The present invention discloses compounds of formula (I), and tautomeric forms, pharmaceutically acceptable salts, or solvates thereof. Preferably, the compounds of the invention are dual activators of hPPARxcex3 and hPPAR{acute over (xcex1)}.

The present invention relates to certain novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it relates to compounds which exhibit activation, including dual agonist activity, to peroxisome proliferator-activated receptors gamma (PPARxcex3) and alpha (PPARxcex1) thereby enabling them to modulate the blood glucose and lipid levels in mammals.
Treatment of type 2 diabetes mellitus usually begins with a combination of diet and exercise, with progression to oral hypoglycaemics (e.g. sulfonylureas) and in more severe cases, insulin. In the last decade a class of compounds known as thiazolidinediones (e.g. U.S. Pat. Nos. 5,089,514, 4,342,771, 4,367,234, 4,340,605, 5,306,726) have emerged as effective antidiabetic agents that enhance the insulin sensitivity of target tissues (skeletal muscle, liver, adipose) in animal models of type 2 diabetes mellitus and also reduce lipid and insulin levels in these animal models.
It has been reported that thiazolidinediones are potent and selective activators of PPARxcex3 and bind directly to the PPARxcex3 receptor (J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPARxcex3 is a possible target for the therapeutic actions of the thiazolidinediones.
PCT patent publication WO 97/31907 discloses certain novel compounds that bind to and activate PPARxcex3. These compounds are indicated to be useful for the treatment of type 2 diabetes mellitus and other diseases.
Activators of the nuclear receptor PPARxcex3, for example troglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E. Kelly et al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al., Ann. Pharmacother., 337-348, 32 (3), (1997); and M. Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997).
The mechanism for this triglyceride lowering effect appears to be predominantly increased clearance of very low density lipoproteins (VLDL) through induction of liporotein lipase (LPL) gene expression. See, for. example, B. Staels et al., Arterioscler. Thromb., Vasc. Biol., 1756-1764, 17 (9), (1997).
Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10-15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and increase HDLc 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPARxcex1. See, for example, B. Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation of PPARxcex1 results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion. In addition, PPARxcex1 activation decreases production of apoC-III. Reduction in apoC-III, an inhibitor of LPL activity, increases clearance of VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996).
In addition, a dual agonist of PPARxcex1 and PPARxcex3 could be effective in reducing the dyslipidemia and hyperinsulinemia associated with impaired glucose tolerance (IGT) or metabolic syndrome and could be effective in patients with mixed hyperlipidemia. See, for example, U.S. Pat. Nos. 5,478,852.
PCT patent publication WO 98/05331 (Paterniti et al.) relates to methods for treating diabetes and cardiovascular disease using a PPARxcex3 agonist in combination with a PPARxcex1 agonist, or a compound that activates both PPARxcex3 and PPARxcex1.
Briefly, in one aspect, the present invention provides compounds of formula (I), and tautomeric forms, pharmaceutically acceptable salts and solvates thereof,
wherein;
R1 is hydrogen or C1-3alkyl;
R2 is hydrogen, or C1-8alkyl optionally substituted by one or more halogens;
R3 is C1-6alkyl, C4-7cycloalkyl or cycloalkenyl, xe2x80x94OC1-6alkyl, xe2x80x94NRxe2x80x2Rxe2x80x2 (where each Rxe2x80x2 is independently hydrogen or C1-3alkyl), a 5 or 6 membered heterocyclic group containing at least one oxygen, nitrogen, or sulfur ring atom (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2), or phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2);
R4 is a 5 or 6 membered heterocyclic group containing at least one oxygen, nitrogen, or sulfur ring atom (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2), or phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94NRxe2x80x2Rxe2x80x2 (as defined above), xe2x80x94CN, or xe2x80x94NO2);
R5 is hydrogen, halogen, or C1-3alkyl optionally substituted by one or more halogens;
R6 is hydrogen or C1-3alkyl;
X is O or S; and
n is 1, 2, or 3.
Preferably, the compounds of this invention activate both the hPPARxcex3 and hPPARxcex1 receptors.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention. As used herein, xe2x80x9ca compound of the inventionxe2x80x9d means a compound of formula (I) or a tautomeric form, pharmaceutically acceptable salt, or solvates thereof.
The invention further provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides a method for treatment or prevention of a hPPARxcex3 and/or hPPARxcex1 mediated disease, risk factor, or condition, comprising administration of a therapeutically effective amount of a compound of this invention.
According to another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the is treatment or prevention of a hPPARxcex3 and/or hPPARxcex1 mediated disease.
hPPARxcex3 and/or hPPARxcex1 mediated diseases, risk factors, or conditions include hyperglycemia, dyslipidemia, type II diabetes mellitus including associated diabetic dyslipidemia, type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, hyperlipidemia, hypercholesteremia, hypertension, cardiovascular disease, including atherosclerosis, regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the compounds of the present invention are useful in the treatment or prevention of hyperglycaemia, dyslipidemia, and type II diabetes mellitus including associated diabetic dyslipidemia.
Preferably, R1 is hydrogen or methyl. Most preferably, R1 is hydrogen.
Preferably, R2 is C1-8alkyl optionally substituted by one or more halogens. Preferably, said halogen is fluorine. Most preferably, R2 is straight-chain.
Preferably, R3 is pyridine, pyrazine, thiophene, furan, thiazole, or phenyl (any of which may be optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2), or C4-7cycloalkyl. Most preferably, R3 is phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, xe2x80x94OC1-6alkyl optionally substituted by one or more halogens, xe2x80x94CN, or xe2x80x94NO2).
Preferably R4 is phenyl (optionally substituted by one or more halogen, C1-6alkyl optionally substituted by one or more halogens, or xe2x80x94OC1-6alkyl optionally substituted by one or more halogens). Preferably, said halogen is fluorine. Most preferably R4 is phenyl either unsubstituted or substituted with 1, 2, or 3 fluorine atoms.
Preferably, R5 is hydrogen, halogen, or C1-3alkyl optionally substituted by one or more halogens. Most preferably R5 is hydrogen.
Preferably R6 is methyl or ethyl.
Preferably n is 2.
Preferably, the carbon atom bonded to CO2R1 is in the S configuration. In other words, preferably, the absolute configuration around that carbon is:
Suitable compounds of the present invention include:
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4 -(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-([2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(4-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino{-3-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(3-nitrophenyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-({(Z)-3-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-3-oxo-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-isopropoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-chlorophenylyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-furyl)-1-methyl-3-oxo-1-propenylamino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyrazinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2,4-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(1,3-thiazol-2-yl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(3-thienyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2-pyridinyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-(4-fluorophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-fluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2,3-difluorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(2-hydroxyphenyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-3-(4-methoxyphenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-3-cyclohexyl-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-isopropoxyphenyl)-5methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-heptyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(3-methylphenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-(4-{2-[2-(4 -methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{-[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-isopropoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(2-phenyl-5-propyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3oxo-3-phenyl-1-propenyl]amino}-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-{[(Z)-3oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{[5ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[(5ethyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}propanoic acid, and pharmaceutically acceptable salts and solvates thereof.
Preferred compounds of the invention include
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-[4-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,3,4-trifluorophenyl)-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-(4-nitrophenyl)-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-(2,4,5-trifluorophenyl)-1-propenyl]amino}-3-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-1-ethyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl-5-methyl-1,3-thiazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-{[(Z)-1-butyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-2-{[(Z)-3-(4-chlorophenyl)-1-methyl-3-oxo-1-propenyl]amino}-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propyl-1-propenyl]amino}propanoic acid
(2S)-3-{4-[2-(5methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-(4-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)propanoic acid
(2S)-3-(4-{2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino}-3-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}-2-{[(Z)-3-oxo-3-phenyl-1-propenyl]amino}propanoic acid
(2S)-2-{[(Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]amino{-3-4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-{4-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl)-2-{[(Z)-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[2-(5ethyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl}-2[(Z)-3-oxo-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl )-1,3-oxazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy)}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)1-propenyl]amino}propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenyl}propanoic acid
(2S)-3-(4-{3-[5-ethyl-2-4-fluorophenyl)-1,3-oxazol-4-yl]propoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-{4-[3-(5-ethyl-2-phenyl-1,3-oxazol-4-y)propoxy]pheny}-l2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{[5ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-{[(Z)-3-oxo-3-phenyl-1-(trifluoromethyl)-1-propenyl]amino}propanoic acid
(2S)-3-{4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yL)methoxy]phenyl}-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{[5-ethyl-2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)-2-({(Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid
