The invention encompasses the novel class of compounds represented by formula I, 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 receptor, most notably on tyrosines 1146, 1150, and 1151 in the kinase catalytic 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.
Thus, inhibitors of PTP-1B improve insulin-sensitivity. They have utility in controlling or treating Type 1 and 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 preventing cancer, neurodegenerative diseases and the like.
Compounds represented by Formula I, and pharmaceutically acceptable salts thereof, and prodrugs thereof, are PTP-1B inhibitors and are useful in the treatment of diabetes, obesity and related conditions.
In the compounds having Formula I, R1 and R2 are selected from the group consisting of:
C1-10alkyl(Ra)0-7, C2-10alkenyl(Ra)0-7, Aryl(Ra)0-3 and Het(Ra)0-3;
wherein, each Ra independently represents a member selected from the group consisting of: Aryl, OH, CN, halogen, CO2H, CO2C1-6alkyl, OC1-6alkyl, C1-6alkyl, OC1-10alkyleneCO2H, O Aryl, C0-6alkyleneSO3H, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl, C0-6alkyleneCO2C2-6alkenyl, C0-6alkyleneC(O)C1-6alkyl, C(O)NR3xe2x80x2R4xe2x80x2, NR3xe2x80x2R4xe2x80x2, C1-6haloalkyl, OC1-6haloalkyl, S(O)YC1-6alkyl, S(O)yNR3xe2x80x2R4xe2x80x2, and Het, wherein y is 0, 1, or 2, wherein Het, Aryl, alkyl, and alkenyl in Ra are optionally substituted with 1-3 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-10alkyl, OH, Het and Aryl, where said Het and Aryl are optionally substituted with 1-2 substituents independently selected from halogen, C1-3alkyl, OC1-3alkyl, CF3, and OCF3;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein said rings are fused together so that adjacent rings share a common side when there is more than one aromatic ring;
Het represents a 5-10 membered aromatic ring system comprising one ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)y wherein y is 0-2, and 0-2 carbonyl groups;
Y, Z1 and Z2 each independently represent xe2x80x94(CR3R4)axe2x80x94Xxe2x80x94(CR3R4)bxe2x80x94 wherein a and b are either 0 or 1, such that the sum of a and b equals 0, 1 or 2;
X represents a bond, O, S(O)y, NR3xe2x80x2, C(O), OC(O), C(O)O, C(O)NR3xe2x80x2, NR3xe2x80x2C(O) or xe2x80x94CHxe2x95x90CHxe2x80x94, where y is as previously defined;
R3 and R4 are independently H, halo, C1-3alkyl, or C1-3haloalkyl;
each R3xe2x80x2 is independently selected from the group consisting of: H, C1-6alkyl, C1-6haloalkyl, OH, C(O)C1-6alkyl, C(O)Aryl, C(O)Het, C(O)C1-6haloalkyl, Aryl and Het;
each R4xe2x80x2 is independently selected from the group consisting of: H, C1-6alkyl, C1-6haloalkyl, Aryl and Het; and
each W1 is independently selected from the group consisting of: H, OH, CN, halogen, OC1-6alkyl(Ra)0-3, S(O)yC1-6alkyl(Ra)0-3, with y equal to 0-2, S(O)3H, C1-6alkyl(Ra)0-3, C1-6haloalkyl(Ra)0-3, CO2H, CO2C1-6alkyl(Ra)0-3, CO2C1-6haloalkyl(Ra)0-3, CO2C2-6 alkenyl(Ra)0-3, C(O)C1-6alkyl(Ra)0-3, C(O)NR3xe2x80x2R4xe2x80x2, S(O)y NR3xe2x80x2R4xe2x80x2, NR3xe2x80x2R4xe2x80x2, Aryl and Het, wherein R3xe2x80x2 and R4xe2x80x2 are as defined above, and wherein Aryl and Het may be unsubstituted or are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-6alkyl, OC1-6haloalkyl, and OH; or the two W1 groups are on adjacent positions of the aromatic ring and are taken in combination to represent a fused phenyl ring.
Methods of treating, controlling and preventing diabetes, obesity, and other related diseases and conditions using the compounds of Formula I are taught herein. Pharmaceutical compositions and combination therapies are also disclosed herein.
In a subset of compounds of Formula I, each W1 represents H or halogen. In a preferred subset of these compounds, one W1 group represents H and the other W1 group represents a halogen in the position adjacent to xe2x80x94CF2P(O)(OH)2 on the aromatic ring.
In a subset of any of the groups of compounds above, each Het is selected from the group consisting of pyridinyl, 1H-1,2,3-benzotriazolyl, 1,2,4-oxadiazolyl and 1,3-thiazolyl.
In one embodiment of this invention, Y is xe2x80x94CH2xe2x80x94.
In another embodiment of compounds in accordance with claim 1, Z1 and Z2 are each independently selected from the group consisting of CH2, xe2x80x94C(O)xe2x80x94, and a direct bond.
Another embodiment comprises compounds in which R1 and R2 are each independently selected from the group consisting of Aryl(Ra)0-3 and Het(Ra)0-3.
In another embodiment, R1 and R2 of Formula I are each independently selected from the group consisting of
(a) (CH2)0-3phenyl, which is optionally mono, di-, or trisubstituted, wherein the substituents are selected from the group consisting of:
(1) halo,
(2) C1-6alkoxy,
(3) C1-6alkylthio,
(4) C1-6alkyl,
(5) C1-6fluoroalkyl,
(6) xe2x80x94CO2H,
(7) xe2x80x94CO2xe2x80x94C1-4alkyl,
(8) xe2x80x94CO2C1-4fluoroalkyl,
(9) heteroaryl, which is optionally mono, di-, or trisubstituted, wherein the substituents are independently selected from the group consisting of halogen, C1-6alkoxy, C1-6alkylthio, C1-C6fluoroalkyl, C1-6alkyl, xe2x80x94CO2H, xe2x80x94CO2C1-4alkyl, xe2x80x94CO2C1-4fluoroalkyl, phenyl, and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this paragraph, and
(10) phenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-6alkoxy, C1-6alkylthio, C1-6alkyl, C1-6fluoroalkyl, xe2x80x94CO2H, xe2x80x94CO2C1-4alkyl, xe2x80x94CO2C1-4fluoroalkyl, phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this paragraph, and
(b) heteroaryl, which is optionally mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of:
(1) halo,
(2) C1-6alkoxy,
(3) C1-6alkylthio,
(4) C1-6fluoroalkyl,
(5) C1-6alkyl,
(6) xe2x80x94CO2H,
(7) xe2x80x94CO2xe2x80x94C1-4alkyl,
(8) xe2x80x94CO2C1-4fluoroalkyl,
(9) phenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-6alkoxy, C1-6alkylthio, C1-6alkyl, C1-6fluoroalkyl, CO2H, xe2x80x94CO2C1-4alkyl, xe2x80x94CO2C1-4fluoroalkyl, phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this paragraph, and
(10) heteroaryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-6alkoxy, C16alkylthio, C1-6-alkyl, C1-6fluoroalkyl, phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this paragraph,
wherein each W1 is independently selected from the group consisting of: halogen, C1-6alkyl, and C1-6fluoroalkyl;
Y is xe2x80x94CH2xe2x80x94; and
Z1, and Z2 are independently selected from the group consisting of CH2, CH2CH2, C(O), C(O)CH2, CH2C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94, C(O)O, and a direct bond.
In another subset of compounds,
R1 and R2 are each independently selected from the group consisting of xe2x80x94(CH2)phenyl, phenyl, 1,2,4-oxadiazolyl, pyridinyl, and 1H-1,2,3-benzotriazolyl, each of which is optionally substituted with 1-3 substituents independently selected from halogen, C1-3alkyl, CF3, phenyl and 1,2,4-oxadiazolyl, wherein phenyl and 1,2,4-oxadiazolyl are optionally substituted with 1-3 substituents independently selected from C1-3alkyl, CF3, phenyl, and 1,2,4-oxadiazolyl,
Z1 and Z2 are each CO, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, or a direct bond,
