The invention encompasses the novel class of compounds represented by the formula below, which are inhibitors of the PTP-1B enzyme.

This invention relates to a novel class of phosphonic acid derivatives that are inhibitors of PTP-1B.
Protein tyrosine phosphatases are a large family of transmembrane or intracellular enzymes that dephosphorylate substrates involved in a variety of regulatory processes (Fischer et al., 1991, Science 253:401-406). Protein tyrosine phosphatase-1B (PTP-1B) is a xcx9c50 kd intracellular protein present in abundant amounts in various human tissues (Charbonneau et al., 1989, Proc. Natl. Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1-15).
Determining which proteins are substrates of PTP-1B has been of considerable interest. One substrate which has aroused especial interest is the insulin receptor. The binding of insulin to its receptor results in autophosphorylation of the domain (White and Kahn, 1994, J. Biol. Chem. 269:1-4). This causes activation of the insulin receptor tyrosine kinase, which phosphorylates the various insulin receptor substrate (IRS) proteins that propagate the insulin signaling event further downstream to mediate insulin""s various biological effects.
Seely et al., 1996, Diabetes 45:1379-1385 (xe2x80x9cSeelyxe2x80x9d) studied the relationship of PTP-1B and the insulin receptor in vitro. Seely constructed a glutathione S-transferase (GST) fusion protein of PTP-1B that had a point mutation in the PTP-1B catalytic domain. Although catalytically inactive, this fusion protein was able to bind to the insulin receptor, as demonstrated by its ability to precipitate the insulin receptor from purified receptor preparations and from whole cell lysates derived from cells expressing the insulin receptor.
Ahmad et al., 1995, J. Biol. Chem. 270:20503-20508 used osmotic loading to introduce PTP-1B neutralizing antibodies into rat KRC-7 hepatoma cells. The presence of the antibody in the cells resulted in an increase of 42% and 38%, respectively, in insulin stimulated DNA synthesis and phosphatidyinositol 3xe2x80x2 kinase activity. Insulin receptor autophosphorylation and insulin receptor substrate-1 tyrosine phosphorylation were increased 2.2 and 2.0-fold, respectively, in the antibody-loaded cells. The antibody-loaded cells also showed a 57% increase in insulin stimulated insulin receptor kinase activity toward exogenous peptide substrates.
Recently, Kennedy et al., 1999, Science 283: 1544-1548 showed that protein tyrosine phosphatase PTP-1B is a negative regulator of the insulin signalling pathway, suggesting that inhibitors of this enzyme may be beneficial in the treatment of Type 2 diabetes. Mice lacking PTP-1B are resistant to both diabetes and obesity.
Therefore, inhibitors of PTP-1B improve insulin-sensitivity. They may have utility in controlling or treating Type 2 diabetes, in improving glucose tolerance, and in improving insulin sensitivity in patients in need thereof. The compounds may also be useful in treating or controlling other PTP-1B mediated diseases, and may be useful in the treatment of cancer, neurodegenerative diseases and the like.
Compounds represented by formula I, including pharmaceutically acceptable salts thereof, and prodrugs thereof, are PTP-1B inhibitors that may be useful in the treatment of diabetes and related medical conditions. They may also be useful in the treatment of other PTP-1B mediated diseases.
In the compounds of formula I:
X1 and X2 are each independently selected from the group consisting of: H, OH, halogen, CN, CO2H, CO2C1-6alkyl, CO2C1-6alkenyl, OC1-6alkyl, OC2-6alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, OC(O)C1-6alkyl, OC(O)C2-6alkenyl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, S(O)2NR1R2, C(O)NR1R2, and NR1R2, wherein each alkyl group and each alkenyl group in each substituent may optionally be substituted with one or more substituents that are independently selected from the following groups of substituents: (a) 1-13 halogen atoms, and (b) 1-2 substituents independently selected from OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl;
R5 is H;
R1 and R2 are each independently selected from the group consisting of H and C1-4alkyl, wherein said alkyl substituents are optionally substituted with 1-9 halogen atoms;
Each halogen is independently selected from I, Cl, Br and F;
Each x is independently 0, 1, or 2;
Y1 is selected from the group consisting of a bond, a C1-6 alkylene group, and a C2-6 alkenylene group, wherein said alkylene group and said alkenylene group are optionally substituted with one or more substituents independently selected from (a) 1-12 halogen atoms and (b) 1-2 substituents independently selected from OH and OC1-4 alkyl, said OC1-4 alkyl being optionally substituted with 1-9 halogen atoms;
R is selected from the group consisting of C1-10 alkyl, C2-10alkenyl, C2-10alkadienyl, C2-10alkynyl, Ar1, and Het1, wherein said alkyl, alkenyl, alkadienyl, and alkynyl are optionally substituted with one or more substituents independently selected from (a) 1-21 halogen atoms, (b) one substituent selected from Ar1 and Het1, and (c) 1-2 substituents independently selected from OH, CN, CO2H, CO2C1-6 alkyl, CO2C2-6 alkenyl, OC1-3alkyleneOC1-3alkyl, OC1-6alkyl, OC2-6 alkenyl, OC(O)C1-6alkyl, OC(O)C2-6alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, Aryl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, S(O)xAryl, S(O)2NR1R2, C(O)NR1R2, NR1R2, and a 5-6-membered heterocycle having 1-2 heteroatoms selected from N, S and O in the ring, wherein said alkyl groups and said alkenyl groups of said substituents are optionally substituted with 1-13 halogen atoms;
Het1 is a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, and said Het1 is optionally substituted with one or more groups independently selected from (a) one group selected from CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-3 groups independently selected from R3;
Ar1 is phenyl or napthyl, wherein phenyl is optionally substituted with one or more groups independently selected from (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, SO2R4, and Ar2, and (b) 1-5 groups selected from R3, and wherein naphthyl is optionally substituted with one or more groups independently selected from (a) one group selected from CO2H, CF2CO2H, P(O)(OR5)2, SO2R4, and Ar2, and (b) 1-5 groups selected from R3;
Ar2 is phenyl, naphthyl or a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms independently selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, wherein Ar2 is optionally substituted with one or more substituents independently selected from (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-2 groups selected from R3;
R3 is selected from the group consisting of halogen, OH, CN, CO2H, NO2, CO2C1-10alkyl, CO2C2-10 alkenyl, OC1-10alkyl, OC2-10 alkenyl, C1-10 alkyl, C2-10 alkenyl, OC(O)C1-10alkyl, OC(O)C2-10alkenyl, C(O)C1-10alkyl, C(O)C2-10alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)x, C1-10alkyl, C1-3alkyleneS(O)xC1-10alkyl, S(O)xC2-10alkenyl, S(O)2NR1R2, C(O)NR1R2, NR1R2, NR1S(O)2R2, NR1C(O)C1-6alkyl, NR1C(O)H, Aryl, and Het, wherein each alkyl group and each alkenyl group of each substituent is optionally substituted with one or more substituents independently selected from (a) 1-21 halogen atoms and (b) 1-2 substituents independently selected from OH, OC1-3 alkyl, CO2H, CO2C1-3alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, S(O)xAryl, S(O)xC1-3alkyl and phenyl, wherein said phenyl is optionally substituted with 1-3 substituents independently selected from OCH3, OCF3, S(O)2 NR1R2, Br, Cl, and F, wherein the C1-3 alkyl groups of said substituents are optionally substituted with one or more substituents independently selected from (a) 1-7 halogen atoms and (b) 1-2 phenyls which are optionally substituted with 1-3 substituents independently selected from halogen and SO2NR1R2;
Aryl is a 6-14 membered aromatic carbocyclic moiety comprising 1 ring or 2-3 fused rings, wherein said Aryl is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, halogen, OH, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, CO2C1-3alkyl, NR1R2, S(O)xC1-4alkyl and SO2NR1R2, wherein said alkyl groups in said substituents are optionally substituted with 1-7 halogen atoms;
Het is a 5-10 membered aromatic ring system containing 1-4 heteroatoms selected from N, S(O)x, O, and mixtures thereof, and 0-2 carbonyl groups, wherein said Het comprises 1 ring or 2 fused rings, one of which fused rings may be a benzene ring, and said Het is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, halogen, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, CO2C1-3alkyl, NR1R2, S(O)xC1-4alkyl and SO2NR1R2, wherein said alkyl groups are optionally substituted with 1-7 halogen atoms;
Alkyl, alkenyl, alkadienyl and alkynyl are linear, branched or cyclic hydrocarbon structures, or combinations thereof containing the indicated number of carbon atoms and substituted as indicated, wherein alkyl, alkenyl, alkadienyl and alkynyl are respectively saturated, contain one double bond, contain 2 double bonds, or contain one triple bond; and
R4 is phenyl or C1-4 alkyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from (a) 1-3 halogen atoms and (b) 1-2 C1-3 alkyl or C1-3alkoxy groups, which are optionally substituted with 1-7 halogen atoms, and said C1-4 alkyl is optionally substituted with one or more substituents independently selected from (a) 1-9 halogen atoms and (b) 1-2 C1-3 alkoxy groups, which are optionally substituted with 1-7 halogen atoms.
Methods of treating and controlling diabetes, obesity, and other diseases and conditions using the compounds of Formula I are taught herein. Pharmaceutical compositions and combination treatments are also disclosed herein.
The compounds of Formula I have numerous embodiments.
One embodiment includes compounds of Formula I as described below:
X1 and X2 are each independently selected from the group consisting of: H, OH, halogen, CN, CO2H, CO2C1-6alkyl, CO2C2-6alkenyl, OC1-6alkyl, OC2-6alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, OC(O)C1-6alkyl, OC(O)C2-6alkenyl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, C1-6 alkyl, C2-6alkenyl, S(O)2NR1R2, C(O)NR1R2, and NR1R2, wherein each alkyl group and each alkenyl group in each substituent is optionally substituted with one or more substituents independently selected from (a) 1-13 halogen atoms and (b) 1-2 substituents independently selected from OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl;
R5 is H;
R1 and R2 are each independently selected from the group consisting of H and C1-4alkyl, wherein said alkyl substituents are optionally substituted with 1-9 halogen atoms;
Each halogen is independently selected from I, Cl, Br and F;
Each x is independently 0, 1, or 2;
Y1 is selected from the group consisting of a bond, a C1-4 alkylene group, and a C2-4 alkenylene group, wherein said alkylene group and said alkenylene group are optionally substituted with one or more substituents independently selected from (a) 1-8 halogen atoms and (b) 1-2 substituents independently selected from OH and OC1-4 alkyl, said OC1-4 alkyl being optionally substituted with 1-9 halogen atoms;
R is selected from the group consisting of C1-10 alkyl, C2-10alkenyl, C2-10alkadienyl, C2-10alkynyl, Ar1, and Het1, wherein said alkyl, alkenyl, alkadienyl, and alkynyl are optionally substituted with one or more substituents independently selected from (a) 1-21 halogen atoms, (b) one substituent selected from Ar1 and Het1, and (c) 1-2 substituents independently selected from OH, CN, CO2H, CO2C1-6 alkyl, CO2C2-6 alkenyl, OC1-6alkyl, OC2-6 alkenyl, OC(O)C1-6alkyl, OC(O)C2-6alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, S(O)2NR1R2, C(O)NR1R2, and NR1R2, wherein said alkyl groups and said alkenyl groups of said substituents are optionally substituted with 1-13 halogen atoms;
Het1 is a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, and said Het1 is optionally substituted with one or more substituents independently selected from (a) one group selected from CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-2 groups independently selected from R3;
Ar1 is phenyl or napthyl, wherein phenyl is optionally substituted with one or more groups independently selected from (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, SO2R4, and Ar2, and (b) 1-2 groups selected from R3, and wherein naphthyl is optionally substituted with one or more groups independently selected from (a) one group selected from CO2H, CF2CO2H, P(O)(OR5)2, SO2R4, and Ar2, and (b) 1-2 groups selected from R3;
