitor and optionally the prophylactic or therapeutic agent can
also be administered by infusion or bolus injection and can be
administered together with other biologically active agents.
Administration can be local or systemic. The JNK2 inhibitor and
optionally the prophylactic or therapeutic agent and their
physiologically acceptable salts and solvates can also be
administered by inhalation or insufflation (either through the
mouth or the nose). In a preferred embodiment, local or systemic
parenteral administration is used.
[0438] In specific embodiments, it can be desirable to administer
the JNK2 inhibitor locally to the area in need of treatment. This
can be achieved, for example, and not by way of limitation, by
local infusion during surgery, topical application, e.g., in
conjunction with a wound dressing after surgery, by injection, by
means of a catheter, by means of a suppository, or by means of an
implant, said implant being of a porous, non-porous, or gelatinous
material, including membranes, such as silastic membranes, or
fibers. In one embodiment, administration can be by direct
injection at the site (or former site) of an atherosclerotic plaque
tissue.
[0439] Pulmonary administration can also be employed, e.g., by use
of an inhaler or nebulizer, and formulation with an aerosolizing
agent, or via perfusion in a fluorocarbon or synthetic pulmonary
surfactant. In certain embodiments, the JNK2 inhibitor can be
formulated as a suppository, with traditional binders and vehicles
such as triglycerides.
[0440] In another embodiment, the JNK2 inhibitor can be delivered
in a vesicle, in particular a liposome.
[0441] In yet another embodiment, the JNK2 inhibitor can be
delivered in a controlled release system. In one embodiment, a pump
can be used. In another embodiment, polymeric materials can be
used.
Dosages
[0442] The amount of the JNK2 inhibitor that is effective in the
treatment or prevention of type I diabetes can be determined by
standard research techniques. For example, the dosage of the JNK2
inhibitor which will be effective in the treatment or prevention of
type I diabetes can be determined by administering the JNK2
inhibitor to an animal in a model such as, e.g., the animal models
known to those skilled in the art. In addition, in vitro assays can
optionally be employed to help identify optimal dosage ranges.
[0443] Selection of a particular effective dose can be determined
(e.g., via clinical trials) by a skilled artisan based upon the
consideration of several factors which will be known to one skilled
in the art. Such factors include the disease to be treated or
prevented, the symptoms involved, the patient's body mass, the
patient's immune status and other factors known by the skilled
artisan.
[0444] The precise dose to be employed in the formulation will also
depend on the route of administration, and the seriousness of the
disease-related wasting, and should be decided according to the
judgment of the practitioner and each patient's circumstances.
Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
[0445] The dose of a JNK2 inhibitor to be administered to a
patient, such as a human, is rather widely variable and can be
subject to independent judgment. It is often practical to
administer the daily dose of a JNK2 inhibitor at various hours of
the day. However, in any given case, the amount of a JNK2 inhibitor
administered will depend on such factors as the solubility of the
active component, the formulation used, patient condition (such as
weight), and/or the route of administration.
[0446] The general range of effective amounts of the JNK2 inhibitor
alone or in combination with the prophylactic or therapeutic
agent(s) are from about 0.001 mg/day to about 1000 mg/day, more
preferably from about 0.001 mg/day to 750 mg/day, more preferably
from about 0.001 mg/day to 500 mg/day, more preferably from about
0.001 mg/day to 250 mg/day, more preferably from about 0.001 mg/day
to 100 mg/day, more preferably from about 0.001 mg/day to 75
mg/day, more preferably from about 0.001 mg/day to 50 mg/day, more
preferably from about 0.001 mg/day to 25 mg/day, more preferably
from about 0.001 mg/day to 10 mg/day, more preferably from about
0.001 mg/day to 1 mg/day. Of course, it is often practical to
administer the daily dose of compound in portions, at various hours
of the day. However, in any given case, the amount of compound
administered will depend on such factors as the solubility of the
active component, the formulation used, subject condition (such as
weight), and/or the route of administration.