Y is CH2, and
each W1 is independently selected from the group consisting of hydrogen, halogen, and C1-3alkyl, and is in a position on the aromatic ring adjacent to the xe2x80x94CF2P(O)(OH)2 group.
Finally, specific embodiments of compounds of Formula I are provided in Table 1, Table 2 , and/or the compounds exemplified in Examples 1-24, which are named below:
Example 1: [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonic acid;
Example 2: Difluoro(4-(3-oxo-2,3-diphenylpropyl)phenyl]methylphosphonic acid;
Example 3: 4-[2-(Benzyloxy)-1-(methoxycarbonyl)-2-oxoethyl]phenyl(difluoro) methylphosphonic acid;
Example 4: 2-Bromo-4-[2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl) ethyl]phenyl (difluoro)methylphosphonic acid;
Example 5: 2-Bromo-4-[2-phenyl-2-(5-phenyl- 1,2,4-oxadiazol-3-yl)ethyl]phenyl (difluoro)methylphosphonic acid;
Example 6: [4-(2-Benzotriazol-1-yl-2-m-tolylethyl)-phenyl]difluoromethylphosphonic acid;
Example 7: {4-[2-Benzotriazol-1-yl-2-(4-fluorophenyl)-ethyl]-2-bromophenyl }difluoromethyl phosphonic acid;
Example 8: {4-[2-Benzotriazol-1-yl-2-(4-trifluoromethylphenyl)-ethyl]phenyl}difluoromethylphosphonic acid disodium salt;
Example 9: (4-2-(1H-1,2,3-Benzotriazol-1-yl)-2-[4-(methyloxycarbonyl)phenyl]ethylphenyl)(difluoro)methylphosphonic acid;
Example 10: {4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-(4-fluorophenyl)ethyl]phenyl } (difluoro)methylphosphonic acid;
Example 11: {4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro) methylphosphonic acid;
Example 12: {[(2,2-dimethylpropanoyl)oxy]methyl}hydrogen [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;
Example 13: Bis {[(2,2-dimethylpropanoyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl) phenyl](difluoro)methylphosphonate;
Example 14: 1-{[[[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl)(difluoro)methyl](hydroxy)phosphoryl]oxy}-2-methylpropyl propionate;
Example 15: [1-(isobutyryloxy)ethyl]hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;
Example 16: Bis[(isobutyryloxy)methyl][2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;
Example 17: [(isobutyryloxy)methyl]hydrogen [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;
Example 18: Bis{[(isopropoxycarbonyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl) phenyl](difluoro)methylphosphonate;
Example 19: [(isopropoxycarbonyl)oxy]methyl hydrogen [2-bromo-4-(3-oxo-2,3-diphenyl)phenyl](difluoro)methylphosphate;
Example 20: Dibenzyl[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;
Example 21: Benzyl hydrogen [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro) methylphosphonate;
Example 22: [2-bromo-4-(3-oxo-2-phenylbutyl)phenyl](difluoro)methylphosphonic acid;
Example 23: {2-bromo-4-[3-oxo-2-phenyl-3-(1,3-thiazol-2-yl)propyl]phenyl}(difluoro) methylphosphonic acid; and
Example 24: {2-bromo-4-[2-(4-methoxy-1,3-thiazol-2-yl)-3-oxo-3-phenylpropyl)phenyl}(difluoro) methylphosphonic acid.
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 the administration 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 HDL 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 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 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.
The following abbreviations have the indicated meanings:
Ac=acetyl
AIBN=2.2-azobisisobutyronitrile
Bn=benzyl
Bz=benzoyl
DIBAL=diisobutyl aluminum hydride
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
HBSS=Hanks balanced salt solution
HEPES=N1-[2-Hydroxyethyl]piperazine-N4-[2-ethanesulfonic acid]
KHMDS=potassium hexamethyldisilazide
KOtBu=potassium tert-butoxide
LHMDS=lithium hexamethyldisilazide
LDA=lithium diisopropylamide
LPS=lipopolysaccharide
mCPBA=metachloro perbenzoic acid
MMPP=magnesium monoperoxyphthalate
Ms=methanesulfonyl=mesyl
Ms0=methanesulfonate=mesylate
NBS=N-bromosuccinimide
nBuLi=n-butyl lithium
tBuLi=t-butyl lithium
NCS=N-chlorosuccinimide
NIS=N-iodosuccinimide
Oxone(copyright)=potassium peroxymonosulfate
PTP=protein tyrosine phosphatase
r.t.=room temperature
rac.=racemic
Tf=trifluoromethanesulfonyl=triflyl
TFA=trifluoroacetic acid
TFAA=trifluoroacetic anhydride
TfO=trifluoromethanesulfonate=triflate
THF=tetrahydrofuran
TLC=thin layer chromatography
Ts=p-toluenesulfonyl=tosyl
TsO=p-toluenesulfonate=tosylate
Tz=1H (or 2H)-tetrazol-5-yl
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
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, 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 attachments.
Aryl means a 6-14 membered carbocyclic aromatic ring system 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.
Heteroaryl (Het) as used herein represents a 5-10 membered aromatic ring system containing one ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)y wherein y is as previously defined, and 0-2 carbonyl groups. Carbonyl groups, when present, are not counted as heteroatoms. Het includes, but is not limited to, furanyl, diazinyl, imidazolyl, isooxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrrolyl, tetrazinyl, thiazolyl, thienyl, triazinyl, triazolyl, 1H-pyrrole-2,5-dionyl, 2-pyrone, 4-pyrone, pyrrolopyridine, furopyridine and thienopyridine.
Benzoheteroaryl, which is a subset of Het 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.
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 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 says otherwise.
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 compounds or salts of the claimed 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 the phosphonic acid group, where the ester functionality has a structure that makes it easily hydrolyzed or metabolized after administration to a patient. Examples of such prodrugs are the compounds shown below, where Rxe2x80x2xe2x95x90H or a C1-6alkyl group, and Rxe2x80x3xe2x95x90a C1-6alkyl group or xe2x80x94OC1-6alkyl group, where Q is the residue of the molecule that is attached to the xe2x80x94CF2PO3H2 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 in general as defined 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 related prodrug structures, 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 Ia shown below:
In the compound having Formula Ia, one group G is independently selected from H, phenyl, xe2x80x94CHRxe2x80x2phenyl, and xe2x80x94CHRxe2x80x2OC(xe2x95x90O)Rxe2x80x3, and one group G is selected from phenyl, xe2x80x94CHRxe2x80x2phenyl and xe2x80x94CHRxe2x80x2OC(xe2x95x90O)Rxe2x80x3, where 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, where G is phenyl, may optionally be substituted with 1-3 groups independently selected from halogen, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94OCH3 and xe2x80x94OCF3. By this definition, the phosphonic acid group is a monoester or diester. In preferred compounds, the groups G that are not H in diesters are the same because of the difficulty of synthesizing different G groups on the same phosphonate.
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.
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.