Ar2 is phenyl, naphthyl or a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, wherein Ar2 is optionally substituted with one or more substituents independently selected from (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-2 groups selected from R3;
R3 is selected from the group consisting of halogen, OH, CN, CO2H, CO2C1-10 alkyl, CO2C2-10 alkenyl, OC1-10alkyl, OC2-10 alkenyl, C1-10 alkyl, C2-10 alkenyl, OC(O)C1-10alkyl, OC(O)C2-10alkenyl, C(O)C1-10alkyl, C(O)C2-10alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)C1-10alkyl, S(O)xC2-10alkenyl, S(O)2NR1R2, C(O)NR1R2, NR1R2, Aryl, and Het, wherein each alkyl group and each alkenyl group of each substituent is optionally substituted with one or more substituents independently selected from (a) 1-21 halogen atoms and (b) 1-2 substituents independently selected from OH, OC1-3 alkyl, CO2H, CO2C1-3alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, and phenyl, wherein said phenyl is optionally substituted with OCH3, OCF3, or 1-3 halogen atoms selected from Cl and F, and said C1-3 alkyl groups of said substituents are optionally substituted with one or more substituents independently selected from (a) 1-7 halogen atoms and (b) 1-2 phenyls, wherein said phenyls are optionally substituted with 1-3 halogen atoms;
Aryl is a 6-14 membered aromatic carbocyclic moiety comprising 1 ring or 2-3 fused rings, wherein said Aryl is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, halogen, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl, wherein said alkyl groups in said substituents are optionally substituted with 1-7 halogen atoms;
Het is a 5-10 membered aromatic ring system containing 1-4 heteroatoms selected from N, S(O)x, O, and mixtures thereof, and 0-2 carbonyl groups, wherein said Het comprises 1 ring or 2 fused rings, one of which fused rings may be a benzene ring, and said Het is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, halogen, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl, wherein said alkyl groups are optionally substituted with 1-7 halogen atoms; and
R4 is phenyl or C1-4 alkyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from (a) 1-3 halogen atoms and (b) 1-2 C1-3 alkyl or C1-3alkoxy groups, which are optionally substituted with 1-7 halogen atoms, and said C1-4 alkyl is optionally substituted with one or more substituents independently selected from (a) 1-9 halogen atoms and (b) 1-2 C1-3 alkoxy groups, which are optionally substituted with 1-7 halogen atoms.
In one embodiment of the compounds of Formula I, the halogen atom substituents are independently selected from Cl, Br, and F.
In another embodiment, X1 is H, and X2 is a halogen atom, CH3, OCH3, OH or CO2H.
Another embodiment comprises compound of Formula I, wherein X1 is H, X2 is selected from the group consisting of Cl, F, and Br, and the Y1substituent on the phenyl ring to which Y1 is attached is in the position para to CF2 P(O)(OR5)2. In one subset of compounds of this embodiment, X2 is Br and is ortho to CF2P(O)(OR5)2.
Other embodiments comprise compounds in which Y1 is a bond, CH2, or linear C2-4alkylene. A subset of these includes compounds in which Y1 is a bond, CH2, or C2H4.
Another preferred group of compounds comprises those compounds in which the group Y1 of Formula I is alkylene or alkenylene, where each carbon atom that makes up Y1 is linear or monobranched. Similarly, all the carbon atoms that make up the main carbon chain in the group R are linear or monobranched, where R can be alkyl, alkenyl, alkadienyl or alkynyl. Carbon atoms are defined as linear when they are bonded by only single bonds and they have no hydrocarbon branches on any carbon atom, and are defined as monobranched when there is one hydrocarbon branch on the carbon. Dibranched carbons have two hydrocarbon substituents (i.e. they are quaternary carbon atoms). In other embodiments, only the first two carbons of Y1 and R on each side of the S atom must be linear or monobranched.
Another preferred embodiment comprises compounds in which R is C1-4 alkyl, C2-4 alkenyl or C2-4alkynyl, and is substituted with one Ar1 and optionally with 1-2 substituents selected from Aryl and (Cxe2x95x90O)Aryl; and Ar1 is phenyl which is optionally substituted with (a) one group CF2P(O)(OR5)2 and/or (b) 1-2 groups R3, or a combination of these. In preferred compounds, Ar1 is phenyl optionally substituted with 1-2 R3. R3 is selected from Br, Cl, F, OH, and C1-3 alkyl. A preferred embodiment includes compounds in which R3 is Br. Compounds in which R is selected from C1-4 alkyl and C2-4 alkenyl are also preferred, as are compounds in which Y1 is a bond, C1-4alkylene or C1-4 alkenylene.
Another subset of compounds includes compounds in which R is selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, and C2-4alkynyl, and R is substituted with one Ar1;
Ar1 is phenyl or naphthyl and is substituted with Ar2;
Ar2 is a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, and Ar2 is optionally substituted with one or more substituents independently selected from (a) one group selected from P(O)(OH)2 and CO2H and (b) 1-2 groups R3;
R3 is selected from halogen, C1-10 alkyl, OC1-10 alkyl, C(O)Aryl, and Aryl, where said C1-10 alkyl and OC1-10 alkyl are optionally substituted with 1-2 substituents independently selected from OC1-3 alkyl, phenyl, and CO2H; and
X1, X2, R1, R2, R4, R5, x, Y1, Aryl, Het, and Het1 are as defined prevously.
Another group of desirable compounds includes compounds in which R is selected from the group consisting of C1-4 alkyl and C2-4 alkenyl, and R is substituted with one Ar1;
Ar1 is phenyl or naphthyl and is substituted with Ar2;
Ar2 is a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, and Ar2 is optionally substituted with one or more substituents independently selected from (a) one group selected from P(O)(OH)2 and CO2H and (b) 1-2 groups R3;
R3 is selected from C1-10 alkyl, OC1-10 alkyl, C(O)Aryl, and Aryl, where said C1-10 alkyl and OC1-10 alkyl are optionally substituted with 1-2 substituents independently selected from OC1-3 alkyl, phenyl, and CO2H; and
X1, X2, R1, R2, R4, R5, x, Y1, Aryl, Het, and Het1 are as defined previously.
In preferred embodiments of the two groups of compounds described above, Ar2 is quinoline.
In another embodiment of the compounds having formula I:
R is selected from the group consisting of C1-4 alkyl, C2-4 alkenyl and C2-4alkynyl and is substituted with one Ar1;
Ar1 is phenyl and is substituted with one Ar2;
Ar2 is phenyl, and is optionally substituted with one or more substituents which are independently selected from (a) one substituent selected from P(O)(OR5)2, CO2H, and SO2R4, and/or (b) 1-2 groups R3;
R4 is phenyl or C1-4 alkyl;
R3 is selected from OH, Br, OC1-10 alkyl, C1-10 alkyl, Aryl, and C2-10 alkenyl, where each alkyl group and each alkenyl group is optionally substituted with OC1-3 alkyl or phenyl; and
X1, X2, R1, R2, R5, x, Y1, Aryl, Het and Het1 are as defined previously.
Another embodiment of the invention includes compounds in which X1 and X2 are each independently selected from the group consisting of H, Cl, Br, F, C1-3alkyl, OC1-3alkyl, OH, CO2H, and CO2C1-3alkyl;
R5 is H;
Y1 is selected from the group consisting of a bond and a C1-4 alkylene group;
R is selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, Ar1, and Het1, wherein said C1-8alkyl, C2-8 alkenyl and C2-8alkynyl are optionally substituted with one or more groups independently selected from (a) 1-5 halogen atoms selected from Cl, Br, and F, (b) one Ar1 or Het1, and (c) 1-2 substituents independently selected from OH, CN, CO2H, CO2C1-6 alkyl, CO2C2-6 alkenyl, OC1-6alkyl, OC2-6 alkenyl, OC(O)C1-6alkyl, OC(O)C2-6 alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, Aryl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, S(O)2NR1R2, C(O)NR1R2, and NR1R2, wherein said alkyl groups and said alkenyl groups of said substituents are optionally substituted with 1-5 halogen atoms selected from Cl, Br, and F;
x is 0, 1, or 2;
R1 and R2 are each independently selected from the group consisting of H and C1-4alkyl, wherein said alkyl substituents are optionally substituted with 1-5 halogen atoms selected from Cl, Br, and F;
Het1 is a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, and said Het1 is optionally substituted with (a) one group selected from CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and/or (b) 1-2 groups independently selected from R3;
Ar1 is phenyl, optionally substituted with (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, SO2R4, and Ar2, and (b) 1-2 groups selected from R3;
Ar2 is phenyl, naphthyl or a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, wherein Ar2 is optionally substituted with (a) one group selected from CF2P(O)(OR5)2, CO2H, CF2CO2H, P(O)(OR5)2, and SO2R4, and (b) 1-2 groups selected from R3;
R3 is selected from the group consisting of Cl, Br, F, OH, CN, CO2H, CO2C1-3 alkyl, CO2C2-3 alkenyl, OC1-10alkyl, OC2-10 alkenyl, C1-10 alkyl, C2-10 alkenyl, OC(O)C1-3alkyl, OC(O)C2-3alkenyl, C(O)C1-3alkyl, C(O)C2-3alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O) C1-6alkyl, S(O)xC2-6alkenyl S(O)2NR1R2, C(O)NR1R2, NR1R2, NR1S(O)2R2, NR1C(O)C1-6alkyl, NR1C(O)H, Aryl, and Het, wherein each alkyl group and each alkenyl group of each substituent is optionally substituted with one or more groups independently selected from (a) 1-3 halogen atoms selected from Cl, Br, and F, and (b) 1-2 substituents independently selected from OH, OC1-3 alkyl, CO2H, CO2C1-3alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, and phenyl, wherein said phenyl is optionally substituted with 1-3 groups independently selected from OCH3, OCF3, Cl and F, and said C1-3 alkyl groups of said substituents are optionally substituted with one or more substituents independently selected from (a) 1-3 halogen atoms independently selected from Cl, Br and F, and (b) 1-2 phenyl moieties;
Aryl is a phenyl or naphthyl moiety, wherein said Aryl is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, Cl, F, Br, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl, wherein said alkyl groups in said substituents are optionally substituted with 1-3 halogen atoms selected from Cl, Br, and F;
Het is a 5-10 membered aromatic ring system containing 1-4 heteroatoms selected from N, S(O)x, O, and mixtures thereof, and 0-2 carbonyl groups, wherein x is 0, 1, or 2, wherein said Het comprises 1 ring or 2 fused rings, one of which fused rings may be a benzene ring, and said Het is optionally substituted with 1-3 substituents independently selected from C1-3alkyl, Cl, Br, F, OC1-3 alkyl, C(O)C1-3alkyl, OC(O)C1-3alkyl, CO2H, and CO2C1-3alkyl, wherein said alkyl groups in said substituents are optionally substituted with 1-3 halogen atoms selected from Cl, Br, and F; and
R4 is phenyl or C1-4 alkyl.
Preferred compounds from the group described immediately above include those compounds in which:
Y1 is selected from the group consisting of a bond and a C1-3 alkylene group; and
R is selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, Ar1, and Het1, wherein said C1-8alkyl and C2-8 alkenyl are optionally substituted with one or more groups independently selected from (a) 1-5 halogen atoms selected from Cl, Br, and F, (b) one Ar1 or Het1, and (c) 1-2 substituents independently selected from OH, CN, CO2H, CO2C1-6 alkyl, CO2C2-6 alkenyl, OC1-6alkyl, OC2-6 alkenyl, OC(O)C1-6alkyl, OC(O)C2-6 alkenyl, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO2Aryl, S(O)xC1-6alkyl, S(O)xC2-6alkenyl, S(O)2NR1R2, C(O)NR1R2, and NR1R2, wherein said alkyl groups and said alkenyl groups of said substituents are optionally substituted with 1-5 halogen atoms selected from Cl, Br, and F.
The invention also comprises prodrugs of the compounds of Formula I. In these, one or more of R5 is a moiety that is converted to H or a pharmaceutically acceptable salt under physiological conditions during or after administration to a mammalian patient, and the remainder of R5 moieties are each H or a pharmaceutically acceptable salt therof.
Finally, a large number of specific compounds are disclosed. The structures of 209 compounds are illustrated in Table 1, and their syntheses are described in Examples 1-209. Structures of additional compounds are illustrated as Examples 210-258 in Table 2.