(2S)-3-(4-{2-[5-ethyl-2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethoxy}phenyl)-2-({(Z)-1-ethyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl}amino)propanoic acid and pharmaceutically acceptable salts and solvates thereof.
Many of the compounds of formula (I) are dual activators of hPPARxcex3 and hPPARxcex1 As used herein, by xe2x80x9cactivating compoundxe2x80x9d, or xe2x80x9cactivatorxe2x80x9d, or the like, is meant those compounds which achieve at least 50% activation of human PPARxcex3 (xe2x80x9chPPARxcex3xe2x80x9d) or hPPARxcex1 (relative to the appropriate indicated positive control) in the transfection assay described below at concentrations of 10xe2x88x927 M or less. As used herein, a xe2x80x9cdual activatorxe2x80x9d is a compound that is an activator of both PPARxcex3 and PPARxcex1.   The        xe2x80x83      ratio        xe2x80x83                        EC        50                          xe2x80x83                  hPPAR                    xe2x80x83                  α                      EC        50                          xe2x80x83                  hPPAR                    xe2x80x83                  γ
defines the relative activity of hPPARxcex1 to hPPARxcex3. Preferably, the dual activators of this invention have a relative hPPARxcex1 to hPPARxcex3 activity of from 0.02 to 50.
Those skilled in the art will recognize that stereocenters exist in compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable s acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
The terms C1-3alkyl, C4-6cycloalkyl, C1alkylene, C2-6alkenyl and the like, as used herein, indicate groups that may contain the indicated range of carbon atoms, for example 1 to 3 carbon atoms. Unless otherwise indicated, such groups can be straight chained or branched.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6-membered substituted or unsubstituted heterocycloalkyl and heteroaryl groups, e.g. substituted or unsubstituted imidazolidinyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl or tetrazolyl. Particularly preferred heterocycles are pyridine, pyrazine, thiophene, furan, and thiazole.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
Formulations of the present invention include those especially formulated for oral, buccal, parenteral, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration, however, oral administration is preferred. For buccal administration, the formulation may take the form of tablets or lozenges formulated in conventional manner. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Additionally, formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
The formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins or as sparingly soluble derivatives as a sparingly soluble salt, for example.
The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
There is further provided by the present invention processes for the preparation of compounds of the invention Unless otherwise indicated, Rxe2x80x2, R1, R2, R3, R4, R5, R6, n, and X are as defined above.
A compound of structural formula (I) may be prepared from the condensation of a compound of formula (II):
with a compound of formula (III), for example, in a polar organic solvent, such,
as methanol, at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 65xc2x0 C., in the presence of a dehydrating agent such as trimethylorthoformate and/or molecular sieves.
Alternatively, a compound of formula (I) where R5 is hydrogen may be prepared by reaction of a compound of formula (II) with a compound of:
formula (IVa) in an organic solvent such as methanol at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 65xc2x0 C., in the presence of a base, such as diisopropylethylamine.
Compounds of Formula (I) where R2 is CF3 may be prepared from the reaction of compounds of formula (II) with compounds of formula (IVb) in an organic solvent such as methanol at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 23xc2x0 C., in the presence of a base such as diisopropylamine.
Compounds of formula (II) may be prepared via alkylation of compounds of formula (V), preferably where R1 is hydrogen, with compounds of formula (VI), where Rxe2x80x3 is an activating group such as mesylate followed by:
deprotection of the amine under acidic conditions such as 4.0 N HCl in dioxane solution at 20xc2x0 C., or trifluoroacetic acid in dichloromethane at 20xc2x0 C.
Alternatively, compounds of formula (II) may be prepared from reaction of compounds of formula (V), preferably where R1 is methyl, with compounds of formula (VI), preferably where Rxe2x80x3 is hydrogen, in an organic solvent such as toluene at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C. such as 20xc2x0 C. in the presence of triphenylphosphine and diethylazodicarboxylate in a Mitsunobu type procedure. Standard methyl ester hydrolysis conditions such as lithium hydroxide in tetrahydrofuran and water at 20xc2x0 C. followed by amine deprotection as hereinbefore described (see also Greene, T. W. and Wutz, P. G. M. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 2nd edition, 1991, John Wiley and Sons for a general discussion on protective group installation/removal) provides compounds of structural formula (II).
Compounds of formula (V) are commercially available and may also be prepared by someone skilled in the art from commercially available compounds.
Compounds of formula (VI), for example where Rxe2x80x3 is mesylate, may be prepared by reaction of an alcohol of formula (VI) where Rxe2x80x3 is hydrogen, with methanesulfonyl chloride in an organic solvent such as tetrahydrofuran at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C. such as 0xc2x0 C. in the presence of an amine base such as triethylamine.
Alcohols of formula (VI) where Rxe2x80x3 is hydrogen, may be prepared via reduction of the corresponding carboxylic acid or ester of formula (IX) in an organic solvent such as diethyl ether at temperatures of from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 0xc2x0 C., in the presence of a metal hydride reagent such as lithium aluminum hydride. These acids or esters of formula (IX) may be prepared by a two stage alkylation/cyclization process between an amide or thioamide compound of formula (VII), and a bromoketoester compound of formula (VII), where Rxe2x80x2xe2x80x3 is alkyl. The alkylation/cyclization reaction may be performed in an organic solvent such as toluene or ethanol at temperatures of from xe2x88x9220xc2x0 C. to 200xc2x0 C., such as 110xc2x0 C., in the presence of a base such as triethylamine. For the preparation of (VIII), see: Chem. Pharm. Bull. (1986), 34(7), 2840-51, J. Med. Chem. (1992), 35(14), 2617-26, patent WO 9731907.
Amides or thioamides of formula (VII) are commercially available or may be prepared from readily available compounds by one skilled in the art.
Compounds of formula (III) are commercially available or may be readily prepared by one skilled in the art, for example, by reacting a ketone of formula (X) with an ester of formula (XII), or by reacting a ketone of formula (XIII) with an ester of formula (XI), by reaction in an organic solvent, such as tetrahydrofuran, at temperatures from xe2x88x9220xc2x0 C. to 150xc2x0 C., such as 20xc2x0 C., in the presence of a base, such as sodium hydride, a metal cation scavenger, such as dibenzo-18-crown-6, and catalytic quantities of an alcohol, such as ethanol (See: Popic, V. V. et al. Synthesis 1991, 195-197).
Compounds of formula (IVa) may be prepared from the addition of compounds of formula (XV) to compounds of formula (XIV) in an organic solvent such as tetrahydofuran at temperatures of from xe2x88x92100xc2x0 C. to 100 xc2x0 C. such as xe2x88x9278 xc2x0 C. followed by oxidation of the intermediate propargyllic alcohol with an oxidant, such as manganese dioxide, in an organic solvent, such as dichloromethane, at temperatures from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 20xc2x0 C.
Alternatively, certain yne-one compounds of formula (IVa) may be prepared by dehydration of a compound of formula (III) where R5 is hydrogen in an organic solvent, such as dichloromethane, at temperatures from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 20xc2x0 C., in the presence of triphenylphosphine, bromine, and a base, such as triethylamine. When R2 is CF3, R5 is hydrogen, and R3 is phenyl, a compound of formula (III) in an organic solvent, such as dichloromethane, at temperatures from xe2x88x9220xc2x0 C. to 100xc2x0 C., such as 20xc2x0 C., in is the presence of triphenylphosphine, bromine, and a base, such as triethylamine yields a compound of formula (IVb). Compounds of formula (X), (XI), (XII), (XIII), (XIV), and (XV) are commercially available or may be prepared from readily available materials from one skilled in the art.
Suitable reaction conditions are described below and in the accompanying Examples. See also, for example, Chung et al., Selective Functionalization of (S)Tyrosine, Tetrahedron, 49(26), pp. 5767-5776, (1993), Solar et al., Selective O-Alkylation of Tyrosine, Journal of Organic Chemistry, 31, pp 1996-1997 (1966), O. Mitsunobu, Synthesis, p 1 (1981), and D. L. Hughes, Org. React. Vol. 42, p 335 (1992).
A compound of formula (I) can be converted to another compound of formula (I). A particular interconversion reaction involves conversion of a compound of formula (I) wherein Rxe2x80x2 represents C1-3alkyl, to a compound of formula (I) wherein Rxe2x80x2 represents hydrogen, suitably employing hydrolytic techniques e.g. an alkali metal hydroxide, in the presence of an ether solvent e.g. tetrahydrofuran and an alcoholic solvent e.g. methanol or the like. It will therefore be appreciated by persons skilled in the art that compounds which fall within general formula (I), may in some instances, be hereinafter described in the intermediate section, as they are useful for the preparation of other compounds of formula (I).
For any of the general processes and schemes described above, it may be necessary and/or desirable to protect sensitive or reactive groups. Protecting groups are employed according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley and Sons). These groups are removed at a convenient stage of synthesis using methods known from the art. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl, or sulfonyl, e.g. allylsulfonyl, tert-butoxycarbonyl, phthalimide, or tosyl; subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Thus, for example, tert-butoxycarbonyl groups may be removed by hydrolysis under acidic conditions. Hydroxyl and carboxyl groups may be protected using any conventional hydroxyl or carboxyl protecting group. Examples of suitable hydroxyl and carboxyl protecting groups include groups selected from alkyl, e.g. methyl, tert-butyl, or methoxymethyl, aralkyl, e.g. benzyl, diphenylmethyl, or triphenylmethyl, heterocyclic groups such as tetrahydropyranyl, acyl. e.g. acetyl or benzoyl, and silyl groups such as trialkylsilyl, e.g. tert-butyldimethylsilyl. The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl, and heterocyclic groups may be removed by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl may similarly be removed by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved by hydrogenolysis in the presence of a Noble metal catalyst such as palladium-on-charcoal. Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to further exemplify particular applications of general processes described above. Accordingly, the following Example section is in no way intended to limit the scope of the invention contemplated herein.