Inhibitors of PTP-1B improve insulin-sensitivity and thus have utility in preventing or treating Type 1 and Type 2 diabetes, improving glucose tolerance and insulin-sensitivity when there is insulin-resistance, and in treating or preventing obesity, all in mammals that are in need of such treatments or that might benefit from such treatments. The compounds also exhibit a beneficial reduction in triglycerides and lipids. Compounds in the present class of phosphonic acids are advantageous over known phosphonic acids previously investigated as candidate PTP 1B inhibitors. The compounds of this invention show improved pharmacokinetics when compared with known phosphonates. These compounds are active in intact cell-based assays.
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.
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, coloring 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 coloring 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 coloring 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 coloring 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.
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.
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 such as 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, 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.
The compounds of the present invention can be prepared according to the following methods.
Toluic acid derivative 1 can be treated with NBS in 1,2-dichloroethane with AIBN under light at reflux to give bromide 2. The acid can be reduced with borane in THF to provide the alcohol 3 which in turn is oxidized with MnO2 to afford aldehyde 4. Di-tert-butyl phosphite can be deprotonated with a base such as LiN(TMS)2 and reacted with aldehyde 4. The resulting alcohol 5 is then oxidized with MnO2 to provide ketone 6. The ketone 6 is treated with DAST to afford compound 7.
Method A
The methyl ester of 4-aminobenzoic acid II can be brominated with pyridinium tribromide to give III, which is treated with NaNO2/HCl and KCN/CuCN to give nitrile IV. DIBAL reduction followed by bromination with POBr3, gives VI, which is treated with lithium dialkyl phosphite to afford the phosphonate alcohol VII. Swern oxidation followed by fluorination with DAST provide the desired difluoromethyl phosphonate IX.
Method A-1
xcex1-Bromo-p-tolunitrile is reduced with DIBAL to provide aldehyde 9. Di-tert-butyl phosphite can be deprotonated with a base such as LHMDS and reacted with aldehyde 9 to provide alcohol 10. Alcohol 10 can be oxidized with MnO2 to afford ketone 11 which in turn is treated with DAST to give 12.
Method B
2-Fluoro-4-methyl aniline A is treated with NaNO2/HCl followed by KCN/CuCN to give nitrile B which in turn is hydrolyzed to give C. Compound C is converted to D using sequence described in Method A. This sequence can also be applied to the ortho chloro analog.
Method B-1
Deoxybenzoin 13 can be deprotonated with potassium tert-butoxide and treated with compound 7 to give 14 (A similar alkylation can be performed using compound 12.) The ester is then hydrolyzed with AcOH-H2O to give acid 15.
Method C
Template 16 is treated with a suitable base such as NaH, KOtBu, LHMDS, KHMDS, LDA, nBuLi, tBuLi or a combination of these, and the anion is alkylated with 17 to provide 18 which is then deprotected with acid to provide the desired compound I.
Method D
The disodium phosphonate 19 can be alkylated with a chloroalkyl ester (Synth. Com. 25(18) 2739 (1995)) or carbonate (Antiviral Chemistry and Chemotherapy 8, 557 (1997)) to give both the mono and diprotected phosphonates which can be separated by flash chromatography on silica gel. Q is the residue of the molecule that is attached to the xe2x80x94CF2PO3H2 group.
Method E
METHOD F
The phosphonic acid 22 can be treated with Cs2CO3 and a chloroalkyl ester or carbonate in CH3CN to give a mixture of mono and diprotected phosphonates which can be separated by flash chromatography on silica gel. Q is the residue of the molecule that is attached to the xe2x80x94CF2PO3H2 group.
Method F
The phosphonic acid 22 can be treated with silver trifluoroacetate to give the disilver salt 23 which can be treated with an iodoalkyl ester (Eur. J. Phar. Sci. 4, 49 (1996)) or carbonate to give a mixture of the mono and diprotected phosphonates which are separable by flash chromatography. This method can also be used to obtain the benzyl ester using benzyl bromide as alkylating agent. Q is the residue of the molecule that is attached to the xe2x80x94CF2PO3H2 group.
Method G
Benzonitrile 24 can be treated with hydroxylamine hydrochloride to give 25. Compound 25 can be treated with phenyl acetic acid to afford compound 26 which in turn is alkylated with 7 from Method A to provide 27. The free acid 28 is obtained by treatment of 27 with an acid.
Method H
Benzyl nitrile 29 can be treated with hydroxylamine to give 30. Compound 30 can react with phenylacetic acid to afford 31 which in turn can be alkylated with 7 from Method A and a base to provide 32. The free acid 33 can be obtained from 32 by acid treatment.
Method I
Activity in the compounds of this application is demonstrated using the following assays for PTP-1B-inhibiting activity.
Materials:
EDTA-ethylenediaminetetraacetic acid (Sigma)
DMH-N,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 DTT-dithiothreitol Bistris-2,2-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
Stock Solutions
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.
Assay buffer 50 mM Bis-Tris (pH=6.3)
2 mM EDTA
5 mM N,Nxe2x80x2-dimethyl-N,Nxe2x80x2-bis(mercaptoacetyl)hydrazine (DMH)
Substrate 10 mM fluorescein diphosphate (FDP) store at xe2x88x9220xe2x96xa1C
Enzyme dilution buffer 50 mM Bis-Tris (pH=6.3)
2 mM EDTA
5 mM DMH
20 %(v/v) glycerol
0.01% Triton X-100
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.
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, 3xe2x80x3 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.
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                  DOSE                iv                    DOSE                po              xc3x97    100              xe2x80x83            %
Clearance rates are calculated from the following relation:   CL  =            DOSEiv                    (                  mg          /          kg                )              AUCiv
The units of CL are mL/hxc2x7kg (milliliters per hour kilogram)
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.
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-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                  DOSE                iv                    DOSE                po              xc3x97    100              xe2x80x83            %
Clearance rates are calculated from the following relation:   CL  =            DOSEiv                    (                  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.
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).
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 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.