Methods of treating, preventing, or controlling diabetes and other diseases using the compounds of Formula I are disclosed herein. A method of treating, controlling or preventing diabetes and complications thereof in a mammalian patient in need of such treatment includes administering to the patient an anti-diabetic effective amount of a compound of Formula I. A method of treating, controlling or preventing obesity in a mammalian patient in need of such treatment comprises the administration to the patient of an anti-obesity effective amount of a compound in accordance with claim 1. Such methods also include the administration of a second compound, which may be an anti-diabetic compound, an anti-obesity compound, or an HMG-CoA reductase inhibitor, in an amount effective to treat, control or prevent diabetes or obesity, or to improve a poor lipid profile.
A method of treating, controlling or preventing atherosclerosis in a mammalian patient in need of such treatment comprises administering to the patient an effective amount of a compound of Formula I and an effective amount of an HMG-CoA reductase inhibitor.
More generally, compounds of Formula I may be used as the active compound in a method for treating, preventing, or controlling one or more diseases or conditions selected from Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low xe2x80x9cH levels, atherosclerosis, vascular restenosis, inflammatory bowel disease, pancreatitis, adipose cell tumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, and neurodegenerative disease. The method comprises the administration of an effective amount of the compound of Formula I. Combination treatments can also be used in which case, the method comprises the administration of a compound of Formula I and an effective amount of one or more pharmaceutically active compounds selected from the group consisting of an HMG-CoA reductase inhibitor, an anti-obesity agent, and an antidiabetic compound.
Pharmaceutical compositions also can be made using the compounds of Formula I. Compositions that are suitable for the treatment, prevention or control of one or more diseases or conditions selected from Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, atherosclerosis, vascular restenosis, inflammatory bowel disease, pancreatitis, adipose cell tumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, and neurodegenerative disease contain an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
Such pharmaceutical compositions may also include a second anti-diabetic agent or an anti-obesity agent. They may also include a cholesterol lowering agent. Pharmaceutical compositions may therefore include: (1) an effective amount of a compound of Formula I, (2) an effective amount of one or more pharmaceutically active compounds selected from the group consisting of an HMG-CoA reductase inhibitor, an anti-obesity agent, and an anti-diabetic agent, and (3) a pharmaceutically acceptable carrier.
Such pharmaceutical compositions that contain a second active compound or composition and that are suitable for the treatment, prevention or control of one or more diseases or conditions selected from the group consisting of Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, atherosclerosis, vascular restenosis, inflammatory bowel disease, pancreatitis, adipose cell tumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, and neurodegenerative disease, may be comprised of the following:
(1) an effective amount of a compound of Formula 1;
(2) an effective amount of one or more pharmaceutically active compounds listed below; and
(3) a pharmaceutically acceptable carrier; where the pharmaceutically active compounds are selected from the group consisting of:
(a) insulin sensitizers including (i) PPARxcex3 agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like), and compounds disclosed in WO 97/27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;
(b) insulin or insulin mimetics;
(c) sulfonylureas such as tolbutamide and glipizide, or related materials;
(d) xcex1-glucosidase inhibitors (such as acarbose);
(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, rivastatin and other statins), (ii) sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARxcex1 agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) inhibitors of cholesterol absorption for example beta-sitosterol and acyl CoA:cholesterol acyltransferase inhibitors, such as for example melinamide and (vi) probucol;
(f) PPARxcex1/xcex3 agonists;
(g) antiobesity compounds such as appetite suppressants, fenfluramine, dexfenfluramine, phentirarnine, sulbitramine, orlistat, neuropeptide Y5 inhibitors (NP Y5 receptor antagonosts), leptin, which is a peptidic hormone, xcex23 adrenergic receptor agonists, and PPARxcex3 antagonists and partial agonists;
(h) ileal bile acid transporter inhibitors; and
(i) insulin receptor activators.
The pharmaceutically active compounds that are used in the combination pharmaceutical compositions with the compounds of this invention may be summarized as follows:
(a) insulin sensitizers, PPAR-gamma agonists, partial agonists, and antagonists, PPAR-alpha agonists, PPAR-delta agonsts, and biguanides;
(b) insulin and insulin mimetics;
(c) sulfonylureas;
(d) xcex1-glucosidase inhibitors;
(e) cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors; (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts thereof, (iv) PPARxcex1 agonists, (v) inhibitors of cholesterol absorption; and (vi) probucol;
(f) PPARxcex1/xcex3 agonists;
(g) antiobesity compounds selected from the group consisting of appetite suppressants, fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide Y5 inhibitors (NP Y5 receptor antagonosts), leptin, xcex23 adrenergic receptor agonists, and PPARxcex3 antagonists and partial agonists;
(h) ileal bile acid transporter inhibitors; and
(i) insulin receptor activators.
Abbreviations
The following abbreviations have the indicated meanings:
AA=arachidonic acid
Ac=acetyl
AIBN=2.2xe2x88x92-azobisisobutyronitrile
Bn=benzyl
BSA=bovine serum albumin
Bz=benzoyl
CHO=chinese hamster ovary
CMC=1-cyclohexyl-3-(2-morpholinoethyl) carbodiimidemetho-p-toluenesulfonate
DAST=diethylamino sulfur trifluoride
DBU=diazabicyclo[5.4.0]undec-7-ene
DMAP=4-(dimethylamino)pyridine
DMF=N,N-dimethylformamide
DMSO=dimethyl sulfoxide
Et3N=triethylamine
HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HBSS=Hanks balanced salt solution
HEPES=N1-[2-Hydroxyethyl]piperazine-N4-[2-ethanesulfonic acid]
HWB=human whole blood
KHMDS=potassium hexamethyldisilazane
LDA=lithium diisopropylamide
LPS=lipopolysaccharide
mCPBA=metachloro perbenzoic acid
MMPP=magnesium monoperoxyphthalate
Ms=methanesulfonyl=mesyl
Ms0=methanesulfonate=mesylate
NBS=N-bromosuccinimide
NCS=N-chlorosuccinirnide
NIS=N-iodosuccinimide
NSAID=non-steroidal anti-inflammatory drug
Oxone(copyright)=potassium peroxymonosulfate
PCC=pyridinium chlorochromate
PDC=pyridinium dichromate
PPA=polyphosphoric acid
PTP=protein tyrosine phosphatase
r.t.=room temperature
rac.=racemic
Tf=trifluoromethanesulfonyl=triflyl
TFA=trifluoroacetic acid
TFAA=trifluoroacetic anhydride
Tf0=trifluoromethanesulfonate=triflate
THF=tetrahydrofuran
TLC=thin layer chromatography
Ts=p-toluenesulfonyl=tosyl
TsO=p-toluenesulfonate=tosylate
Tz=1H (or 2H)-tetrazol-5-yl
Alkyl group abbreviations
Me=methyl
Et=ethyl
n-Pr=normal propyl
i-Pr=isopropyl
n-Bu=normal butyl
i-Bu=isobutyl
s-Bu=secondary butyl
t-Bu=tertiary butyl
c-Pr=cyclopropyl
c-Bu=cyclobutyl
c-Pen=cyclopentyl
c-Hex=cyclohexyl
Dose Abbreviations
bid=bis in die=twice daily
qid=quater in die=four times a day
tid=ter in die=three times a day
Alkyl means linear, branched and cyclic structures, and combinations thereof, containing the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclopropyl, cyclopentyl, cycloheptyl, cyclopropylmethyl, methylcyclopropy, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyl and the like.
Fluoroalkyl means alkyl groups of the indicated number of carbon atoms in which one or more hydrogens is replaced by fluorine. Examples are xe2x80x94CF3, xe2x80x94CH2CH2F, xe2x80x94CH2CF3, c-Pr-F5, c-Hex-F11 and the like. Haloalkyl has the analogous meaning for replacement of one or more hydrogen atoms with any halogen (Cl, Br, F, and/or I).
Alkenyl means linear, branched and cyclic structures, and combinations thereof containing a double bond with the indicated number of carbon atoms. Examples of alkenyl groups include allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 2-methyl-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like. Alkadienyl means the diunsaturated counterpart to alkenyl.
Alkynyl means linear, branched and cyclic structures, and combinations thereof containing a triple bond with the indicated number of carbon atoms. Examples of alkynyl groups include propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, cyclopropylethynyl, and the like.
Alkylene, alkenylene, alkynylene, fluoroalkylene, alkadienylene, and the like, where the suffix xe2x80x9cenexe2x80x9d has been added to the name of the monovalent radicals alkyl, alkenyl, alkynyl, fluoroalkyl, alkadienyl, and the like, describe divalent radicals that are the same as their monovalent counterparts, except that two hydrogen atoms rather than one are removed so that the radical will have two points of attachment, in addition to attachments to substituents which may also be present.
Aryl groups include 6-14 membered carbocyclic aromatic ring systems comprising 1-3 phenyl rings. If two or more aromatic rings are present, then the rings are fused together, so that adjacent rings share a common side. Examples are benzene, naphthalene, anthracene and phenanthrene. Preferred aryl groups are benzene and naphthalene. Substitutions on these are defined herein.
Heteroaryl as used herein represents a 5-10 membered aromatic ring system comprising one ring or two fused rings, 1-4 heteroatoms selected from the groups consisting of N, O, S(O)x, and mixtures thereof wherein x is 0, 1 or 2, and 0-2 carbonyl groups. Carbonyl groups, when present, are not counted as heteroatoms. Heteroaryl includes, but is not limited to, furanyl, diazinyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrrolyl, tetrazinyl, thiazolyl, thienyl, triazinyl, triazolyl, 1H-pyrrole-2,5-dionyl, 2-pyrone, 4-pyrone, pyrrolopyridine, furopyridine and thienopyridine. Heteroaryl also includes benzoheteroaryl, defined below. Preferred heteroaryls include imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyridyl, thiazolyl, and thienyl.
Benzoheteroaryl is a subset of heteroaryl and includes aromatic ring systems containing one or more heteroatoms which also have a fused 6-membered benzene ring, such as 2H-1-benzopyran-2-one, 4H-1-benzopyran-4-one, 2(3H)benzofuranone, 3(2H)benzofuranone, 2,3-dihydrobenzofuran, 2,3-dihydrobenzothiophene, indole, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzotriazole, benzothiadiazole, 1H-isoindole-1,3(2H)-dione, quinoline, and isoquinoline. Preferred benzoheteroaryl compounds include benzothiophene, benzothiazole, benzotriazole, benzothiadiazole, quinoline, and isoquinoline. Specific heteroaryls used in this invention include quinoline, thiazole, tetrazole, pyridine, pyrazole, oxadiazole, oxathiazole and oxazole.
Another subset of heteroaryls includes 5-membered heteroaryls, such as the following:
When a heteroaromatic ring is specified as optionally having one or more heteroatoms, this means that at least one heteroatom is present, selected from O, S, SO, SO2 and N, and up to 4 such heteroatoms may be present, depending upon the size of the ring specified.
When a moiety is specified as being optionally substituted, then the same moiety may also remain unsubstituted, unless otherwise stated.
Finally, when a list of possible choices is provided for a given moiety, and the moiety is used in more than one position in a chemical formula, the selection of a choice for the moiety in each position is independent of other selections, unless the definition specifically says otherwise.
Metabolitesxe2x80x94Prodrugs