Substituted oxazoles and thiazoles derivatives as hPPARxcex3 and hPPARxcex1 activators


A non-round fiber optic cable that has improved crush performance is disclosed. The fiber optic cable includes at least one optical fiber, at least one strength element, and a cable jacket having a cavity. The at least one optical fiber is disposed within the cavity. The cable jacket further includes a concave upper wall and a concave lower wall disposed on opposite sides of the cavity, thereby improving the crush performance along the major axis of the optical fiber cable. In other embodiments, the fiber optic cable is a portion of a cable assembly.

Communications networks employ fiber optic cables to transport a variety of signals such as voice, video, data and the like. Fiber optic cables were first deployed for long-haul applications and generally used round cable cross-sections. These long-haul cables were designed to meet expected outdoor environmental and mechanical requirements. One example of the mechanical requirements is crush resistance. Simply stated, fiber optic cables in the field experience crush in the form of people walking on them, cars or other vehicles driving over them, having doors closed on them and many other situations where the fiber optic cable experiences crush forces. Generally speaking, because the round fiber optic cables used a generally symmetrical cross-section the crush performance was similar along any cross-sectional orientation.
One generally accepted method for testing fiber optic cable crush performance is to place the cable between two parallel plates and apply a crushing force. The two plates are of known length such as about 100 millimeters long with rounded edges on the plates to keep them from cutting into the optical fiber cable. Either a weight or device such as an Instron laboratory test unit is used to apply a compressive load to the optical fiber cable through the plates for a given time, while keeping the plates parallel. The load applied during testing can depend on the size and application for the fiber optic cable. By way of example, a common load for small optical fiber cables is 1100 Newtons applied for 10 minutes; however, other crush loads and times are possible. While the compressive load is applied, held, and/or removed optical tests, such as attenuation and continuity, are performed on the optical fibers in the cable to determine the optical performance. Additionally, the crushing test normally includes inspections for physical damage to the optical fiber cable and may include measurement of optical fiber cable deformation for analysis since these can also affect performance. One such crush procedure used by the industry is described in TLA/EIA 355.41, FOTP-41 Compressive Loading Resistance of Optical fiber cables.
As the deployment of fiber optic cables continues, the use of non-round fiber optic cable designs is increasing. For instance, as optical fiber cables push toward the subscriber non-round cable designs are being deployed. One reason non-round fiber optic cables are being deployed is because they are easy to install using a pressure type clamp, typically called a P-clamp. U.S. Pat. No. 2,068,368 shows one type of P-clamp for securing a cable to a structure such as a building or a pole in aerial applications. P-clamps are typically used for securing non-round drop cables since it makes the cable deployment efficient, reliable, and cost-effective. The P-clamp grips or clamps the non-round cable along the minor axis of cable. U.S. Pat. No. 6,493,491 discloses a non-round fiber optic cable design 10 like shown in FIG. 1 useful with P-clamps. More specifically, fiber optic cable design 10 uses a cross-sectional area of the reinforcing members 16 that is larger than the cross-sectional area of the cavity 14 for protecting the optical fibers 12 from crushing forces along the direction of the minor axis. The relatively small cavity size also helps crush performance in the direction of the major axis of fiber optic cable design 10. However, the use of a relatively small cavity limits the number of optical fibers within the cavity.
As the size of the cavity increases for non-round fiber optic cables providing suitable crush performance becomes difficult. In other words, designing a non-round fiber optic cable having a relatively large cavity with a reasonable cable cross-section, and suitable crush resistance along both the major axis and minor axis is challenging. The conventional design wisdom for providing acceptable major axis crush performance is to increase the wall thickness of the cable jacket between the cavity and the perimeter of the jacket. Although increasing the jacket thickness improves major axis crush performance, it also has the disadvantages of increasing the cross-sectional footprint along with increased material usage for the fiber optic cable. The present invention is directed to improving the major-axis crush performance of non-round fiber optic cables.

Non-round fiber optic cable having improved major axis crush resistance


Provided is a living organism information measurement device which users can easily and reliably operate. A living organism information measurement device for acquiring living organism information and generating measurement data relating to the information is provided with a device body, and a panel detachably attached to the device body. The device body comprises a control unit which executes a plurality of functions of the device body, a living organism information measurement unit which is connected to the control unit and generates the measurement data, and a first communication unit connected to the control unit. The panel comprises a second communication unit including a memory storing predetermined information. When the panel is attached to the device body, the first communication unit receives the predetermined information from the second communication unit. The control unit selects and executes a function corresponding to the received predetermined information among the plurality of functions.