Phosphonic acid derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B)

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


In a non-aqueous electrolyte secondary cell including a positive electrode, a negative electrode and a non-aqueous electrolyte, the negative electrode includes a material capable of absorbing or releasing lithium and wherein the non-aqueous electrolyte contains a room-temperature molten salt having a melting point of 60° C. or less and a lithium salt.

As one of modern secondary cells of high output and high energy density, a non-aqueous electrolyte secondary cell has come into use, the cell employing a non-aqueous electrolyte and offering a high electromotive force based on oxidization and reduction of lithium.
Such a non-aqueous electrolyte secondary cell generally employs a non-aqueous electrolyte wherein a solute of lithium salt, such as LiBF4 or LiPF6, is dissolved in an organic solvent such as ethylene carbonate or diethyl carbonate.
Unfortunately, the aforesaid organic solvent for use in the non-aqueous electrolyte is flammable, involving a fear of burning in abnormal operation such as overcharge. Hence, it has been a conventional practice in the art to provide a protection circuit such as to prevent the cell from being overcharged. This leads to a problem of cost increase.


A circumferential length of a belt is measured within a short period of time. A plurality of marks is provided on a belt. Distances between the marks are set to be all different from each other. The distance between the marks is set to allow the mark to be identified by measuring a period of time between the detection of one mark and that of the next mark even if the length of the belt is changed to some degree by the expansion of the belt or the like. Then, a period of time between the identified mark and the next mark is accurately measured. The total circumferential length of the belt is measured based on the results of measurement.