Metabolites of the compounds of this invention that are therapeutically active and that are described by formula I also are within the scope of the claimed invention, as are prodrugs, which are compounds that are converted to the claimed active compounds or salts of the claimed active compounds after they have been administered to a patient. A non-limiting example of a prodrug of the phosphonic acids of this invention would be a monoester or diester of one or more phosphonic acid groups, where the ester functionality preferably has a structure that makes it easily hydrolyzed or metabolized after administration to a patient. Examples of prodrugs include C1-6 alkyl esters of the phosphonic acids. Prodrugs that have structures that are more easily hydrolyzed or metabolized are generally more preferred. Examples are illustrated by the structures below, where Rxe2x80x2xe2x95x90H or a C1-6 alkyl group, and Rxe2x80x3xe2x95x90C1-6 alkyl group or xe2x80x94OC1-6 alkyl group, and Q is the residue of the molecule that is attached to the xe2x80x94CF2PO3H2 or xe2x80x94PO3H2 group in formula I. The alkyl groups and alkoxy groups may optionally be substituted with one or more substituents independently selected from 1-5 halogen atoms, a phenyl group, or a mixture of these. The phenyl group, if present, may optionally be substituted with 1-3 substituents independently selected from halogen, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94OCH3 and xe2x80x94OCF3. In these compounds, and as defined in general throughout this application, the alkyl groups and the alkyl portions of Oalkyl groups may be linear or branched and may optionally be cycloalkyl or may include a cycloalkyl group in their structure. For examples of prodrug structures related to those shown below, see D. N. Srinivasta et al., Bioorganic Chemistry 12, 118-129 (1984).
Other ester functionalities that may be used in the monoester or diester phosphonate prodrugs include phenyl esters and benzyl esters, where the phenyl ester groups have the structure xe2x80x94Ophenyl, and the benzyl ester groups have the structure xe2x80x94OCHRxe2x80x2phenyl, in which Rxe2x80x2 is H or C1-6alkyl, and C1-6alkyl is substituted as described above. In either case, phenyl is substituted as described above.
The prodrugs of this invention may therefore be defined as compounds having the formula I, in which at least one group R5 is selected from the group consisting of C1-6alkyl, phenyl, xe2x80x94CHRxe2x80x2phenyl, and xe2x80x94CHRxe2x80x2OC(xe2x95x90O)Rxe2x80x3, and the remaining groups R5 are selected from H, C1-6alkyl, phenyl, xe2x80x94CHRxe2x80x2phenyl and xe2x80x94CHRxe2x80x2OC(xe2x95x90O)Rxe2x80x3, wherein each group Rxe2x80x2 is H or C1-6alkyl and each group Rxe2x80x3 is xe2x80x94C1-6alkyl or xe2x80x94OC1-6alkyl, where C1-6alkyl and the alkyl portion of xe2x80x94OC1-6alkyl may optionally be substituted with one or more substituents independently selected from 1-5 halogen atoms, a phenyl group, or a mixture of these. The phenyl group in xe2x80x94CHRxe2x80x2phenyl, the phenyl group that is an optional substituent on C1-6alkyl and xe2x80x94OC1-6alkyl, and the phenyl ester group that is obtained when R5 is phenyl may optionally be substituted with 1-3 groups independently selected from halogen, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94OCH3 and xe2x80x94OCF3. By this definition, at least one of the phosphonic acid groups is a monoester or diester, and each of the remaining phosphonic acid groups, if any, may be a free acid or a monoester or diester.
In preferred compounds, the groups R5 that are not H may all be the same because of the difficulty of synthesizing different R5 groups on the same phosphonates. In many cases, the prodrug will be a mixture of compounds having different levels of esterification on the phosphonic acid groups because of the difficulty of synthesizing and separating a discrete pure compound.
Optical Isomersxe2x80x94Diastereomersxe2x80x94Geometric Isomers
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and enantiomers, which in turn can be resolved as optical isomers. The present invention includes all such diastereomers and enantiomers, including racemic mixtures and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, include both E and Z geometric isomers.
Salts
The pharmaceutical compositions of the present invention comprise a compound of the current invention as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, adipic, aspartic, 1,5-naphthalenedisulfonic, benzenesulfonic, benzoic, camphorsulfonic, citric, 1,2-ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydriodic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, 2-naphthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, pivalic, propionic, salicylic, stearic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, undecanoic, 10-undecenoic, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, methanesulfonic, phosphoric, sulfuric and tartaric acids.
It will be understood that in the discussion of methods of treatment or of specific compounds which follows, references to the compounds of Formula I and other formulae are meant to include the pharmaceutically acceptable salts.
Utilities
Inhibitors of PTP-1B may improve insulin-sensitivity and thus may have utility in preventing or treating diabetes, particularly Type 2 diabetes. They may also be useful for improving glucose tolerance and insulin-sensitivity when there is insulin-resistance, and for treating or preventing obesity in mammals that are in need of such treatments or that might benefit from such treatments. The compounds are expected to be useful for treating Type 2 diabetes (non-insulin dependent diabetes, or NIDDM). The compounds may also cause a beneficial reduction in triglycerides and lipids.
Compounds in the present class of phosphonic acids may have certain unexpected advantages. Some of the compounds may be selective in inhibiting PTP-1B in preference to T-Cell Protein Tyrosine Phosphatase (TCPTP). This may make it possible to avoid toxic side effects due to T-Cell inhibition.
The compounds of this invention in general exhibit good in vitro activity for inhibiting the PTP-1B enzyme. The compounds exemplified in this application in general have an IC50 value of less than 1 xcexcM for inhibition of the PTP-B enzyme, and in some cases less than 0.1 xcexcM, as measured using the enzyume assay described herein in the assays section.
The PTP-1B inhibitors may also be useful in the treatment, prevention or control of a number of conditions that accompany type 2 diabetes, including hyperlipidemia, hypertriglyceridemia, hypercholesterolemia (including beneficially raising low HDL levels), atherosclerosis, vascular restenosis, pancreatitis, adipose cell tumors, adipose cell carcinomas such as liposarcoma, dyslipidemia, inflammatory bowel disease, inflammation in general, and other disorders where insulin resistance is a component. Finally, the compounds may be used to treat or prevent cancer, such as prostate cancer, neurodegenerative diseases and the like.
Pharmaceutical Compositions
For the treatment of any of these PTP-1B-mediated diseases the active compound may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage units containing conventional pharmaceutically acceptable carriers. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular and intrasternal injection and infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are useful for the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxy-ethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Examples of vehicles and solvents include water, Ringer""s solution and isotonic sodium chloride. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds may also be administered in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but molten at the body temperature and will therefore release the drug. Such materials include cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or suspensions containing the compound are employed. (For purposes of this application, topical application includes mouth washes and gargles.) Topical formulations may include cosolvents, emulsifiers, penetration enhancers, preservatives, emollients and the like.
The pharmaceutical composition may also be further comprised of a second anti-diabetic or anti-obesity effective compound.
Dose Ranges
Dosage levels on the order of from about 0.01 mg to about 100 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, the diseases and conditions described herein may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
The active ingredient is typically combined with the carrier to produce a dosage form suitable for the particular patient being treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from about 0.5 mg to about 5 g of the active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Representative dosage forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It is understood that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Combinations with Other Drugs
In further aspects, the invention encompasses pharmaceutical compositions for treating PTP-1B mediated diseases as defined above comprising an effective amount of the active compound and one or more other pharmaceutically active compounds, such as anti-diabetic compounds (for example, insulin, sulfonyl ureas, PPAR-alpha and/or -gamma ligands, including ligands that have both PPAR-alpha and -gamma activity), anti-obesity compounds, and compounds that improve the lipid profile of the patient.
Thus, the methods of treatment or prevention described herein may further be comprised of administering to said patient a second anti-diabetic compound in an amount effective to treat, control, or prevent diabetes, alone or in combination with the PTP-1B inhibitors of this invention.
Similarly, the methods of treatment or prevention described herein may further be comprised of administering to said patient an anti-obesity compound in an amount effective to treat, control or prevent obesity, alone or in combination with the PTP-1B inhibitors of this invention.
Similarly, the methods of treatment of diabetes may comprise the administration of a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin, in an amount effective to improve the lipid profile. In combination with a PTP-1B inhibitor, this may be beneficial in treating or preventing atherosclerosis and other conditions that often are associated with Type 2 diabetes.
Examples of other pharmaceutically active compounds that may be combined with a compound of Formula I and administered in combination with the PTP-1B inhibitors include, but are not limited to, the following compounds or compositions or groups of compounds or compositions that are used as anti-diabetes compounds (a, b, c, d, f, and i below), anti-obesity compounds (g below), and/or compounds or compositions for lipid profile control (e and h below):
(a) insulin sensitizers including (i) PPARxcex3 agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like), and compounds disclosed in WO97/27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;
(b) insulin or insulin mimetics;
(c) sulfonylureas such as tolbutamide and glipizide, or related materials;
(d) xcex1-glucosidase inhibitors (such as acarbose);
(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, rivastatin and other statins), (ii) sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARxcex1 agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (v) inhibitors of cholesterol absorption for example beta-sitosterol and acyl CoA:cholesterol acyltransferase inhibitors for example melinamide and (vi) probucol;
(f) PPARxcex1/xcex3 agonists;
(g) antiobesity compounds such as appetite suppressants, fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide Y5 inhibitors (NP Y5 receptor antagonosts), leptin, which is a peptidic hormone, xcex23 adrenergic receptor agonists, and PPARxcex3 antagonists and partial agonists;
(h) ileal bile acid transporter inhibitors; and
(i) insulin receptor activators, such as those disclosed in copending, commonly assigned U.S. application Ser. Nos. 09/095,244 and 09/280,602.
Where a second pharmaceutical is used in addition to an active compound taught herein, the two pharmaceuticals may be administered together in a single composition, separately at approximately the same time, or on separate dosing schedules. The important feature is that their dosing schedules comprise a treatment plan in which the dosing schedules overlap in time and thus are being followed concurrently.
Activity in the compounds of this application is demonstrated using the following assays for PTP-1B-inhibiting activity.
Phosphatase Assay Protocol
Materials:
EDTAxe2x80x94ethylenediaminetetraacetic acid (Sigma)