The biological information measuring apparatus, for example, a blood sugar level measuring apparatus can be carried by a user, and is used to measure the blood sugar level by the user themself. The blood sugar level is measured in the following manner: a disposable blood sugar level sensor chip is mounted on the blood sugar level measuring apparatus, skin of a finger or the like is stuck by a separate puncture apparatus, and a small drop of blood effused from the skin is adhered thereon.
Since such a blood sugar level measuring apparatus is an electronic device, the apparatus is not limited to measurement of the blood sugar level, and it suffices to switch the measurement mode into a different function mode or change the display mode of the measurement result in accordance with a user (for example, refer to Patent Literature (hereinafter, abbreviated as PTL) 1), and it is possible to design the apparatus such that it has multiple functions such as transmission of an urgency signal (for example, refer to PTL 2).
Meanwhile, most of users of the blood sugar level measuring apparatus are the elderly or patients, and it is difficult for them to operate small buttons. Accordingly, in order to minimize the burden of the troublesome button operation, for example, a method of mounting a chip for switching functions in place of a blood sugar level sensor chip for measurement when a user changes the setting of the apparatus is disclosed (for example, refer to PTL 1).

Living organism biological information measurement device


An ultrasonic sensor has a built-in temperature compensation capacitor housed in a casing and facilitates an inside-the-casing lead-wire bonding connection process and a connection verifying process while increasing reliability. The ultrasonic sensor is provided with a piezoelectric vibration element and a capacitor for temperature compensation capacitor both housed in a casing. The temperature compensation capacitor includes a pair of electrodes located on one common surface of a dielectric body thus allowing the ultrasonic sensor to be electrically connected to lead wires on the one common surface.

1. Field of the Invention
The present invention relates in general to ultrasonic sensors for use in detecting obstacles or the like by transmission and reception of ultrasonic waves and, more particularly, to improvements in ultrasonic sensors having a piezoelectric element and temperature compensation capacitor contained in a casing.
2. Description of the Prior Art
Conventionally, known ultrasonic sensors have been adapted for use as obstacle detection sensors in land vehicles, for example. FIG. 12 is a cross-sectional diagram for explanation of one example of the ultrasonic sensors of this type.
As shown in FIG. 12, an ultrasonic sensor 61 includes a cylindrical casing 62 made of a desired metal having one closed end. A closed end surface 62a of the casing 62 is adapted for transmission and reception of ultrasonic waves.
A piezoelectric vibration element 63 is secured inside the end surface 62a of casing 62. The piezoelectric vibration element 63 includes a piezoelectric ceramic plate which has a structure for allowing electrodes (not shown) to be disposed on the two principal surfaces of the piezoelectric ceramic plate comprised of PZT-based piezoelectric ceramics.
A sound-absorbing member 64 made of a desired polyester felt material is disposed near the piezoelectric vibration element 63. Also within the casing 62, a temperature compensation capacitor 65 is disposed above the sound-absorbing member 64. The temperature compensation capacitor 65 has a structure which allows for electrodes to be formed on the both principal surfaces of the temperature compensation capacitor 65. One principal-surface electrode of the temperature compensation capacitor 65 is electrically connected by a lead wire 66a to the piezoelectric vibration element 63. The remaining principal-surface electrode of temperature compensation capacitor 65 is electrically connected via a lead wire 66b to the casing 62. Note that the casing 62 is electrically coupled to the other principal surface (a lower surface as visible in the drawing) of the piezoelectric vibration element 63.
A couple of take-out or "external" lead wires 67a, 67b are connected to the electrodes on the both principal surfaces of temperature compensation capacitor 65, respectively. The external lead wires 67a, 67b are electrically coupled to a connector 68 provided outside of the casing.
The inside space of the casing 62 is filled with sound-absorbing silicon adhesive 69 for purposes of elimination of unwanted reflection of ultrasonic waves. Also, a sound-absorbing member 70 is arranged so as to cover the open end side of the casing 62. The sound-absorbing member 70 may be made of expanded polyurethane.
In the ultrasonic sensor 61, the temperature compensation capacitor 65 is arranged and constructed in consideration of the fact that the electrostatic capacitance of the piezoelectric vibration element 63 can significantly vary with a change in temperature resulting in the resonance characteristics being varied or deviated.
However, elimination of the temperature compensation capacitor 65 would reduce workability of the bonding connections made via soldering of lead wires 66a, 66b, 67a, 67b during assembly of the ultrasonic sensor 61.
More specifically, during assembly of the ultrasonic sensor 61, it is necessary that the bonding connections by use of the lead wires 66a, 66b be completed prior to injection or packing of the silicon resin 69 in the casing 62. Unfortunately, since the temperature compensation capacitor 65 is structured and arranged so that the electrodes are disposed on the two principal surfaces of the temperature compensation capacitor 65, it is necessary to connect each individual one of such lead wires 66a, 66b by soldering techniques to a corresponding one of the electrodes on respective principal surfaces of the temperature compensation capacitor 65 individually while simultaneously forcing the temperature compensation capacitor 65 to be kept stationary at a certain position shown in FIG. 12, which increases the complexity and difficulty of the wire-bonding process.
In addition, it is required during injection of the silicon resin 69 that workers verify by visual inspection whether the lead wires 66a, 66b are reliably and securely in contact with the temperature compensation capacitor 65 and make sure that the lead wires 66a, 66b have not accidentally become detached from the temperature compensation capacitor 65. Because this structure has the lead wires 66a, 66b coupled to both principal surfaces of the temperature compensation capacitor 65, it is necessary to visually check a respective one of the two principal surfaces of temperature compensation capacitor 65 by time-consuming visual inspection methods which are subject to human error and errors in judgment.
Further, with regard to the bonding connection of lead wires 67a, 67b, it has been necessary for workers to verify--prior to hardening of the sound-absorbing material 70--that the lead wires 67a, 67b are reliably coupled with the temperature compensation capacitor 65. It has also been necessary that workers inspect a respective one of the two principal surfaces of the temperature compensation capacitor 65 due to the fact that such lead wires 67a, 67b are to be connected to the electrodes on both principal surfaces of the temperature compensation capacitor 65, respectively.
Furthermore, since the temperature compensation capacitor 65 has a structure for eliminating the electrostatic capacitance from the electrodes located on both principal surfaces of the temperature compensation capacitor 65, the resulting overall size of the device remains relatively large. Accordingly, distortion can take place upon application of thermal shocks from outside of the device. Another problem experienced in the prior art devices is that during injection of silicon resin 69, gas bubbles or air voids can appear within the casing 62 due to ultrasonic wave reflection because of the relatively large size of the temperature compensation capacitor 65 and also because of an increased area required for contact between the silicon resin 69 and the temperature compensation capacitor 65.
A further problem is that ultrasonic-wave reflection caused by the temperature compensation capacitor 65 per se can be present above negligible levels because of the fact that the temperature compensation capacitor 65 must have a relatively large size.
In addition, arranging the temperature compensation capacitor 65 in a specific orientation in which the principal surfaces of the temperature compensation capacitor 65 are at right angles to the piezoelectric vibration element 63 results in a noticeable increase in distance from the upper end of the temperature compensation capacitor 65 to the piezoelectric vibration element 63. For this reason, the temperature sensitivity or tracking ability of the capacitor 65 with respect to temperature variations of vibration element 63 is insufficient which makes it impossible to achieve sufficient temperature compensation functions.