[0447] For antibodies, the dosage administered to a patient is
typically 0.1 mg/kg to 100 mg/kg of the patient's body weight.
Preferably, the dosage administered to a patient is between 0.1
mg/kg and 20 mg/kg of the patient's body weight, more preferably 1
mg/kg to 10 mg/kg of the patient's body weight. Generally, human
and humanized antibodies have a longer half-life within the human
body than antibodies from other species due to the immune response
to the foreign polypeptides. Thus, lower dosages of human
antibodies and less frequent administration is often possible.
[0448] The invention provides for any method of administrating
lower doses of known agents (e.g., insulin) than previously thought
to be useful for the prevention or treatment of type I
diabetes.
Kits
[0449] The invention provides a pharmaceutical pack or kit
comprising one or more containers containing a JNK2 inhibitor and
optionally one or more other prophylactic or therapeutic agents
useful for the treatment of type I diabetes (e.g insulin). The
invention also provides a pharmaceutical pack or kit comprising one
or more containers containing one or more of the ingredients of the
pharmaceutical compositions. Optionally associated with such
container(s) can be a notice in the form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects
approval by the agency of manufacture, use or sale for human
administration; or instructions for the composition's use.
[0450] The present invention provides kits that can be used in the
above methods. In one embodiment, a kit comprises a JNK Inhibitor,
in one or more containers, and optionally one or more other
prophylactic or therapeutic agents useful for the treatment of type
I diabetes, in one or more containers.
Example 1
[0451] Spontaneous diabetes is decreased in JNK2-deficient mice. We
used the non-obese diabetic (NOD) mouse model of autoimmune
diabetes as disclosed in Delovitch & Singh, The non-obese
diabetic mouse as a model of autoimmune diabetes: immune
dysregulation gets the NOD. Immunity 7, 727-38 (1997). NOD and
NOD/Scid mice were obtained from The Jackson Laboratory (Bar
Harbor, Me.). Mapk9-/- mice (Yang, D. D. et al. Differentiation of
CD4+ T cells to Th1 cells requires MAP kinase JNK2. Immunity 9,
575-85 (1998)) were back-crossed with NOD mice for 6 generations
and Jnk2-/+ mice that are homozygous for the 15 Idd NOD alleles
were identified by PCR genotyping, as described previously (Mora et
al., Role of L-selectin in the development of autoimmune diabetes
in non-obese diabetic mice. Int Immunol 16, 257-64 (2004)). These
NOD/Mapk9-/+ mice were back-crossed for an additional four
generations onto the NOD background. NOD/Mapk9-/- mice were
obtained by crossing NOD/Mapk9-/+ mice. The Mapk9 genotype was
examined by PCR analysis. Blood glucose levels were monitored
weekly with a Dex-Glucometer (Bayer). Animals with a blood glucose
level higher than 200 mg/dl for 2 consecutive weeks were considered
diabetic.
[0452] The presence of hyperglycemia (blood glucose>200 mg/dl)
was examined in a cohort of 32 NOD mice and 28 female NOD/Mapk9-/-
mice. The data in FIG. 1 is presented as the % of mice with
hyperglycemia. Comparison of the spontaneous incidence of disease
in female NOD and NOD/Mapk9-/- mice indicated that JNK2-deficiency
decreases the cumulative incidence of diabetes.
Example 2
[0453] JNK2-defiency causes reduced insulitis in NOD mice. We
performed histological analysis of the pancreas. At 13 weeks of
age, control NOD mice exhibited severe islet infiltration with less
than 20% normal islets and greater than 50% of the islets showing
invasive and destructive insulitis. In contrast, more than 70% of
the islets in JNK2-deficient mice were not infiltrated and the
residual 30% showed mostly peri-insulitis (FIG. 2a,b). At 30 weeks
of age, all the islets of NOD mice showed severe destructive
insulitis, but normal un-infiltrated islets were detected in
JNK2-deficient NOD mice. Control studies demonstrated that the
extent of islet infiltration in JNK1-deficient (Mapk8-/-) NOD mice
was similar to wild type NOD mice, indicating a selective role for
JNK2 in the regulation of islet infiltration in NOD mice.