DMHxe2x80x94N,Nxe2x80x2-dimethyl-N,Nxe2x80x2-bis(mercaptoacetyl)-hydrazine (synthesis published in J. Org. Chem. 56, pp. 2332-2337,(1991) by R. Singh and G. M. Whitesides and can be substituted with DTTxe2x80x94dithiothreitol Bistris xe2x80x942,2-bis(hydroxymethyl)2,2xe2x80x2,2xe2x80x3-nitrilotriethanol-(Sigma) Triton X-100-octylphenolpoly(ethylene-glycolether) 10 (Pierce)
Antibody: Anti-glutathione S-transferase rabbit (H and L) fraction (Molecular Probes)
Enzyme: Human recombinant PTP-1B, containing amino acids 1-320, fused to GST enzyme (glutathione S-transferase) or to FLAG peptide purified by affinity chromatography (Huyer et al, 1997, J. Biol. Chem., 272, 843-852). Wild type contains active site cysteine(215), whereas mutant contains active site serine(215).
Tritiated peptide: Bz-NEJJ-CONH2, Mwt. 808, empirical formula, C32H32T2O12P2F4
IC50 Binding Assay Protocol:
Compounds (ligands) which potentially inhibit the binding of a radioactive ligand to the specific phosphatase are screened in a 96-well plate format as follows:
To each well is added the following solutions @ 25xc2x0 C. in the following chronological order:
1. 110 xcexcl of assay buffer.
2. 10 xcexcl. of 50 nM tritiated BzN-EJJ-CONH2 in assay buffer (1xc3x97) @ 25xc2x0 C.
3. 10 xcexcl. of testing compound in DMSO at 10 different concentrations in serial dilution (final DMSO, about 5% v/v) in duplicate @ 25xc2x0 C.
4. 10 xcexcl. of 3.75 xcexcg/ml purified human recombinant GST-PTP-1B in enzyme dilution buffer.
5. The plate is shaken for 2 minutes.
6. 10 xcexcl. of 0.3 xcexcg/ml anti-glutathione S-transferase (anti-GST) rabbit IgG (Molecular Probes) diluted in antibody dilution buffer @ 25xc2x0 C.
7. The plate is shaken for 2 minutes.
8. 50 xcexcl. of protein A-PVT SPA beads (Amersham) @ 25xc2x0 C.
9. The plate is shaken for 5 minutes. The binding signal is quantified on a Microbeta 96-well plate counter.
10. The non-specific signal is defined as the enzyme-ligand binding in the absence of anti-GST antibody.
11. 100% binding activity is defined as the enzyme-ligand binding in the presence of anti-GST antibody, but in the absence of the testing ligands with the non-specific binding subtracted.
12. Percentage of inhibition is calculated accordingly.
13. IC50 value is approximated from the non-linear regression fit with the 4-parameter/multiple sites equation (described in: xe2x80x9cRobust Statisticsxe2x80x9d, New York, Wiley, by P. J. Huber (1981) and reported in nM units.
14. Test ligands (compounds) with larger than 90% inhibition at 10 xcexcM are defined as actives.
The assay was carried out at room temperature in 96 well plates. The reaction mixture in 170 xcexcl contained 50 mM Bis-Tris (pH=6.3), 2 mM EDTA, 5 mM N,Nxe2x80x2-dimethyl-N,Nxe2x80x2bis(mercaptoacetyl)hydrazine (DMH) and 10 xcexcM fluorescein diphosphare (FDP). 10 xcexcl of 10 concentrations (serial dilution) of the test compound (inhibitor) dissolved in DMSO or DMSO alone for control was added to each well and the plate was mixed for 2 min. The reaction was initiated by adding 20 xcexcl of diluted PTP-1B (50 nM in 50 mM Bis/Tris (pH=6.3), 2 mM EDTA, 5 mM DMH, 20% glycerol and 0.01% Triton X-100. The phosphatase activity was followed by monitoring the appearance of the fluorescent product fluorescein monophosphate (FMP) continuously for 15-30 min, using the Cytofluor II plate reader (PerSeptive Biosystems Inc.) with excitation of 440 nm (slit width 20 nm) and emission at 530 nm (slit width 25 nm). All the assays were done at least in duplicate. The initial rate of FMP formation is plotted against the concentration of inhibitor and the data was fitted to 4-parameter equation and the inflection point of the fit is the IC50.
Pharmacokinetics in Rats
Per Os Pharmacokinetics in Rats
Procedure:
The animals are housed, fed and cared for according to the Guidelines of the Canadian Council on Animal Care.
Male Sprague Dawley rats (325-375 g) are fasted overnight prior to each PO blood level study.
The rats are placed in the restrainer one at a time and the box firmly secured. The zero blood sample is obtained by nicking a small (1 mm or less) piece off the tip of the tail. The tail is then stroked with a firm but gentle motion from the top to the bottom to milk out the blood. Approximately 1 mL of blood is collected into a heparinized vacutainer tube.
Compounds are prepared as required, in a standard dosing volume of 10 mL/kg, and administered orally by passing a 16 gauge, 3xe2x80x9d gavaging needle into the stomach.
Subsequent bleeds are taken in the same manner as the zero bleed except that there is no need to nick the tail again. The tail is cleaned with a piece of gauze and milked/stroked as described above into the appropriately labelled tubes.
Immediately after sampling, blood is centrifuged, separated, put into clearly marked vials and stored in a freezer until analysed.
Typical time points for determination of rat blood levels after PO dosing are:
0, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h
After the 4 hr time point bleed, food is provided to the rats ad libitum. Water is provided at all times during the study.
Vehicles:
The following vehicles may be used in PO rat blood level determinations:
Compounds for PO blood levels can be in suspension form. For better dissolution, the solution can be placed in a sonicator for approximately 5 minutes.
For analysis, aliquots are diluted with an equal volume of acetonitrile and centrifuged to remove protein precipitate. The supernatant is injected directly onto a C-18 HPLC column with UV detection. Quantitation is done relative to a clean blood sample spiked with a known quantity of drug. Bioavailability (F) is assessed by comparing area under the curve (AUC) i.v. versus p.o.   F  =            AUCpo      AUCiv        xc3x97          DOSEiv      DOSEpo        xc3x97    100        %
Clearance rates are calculated from the following relation:   CL  =            DOSEiv                    xe2x80x83                          (                  mg          /          kg                )              AUCiv
The units of CL are mL/hxc2x7kg (milliliters per hour kilogram)
Intravenous Pharmacokinetics in Rats
Procedure:
The animals are housed, fed and cared for according to the Guidelines of the Canadian Council on Animal Care.
Male Sprague Dawley (325-375 g) rats are placed in plastic shoe box cages with a suspended floor, cage top, water bottle and food.
The compound is prepared as required, in a standard dosing volume of 1 mL/kg.
Rats are bled for the zero blood sample and dosed under CO2 sedation. The rats, one at a time, are placed in a primed CO2 chamber and taken out as soon as they have lost their righting reflex. The rat is then placed on a restraining board, a nose cone with CO2 delivery is placed over the muzzle and the rat restrained to the board with elastics. With the use of forceps and scissors, the jugular vein is exposed and the zero sample taken, followed by a measured dose of compound which is injected into the jugular vein. Light digital pressure is applied to the injection site, and the nose cone is removed. The time is noted. This constitutes the zero time point.
The 5 min bleed is taken by nicking a piece (1-2 mm) off the tip of the tail. The tail is then stroked with a firm but gentle motion from the top of the tail to the bottom to milk the blood out of the tail. Approximately 1 mL of blood is collected into a heparinized collection vial. Subsequent bleeds are taken in the same fashion, except that there is no need to nick the tail again. The tail is cleaned with a piece of gauze and bled, as described above, into the appropriate labelled tubes.
Typical time points for determination of rat blood levels after I.V. dosing are either:
0, 5 min, 15 min, 30 min, 1 h, 2 h, 6 h or 0, 5 min, 30 min, 1 h, 2 h, 4 h, 6 h.
Vehicles:
The following vehicles may be used in IV rat blood level determinations:
With Dextrose, either sodium bicarbonate or sodium carbonate can be added if the solution is cloudy.
For analysis, aliquots are diluted with an equal volume of acetonitrile and centrifuged to remove protein precipitate. The supernatant is injected directly onto a C-18HPLC column with UV detection. Quantitation is done relative to a clean blood sample spiked with a known quantity of drug. Bioavailability (F) is assessed by comparing area under the curve (AUC) i.v. versus p.o.   F  =            AUCpo      AUCiv        xc3x97          DOSEiv      DOSEpo        xc3x97    100        %
Clearance rates are calculated from the following relation:   CL  =            DOSEiv                    xe2x80x83                          (                  mg          /          kg                )              AUCiv
The units of CL are mL/hxc2x7kg (milliliters per hour kilogram).
This assay is the subject of copending, commonly assigned U.S. Provisional Application No. 60/123,243, filed Mar. 8, 1999, which patent application is incorporated herein by reference, and was recently published in Cromlish, Wanda A., Paul Payette and Brian P. Kennedy (1999) Biochem Pharmocol 58: 1539-1546.
Construction of Recombinant Baculovirus Transfer Vectors And Insect Cells
Briefly, using the Bac-to-Bac Baculovirus Expression System (Gibco-BRL, Mississauga, Ontario, Canada) PTP 1B cDNA (obtained from Dr. R. L. Erikson, Harvard University, USA), is cloned into the pFASTBAC donor plasmid engineered to include a FLAG sequence at the 5xe2x80x2 end of the cDNA (PTP1B-FL). The recombinant plasmid is transformed into competent DH10BAC E. Coli cells. Following transposition and antibiotic selection, the recombinant bacmid DNA is isolated from selected E. Coli colonies and used to transfect sf9 insect cells (Invitrogen, San Diego, Calif., U.S.A.). The sf9 cells are cultured in spinner flasks at 28xc2x0 C. in Graces supplemented medium (Gibco-BRL, Mississauga, Ontario, Canada) with 10% heat-inactivated fetal bovine serum (Gibco-BRL) following the protocol of Summers and Smith (A manual for Methods for Baculovirus Vectors and Insect Culture Procedures (Bulletin No. 1555). Texas A and M University, Texas Agricultural Experiment Station, College Station, Tex., 1987).
Intact Cell Assay
Infected sf9 cells expressing PTP1B-FL and mock infected cells, are harvested at 29 hpi (hours post infection) by gentle centrifugation (Beckman GS-6R) at 460 rpm, (48 g) for 5 min. Cells are washed once in assay buffer (Hanks"" solution buffered with 15 mM Hepes, pH 7.4, obtained from Sigma, St. Louis, Mo., U.S.A.) and recentrifuged at 300 rpm (21 g) for 10 min. The cells are then gently resuspended in assay buffer and examined using a hemacytometer for cell density and viability by trypan blue exclusion. Assays are performed using a Tomtec Quadra 96 pipeting robot, programmed to mix the cells gently after each addition. In 200 xcexcL of assay buffer, 2xc3x97105 PTP expressing cells or mock infected cells are dispensed into each well of 96-well polypropylene plates and pre-incubated either with a test compound or DMSO vehicle (3 xcexcL), for 15 min at 37xc2x0 C. The pre-incubated cells are challenged with a final concentration of 10 mM pNPP (p-nitrophenyl phosphate, obtained from Sigma-Aldrich Canada Ltd., Oakville, Ontario) for 15 min, centrifuged at 4xc2x0 C. and the amount of substrate hydrolysis is determined spectrophotometerically at OD405.
Oral Glucose Tolerance Test
Oral glucose tolerance tests are done on conscious Zucker obese fa/fa rats or obese ob/ob mice (age 12 weeks or older). The animals are fasted for 16-18 hours before use for experiments. A test compound or a vehicle is given either intraperitoneally or orally 60 minutes before oral administration of a glucose solution at a dose of 2 g/kg body weight. Blood glucose levels are measured using a Medisense glucometer from tail bled samples taken at different time points before and after administration of glucose. A time curve of the blood glucose levels is generated and the area-under-the-curve (AUC) for 120 minutes is calculated (the time of glucose administration being time zero). Percent inhibition is determined using the AUC in the vehicle-control group as zero percent inhibition.
In separate studies, C57BL/6J mice are fed a high fat (35%) and high carbohydrate (36%) diet obtained from Bioserv (Frenchtown, N.J.) for 3 to 4 weeks, at which time the mice gained 50-100% of the baseline body weight. Oral glucose tolerance tests are done in the same manner as described above.

