Claims for Patent: 6,696,474

Summary for Patent: 6,696,474

Title:	Antidiabetic agents
Abstract:	Compounds of formula I: ##STR1## wherein X, Y, B, E, J, K, L, Z, and R.sub.9 -R.sub.12 have any of the meanings described herein, their pharmaceutically acceptable salts, lower blood glucose levels and are useful for treating diseases in mammals such as Non-Insulin Dependent Diabetes Mellitus. Also disclosed are pharmaceutical compositions, processes for preparing compounds of formula (I) and intermediates useful for preparing compounds of formula I.
Inventor(s):	Bigge; Christopher F. (Ann Arbor, MI), Schaum; Robert P. (Ann Arbor, MI)
Assignee:	Warner Lambert Co. LLC. (Ann Arbor, MI)
Application Number:	10/390,466
Patent Claims:	1. A compound according to formula (I) ##STR50## or a pharmaceutically acceptable salt thereof, wherein: X is (CR.sub.1 R.sub.2).sub.x wherein x is 1, 2, or 3, or X is --(CR.sub.3 R.sub.4)--CH.dbd.CH--, --CH.dbd.CH--(CR.sub.3 R.sub.4)--, --(CR.sub.3 R.sub.4)--C.ident.C--, --C.ident.C--(CR.sub.3 R.sub.4)--, wherein R.sub.1 -R.sub.4 are each independently H, OH or (C.sub.1 -C.sub.6) alkoxy, or R.sub.3 and R.sub.4 taken together are .dbd.O, or R.sub.3 -R.sub.6 are each independently or (C.sub.1 -C.sub.6)alkyl; Y and Z are (CR.sub.1 R.sub.2).sub.n and (CR.sub.3 R.sub.4).sub.m wherein m and n are each independently 0, 1, 2, or 3; B is H or (C.sub.1 -C.sub.6)alkyl; E is COR.sub.5, wherein R.sub.5 is (C.sub.1 -C.sub.6)alkyl, OH, (C.sub.1 -C.sub.6)alkoxy, NR.sub.6 R.sub.7, wherein R.sub.6 and R.sub.7 are each independently H or (C.sub.1 -C.sub.6)alkyl, or one of R.sub.6 and R.sub.7 is H or (C.sub.1 -C.sub.6)alkyl and the other is SO.sub.2 R.sub.8, wherein R.sub.8 is H or (C.sub.1 -C.sub.6)alkyl, or E is substituted heteroaryl or ##STR51## R.sub.9 -R.sub.12 are each independently H, halo, aryl, (C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkanoyl, halo(C.sub.1 -C.sub.6)alkanoyl, benzoyl, or halo(C.sub.2 -C.sub.6)alkanoyl; and one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R.sub.9, R.sub.10, and R.sub.13 are absent at that position. 2. The compound of claim 1, wherein X is --CH.sub.2 CH.sub.2 CH.sub.2 --, ##STR52## B is H; E is CO.sub.2 H; and Y is --CH.sub.2 --; and R.sub.9 -R.sub.12 are each independently H, halo, aryl, (C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkanoyl, halo(C.sub.1 -C.sub.6)alkanoyl, (C.sub.3 -C.sub.7)cycloalkylcarbonyl, benzoyl, or halo(C.sub.2 -C.sub.6)alkanoyl; and one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R.sub.9, R.sub.10, and R.sub.12 are absent at that position. 3. The compound of claim 2, wherein X is --CH.sub.2 CH.sub.2 CH.sub.2 --; B is H; E is CO.sub.2 H; and Y is --CH.sub.2 --; and R.sub.9 -R.sub.12 are each independently H, halo, aryl, (C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkanoyl, halo(C.sub.1 -C.sub.6)alkanoyl, (C.sub.3 -C.sub.7)cycloalkylcarbonyl, benzoyl, or halo(C.sub.2 -C.sub.6)alkanoyl; and one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R.sub.9, R.sub.110, and R.sub.12 are absent at that position. 4. The compound of claim 3, wherein R.sub.11 is H; J--R.sub.9 is N or CH; K--R.sub.12 is N or CH; and L--R.sub.10 is CH. 5. The compound of claim 3, wherein R.sub.11 is H; J--R.sub.9 is N or CH; K--R.sub.12 is CH; and L--R.sub.10 is N. 6. The compound of claim 3, wherein R.sub.11 is H; J--R.sub.9 is CH; K--R.sub.12 is N or CH; and L--R.sub.10 is N or CH. 7. The compound of claim 2, wherein ##STR53## B is H; E is CO.sub.2 H; Y is --CH.sub.2 --; R.sub.11 is H; J--R.sub.9 is N or CH; K--R.sub.12 is N or CH; and L--R.sub.10 is CH. 8. The compound of claim 2, wherein ##STR54## B is H; E is CO.sub.2 H; Y is --CH.sub.2 --; R.sub.11 is H; J--R.sub.9 is N or CH; K--R.sub.12 is CH; and L--R.sub.10 is N. 9. The compound of claim 