Ultrasonic sensor with temperature compensation capacitor


A telephone headset system having a network interface device, a head set including a headphone and a microphone, and a foot operated, hands free call answering and call ending element. The network interface device, headset, and call answering and call ending element are electronically in communication with each other.

1. Field of the Invention
The invention relates to hands free headsets for home telephone systems, offices, and small businesses, such as hair/nail salons
2. Background Art
Headset users who are at home, at work, or in other places often have their hands busy when the phone rings. For example, users may be working with both hands in the kitchen, in the office, in a hair and nail salon, at a computer terminal or a CAD-CAM work station. Alternatively, the user in question might be a handicapped individual with a partial or complete immobility of the hands. As a result, when the phone rings, it may be very inconvenient for the user to stop their then current manual activity to push a button located on the headset or remote dial pad to answer the call, or to end the call.
Handset lifters are used in the office for remotely answering telephones. In one example of a lifter device, an arm or paddle slightly lifts the handset off the telephone cradle, to a position that allows the hook switch of the telephone to attain the off-hook position. This action is in response to an electrical signal to a motor or solenoid driving the arm. The electrical signal is in response to a button-push at the lifter or some remote device. Automatic call answering can be set on a cell phone or in a telemarketing or call center situation, but then the user can not screen out unwanted calls, like telemarketers. In addition, home automatic call answering does not have an infrastructure or market acceptance.
Thus, a need exists for a totally hands free solution for answering and ending calls, combining a hands free headset and a hands free call answering and call ending element.


A female electrical connector adapted to be lowered down a well on an electrical cable for remote connection to a down hole male connector. The connector includes a housing with an attachment for securing the female electrical connector to the cable, a female electrical contact within the housing, and an insulator disposed between the housing and the female electrical contact. The female electrical contact is in electrical communication with the cable and includes a circumferential ring defining a central axis, and a cantilever finger extending generally axially from the ring. The finger has a first portion extending generally radially inward from the ring, and a second portion extending generally radially outward from the first portion to an axially-directed, distal end. The first and second portions of the finger define therebetween a radially innermost contact surface. The insulator includes an outer shell between the circumferential ring of the female electrical contact and the inner bore of the housing, and an inner lip axially overlapping the distal end of the cantilever finger. The inner lip shields the finger end against engagement with the male connector moving within the female connector. Some embodiments have a wiper seal arranged to wipe debris from the male connector as it enters the housing. Preferred materials and methods of use are disclosed.

This invention relates to female connectors adapted to be connected down hole with male connectors of wireline tools in oil wells.
Once an oil well is drilled, it is common to log certain sections of the well with electrical instruments. These instruments are sometimes referred to as "wireline" instruments, as they communicate with the logging unit at the surface of the well through an electrical wire or cable with which they are deployed. In vertical wells, often the instruments are simply lowered down the well on the logging cable. In horizontal or highly deviated wells, however, gravity is frequently insufficient to move the instruments to the depths to be logged. In these situations, it is sometimes necessary to push the instruments along the well with drill pipe.
Wireline logging with drill pipe can be difficult, however, because of the presence of the cable. It is cumbersome and dangerous to pre-string the electrical cable through all of the drill pipe before lowering the instruments into the well. Some deployment systems have therefore been developed, such as Schlumberger's Tough Logging Conditions System (TLCS), that make the electrical connection between the instruments and the cable down hole, after the instruments have been lowered to depth. In these systems, the electrical instruments are easily deployed with standard drill pipe, and the cable is then run down the inside of the drill pipe and connected. After logging, the cable can be easily detached from the logging tool and removed before the tool is retrieved. The TLCS has been very effective and has achieved strong commercial acceptance.
In the TLCS and other systems, the cable is remotely connected to the instrumentation with a down hole connector. One half portion of this connector is attached to the instrumentation and lowered into the well on drill pipe. The other half portion of the connector is attached to the end of the cable and pumped down the drill pipe with a flow of mud that circulates out of open holes at the bottom of the drill pipe and into the well bore. The connector is sometimes referred to as a "wet connector" because the connection is made in the flow of drilling mud under conditions that challenge electrical connection reliability.
The female contacts of the wet connector must provide a positive contact pressure against the male contact surfaces in order to ensure a reliable electrical connection. Providing a female contact having cantilevered spring fingers has been shown to work well for applying such pressure, although the exposed distal ends of the fingers can occasionally snag on the male connector during disengagement, damaging the female connector. Formed by bending thin sheet stock, such fingers also tend to be eventually displaced permanently radially outward, reducing their ability to provide a positive contact pressure and resulting in poor, sometimes intermittent, contact.


An AC coupled receiver incorporates a decision feedback restore technique that is readily implemented on a monolithic integrated circuit to reduce or eliminate effects of baseline wander in a non-return-to-zero (NRZ) data receiver. In at least one embodiment of the invention, a method includes at least substantially attenuating at least a DC portion of a received signal to generate a first signal. The method includes generating a low frequency signal based at least in part on a reference signal selected from a plurality of reference signals. The method includes generating a restored signal based at least in part on the first signal and the low frequency signal.

1. Field of the Invention
This application is related to integrated circuits and more particularly to communications interfaces of integrated circuits.
2. Description of the Related Art
A communications system may use AC coupling techniques to reduce effects of low frequency disturbances, e.g., undesirable DC offsets. Typically, AC coupling of circuit nodes is implemented by high-pass filtering a received signal. However, time-domain characteristics of the high-pass filter may introduce baseline wander in a non-return-to-zero (i.e., NRZ) data receiver. The baseline wander can substantially affect receiver data recovery and increase receiver bit error rates.

Decision feedback restore of DC signals in a receiver


A filling device for bulk materials includes a filling hopper, a housing surrounding an open end of the filling hopper and two hopper outlet doors which are pivoted in the the housing. In order to achieve the object of further developing the filling hopper so as to enable loss-free operation to take place, the filling hopper or, respectively, a casing surrounding the same has an external encircling section. Furthermore rubber sealing strips are provided on the hopper outlet doors, which come into sealing engagement with the encircling section when the hopper outlet doors are moved by a control system into the open position thereof.

Such filling devices are for instance utilized for the filling of previously weighed out quantities of bulk materials into sacks. In this case it is possible for the bulk material, dependent on its granule size, to have a pronounced tendency to form dust.
Thus in the case of filling devices of this type it has been found that between the upper end of the hopper outlet doors and the open end of the filling hopper, which when the hopper outlet doors are open come into the position alongside each other, approximately 1% by weight of the bulk material is lost, for example when working with pulverulent PVC. This means that when 100 sacks are filled the contents of a whole sack are lost.


An artificial Christmas tree 10 having several branch segment assemblies 14-18 is disclosed, and further having electrically activated lights 46, 48, and 50 which are predisposed or preassembled upon the tree. Also disclosed is a method for automatically winding or placing the lights upon tree 10.

Artificial Christmas trees are becoming very popular since they only require a "one-time" purchase, thereby obviating the need for annual or yearly purchases of Christmas trees, prices of which have gone up dramatically in prior years. Moreover, these artificial Christmas trees are generally becoming more popular since they require less or no maintenance such as watering, are not as great a fire hazard as are "real trees", and do not shed needles or other such materials which causes the surrounding area to become unsightly or unkept, and obviate the need to harvest or destroy valuable timber stock.
While these artificial Christmas trees are becoming popular, they suffer from some drawbacks. For instance, and without limitation, many of these prior artificial Christmas trees are very difficult to assemble, are relatively bulky to store, and require a user or owner to "string" or physically place lights upon the tree, thereby requiring the same sort of undesirable light placement activity as do the "real trees". Applicant has found it to be highly desirable to have the electrically actuated lights predisposed or mounted upon the unassembled tree portions in order to obviate the need for a user to "string" or place the lights thereon, once the tree is assembled.
There is therefore a need for, and it is a principal object of this invention to provide, an artificial Christmas tree which overcomes the aforedescribed drawbacks of the prior art and which has electrically powered lights disposed thereon, thereby obviating the need for a user to string or place electrically powered lights on the tree after it is installed and assembled.