Aryldifluoromethylphosphonic acids with sulfur-containing substituents as PTP-1B inhibitors

Abstract: The invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP-1B mediated diseases, including diabetes.


A semiconductor device includes a plurality of circuits each independently conducting a predetermined process, and a circuit operation control part controlling operation start timings and operation suspend timings so as to mutually interfere with power voltage fluctuations caused by a state transition between an operation start and an operation suspend for each of the plurality of circuits.

Recently, in a semiconductor device (hereinafter, called an LSI (Large Scale Integration)), a plurality of processors has been formed and arranged as a multi-core. For example, in an LSI 1 illustrated in FIG. 1, a plurality of processors are arranged as a core 0, a core 1, a core 2, a core 3, . . . and a power supply voltage VDD and a ground voltage VSS are applied to the core 0, the core 1, the core 2, the core 3, . . . as an internal power voltage ivdd(V) and an internal ground ivss(V) connected through an inductance Ldd(H) and an inductance Lss(H). Also, the internal power voltage is fluctuated since a power current I(A) flows through their inductances when the core 0, the core 1, the core 2, the core 3, . . . operate. An internal power capacitor C(F) is inserted in order to suppress its voltage fluctuation.
While increasing the number of processors being arranged, a scale of power consumed in the LSI tends to be larger. On the other hand, it has been requested to reduce power consumption. In addition to a configuration of the LSI 1 illustrated in FIG. 1, an LSI 1a illustrated in FIG. 2 is configured so that operations of the core 0, the core 1, the core 2, the core 3, . . . are controlled in response to ON and OFF of an operation enable signals en0, en1, en2, en3, . . . by synchronizing with a system clock sclk. This configuration realized to suspend a circuit with respect to each of the core 0, the core 1, the core 2, the core 3, . . . .
However, in response to a request of reducing the power consumption, it is desired to increase frequency of switching an operation of each core in a circumstance of configuring a multi-core and under an operation control of each core. A difference between the power consumptions when the LSI is operating and when the LSI is suspending becomes bigger, and the power supply voltage in the LSI fluctuates greater due to its step response. Accordingly, there are problems in which internal circuits of the LSI 1 and LSI 1a malfunction. If the internal power capacitor C(F) is increased, the fluctuation of the internal voltage will be suppressed even though a production cost will be increased.
The fluctuation of the internal power voltage of the LSI due to the step response means a power supply noise caused by a rapid change of the internal current of the LSI in a transition from a circuit suspend state to a circuit operation state or a transition from the circuit operation state to the circuit suspend state.
As depicted in FIG. 3, it is a feature of the power supply noise in that the internal power voltage of the LSI begins to fluctuate with significantly great amplitude of a resonance period Tres immediately after an operation state of the LSI is transited, and presently converges when the operation state becomes stable. Also, transitions of the operation state are transiting from the circuit suspend state to the circuit operation state and transiting from the circuit operation state to the circuit suspend state.
When the operation enable signals en0 through en3 turn ON while synchronizing with the system clock sclk and the internal power current I starts to flow, the core 0, the core 1, the core 2, the core 3, . . . simultaneously transit from the circuit suspend state to the circuit operation state. In this case, the internal power voltage ivdd begins to greatly fluctuate toward a negative direction. When the circuit operation state becomes stable, the voltage converges presently. As described, when the circuit suspend state transits to the circuit operation state, the internal power voltage ivdd is significantly amplified due to the resonance period Tres.
On the other hand, when the operation enable signals en0 through en3 turn OFF and the internal power current I stops, the core 0, the core 1, the core 2, the core 3, . . . transit from the circuit operation state to the circuit suspend state. The internal power voltage ivdd begins to greatly fluctuate toward a positive direction. Then, when the circuit suspend state becomes stable, the voltage converges presently. As described, when the circuit operation state transits to the circuit suspend state, the internal power voltage ivdd is significantly amplified due to the resonance period Tres with a reversed phase of the case of transiting from the circuit suspend state to the circuit operation state.
The resonance period Tres is mainly determined based on the internal power capacitor C and the inductance L (Ldd+Lcc) for the LSI 1 and LSI 1a and is expressed as follows:Tres=2×π×√{square root over ( )}(L×C)  (1)when π denotes circle ratio.
In a conventional LSI design, in order to prevent a simple switching noise, an approach through shifting an operation timing of each circuit is applied. Moreover, regarding the power supply noise due to the step response as described above, for example, as depicted in FIG. 4, Tim Fischer et al. proposed to detect a noise being occurred and decrease a clock frequency (a) when the power supply noise occurs, in order for the LSI 1 and the LSI 1a to prevent an internal malfunction (for example, see the following reference document 1).
However, since the approach discussed in the conventional technique decreases the clock frequency when the power supply noise occurs, an LSI performance is degraded. Also, in this approach, since a frequency of a circuit operation is modulated, a resonance phenomenon is promoted. There is a risk in that the power supply noise is further amplified. Moreover, since the power supply noise itself due to the step response can not be controlled, it is impossible to suppress the power supply noise (see FIG. 4 of Fischer et al.).