Example 3
[0454] JNK2-deficiency causes reduced diabetes in adoptive transfer
studies. Autoimmune diabetes can be adoptively transferred to
euglycemic recipients by injection of splenic T cells. In order to
examine the diabetogenic potential of T cells from JNK2-deficient
mice, T cells from young (13 week old) non-diabetic NOD and
NOD/Mapk9-/- mice were transferred into NOD/Scid recipients.
NOD/Scid mice were injected intravenously with 2.times.10.sup.7
total splenocytes and were monitored (14 weeks) for diabetes. NOD
mice (7 weeks old males) were irradiated (725 rad) one day prior to
adoptive transfer of 2.times.10.sup.7 total splenocytes from
recently diagnosed diabetic donors by intravenous injection; the
mice were monitored (8 weeks) for diabetes. The incidence of
diabetes was significantly reduced if recipient mice received
splenic T cells from JNK2-deficient donors compared to control NOD
donors (FIG. 3a). This observation indicates that the generation of
beta-cell specific diabetogenic T cells may be impaired in
JNK2-deficient mice.
Example 4
[0455] Analysis of the distribution of T cell populations and their
activation markers in lymph nodes and spleen showed no difference
between non-diabetic NOD and NOD/Mapk9-/- mice. The presence of T
cells in infiltrated islets was examined by immunohistochemistry on
frozen pancreatic sections. Pancreata were fixed in 10% formalin,
embedded in paraffin, sectioned and stained with hematoxylin-eosin.
Immunohistochemistry was performed using tissue embedded in
Tissue-Tek OCT and frozen in 2-methylbutane. 5 .mu.m sections were
stained with FITC-conjugated antibodies to CD4 and CD8 (PharMingen)
and mounted in Vectashield with DAPI (Vector Laboratories).
[0456] Although the number of infiltrated islets in NOD mice was
greater than the number of infiltrated islets in NOD/Mapk9-/- mice
(FIG. 2), the percentage of CD4+ and CD8+ T cells within the
infiltrated islets was similar in NOD and NOD/Mapk9-/- mice (FIG.
4a). A Th1 (IFN-gamma) environment accelerates the recruitment of
islet-specific CD4+ T cells and also accelerates the onset of
diabetes, while a Th2 environment protects against autoimmune
diabetes. We therefore examined whether JNK2-deficiency in NOD CD4+
T cells could promote the differentiation of these cells into Th2
effector cells. CD4+ T cells were isolated from non-diabetic
8-week-old NOD and JNK2-deficient NOD mice and activated with
immobilized anti-CD3 monoclonal antibody (mAb) and soluble
anti-CD28 mAb in the presence of IL-4 (to promote Th2
differentiation) or IL-12 (to promoteTh1 differentiation). After 4
days of differentiation, the cells were washed and re-restimulated
with immobilized anti-CD3 mAb. Culture supernatants were then
harvested 24 h later for analysis of cytokine production. Although
IFN-gamma secretion by Th1 cells was not significantly affected in
JNK2-deficient mice (FIG. 4a), the production of IL-4 by Th2 cells
and Th1 cells was substantially increased in these mice compared
with wild-type mice (FIG. 4a). Similarly, the secretion of IL-5,
another Th2 cytokine, was also augmented in Th2 and Th1 cells from
JNK2-deficient mice (FIG. 4b).
Example 5
[0457] To demonstrate that JNK2-deficiency promoted the production
of Th2 cytokines, we examined the cytokine profile of non-polarized
effector (Th0) cells differentiated with anti-CD3 and anti-CD28
mAbs in the absence of exogenous cytokines. Although IL-4 secretion
by wild-type NOD Th0 cells was not detected, high levels of IL-4
were produced by JNK2-deficient NOD Th0 cells (FIG. 4A).