1. Field of the Invention
The present invention relates to an image forming apparatus having a mechanism for detecting a mark on a belt to prevent the misregistration of a toner image to be formed.
2. Description of the Related Art
In recent years, a tandem image forming apparatus has been proposed as a full-color image forming apparatus using an electrophotographic process. The tandem image forming apparatus includes a plurality of photosensitive drums arranged in a row, which respectively correspond to toner colors, to sequentially superimpose toner images on an image bearing belt (intermediate transfer belt), thereby obtaining a desired image.
FIG. 9 illustrates a schematic configuration of an image forming apparatus in the background art. The image forming apparatus illustrated in FIG. 9 is provided with image forming units (1Y, 1M, 1C and 1K) for yellow (Y), magenta (M), cyan (C) and black (K) toners, respectively. In the respective image forming units 1, toner images are sequentially transferred onto an intermediate transfer belt 18.
The transfer of the toner images onto the intermediate transfer belt 18 is performed in nip portions (primary transfer portions N) between photosensitive drums (2Y, 2M, 2C and 2K) respectively provided for the image forming units 1 and primary transfer rollers (5Y, 5M, 5C and 5K).
Specifically, a transfer bias is applied from a primary transfer bias supply (not illustrated) to each of the primary transfer rollers 5 to transfer the toner image from a surface of the photosensitive drum 2 onto the intermediate transfer belt 18 by an electrostatic force. The toner images on the surfaces of the photosensitive drums 2 are formed by the following process.
The surfaces of the photosensitive drums 2 are uniformly charged by charging rollers (3Y, 3M, 3C and 3K) provided in contact with the photosensitive drums 2. A modulated laser beam is emitted from each of exposure devices (7Y, 7M, 7C and 7K) based on image information to form an electrostatic latent image on the surface of each of the photosensitive drums 2.
For the electrostatic latent images respectively formed on the surfaces of the photosensitive drums 2, development units (4Y, 4M, 4C and 4K) respectively containing the yellow (Y), magenta (M), cyan (C) and black (K) toners feed the toners to visualize the electrostatic latent images as the toner images. Then, in each of the primary transfer portions N, the toner image is transferred onto the intermediate transfer belt 18. The residual toner remaining on the surfaces of the photosensitive drums 2 without being transferred to the intermediate transfer belt 18 is cleaned by each of cleaning units (6Y, 6M, 6C and 6K).
The toner image transferred onto the intermediate transfer belt 18 is conveyed to a secondary transfer portion M (nip portion between a secondary transfer opposing roller 12 and a secondary transfer roller 14) with the movement of the intermediate transfer belt 18 to be transferred onto a sheet material. The intermediate transfer belt 18 is movably looped around a driving roller 11, the secondary transfer opposing roller 12, and a tension roller 13. In other words, a driving roller 11 and a tension roller 13 are stretching members for stretching the intermediate transfer belt 18. The driving roller 11 is rotationally driven to move the intermediate transfer belt 18 in a direction indicated by an arrow of FIG. 9.
For transferring the toner image onto the sheet material in the secondary transfer portion M, the sheet materials fed one by one from a feeding portion (not illustrated) are temporarily stopped to wait between a registration roller pair 20 provided before the secondary transfer portion M.
Thereafter, the registration roller pair 20 is rotated according to arrival timing of the toner image at the secondary transfer portion M to feed the sheet material to the secondary transfer portion M, thereby transferring the toner image to a desired position of the sheet material.
If a deviation occurs between the timing for feeding the sheet material to the secondary transfer portion M and the timing for conveying the toner image on the intermediate transfer belt 18 to the secondary transfer portion M, it becomes difficult to transfer the toner image to a desired position of the sheet material. As a result, defect such as image quality degradation occurs.
In the image forming apparatus in this background art, on the assumption that a circumferential length of the intermediate transfer belt and a conveying speed of the toner image remain constant, a time length required for the toner image to reach the secondary transfer portion M is calculated based on writing start timing of the electrostatic latent image onto the photosensitive drum.
Specifically, a period of time required for the toner image to reach the secondary transfer portion M is pre-calculated. The registration roller pair feeds the sheet material to the secondary transfer portion M based on the calculated time to synchronize the arrival timing of the toner image with the conveying timing of the sheet material.
In this case, on the assumption that the circumferential length of the intermediate transfer belt remains constant, the time required for the toner image to reach the secondary transfer portion M is calculated. Therefore, it is difficult to cope with the occurrence of expansion and contraction of the intermediate transfer belt due to an environmental change such as a change in temperature or humidity or a change with time.
Specifically, when the circumferential length of the intermediate transfer belt changes, the time required for the toner image on the intermediate transfer belt to reach the secondary transfer portion also changes. Therefore, the deviation between the arrival timing of the toner image and the conveying timing of the sheet material is occurred, and the image quality degrades.
Therefore, as described in Japanese Patent Application Laid-Open No. 2001-215857, the invention relating to an image forming apparatus for correcting a deviation between the arrival timing of the toner image and the conveying timing of the sheet material to cope with a variation in circumferential length of the intermediate transfer belt is presented.
Japanese Patent Application Laid-Open No. 2001-215857 discloses a constitution including a mark provided at one position on the intermediate transfer belt and a sensor for detecting the passage of the mark. The passage of the mark is detected with the sensor to calculate a circumferential length variation of the intermediate transfer belt.
However, the following problem arises in the image forming apparatus described in Japanese Patent Application Laid-Open No. 2001-215857.
When the passage of the mark provided at one position on the intermediate transfer belt is detected to calculate the circumferential length variation of the intermediate transfer belt, the intermediate transfer belt moves approximately two circumferential lengths to measure the circumferential length of the intermediate transfer belt at some detection start timing.

Image forming apparatus having a mechanism for detecting a mark on a belt


A vertebral locking and retrieving system comprising a locking pin, a connector, a locking component, a coupling component, a remedial component, and securing components is disclosed. The locking pin includes a threaded end and a locking end. The threaded end is adapted to be secured to a normal, healthy vertebra. The connector comprises a through hole and an integrally formed cubic portion at one lateral side of the through hole. The cubic portion has a locking aperture adapted to non-rotatably accept the locking end of the locking pin. The locking component is engaged with the locking end of the locking pin after it has passed through the locking aperture of the cubic portion to hold the connector onto the locking pin. The coupling component is threadably connected one end thereof to the through hole of the connector. The remedial component is secured at one end thereof to a deformed vertebra immediately adjacent to the healthy vertebra to which the locking pin is secured or a vertebra next to the deformed vertebra and different from this healthy vertebra and is connected at its other end thereof to the other end of the coupling component. The securing components enable the remedial component to be fixedly secured to the coupling component.

1. Field of the Invention
The present invention relates to a vertebral locking and retrieving system.
2. Description of the Prior Art
In general, conventional vertebral locking and retrieving systems of the prior art involve a locking process of multiple vertebrae, as exemplified by the LUGUE rod and the HARRINGTON rod, both made by Zimmer Company of U.S.A., and the ROY-CAMILLE plate produced by Howmedia Corporation of U.S.A. Such known prior art arrangements require a surgeon to make a long incision, which generally takes up too much of a surgeon's time and may bring about excessive bleeding by a patient receiving the treatment. The case in point is the LUGUE rod, which must be secured to two upper and lower vertebrae immediately adjacent to the injured or the deformed vertebra. This means that a surgeon is required to make a large incision to fix at least five segments of the spinal column. As a result, the patient's ability to move about is greatly hampered in the wake of such a surgical operation. In addition, the pressure exerting on the patient's nervous system by the locking and retrieving system of the prior art can not be effectively mitigated in view of the facts that the locking process is confined to a rear plate and that the retrieval of a front plate is not possible.
Furthermore, the surgical implantation of the conventional vertebral locking and retrieving systems of the prior art is further complicated by the fact that seven cervical vertebrae, twelve thoracic vertebrae, five lumbar vertebrae, and one caudal vertebra of the human spinal column differ in curvatures.
Other types of prior art vertebral locking and retrieving systems are disclosed respectively in U.S. Pat. Nos. 4,611,581 and 4,696,290. Such systems have also failed to deal with the surgical problems described above. In short, the existing vertebral locking and retrieving systems of the prior art have failed to address the surgical problems that are derived mainly from the fact that the curvatures of various vertebrae of the human spinal column are different from one another.
It is therefore the primary object of the present invention to provide a vertebral locking and retrieving system with a locking pin and a connector, in which said locking pin and/or said connecor are designed in such unique manners that they have specific angles permitting the locking pin to cooperate with the specific curvatures of various vertebrae and that they serve to overcome the problems during and after the surgical operation having to do with locking multiple vertebrae.
It is another object of the present invention to provide a vertebral locking and retrieving system with means which can be used to lock two vertebrae of the spinal column.
It is still another object of the present invention to provide a vertebral locking and retrieving system with a locking pin and a connector, in which said locking pin and/or said connector are designed to have specific angles for correcting the position of various vertebrae having different curvatures.