A method for improving the quality of full-color images is disclosed. An original image is divided into a plurality of pixels. A neutral intensity value is determined for each pixel. A desired black-color intensity value is determined from the neutral intensity value. A printer-producible black value is determined from the desired value. The printer-producible black-color intensity value is used to rescale the original color intensity values of the pixels. The rescaled color intensity values are used to generate output color intensity values. The output image comprising the output color intensity values and the printer-producible black-color intensity value may then be converted to a continuously varying or halftone output image and output to an image output apparatus.

1. Field of the Invention
The present invention relates to generating full color halftone images having smoothly varying grey-scale levels, and more particularly, to conditioning a generated image prior to a halftoning step, so that the halftoning step generates smoothly varying full color halftone images while avoiding the generation of visible halftone texture patterns and other printer-artifact patterns.
2. Description of the Related Art
Full-color electronic printers use a plurality of inks, such as cyan (C), magenta (M), and yellow (J) in three-color printers and C, M, J and black (K) in four-color printers. In such three- and four-color printers, different levels of color saturation for the three non-black colors (CMJ) are generated by using a halftoning process. In addition, the full spectrum of colors is generated by selectively overlapping each of the different separation colors. In a three-color electronic printer, black is generated by overlapping all three of the separation colors, while in a four-color printer, black can be either generated by combining the three separation colors (process black) or by using the black ink (printer black).
In halftoned image generation, the individual pixels, which comprise the image plane upon which the original image is mapped, are grouped into small or unit cells. A halftone screen is applied to the unit cells of the original image to generate a halftone image suitable for printing on an image reproduction apparatus. For example, U.S. Pat. No. 4,868,587 to Loce et al., assigned to the same assignee as the present invention and incorporated herein by reference, discloses a cell size of 18 pixels. A unit cell of 18 pixels can produce up to 19 different grey-scale levels for each color, from pure white (blank) to fully saturated (all pixels colored). The 18 pixels of a unit cell can be arranged in any shape desired, although it is generally desirable to minimize the radius of a circle which would completely enclose the cell. It is also necessary for the shape to be spaced-filling (i.e., no pixels of the image plane appear between a two adjacent unit cells). An example of such a unit cell is shown in FIG. 1.
However, because only 19 grey-scale levels are obtainable with an 18 pixel unit cell, the discrete shifts between the adjacent grey-scale levels are noticeable to the human eye, as shown in FIG. 2A. The problem of abrupt density shifts can be reduce by employing a larger halftone cell with more grey-scale level. However, this has the undesirable effect of making the halftone pattern more visible. Currently, it has been proposed to also reduce the halftone cell visibility by grouping a plurality of the unit cells into a large halftone cell. Commonly, four such unit cells are grouped into the large halftone cell, which is commonly called a "quad dot". In operation, the halftone screen is dispersed over the four unit cells of the quad dot, such that one pixel of each of the four unit cells of a quad dot is filled in before a second one of any of the unit cells of the quad dot are filled in. In this matter, the 19 levels of a single unit cell can be spread out and duplicated over 4 times the area, generating 76 (4.times.19) different grey-scale levels. Accordingly, as shown in FIG. 2B, the difference between any two adjacent grey-scale levels is indistinguishable to the human eye and the degree of saturation or the density of the image can vary continuously.
However, as is noticeable in FIG. 2B, a quad dot halftone scheme generates vertical lines in approximately one half of the grey-scale levels. These vertical lines are caused by the filled-in pixels within a quad dot aligning, and the aligned pixels within each quad dot aligning with the aligned pixels of its vertically adjacent neighbors. Therefore, while the problem of abrupt density shifts between grey-scale levels when using unit halftone cells is reduced, there is still a problem of artifact patterning or a "visible texture" generated in the image when using a quad dot halftone cell.

Method and apparatus for improving full color images using process black and printer black


An electrically-controlled variable camshaft timing (VCT) system including a sun gear, having an inner axial surface, configured to communicate torque from an output shaft of an electric motor to a gearbox assembly; and a collet sleeve having at least one slot configured to engage the output shaft of the electric motor and a relief section permitting radial-inward compression and an outer axial surface that releasably engages the inner axial surface of the sun gear such that the outer axial surface of the collet sleeve is engaged with the inner axial surface of the sun gear while an amount of torque applied to the sun gear by the output shaft is below a predetermined torque threshold and the sun gear and the collet sleeve are angularly displaced relative to each other when an amount of torque applied to the sun gear by the output shaft is at or above the predetermined torque threshold.

Vehicles can include electric motors that carry out a variety of vehicle functions, including, for example, adjusting the angular position of one or more camshafts with respect to the angular position of a crankshaft or adjusting the position of a passenger or driver seat. Electric motors can be used to operate a camshaft phaser to advance or retard the timing of a camshaft with respect to the crankshaft. The camshaft phaser may include a gearbox that is driven by an electric motor. Mechanical stops that limit the range of authority of the camshaft phaser can be included in the gearbox. When the camshaft phaser reaches an end of the range, gearbox movement can be stopped abruptly and a relatively large amount of torque may be applied to the output shaft of the electric motor. This amount of torque may cause unwanted stress to the camshaft phaser and it would be helpful to reduce this stress.

Compliant coupling for electrically-controlled variable camshaft timing assembly


Optical signal transmission system comprising optical signal transmission board having first optical waveguide, and optical connection board having second optical waveguide and inserted into opening of optical signal transmission board substantially perpendicularly thereto, opening being provided in upper surface of transmission board. The board comprises: a first board; the first optical waveguide extended on an upper surface of the first board; and a second board made parallel to the first board, the opening extended from the upper surface thereof toward the first board is provided in the optical signal transmission board. The optical connection board comprises: a third board; second optical waveguide extended on an upper surface of the third board; and reflection surface provided in end portion of second optical waveguide, reflecting light traveling through the second optical waveguide, and making the light incident onto the first optical waveguide extended in a direction substantially perpendicular to the board.