A quantization circuit includes a plurality of resistors, a plurality of tap points, and a plurality of coarse comparators. Each coarse comparator has a first input coupled to an input voltage and a second input coupled to a corresponding coarse tap point voltage. Each coarse comparator operates during a first phase to produce a “1” only if the input voltage exceeds the corresponding coarse tap point voltage. A plurality of fine comparators each have a first input coupled to the input voltage, and each fine comparator operates during a second phase to produce a fine output level indicative of whether the input voltage exceeds a corresponding tap point voltage of a group of tap points located immediately below the tap point connected to the highest coarse comparator producing a “1”.

The present invention relates generally to multilevel quantizers, particularly two-phase multilevel quantizers designed to be implemented in reduced amounts of chip area and also designed to dissipate reduced amounts of power. The invention also relates more particularly to high-performance, low-power delta-sigma modulators and delta sigma analog-to-digital converters (ADCs) which include such two-stage multilevel quantizers.
The closest prior art is believed to be represented by the article "A 3-mW 74-dB SNR 2-MHz Continuous-Time Delta-Sigma ADC With a Tracking ADC Quantizer in 0.13-μm CMOS" by Lukas Dörrer et al., IEEE Journal of Solid-State Circuits, Volume 40, Number 12, December 2005, pages 2416-2427. This reference discloses a third-order continuous-time 4-bit delta-sigma ADC, and also discloses reduction of power consumption by using a tracking ADC. The foregoing reference does not disclose interpolation of the quantizer output, and suffers from several major shortcomings. One shortcoming is that the disclosed delta-sigma ADC requires a separate circuit to set up the initial modulator DC operational point. It also requires additional digital to analog converter (DAC) circuits, and suffers from potential modulator instability due to parasitic high frequency input signal leakages and the like. The foregoing reference discloses the common technique of using a simplified first order dynamic element matching (DEM) circuit, but that is insufficient to overcome the above mentioned shortcomings.
FIG. 1 shows a typical multibit delta-sigma modulator 1, which includes a summing element 3 that sums an input signal Vin with a negative feedback signal on conductor 4 and applies the summation result via conductor 5 to the input of a linear loop filter 6. The output 7 of loop filter 6 is applied to the input of a conventional multilevel quantizer 8. The output 9 of multilevel quantizer 8 is applied to the input of a DEM circuit 10. There are several well known DEM circuit topologies which could be used for DEM circuit 10, which functions to remove the effect of mismatch between feedback elements of feedback DAC 12. The output conductors 11 of DEM circuit 10 are coupled to the input of DAC 12, the output of which produces the above mentioned negative feedback signal on conductor 4.
FIG. 2 illustrates a typical flash ADC-based quantizer implementation of multilevel quantizer 8 of FIG. 1. Multilevel quantizer 8 includes, for example, a resistor string 15 which includes 16 equal resistors R-0,1,2 . . . 15 connected in series. Tap points 16-0,1 . . . 15 are connected to the (−) inputs of 16 comparators 17-0,1 . . . 15 as shown. The (+) inputs of comparators 17-0,1 . . . 15 are connected to an input signal VQin produced by loop filter 6. Typically, multilevel quantizer 8 operates according to a thermometer code, and produces output voltages designated as Levels 0,1,2 . . . 15 on comparator output conductors 9-0,1,2 . . . 15, respectively, as the input signal VQin is increased from ground voltage to Vref volts. The corresponding thermometer code values, Levels 0,1,2 . . . 15, are applied to the inputs of DEM circuit 10.
Multilevel delta-sigma modulator topology is becoming more common because it further reduces quantization noise and because it relaxes certain analog circuit design constraints, such operational amplifier slew requirements and bandwidth requirements of the first integrator stage in the loop filter.
Since a delta-sigma modulator is a feedback system, the quantizer 8 needs to introduce a minimum delay to ensure stability of the system. This minimum delay requirement seriously limits the practical options for the topology of the multilevel quantizer. Flash type ADCs are normally used as quantizers due to their low latency, which refers to time delay between the outputs and inputs thereof. However, it is well-known that flash ADCs are characterized by low efficiency and low resolution. Compared with other ADCs, such as SAR or pipeline ADCs, a flash ADC consumes more power and requires more die area, even though the latency of a flash ADC is lower than the other types. Although increasing quantizer resolution/quantizer levels inside multilevel delta-sigma ADCs reduces output swings (and hence also the power consumption) of the integrators, reduces quantization noise, and decreases performance sensitivity to clock jitter, the low efficiency of conventional flash-based quantizer designs results in excessive power consumption and excessive die area and therefore diminishes the advantages of increased quantizer resolution/quantizer levels of the conventional flash-based quantizers. Conventional flash type quantizers of the type shown in FIG. 2 are considered to be very inefficient and not suitable for many future converter designs.
Thus, there is an unmet need for an improved multilevel quantizer topology which can be implemented in a substantially reduced amount of chip area and which consumes substantially less power than conventional multilevel quantizers, and also provides the advantage of small internal integrator output signal swings.
There also is an unmet need for an improved ADC which can be implemented in a substantially reduced amount of chip area and which consumes substantially less power than ADCs including conventional multilevel quantizers, and also provides the advantage of a small internal signal swing.
There also is an unmet need for an improved quantizer topology which requires simpler control logic circuitry, consumes much lower power, and requires less die area than the prior art flash-based quantizer designs.