An organizer cover, comprising first and second cover panels and a spine, an external surface, at least one organizer element, and at least one concealment flap. The spine is operatively coupled between the first and second cover panels. The first and second cover panels and the spine each have an exterior. The external surface includes the exteriors of the first and second cover panels and of the spine. The organizer element is located on the external surface of the cover. The concealment flap is connected to the external surface and manually positionable between a closed position against the external surface and an open position. The concealment flap is located and configured to conceal, at least in part, the organizer element when the flap is in the closed position. Neither the external surface nor the organizer element includes thereon any means for securing the concealment flap in the closed position.

1. Technical Field
The present invention relates generally to calendars, planners and organizers, and more particularly to covers or jackets for housing such items.
2. Background Art
External covers have been used to house, for example, organizers, diaries or planners. Such covers are useful to protect and conceal the contents of the organizer, diary, or planner. Many of such covers are equipped with a closure mechanism such as, for example, a zipper or a fold-over flap secured by a snap, clasp or magnet. An example of such a cover is shown and described in U.S. Pat. No. 6,161,979 to Yamamoto et al. While such covers have proven useful, they can be inconvenient when quick and easy access to the cover's internal contents is necessary or desired.
In order to overcome this inconvenience, certain frequently used functions of the organizer, planner, diary, etc., have been relocated to the outside of the cover, for easy access. Examples of such relocation are shown and described in U.S. Pat. No. 6,283,183 to Cooper, U.S. Pat. No. 6,161,979 to Yamamoto et al., U.S. Pat. No. 6,126,012 to Roegner, U.S. Pat. No. 6,047,752 to Southwick, U.S. Pat. No. 5,911,262 to Steinhart, U.S. Pat. No. 5,489,021 to Wallingford, U.S. Pat. No. 4,739,809 to Adams, and U.S. Pat. No. 4,192,365 to Siegel.
The relocation of various organizer functions to the outside of the cover sometimes raises aesthetics issues. The implementation of such functions on the outside of the cover can be unsightly. One approach to improving the aesthetics of such covers is to hide the externally located functions behind a flap or flaps. Examples of such external flaps are shown in U.S. Pat. No. 6,283,183 to Cooper (at FIG. 1), U.S. Pat. No. 6,161,979 to Yamamoto et al. (at FIG. 18), U.S. Pat. No. 6,126,012 to Roegner (at FIGS. 3 and 4), U.S. Pat. No. 6,047,752 to Southwick (at FIG. 4), U.S. Pat. No. 5,911,262 to Steinhart (at FIGS. 4 and 5), U.S. Pat. No. 5,489,021 to Wallingford (at FIG. 4), and U.S. Pat. No. 4,739,809 to Adams (at FIG. 3).
In all such examples, some visible and present means for securing the flap to the outside cover is shown. Snaps are used in the patents to Cooper and Adams; buckles are used in Yamamoto et al.; hook and loop fasteners are used in Wallingford and Roegner; and zippers are used in Steinhart and Southwick. Such visible and present securing means can also be unsightly, or at least undesirable when inconspicuous concealment of organizer functions is the goal.
Moreover, such securing means may interfere with the organizer function or adversely affect the aesthetics of the layout of the function or functions. This is especially of concern with compact cover designs, where the surface area for the function(s) and securing means is limited. This concern is illustrated to some degree in U.S. Pat. No. 6,126,012 to Roegner (at FIG. 4) and U.S. Pat. No. 5,489,021 to Wallingford (at FIG. 4), where hook and loop fasteners are prominently displayed on the outside surface of the cover and/or on the inside of the flap. Such securing means occupy substantial surface area otherwise available for relocated functions. In addition, such securing means significantly influence the aesthetics of the article.

Organizer cover with external concealment flaps


A lantern lighting device includes a base portion defining a user interface, an upper portion coupled to the base portion and having an upper cover, an energy storage device disposed within at least one of the base portion and the upper cover, a first LED and a second LED coupled to the upper cover and configured to provide a first and a second light output, a divider coupled to the base portion and the upper cover, and a controller. The divider forms a partition between the first LED and the second LED that separates the first light output from the second light output. The controller selectively engages the first LED in a first operation mode to provide approximately 180 degrees of illumination or that engages both the first LED and the second LED in a second operation mode to provide approximately 360 degrees of illumination.

The present application relates to a lighting device. Particularly, the present application relates to a mobile lantern lighting device. The present application further relates to charging systems and methods for storing energy within a mobile lantern device. Lanterns convert stored energy into light energy and illuminate a surrounding environment. Lanterns may be used for generally illuminating a surrounding area or for performing a particular task, such as reading. When performing a particular task, a user may wish to direct light toward only a portion of the surrounding environment.
While a large light output from the lantern may be preferred for general lighting, a reduced light output may be preferred to perform a particular task. Traditional lanterns include one or more lighting sources (e.g., mantels, bulbs, etc.) intended to project light toward a surrounding environment. While a user may vary the light output of the lantern using a switch (e.g., a dial that regulates the flow of fuel to the mantel), the light output of each light source is typically increased or decreased together. Therefore, users generally cannot specify the intensity of a particular light source. Further, traditional lanterns do not allow a user to selectively direct light toward only a portion of the surrounding environment. Despite such lack of control, lanterns with lighting sources controlled in unison remain the primary devices used to illuminate a surrounding environment.