Furthermore, the amount of IL-5 secreted by JNK2-deficient NOD Th0
cells was similar to the high level produced by Th2 cells, but no
IL-5 production by NOD Th0 cells was detected. In addition, the
expression of IFN-gamma by Th0 cells from JNK2-deficient mice was
greatly reduced (FIG. 4b). To test whether this phenotype was due
to an impaired differentiation or to an impaired activation of
effector cells, we examined cytokine production during the
differentiation (days 3 and 4) of CD4+ T cells in the absence of
exogenous cytokines. IL-4 was detected in cultures of
differentiating JNK2-deficient CD4+ T cells (FIG. 4b). In contrast,
the JNK2-deficient CD4+ T cells produced lower levels of IFN-gamma
compared with NOD CD4+ T cells (FIG. 4c). Together, these data
indicate that JNK2-deficiency caused an intrinsic polarization of
NOD CD4+ T cells towards Th2 effectors independently of the
cytokine environment. Control studies demonstrated that the Th1/2
polarization of CD4+ T cells from JNK1-deficient (Mapk8-/-) NOD
mice was similar to wild-type NOD mice, indicating a selective role
for JNK2 in the regulation of CD4+ T differentiation in NOD
mice.
[0458] Total CD4+ cells were isolated from spleen and lymph nodes
by negative selection using anti-NK1.1 (Pharmigen), anti-CD8
(TB105), anti-Mac1 (Pharmingen), and anti-MHC class II (m5/115)
mAbs followed by depletion with magnetic beads. CD4+ T cells were
activated (106 cells/ml) with immobilized anti-CD3 mAb (2C11) (5
.mu.g/ml) and anti-CD28 mAb (Pharmingen) (1 .mu.g/ml) in the
presence of medium (for Th0 cells), IL-4 (for Th2 cells) (R&D)
(103 U/ml) or IL-12 (for Th1 cells) (Genetics Institute) (3.5
ng/ml) for four days. Cells were then extensively washed, counted
and equal number of cells were restimulated with immobilized
anti-CD3 mAb for 24 h when supernatant was harvested. Cytokine
production was determine by ELISAs using anti-IL4 or
anti-IFN-.gamma. mAb (2 .mu.g/ml), biotinylated anti-IL4 or
anti-IFN-.gamma. mAb (1 .mu.g/ml) (Pharmingen), horseradish
peroxidase conjugated avidin D (Sigma), peroxidase substrate and
reaction stop solutions
Example 6
[0459] We also tested whether the resistance of JNK2-deficient NOD
mice to insulitis was exclusively due to the Th2 phenotype of CD4+
T cells or whether JNK2 could also contribute to islet .beta. cell
death. Adoptive transfer of T cells isolated from diabetic NOD
donor mice causes rapid development of diabetes in sub-lethally
irradiated NOD host mice within 2 to 4 weeks. We therefore
transferred splenocytes from recently diagnosed diabetic female NOD
mice into irradiated male NOD and NOD/Mapk9-/- mice. The frequency
of diabetes caused by the T cells isolated from diabetic NOD mice
was significantly reduced when these cells were introduced into
JNK2-deficient NOD mice compared to control NOD mice (FIG. 3b). The
JNK2-deficient NOD group of recipient mice exhibited reduced
diabetes compared with the control group of NOD mice after 8 weeks.
These data suggest that JNK2-deficiency may also increase
resistance of P3 cells to apoptosis. Although NOD/Mapk9-/- beta
cells and NOD beta cells were found to be equally sensitive to
apoptosis induced by IL-1beta, TNF-alpha, and IFN-gamma in vitro,
it is possible that JNK2-deficiency might enhance resistance to
death induced by other T cell mediators, including perforin,
granzyme, or Fas ligand.
Example 7
[0460] Islets are taken from a donor pancreas and transferred into
another person. Once implanted, the .beta.-cells in these islets
begin to make and release insulin. A
5-amino-anthra(9,1-cd)isothiazol-6-one is administer to a subject
before, during, or after islet transplant surgery.