Input tracking high-level multibit quantizer for delta-sigma ADC


A frequency tunable device includes a substrate, and a capacitor structure supported by the substrate and including a ferroelectric film and first and second electrodes. The ferroelectric film has two opposite sides, and is made from a ferroelectric material having a formula of Pb1−xBaxZrO3, where x is a positive number greater than 0.3 and less than 0.6. The first and second electrodes are respectively formed on the sides of the ferroelectric film. The dielectric constant of the ferroelectric film varies with a voltage applied to the first and second electrodes.

1. Field of the Invention
This invention relates to a frequency tunable device, more particularly to a frequency tunable device including a substrate and a dielectric film formed on the substrate and made from a Pb1−xBaxZrO3ferroelectric material with a dielectric property being a function of a voltage applied thereto.
2. Description of the Related Art
U.S. Pat. No. 5,589,845 discloses a tunable electric antenna apparatus that includes a component of a thin film ferroelectric material, such as SrTiO3, Pb(Sr, Ti)O3, SrxBa1−xTiO3 (BST), etc. The ferroelectric material has a dielectric property that is a function of a voltage applied to the thin film ferroelectric material. Such a dielectric property enables the ferroelectric material to modulate the dielectric constant and hence the time delay of either microstrip or coplanar delay lines, and allows for use in producing phase shifters, antennas, etc.
BST ferroelectric materials tend to degrade due to the reduction of Ti4+ into Ti3+, which, in turn, results in an increase in dielectric loss. This degradation problem can be alleviated by adding an aliovalent element into the BST ferroelectric materials. The following patents are examples of reducing dielectric loss through the addition of an aliovalent element into the BST ferroelectric materials.
U.S. Pat. No. 5,312,790 discloses a ceramic ferroelectric material consisting essentially of BST and alumina for achieving the desired electric property, such as a low dielectric constant, a low loss tangent, and high tunability. U.S. Pat. No. 5,427,988 discloses a ceramic ferroelectric material consisting essentially of BST and magnesia. U.S. Pat. No. 5,486,491 discloses a ceramic ferroelectric material consisting essentially of BST and zirconia.
Although the addition of an aliovalent element into ferroelectric material can reduce dielectric loss, it also results in reduction in the tunability of the ferroelectric material.
The entire disclosure of U.S. Pat. No. 5,589,845 is incorporated herein by reference.


A system for reprofiling a wheel set of a railway vehicle allows the center of rotation of the wheel set to move relative to supporting rollers. A cutting tool used to reprofile the wheel profile on a wheel set is moved relative to the center of rotation of the wheel set to maintain a constant distance between the center of rotation and the cutter. The rollers are maintained in a fixed position during the cutting process. The system avoids mechanically forcing a constant location of the wheel set relative to the center of rotation.

Railway vehicles operate by using railway wheels which are guided and supported by rails affixed to the ground or other structures. Railway vehicle wheels are typically part of a wheel set which includes, at a minimum, a pair of wheels, an axle, and bearings. In addition, wheel sets are typically mounted on the bottom of a railway vehicle using a bogie or truck which, for example, may support four or more wheels. During operation of a railway vehicle (such as locomotives and railroad cars), their wheels become worn due to their contact with the rails upon which they ride. This wear often increases the risk of train derailment and may accelerate wheel wear or otherwise adversely affect the running characteristics of the wheels and railway vehicles. For example, the wheels of railway vehicles may, with wear, develop flat areas on their circumferences. Such wear often causes a bump or vibratory rotation of the worn wheel against the rail. Moreover, the contours of the wheels of railway wheel sets may be the subject to international standardization. Thus, especially with high-speed trains, the wheels should be periodically reprofiled to reduce or minimize worn areas and resultant bearing or bogie loads of the rail vehicles and the concomitant wear of rail surfaces.
Railway wheel sets may be reprofiled or trued with stock removal carried out, for example, by a turning or milling process. Thus, for example, peripheral milling machines, which are adapted to remove metal by feeding a workpiece through the periphery of a rotating circular cutter (such as a milling cutter), are often used. Typically the wheel set is cut by mechanically constraining the wheel set relative to its center of rotation and rotating the wheel set relative to a cutter to true the periphery of the wheel. However, supporting the wheel set to maintain a fixed center of rotation while rotating the wheel set or cutter to cut the wheel may be challenging. Alternatively, the milling cutters may be locked into a fixed radial position relative to the wheel set while allowing the centerline of the wheel set to move radially during the cutting process. However, locking the cutter into such a fixed radial position on the wheel set is also challenging and typically requires access to the centering holes on the ends of the axle.
It is therefore an object of this invention to provide a railway wheel truing or shaping system which is useable without physically locking into place the centerline of the wheel set, or locking the cutter into a fixed radial position relative to the wheel set centerline.
It is another object of this invention to provide a process for truing or shaping a railway wheel contour which allows for the movement of the center of rotation of the wheel or wheel set.
It is yet another object of this invention to provide a process for truing or shaping the contour of a railway wheel which compensates for movement or changes in the position of the center of rotation of the wheel and/or wheel set during the cutting process.

System for reprofiling a wheel set of a railway vehicle


In a data processing apparatus 2 having a first mode of operation in which JAVA® bytecodes 46, 48 specify the processing operations and a second mode of operation in which other instructions specify the processing operations. In order to speed operation, the JAVA® Local Variable 0, or another such variable, is stored within a register of a register bank 14 to be available for rapid access. This storage is in a write-through manner such that reads of the value will be directly serviced from the register R4 and writes to the data value will be made in both the register R4 and back in the original memory location for that data value as determined by the JAVA® Virtual Machine.

1. Field of the Invention
This invention relates to data processing systems. More particularly, this invention relates to data processing systems operable in a first mode to perform processing operations specified by JAVA® bytecodes and operable in a second processing mode to perform processing operations specified by other instructions.
2. Description of the Prior Art
It is known to provide data processing systems which can operate in a first mode to perform data processing operations specified by JAVA® bytecodes and operable in a second mode to perform data processing operations specified by other instructions. An example of such a system is described in United States Pending Patent Application entitled Unhandled Operation Handling In Multiple Instruction Set Systems and filed on 2 May 2002 and International Published Publication No. WO-A-02/29563. The disclosure of these documents is incorporated herein by reference.
U.S. Pat. No. 6,332,215 discloses a system which translates JAVA® bytecodes into native processor instructions and stores a copy of a JAVA® Local Variable within a register of the register bank of the native processor.
In the context of hardware acceleration of JAVA® bytecode execution measures which can improve execution speed are strongly desirable.

Write-through caching a JAVA® local variable within a register of a register bank


An industrial gear mechanism with a bevel gear stage having a-bevel gear and a bevel pinion in engagement therewith. The bevel gear and the bevel pinion are surrounded by a gear mechanism housing having bearing seats for a bevel gear shaft and a bevel pinion shaft. A first and a second bevel pinion shaft bearing are arranged in an O-arrangement, with the first bevel pinion shaft bearing arranged on a first end of the bevel pinion shaft facing the bevel pinion and the second bevel pinion shaft bearing arranged on a second end of the bevel pinion shaft remote from the bevel pinion. A gearwheel of a spur gear stage on the drive side is arranged axially between the first and second bevel pinion shaft bearings in fixed rotative connection with the bevel pinion shaft and in engagement with a drive pinion of the spur gear stage.

Gear mechanisms for industrial applications or wind power plants, in particular planetary gears, often play a particularly important role in industrial treatment processes and manufacturing processes. A wide range of complex requirements is set for industrial or wind power plant gear mechanisms. For example, one of these requirements is reliable operation, which has to be ensured over a lengthy period of use with minimal maintenance costs. System failures negatively affecting industrial treatment processes and manufacturing processes or energy production processes may be expensive, for example due to costly stoppage times. To monitor and ensure a reliable operation, therefore, numerous sensors or actuators are occasionally installed on rotating components in gear mechanisms.
A bevel spur gear mechanism is disclosed in EP 1 961 993 A1, in which a gear mechanism housing encloses one or more gear mechanism stages and a motor cage is provided for connection to an electric motor. The motor cage is connected via a spacer flange to the gear mechanism housing and the electric motor. In this case, a shaft on the drive side of a bevel gear stage is mounted in a flange bushing. The spacer flange and a front wall on the drive side of the gear mechanism housing have a common bore. Said common bore encloses the flange bushing of the shaft on the drive side. The flange bushing has a cylindrical outer surface which centers the gear mechanism housing, the spacer flange and the flange bushing relative to one another. The flange bushing, the spacer flange and the front wall on the drive side are connected together by screws.
A mounting for a bevel pinion shaft of a bevel spur gear mechanism in a bearing bushing is disclosed in DE 1 000 654 A, in which the bearing bushing is inserted into a long, one-piece housing bore. At one end, the bearing bushing has a flange. Moreover, the bearing bushing surrounds the bevel pinion shaft guided via roller bearings, and with further components forms a sub-assembly which may be easily premounted. The housing bore extends axially over an overall length of a cylindrical outer peripheral surface of the bearing bushing. Moreover, the housing bore easily aligns the premountable sub-assembly and has a high degree of rigidity. The required contact pattern in the tooth engagement of the bevel gear mechanism may be set via shims between the bearing bushing flange and the gear mechanism housing or via axially acting adjusting mechanisms.
The object of the present invention is to provide an industrial gear mechanism comprising at least one bevel gear stage, which permits a short overall length as well as simple and rapid mounting. In this case, the industrial gear mechanism is intended to be designed such that it is able to be inserted in a series of components of different sizes and is suitable for different types of motor.