As a processing speed of an electronic device has been increased, densification of signal wiring connecting the electronic device with the others with the increase in signal speed have become technical challenges. In conventional electric signal transmission technology, as the speed of signal increases, a dielectric loss and electromagnetic radiation in a periphery of the wiring are increasing. For this reason, in order to realize transmission speed equal to or more than several gigabits per second, a technical design is required for selection of a dielectric material, wiring density of transmission channels and the like, and the wiring becomes subject to physical restrictions.
In order to avoid such restrictions and to realize signal transmission at higher speed and with higher density, optical wiring by means of an optical waveguide and an optical fiber (hereinafter, collectively referred to as an "optical waveguide") has been being studied. Here, for the purpose of supply of a power source for driving the electronic device and of low-speed signal transmission, it becomes necessary to make electric wiring coexist simultaneously with the optical wiring because the optical wiring has small economic advantage.
Japanese Patent Laid-Open No. 2000-227524 (hereinafter referred to as "Patent Document 1") and Japanese Patent Laid-Open No. 2000-235127 (hereinafter referred to as "Patent Document 2") disclose optical waveguide structures in each of which the electric wiring and the optical waveguide structure are mixed. In Patent Document 1, the optical waveguide is formed on a board, and on the optical waveguide, a light emitting element and a light receiving element are provided. Then, light emitted from the light emitting element is reflected on one end of the optical waveguide substantially at a right angle, propagated through the optical waveguide, reflected on the other end substantially at a right angle, and made incident onto the light receiving element. The optical waveguide structure of Patent Document 1 is constructed in a manner as described above. In Patent Document 2, while the light emitting element and the light receiving element are provided on an upper surface of the board, the optical waveguide is provided on a lower surface of the board, the light emitted from the light emitting element is guided to the lower surface of the board, and propagated through the optical waveguide. Then, the light is reflected on an end portion of the optical waveguide, and made incident onto the light receiving element located on the upper surface of the board. The optical waveguide structure of Patent Document 2 is constructed in a manner as described above.
There is a possibility that the optical waveguide, for use in the board in which the electric wiring and the optical waveguide structure are mixed, may be exposed to high temperature in a manufacturing process of an electric wiring board and an mounting process of components, and may be subjected to a mechanical impact and the like in use of the completed board. Therefore, it is preferable that the optical waveguide be mounted in an inner layer of the board to the extent possible. Furthermore, in order to avoid an influence of warp of the board, a structure is preferable, in which the optical waveguide is disposed at the center of the board, and boards on both sides of the optical waveguide, which sandwich the optical waveguide, are made of materials equal in thermal expansion coefficient and thickness so as to be arranged symmetrically to each other in a thickness direction.
More specifically, the board is heated in steps shown below in the manufacturing process of the laminated electric wiring board.
In a laminating step of the boards, the boards are stacked with adhesive resin being sandwiched therebetween, and the resin is cured for a few hours at temperature of a hundred and several ten degrees centigrade (180 to 190 degrees centigrade) with pressure. With regard to heat resistance of resin for use as a material of the optical waveguide, in general, phase transition temperature or glass transition temperature using a change of mechanical impedance as an index is conceived as a measure. However, when the resin is heated on exposure to air, a degradation in optical characteristics, such as yellowing, may sometimes be brought by a thermochemical reaction with the air though mechanical strength of the resin is maintained. Hence, in order to prevent such a degradation, it is effective to shield the optical waveguide from the air by disposing the waveguide not on a surface layer of the board but in the inner layer to the extent possible.
Moreover, in the step of mounting (assembling) components on the board, soldering process is performed in almost all the cases. In recent years, solder of lead-free type has used in consideration of the environment, and temperature of approximately 260° C. in the soldering process has become higher than the conventional temperature. Optically transparent acrylic resin and the like, which have heat resistance even to such a relatively high temperature, have been announced, and in the future, problems regarding the heat resistance will be reduced pretty much by using such resins. However, it is thought to be difficult to avoid the degradation of the optical characteristics due to the thermal reaction with the air, and also in order to solve this process problem, it is effective to dispose the optical waveguide in the inner layer of the board. Then, a time for the soldering process is relatively short, and accordingly, if the optical waveguide is disposed in the inner layer protected by resin layers in which heat conduction is relatively small, temperature increase in the inside can be restricted.
As described above, instead of adopting the structure in which the optical waveguide is exposed on the surface of the board as in Patent Documents 1 and 2, the disposition of the optical waveguide in the innermost layer of the board has a great practical advantage in terms of avoiding the problems in the manufacturing process and the assembly. However, in this structure, the optical waveguide in the laminated board and a light receiving/emitting element mounted on the surface of the board will be arranged to be spaced at a distance corresponding to the thickness of the board. For this reason, an optical component connection technology will be required. In this technology, an array of high density optical signal transmission paths is disposed in the inner layer of the laminated wiring board. Then, the light receiving/emitting element, the light receiving/emitting board, and the like, which are mounted on the board, and the array of the high density optical signal transmission paths, are optically connected to each other at a distance ranging from several ten microns to several millimeters.
Specifically, when the optical waveguide is disposed in the inner layer portion of the board, a structure for changing the direction of the light and a structure for guiding the light to the surface of the board will be required between the optical waveguide and the light receiving/emitting element which is mounted on the surface of the board. Here, when the light is propagated in the air between the optical waveguide and the light receiving/emitting element, the most part of the light does not reach the light receiving element but is dispersed in a periphery thereof, and coupling efficiency is significantly lowered. Furthermore, when the optical wiring is mounted with high density, the light is received by adjacent light receiving elements, causing a large interchannel crosstalk. Hence, in such a structure, it is difficult to realize optical connection in which, with regard to the density of the optical wiring, a wiring pitch is shorter than 250 microns realized by the current fiber ribbon, and the connection distance between the optical waveguide and the light receiving/emitting element is set in a range from several ten microns to several millimeters.
In order to avoid this problem, in Patent Document 2, a lens is used between the optical waveguide and the light receiving/emitting element. However, a divergence angle (numerical aperture: NA) of the light of the multimode fiber or optical waveguide or of the light of the light emitting element is generally 0.2 or more, and when the connection distance l is set at 1 mm, a relationship is unwillingly established as:l·sin θ=l·NA=0.2 mm≈wiring pitch
Therefore, signal separation between the adjacent lines of wiring becomes difficult.

Optical connection board and optical signal transmission

International Business Machines Corporation


A portable electronic device includes a touch panel and a vibration unit. The touch panel being capable of detecting at least a distance between a pointer and the touch panel when the pointer is not in contact with the touch panel. The vibration unit vibrates when the distance between the pointer and the touch panel is not larger than a first distance and then reaches a second distance or more.

An example of an input device using a touch panel has been described in Patent Literatures 1 and 2. In a pen-type input device described in Patent Literature 1, a distance between the input device and the touch panel is detected, and vibration is generated when the input device approaches the touch panel within a predetermined distance, so that an advance notice of the approach of a pen tip to the touch panel can be given to a user. On the other hand, in an input device described in Patent Literature 2, vibration is generated to prevent erroneous operation such as erroneous input when a finger moves beyond a predetermined region with reference to a position where the finger has been placed on the touch panel.

PANASONIC INTELLECTUAL PROPERTY CORPORATION OF AMERICA


The present invention discloses a method of sintering of cemented carbide or cermet bodies lying on graphite trays. By using graphite trays coated with a covering layer of Y.sub.2 O.sub.3 containing .ltoreq.20 wt-% ZrO.sub.2, or corresponding volumetric amount of other refractory oxides, e.g., Al.sub.2 O.sub.3 or combinations thereof, with an average thickness of .gtoreq.10 .mu.m, the life of the trays between regrindings and recoatings can be largely extended.