Sequence CWU 1
1
61384PRTHomo sapiens 1Met Ser Arg Ser Lys Arg Asp Asn Asn Phe Tyr
Ser Val Glu Ile Gly 1 5 10 15 Asp Ser Thr Phe Thr Val Leu Lys Arg
Tyr Gln Asn Leu Lys Pro Ile 20 25 30 Gly Ser Gly Ala Gln Gly Ile
Val Cys Ala Ala Tyr Asp Ala Ile Leu 35 40 45 Glu Arg Asn Val Ala
Ile Lys Lys Leu Ser Arg Pro Phe Gln Asn Gln 50 55 60 Thr His Ala
Lys Arg Ala Tyr Arg Glu Leu Val Leu Met Lys Cys Val 65 70 75 80 Asn
His Lys Asn Ile Ile Gly Leu Leu Asn Val Phe Thr Pro Gln Lys 85 90
95 Ser Leu Glu Glu Phe Gln Asp Val Tyr Ile Val Met Glu Leu Met Asp
100 105 110 Ala Asn Leu Cys Gln Val Ile Gln Met Glu Leu Asp His Glu
Arg Met 115 120 125 Ser Tyr Leu Leu Tyr Gln Met Leu Cys Gly Ile Lys
His Leu His Ser 130 135 140 Ala Gly Ile Ile His Arg Asp Leu Lys Pro
Ser Asn Ile Val Val Lys 145 150 155 160 Ser Asp Cys Thr Leu Lys Ile
Leu Asp Phe Gly Leu Ala Arg Thr Ala 165 170 175 Gly Thr Ser Phe Met
Met Thr Pro Tyr Val Val Thr Arg Tyr Tyr Arg 180 185 190 Ala Pro Glu
Val Ile Leu Gly Met Gly Tyr Lys Glu Asn Val Asp Leu 195 200 205 Trp
Ser Val Gly Cys Ile Met Gly Glu Met Val Cys His Lys Ile Leu 210 215
220 Phe Pro Gly Arg Asp Tyr Ile Asp Gln Trp Asn Lys Val Ile Glu Gln
225 230 235 240 Leu Gly Thr Pro Cys Pro Glu Phe Met Lys Lys Leu Gln
Pro Thr Val 245 250 255 Arg Thr Tyr Val Glu Asn Arg Pro Lys Tyr Ala
Gly Tyr Ser Phe Glu 260 265 270 Lys Leu Phe Pro Asp Val Leu Phe Pro
Ala Asp Ser Glu His Asn Lys 275 280 285 Leu Lys Ala Ser Gln Ala Arg
Asp Leu Leu Ser Lys Met Leu Val Ile 290 295 300 Asp Ala Ser Lys Arg
Ile Ser Val Asp Glu Ala Leu Gln His Pro Tyr 305 310 315 320 Ile Asn
Val Trp Tyr Asp Pro Ser Glu Ala Glu Ala Pro Pro Pro Lys 325 330 335
Ile Pro Asp Lys Gln Leu Asp Glu Arg Glu His Thr Ile Glu Glu Trp 340
345 350 Lys Glu Leu Ile Tyr Lys Glu Val Met Asp Leu Glu Glu Arg Thr
Lys 355 360 365 Asn Gly Val Ile Arg Gly Gln Pro Ser Pro Leu Ala Gln
Val Gln Gln 370 375 380 2424PRTHomo sapiens 2Met Ser Asp Ser Lys
Cys Asp Ser Gln Phe Tyr Ser Val Gln Val Ala 1 5 10 15 Asp Ser Thr
Phe Thr Val Leu Lys Arg Tyr Gln Gln Leu Lys Pro Ile 20 25 30 Gly
Ser Gly Ala Gln Gly Ile Val Cys Ala Ala Phe Asp Thr Val Leu 35 40
45 Gly Ile Ser Val Ala Val Lys Lys Leu Ser Arg Pro Phe Gln Asn Gln