2, wherein ##STR55## B is H; E is CO.sub.2 H; Y is --CH.sub.2 --; R.sub.11 is H; J--R.sub.9 is CH; K--R.sub.12 is N or CH; and L--R.sub.10 is N or CH. 10. A compound which is: ##STR56## 8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid methyl ester; ##STR57## 8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid; ##STR58## 8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid; ##STR59## 8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-ynoic acid; ##STR60## 8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-6-en-4-ynoic acid; ##STR61## 8-(5-Methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-6-en-4-ynoic acid; ##STR62## 6-Hydroxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid; ##STR63## 6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol-1-yl-oct-4-ynoic acid; ##STR64## 6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol1-yl-oct-4-ynoic acid; ##STR65## 6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-pyrrol1-yl-oct-4-ynoic acid; ##STR66## 6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-yno ic acid; or ##STR67## 6-Methoxy-8-(5-methyl-2-phenyl-oxazol-4-yl)-2-[1,2,3]triazol-2-yl-oct-4-yno ic acid. 11. A pharmaceutical composition comprising a compound of claim 1 admixed with a carrier, diluent, or excipient. 12. A method of treating, non-insulin dependent diabetes mellitus, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia in a mammal comprising administering to the mammal in need thereof an effective amount of a compound of claim 1. 13. A method of treating a patient suffering from abnormal insulin and/or evidence of glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone, or of reducing body weight in an obese patient, comprising administering to the patient a therapeutically effective amount of a compound of fomula I. 14. A a method of preparing a compound of formula IA ##STR68## wherein R.sub.9 -R.sub.12 are each independently H, halo, aryl, (C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkanoyl, halo(C.sub.1 -C.sub.6)alkanoyl, (C.sub.3 -C.sub.7)cycloalkylcarbonyl, benzoyl, or halo(C.sub.2 -C.sub.6)alkanoyl; and one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R.sub.9, R.sub.10, and R.sub.12 are absent at that position comprising: (a) Conversion of the mesylate to the nitrile; (j) Conversion of the nitrile to the primary alcohol; (k) Conversion of the primary alcohol to the halide; (l) Displacement of the halide with TMSacetylide to to form the TMS acetylene; (m) Removal of the TMS group by hydrolysis; (n) Treatment of the acetylene with base and reaction with formaldehyde to form the propargyl alcohol; (o) Conversion of the primary alcohol to the Halde; (p) Alkylation with "X" follwed by decarboxylation to form the ester; (q) Hydrolysis of the ester: ##STR69## ##STR70## 15. A method of preparing a compound of formula IB ##STR71## wherein R' is H, (C.sub.1 -C.sub.6)alkyl; R.sub.9 -R.sub.12 are independently H, halo, aryl, (C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkanoyl, halo(C.sub.1 -C.sub.6)alkanoyl, benzoyl, or halo(C.sub.2 -C.sub.6)alkanoyl; and one, two, or three of J, K, and L are N, provided that when J, K, or L are N, R.sub.9, R.sub.10, and R.sub.12 are absent at that position comprising: (h) Oxidation of the alcohol to the aldehyde; (i) Addition of TMS acetylide to the aldehyde; (j) Removal of the TMS group by hydrolysis; (k) Treatment of the acetylene with base and reaction with formaldehyde to form the propargyl alcohol; (l) Conversion of the primary alcohol to the halide; (m) Alkylation with "X" to followed byby decarboxylation to form the ester; and (n) Hydrolysis of the ester to provide the compound of formula IB: ##STR72## ##STR73##

Details for Patent 6,696,474

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2022-04-03