An analog-to-digital converter (ADC) includes a modulator and a decimation filter. The modulator includes a sampling circuit, integrator, a quantizer, and feedback circuitry. The sampling circuit includes at least one sampling capacitor and a plurality of dump capacitors. A sum of the capacitance of the dump capacitors is substantially equal to a capacitance of the sampling capacitors. Combined sampling/dump capacitors having approximately equal capacitance may be used with the sampling circuit.

1. Technical Field
This invention relates generally to analog to digital signal conversion and more particularly to a modulator for use within an analog to digital converter.
2. Description of Related Art
The formation and use of integrated circuits is generally known. Integrated circuits are found not only in electronic devices but in machinery, vehicles, aircraft, and a large number of other devices. Most of these devices require interaction with the physical world. Thus, one common circuit present in many integrated circuits is an Analog-to-Digital Converter (ADC). An ADC receives an analog input signal and converts the analog input signal into a digital signal. The integrated circuit subsequently operates upon the digital signal and may even produce an analog output using a Digital-to-Analog Converter (DAC).
ADCs must accurately convert the analog input signal into the digital signal. Such is the case because the overall performance of the integrated circuit is based upon the accuracy with which the analog input signal is measured. Because ADCs include circuit elements formed in semiconductor manufacturing processes having process variations, ADC circuit components having component values that vary from integrated circuit to integrated circuit. Mismatches in ADC circuit components cause the ADC to improperly function and cause the ADC to inaccurately convert the analog input signal to the digital signal. Thus, a need exists for an ADC that overcomes mismatches in its circuit components.

Analog to digital signal converter having sampling circuit with divided integrating capacitance


A method and system for improving signal recovery for tomographic-type detection systems is disclosed which reduces the effect of blurring by obtaining a spatial response function for a plurality of selected detectors and moving the detectors to various positions at various times such that at least two tomographic measurements are taken of substantially the same signal when the object and detection means are at different relative positions. The measurements are then represented as a set of linear equations wherein elements of the response function become weighting factors for corresponding unknown tomographic signal elements. The unknown tomographic signal elements are then estimated by solving the set of linear equations. The tomographic signal elements may then be used as data in projection profiles to generate projection matrices or images directly.