50 55 60 Thr His Ala Lys Arg Ala Tyr Arg Glu Leu Val Leu Leu Lys
Cys Val 65 70 75 80 Asn His Lys Asn Ile Ile Ser Leu Leu Asn Val Phe
Thr Pro Gln Lys 85 90 95 Thr Leu Glu Glu Phe Gln Asp Val Tyr Leu
Val Met Glu Leu Met Asp 100 105 110 Ala Asn Leu Cys Gln Val Ile His
Met Glu Leu Asp His Glu Arg Met 115 120 125 Ser Tyr Leu Leu Tyr Gln
Met Leu Cys Gly Ile Lys His Leu His Ser 130 135 140 Ala Gly Ile Ile
His Arg Asp Leu Lys Pro Ser Asn Ile Val Val Lys 145 150 155 160 Ser
Asp Cys Thr Leu Lys Ile Leu Asp Phe Gly Leu Ala Arg Thr Ala 165 170
175 Cys Thr Asn Phe Met Met Thr Pro Tyr Val Val Thr Arg Tyr Tyr Arg
180 185 190 Ala Pro Glu Val Ile Leu Gly Met Gly Tyr Lys Glu Asn Val
Asp Ile 195 200 205 Trp Ser Val Gly Cys Ile Met Gly Glu Leu Val Lys
Gly Cys Val Ile 210 215 220 Phe Gln Gly Thr Asp His Ile Asp Gln Trp
Asn Lys Val Ile Glu Gln 225 230 235 240 Leu Gly Thr Pro Ser Ala Glu
Phe Met Lys Lys Leu Gln Pro Thr Val 245 250 255 Arg Asn Tyr Val Glu
Asn Arg Pro Lys Tyr Pro Gly Ile Lys Phe Glu 260 265 270 Glu Leu Phe
Pro Asp Trp Ile Phe Pro Ser Glu Ser Glu Arg Asp Lys 275 280 285 Ile
Lys Thr Ser Gln Ala Arg Asp Leu Leu Ser Lys Met Leu Val Ile 290 295
300 Asp Pro Asp Lys Arg Ile Ser Val Asp Glu Ala Leu Arg His Pro Tyr
305 310 315 320 Ile Thr Val Trp Tyr Asp Pro Ala Glu Ala Glu Ala Pro
Pro Pro Gln 325 330 335 Ile Tyr Asp Ala Gln Leu Glu Glu Arg Glu His
Ala Ile Glu Glu Trp 340 345 350 Lys Glu Leu Ile Tyr Lys Glu Val Met
Asp Trp Glu Glu Arg Ser Lys 355 360 365 Asn Gly Val Val Lys Asp Gln
Pro Ser Asp Ala Ala Val Ser Ser Asn 370 375 380 Ala Thr Pro Ser Gln
Ser Ser Ser Ile Asn Asp Ile Ser Ser Met Ser 385 390 395 400 Thr Glu
Gln Thr Leu Ala Ser Asp Thr Asp Ser Ser Leu Asp Ala Ser 405 410 415
Thr Gly Pro Leu Glu Gly Cys Arg 420 323PRTHomo sapiens 3Asp Thr Tyr
Arg Pro Lys Arg Pro Thr Thr Leu Asn Leu Phe Pro Gln 1 5 10 15 Val
Pro Arg Ser Gln Asp Thr 20 421PRTHomo sapiens 4Glu Glu Pro His Lys
His Arg Pro Thr Thr Leu Arg Leu Thr Thr Leu 1 5 10 15 Gly Ala Gln
Asp Ser 20 511PRTArtificial SequenceSynthetic 5Phe Leu Asn Leu Thr
Thr Pro Arg Lys Pro Arg 1 5 10 621PRTArtificial SequenceSynthetic
6Phe Leu Asn Leu Thr Thr Pro Arg Lys Pro Arg Tyr Thr Asp Gly Ser 1
5 10 15 Gly Thr Gly Pro Gly 20
* * * * *