The present invention relates to a tray to be used when sintering powder metallurgical articles such as products of cemented carbides and cermets.
Cemented carbides and cermets are alloys mainly containing hard constituents based on carbides, nitrides and/or carbonitrides of Ti, Zr, Hf, V, Nb, Ta, Cr, Mo and/or W in a binder essentially based on Co and/or Ni and/or Fe. They are normally produced by powder metallurgical methods comprising milling a powder mixture containing powders forming the hard constituents and binder phase, pressing and sintering.
After pressing, the compacted bodies contain about 50% by volume of open porosity. Fully dense products are then produced by liquid phase sintering at a temperature when the binder metal is in liquid state, which in practice is normally in the 1300-1550.degree. C. range depending on composition.
In the production of cemented carbides and cermets, almost all sintering processes are performed in an industrial vacuum, i.e., from about 1 torr upwards and in the presence of various gas atmospheres, such as mixtures of H.sub.2 plus CO, CO.sub.2, Ar, N.sub.2, CH.sub.4 etc., and with the bodies to be sintered lying on graphite trays. In order to minimize the influence of the graphite, both in the contact with the bodies to be sintered and with the atmosphere within the furnace, these trays are normally surface coated, see e.g., H. Kolaska et al., "Powder Metallurgy of Hardmetals", EPMA Lecture Series, Lecture 6, Sintering--Technical and Basic Principles, European Powder Metallurgy Association, Shrewsbury, UK, 1995, p.6/9-6/10. In practice, an A1.sub.2 O.sub.3 or ZrO.sub.2 based coating is used, applied by thermal spraying, preferably plasma powder spraying. Thus, these coatings act as barrier layers preventing reaction from occurring between the sintered body and the tray. Reaction can lead to many problems, i.e., carbon uptake from the trays and distortion of the sintered bodies.
It is essential that these graphite trays with barrier layers be reused for as many sintering cycles as possible without deterioration of the layers occurring, i.e., to maintain inertness and high adhesion to the graphite tray. Normally, the necessity to regrind and recoat the trays is determined by the skilled operator when the coating has been torn off to such an extent that it is easily seen by the naked eye of the operator.
The deterioration is due to metallurgical reactions taking place between the cemented carbide body and the tray leading to unloading problems caused by sticking. When removing such bodies adhering to the tray, cracks may be formed in the coating of the tray. Individual grains from the very surface of the coating or pieces of the coating may be torn off. The problem is especially severe when sintering large bodies of cemented carbides having comparatively large contents of binder phase, these conditions promoting adhesion.


A method and arrangement for transfer between a cordless telecommunication system, preferably DECT, and a cellular mobile telecommunication system, preferably GSM. The cordless telecommunication system includes of a number of cells within a relatively small area, while the mobile telecommunication system includes of a number of cells within a relatively larger area which completely or partly overlaps the area of the cordless system. The system comprises at least one portable terminal capable of communicating with both the cordless and cellular communication systems. Accordingly a transfer zone is fixed by the cordless system and the terminal is monitored with regard to it identity and position so that transfer parameters can be transmitted to the terminal when it is located in the transfer zone. The transfer is prepared by setting up a three-party connection between the terminal and the telecommunication system and between the terminal and the mobile telecommunication system. The terminal disconnects the connection to the cordless telecommunication system and a transfer to the mobile system takes place. The method and arrangement reduce the transfer time between the different systems by transmitting transfer parameters to the portable terminal and setting up the preparatory three-party connection.

1. Field of the Invention
The present invention relates to a method and an arrangement for transfer between a cordless telecommunication system, such as DECT, and a background cellular mobile telecommunication system such as GSM. The invention is in particular conceived to be used when different operators operate the two systems. In a case where both systems are operated by the same operator and the DECT system is connected directly to the background GSM network, transfer can be effected in a more effective manner.
Generally, the present invention reduces the transfer time between the different systems by among other things transmitting transfer parameters to the portable terminal and setting up a preparatory three-party connection.
2. Discussion of the Background
A user requirement of transfer is that the process is to be on the whole imperceptible for the user. That is to say, the transfer is to take place rapidly and without inconvenient background noise so that the transition which the transfer inevitably implies does not become annoying. It should therefore be possible to carry out the transfer in approximately 1 second, preferably even more rapidly. Within the field, there is a number of documents which describe different solutions to this problem.
U.S. Pat. No. 5,260,988, WO 93/16549, U.S. Pat. No. 5,127,042 and U.S. Pat. No. 4,989,230 describe communication systems which consist of both cordless telephony and a cellular mobile telephone system. The system includes portable cordless units which can initiate and receive calls in both the cordless and the cellular system. Calls can be connected automatically to the system in which the subscriber is located. There is also the possibility of automatically connecting a call in progress between the different systems if the subscriber moves between systems. It is possible for the user to select manually a given system by a button procedure, either permanently or at a given time. On transfer between the two systems, a three-party call is utilized.
U.S. Pat. No. 5,235,632 describes a mobile telephone system which consists of an external system which consists of base stations, divided into cells, with high transmitting power connected to a mobile telephone exchange and an indoor system consisting of base stations with low transmitting power connected to a mobile telephone exchange. According to the document, the possibility exists of connecting a call between the internal and the external system by, for example, measuring signal strength from each system.
U.S. Pat. No. 5,309,502 relates to a radio telephone which combines the function of a cordless telephone and a cellular mobile telephone. The possibility exists, on connecting calls, of automatically selecting via which the communication is to take place. Nothing is mentioned about transfer during calls in progress.
U.S. Pat. No. 5,210,785 relates to a cordless communication system and a terminal which combines two different systems such as cordless telephony and cellular mobile telephony. According to the document, selection of the communication method is to take place automatically.
U.S. Pat. No. 5,329,574 describes a method of continuously maintaining telephone communication when a radio communication unit moves between two different communication systems. When the unit discovers that the communication quality is deteriorating in a first system, a connection packet is transmitted via a central control unit to a second system. The communication in the first system is maintained until the second system confirms it has taken over of the communication.
U.S. Pat. No. 5,212,684 relates to a communication system which utilizes portable radio telephones. The system consists of base stations and portable telephone units in accordance with the GSM standard. The portable telephone units can also work in accordance with the DECT standard. The system carries out both internal and external transfer but does not mention transfer between DECT and GSM.
WO91/16772 describes a method of transfer in a mobile radio communication system. According to the document, the mobile measures signal strengths of surrounding base stations. When the transfer is felt to be justified, the signal strength vectors are correlated with stored vectors and, if there is correlation, transfer takes place in a manner which depends on the position.
EP A1 615 392 describes a further example of transfer in a mobile radio system which utilizes the position of the mobile.
U.S. Pat. No. 5,345,499 relates to a method of transfer in a cellular radio system. The system consists of microcells and macrocells. In the system, the possibility exists of making connection and transfer dependent on the speed of the mobile. Thus, a mobile with a high speed can be prevented from connecting itself to a microcell if it exceeds a given threshold speed.
U.S. Pat. No. 5,276,906 shows a cellular radio telephone system which has two threshold levels for transfer. When the signal strength in a first cell falls below a first threshold value, transfer is initiated to a second cell by this cell being selected with the aid of the mobile. When the signal strength in the first cell then falls below a second threshold value, transfer to the second cell is carried out.

Method and arrangement for transfer between a cordless telecommunication system and a cellular mobile telecommunication system


A universal position coding method and system are provided for coding uncompressed data. Data symbols are assigned to a bin portion and a raw portion, and a data tree structure is utilized. A top down approach involves initializing a data tree based on the bit depth of the data; splitting a bin to form two separate bins based on a predetermined splitting condition; and repeating the splitting step until a terminating condition is achieved. A bottom up approach involves forming a data tree; merging two existing bins to form a new bin based on a merging condition; and repeating the merging step until a terminating condition is achieved.

The invention relates generally to coding data, and more specifically to a system and method for coding and compressing data.
Compression refers to representing data using a minimum number of bits. Broadly, compression of data is of two types, namely, lossy and lossless compression. Lossless compression of data refers to that which can be completely recovered when decompressed without losing any data. Typically, in many applications, lossless compression is desirable, especially in medical images.
Typically, medical images are of high dynamic range and large spatial size. The design of coding systems is more complicated when the dynamic range of the data to be coded is relatively large, as is the case with medical images. In such cases, it is desirable to design coding and compression techniques that have low-computational cost and good compression ratio.
Accordingly, it would be desirable to provide a coding technique that can be used to code large amounts of data while maintaining low complexity and a good compression ratio.