Typically, tomographic methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) rely on measurements of poor quality due to broad spatial response functions imposed by properties of the particular system. In general, tomographic systems are used to infer a spatial distribution or estimate of a spatial distribution of a selected property of an object within the object's interior as determined from measurements of emanations from or through the object. For example, gamma rays emanate from an object in PET systems. Tomographic measuring mechanisms typically use an external source and detector as in the case of CT, or internal induced emanations and external detectors as in the case of PET.
Often times these spatial distributions are represented in picture form for visual analysis. Therefore these spatial distributions are commonly referred to as images although they need not necessarily be pictorially represented (e.g., the values at various points may be analyzed by computer to determine biological parameters or other object properties).
When a pictorial representation is displayed, the effect of broad spatial response functions manifests as a visual blurring. When, instead, the spatial distribution of interest is used to form estimates of some biological parameter, the effect causes a kind of numerical inaccuracy known as a partial volume effect.
PET as a biomedical imaging modality, is unique in its ability to provide quantitative information regarding biological function in a living subject. PET is a technique in which the distribution of a radioactive tracer material, introduced into an object, is reconstructed from the gamma rays that are emitted from within the object as a result of decay. PET is a powerful tool for brain research since, through proper selection of tracer materials, it provides non-invasive measurements of brain function through variables such as metabolism and blood flow. PET is also effective in assessing perfusion and tissue viability and, therefore, is widely used in cardiology and oncology.
Unfortunately, its use has been hampered by the poor spatial resolution of the images produced, resulting primarily from the relatively large detectors used to acquire the tomographic measurements. The poor image quality obtained by PET results from a number of factors, the most serious of which are blur due to broad spatial response functions and quantum noise due to detector response characteristics and limitations on permissible radiation dose.
In PET, each radioactive decay event, taking place within the object, leads to the simultaneous emission of two gamma rays in nearly opposite directions. These gamma rays are then counted by a detector system typically including one or more circular rings comprising a plurality of adjacent detectors positioned about the object. The detectors are connected to electronic coincidence circuitry.
An event is assumed to have taken place when two detectors register gamma rays at approximately the same instant of time. Since it is known that the gamma rays travel at 180 degree angles from one another, simultaneous detection serves to provide information regarding the location of the parent event.
FIG. 1 generally illustrates such a PET detection system. The ring of detectors 10 surrounds the object 12. A series of adjacently positioned detectors 14 form the ring 10. A pair of detectors 14a and 14b form a region known as a detector tube 16. With this configuration, an emission event taking place outside of the detector tube 16 cannot generally produce a pair of gamma rays that strike both detectors 14a and 14b. If a point source of emitting materials were placed at point 18 and moved to the right along line 20, the probability of the detection, by detectors 14a and 14b, of one of its emissions would increase as the source approached the center 22 of the detector tube 16 and then decrease as the source proceeded toward the edge of region and beyond.
The probability density function for the detections along such a lateral cross section of the detector tube 16 generally resembles curve 24. Curve 26 represents the probability function for an adjacent tube. The set of probability values, obtainable in this manner throughout the active region of a detector pair, is described herein as a spatial response function. Ideally, the spatial response function should have a value of zero for points outside of the boundaries of the detector tube; in practice, crosstalk between adjacent detectors precludes this.
The effect of a spatial response function is to determine in what proportion the source distribution of the object contributes on average to the number of gamma rays counted by the corresponding detector pair during the measurement process. Mathematically, if the object source distribution and a spatial response function are represented discretely, then, assuming corrections have been made for effects such as attenuation, the average number of gamma ray emissions detected by the corresponding detector pair can be described approximately as a sum of the density of tracer material within discrete elements of the object, weighted by the value of the corresponding spatial response function at that point. Symbolically, the operation can be represented generally by ##EQU1## where the x.sub.m denote the values for the object elements, the h.sub.m represent the corresponding elements of the spatial response function, and d is the average number of gamma ray emissions detected within the integration time of the measurement.
While the physical considerations from which this relationship arises are unique to PET, it is recognized in the art that tomographic measurement system can generally be represented as linear systems. Therefore, the term spatial response function will refer to those linear weighting factors relevant to a selected tomographic application. Since, for computational purposes, it is generally necessary to use discrete representations of continuous functions, spatial response function will refer, herein, to a vector of values that will be described as spatial response function elements.
Since the spatial response functions need not necessarily act mathematically on the object elements, and since the object property being measured varies with the particular application, the term signal will be used to refer generally to the true value of the quantity, of interest in a given situation, which is subject to linear transformation by the spatial response function or functions. For computational purposes, the signal will be considered to be divided into discrete values described herein as tomographic signal elements.
In applications other than PET, the observable quantity will not typically be a count of gamma ray emissions. Therefore, the term tomographic measurement will be used to describe the observed quantity, taking the place of d in Equation (1).
Generally, if the spatial response functions limit system spatial resolution, then the sampling rate afforded by the fixed positions of the detectors is typically insufficient to adequately characterize a signal out to the spatial frequency bandwidth determined by the spatial response functions. One solution, commonly employed in PET, moves the detection system to various positions to enable additional samples to be obtained. Using conventional methods, these extra samples in principle allow the signal to be specified accurately up to the bandwidth associated with the detector response functions, but detector response remains the limit on achievable resolution.
Referring again to FIG. 1, when in a conventional PET system there occurs a simultaneous detection of two gamma rays by two detectors at different points in the ring, a decay event is assumed to have taken place somewhere along a line 28 connecting the centers of the two detectors 14a and 14b. The mathematical foundation for traditional tomographic reconstruction techniques assumes the available measurements to consist of integrals of some object property along idealized rays of infinitesimal width, known as projection lines. In the conventional method for reconstructing PET images, the lines connecting the centers of the detectors take the place of these idealized projection lines. This is a very poor approximation which contributes to the low quality of conventional PET images. In reality, because actual detectors have finite extent, the simultaneous detection of two gamma rays proves that a decay event has taken place, not along an idealized ray, but within a broad region defined by the corresponding spatial response function.
Motion has been incorporated in many PET systems to improve sampling. One type of motion is commonly known as wobble. Wobble refers to an in-plane orbital motion of the entire detection system without rotation.
Referring to FIG. 2, when viewed edge-on, the circular wobbling 30 of the detector ring 10 manifests as a one-dimensional simple-harmonic motion. Hence, in the context of a single angular view in the parallel-beam geometry, the projection lines 28 (detector tubes) sweep back and forth with a sinusoidal time dependence.
In the usual procedure, the detection system travels in a continuous motion, and gamma rays are counted (measured) throughout. The gamma rays counted during time intervals of equal duration are grouped together and are considered as single observations 32 constituting additional samples of the signal along the direction of the projection profile. The gamma rays detected during a single time interval are usually treated as having been observed, not over a range of positions as is actually the case, but at a single point within that range. It is possible to stop the motion at discrete positions to achieve precisely what is approximated by the continuous motion, however, for practical reasons of mechanical design, continuous motion is more commonly employed.
The traditional approach to processing raw tomographic measurements 32 from such a system is to assign the counts observed during the motion to a plurality of equally spaced points 34 along an axis 36 of a projection profile by traditional interpolation methods such as bilinear interpolation. In tomographic imaging applications, this step, known as rebinning, yields a projection matrix (or sinogram). After rebinning, corrections are made to the projection matrix to compensate for such factors as attenuation and scattering of gamma rays through tissue in the brain, and/or system variations such as variation in detector sensitivity and other necessary corrections.
The corrected projection matrix is then used to reconstruct the image using various techniques known in the art. The rebinning step is complicated by the fact that the measurements (samples) are distributed in a highly non-uniform way due to the ring geometry of the data-acquisition system and the nature of the wobble motion.
The bilinear interpolation method typically begins with computation of the radial position and angular orientation of each projection line 28. The gamma-ray counts attributed, in the conventional processing approach, to a particular idealized projection line 38 are divided between two grid points 40 and 42 along the axis of the projection profile 36. The two grid points 40 and 42 neighbor an actual coordinate 44 corresponding to the particular idealized projection line 38. The division of the counts is made in proportion to the relative distances of the grid points 40 and 42 to the actual coordinate 44. For example, if the neighboring grid points 40 and 42 are separated by a distance .DELTA.r, and if the actual coordinate 44 lines at a distance s from A, then the fraction s/.DELTA.r of the counts associated with the true coordinate is assigned to point B and the remaining fraction is assigned to point A.
A blurring problem occurs using this approach since regardless of the number of samples obtained by the moving detection system, the spatial resolution of the signal cannot be improved beyond the limit imposed by the spatial response functions. Such conventional processing techniques used in the practice of PET and other tomography systems typically fail to take into account the broad spatial response functions that degrade the signal. Instead conventional processing techniques assume idealized projection lines and assume infinitesimal detector elements.
Non-moving tomographic systems are known that have improved imaging over conventional moving systems but typically must use a large number of smaller and more expensive detectors to acquire an image. Such non-moving systems that use interpolation methods generally suffer from the same effects of blurring as do conventional moving systems. Also, improving existing moving systems by incorporating the smaller detectors is generally cost prohibitive given the high cost of smaller detectors and the cost of modifying existing hardware. There exists a need for a signal recovery method that improves signals and is compatible with designs for moving systems that use less expensive, larger detectors to help eliminate the need for higher cost detectors while improving the quality of the tomographic images.
Therefore, there exists a need for a method of reducing the effect of blur due to spatial response function in tomographic detection systems. Furthermore, there exists a need for a method of recovering signals in tomographic systems that takes into account effects of spatial response functions rather than assuming idealized conditions. A need also exists for an improved signal recovery method which substantially reduces the computational time for recovering tomographics signals.

Method of recovering tomographic signal elements in a projection profile or image by solving linear equations

Univ. of Chicago Development Corp. Argonne National Laboratories