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US 5,665,745 AGranted
Heterocyclic compounds and their preparation and use
AssigneeEli Lilly and Company
InventorsCharles A. Alt, Leander Merritt, Gary A. Rhodes, Roger L. Robey, Eldon E. Van Meter, John S. Ward, Charles H. Mitch
Life of this patent
Estimating the term…
Abstract
The present invention relates to therapeutically active azacyclic or azabicyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases in the central nervous system caused by malfunctioning of the muscarinic cholinergic system.
Claims31
A compound of formula I, or the quaternized form thereof:
- ##STR19## wherein W is oxygen or sulphur;
- R is hydrogen, amino, halogen, NHR.sup.6, NR.sup.6 R.sup.7, R.sup.4, --OR.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2 R.sup.4, C.sub.3-10 -cycloalkyl, C.sub.4-12 -(cycloalkylalkyl), --Z--C.sub.3-10 -cycloalkyl or --Z--C.sub.4-12 -(cycloalkylalkyl);
- or
- R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more substituents independently selected from halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 and --CSNH.sub.2 ;
- or
- R is --OR.sup.5 Y, --SR.sup.5 Y, OR.sup.5 --Z--Y, --SR.sup.5 ZY, --O--R.sup.5 --Z--R.sup.4 or --S--R.sup.5 --Z--R.sup.4 ;
- Z is oxygen or sulphur;
- R.sup.4 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl or C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, --CF.sub.3, --CN, Y, phenyl and phenoxy, wherein phenyl or phenoxy is optionally substituted with one or more substituents independently selected from halogen, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2 and --CSNH.sub.2 ;
- R.sup.5 is C.sub.1-15 -alkylene, C.sub.2-15 -alkenylene, and C.sub.2-15 -alkynylene;
- Y is a 5 or 6 membered heterocyclic group;
- G is selected from one of the following azacyclic or azabicyclic ring systems:
- ##STR20## or G is C.sub.3 -C.sub.8 cycloalkyl optionally substituted by R.sup.1, R.sup.2 or --NR.sup.6 R.sup.7 ;
- or G is C.sub.1-6 -alkyl optionally substituted by --NR.sup.6 R.sup.7 ;
- R.sup.6 and R.sup.7 independently are hydrogen or C.sub.1-6 -alkyl;
- or R.sup.6 and R.sup.7 together form a C.sub.3 -C.sub.5 -alkylene group which together with the nitrogen atom form a 4- to 6-membered ring;
- R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1-15 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, or C.sub.1-5 -alkyl substituted with one or more substituents independently selected from --OH, --COR.sup.6', CH.sub.2 --OH, halogen, --NH.sub.2, carboxy, and phenyl;
- R.sup.6' is hydrogen or C.sub.1-6 -alkyl;
- R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl;
- m, n, p and r are independently 0, 1 or 2;
- q is 1 or 2;
- and
- ------- is a single or double bond;
- provided that:
- 1) when W is oxygen and G is alkyl, R cannot be halogen;
- and 2) one of m, n, or p must be other than 0;
- or
- a pharmaceutically acceptable salt or solvate thereof.
24 more elements
A compound selected from the group consisting of:
- (.+-.)-3-(2-(5-(2-Thienyl) thienyl) thio)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole;
- (.+-.)-3-(2-(2-(5-(2-Thienyl)thienyl)thio)ethylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole;
- (.+-.)-3-(2-(5-(2-Thienyl)thienyl)thio)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)- 1,2,5-thiadiazole;
- (.+-.)-3-(3-N-(2-Thiazolidinyl)propylthio)-4-(1-azabicyclo[2.2.2]octyl-3-ox y)-1,2,5-thiadiazole;
- 3-Butylthio-4-hydroxy-1,2,5-thiadiazole;
- (.+-.)-3-(2-[3-(1,2,5-Thiadiazolyloxy)]ethoxy)-4-(1-azabicyclo[2.2.2]octyl- 3-oxy)-1,2,5-thiadiazole;
- (.+-.)-trans-3-Butylthio-4-(N-tert-butylcarboxy-4-hydroxy-pyrrolidin-3-oxy) -1,2,5-thiadiazole;
- (.+-.)-trans-3-Butylthio-4-(4-hydroxy-pyrrolidin-3-oxy)-1,2,5-thiadiazole;
- (.+-.)-3-(3-[4-Fluorophenyl]propan-3-onethio)-4-(1-azabicyclo[2.2.2]octyl-3 -oxy)-1,2,5-thiadiazole;
- (.+-.)-exo-3-Propythio-4-(2-methoxycarbonyl-2-azabicyclo[2.2.2]octyl-6-oxy) -1,2,5-thiadiazole;
- (.+-.)-exo-3-Propylsulfonyl-4-(2-methoxycarbonyl-2-azabicyclo[2.2.2]octyl-6 -oxy)-1,2,5-thiadiazole;
- (.+-.)-exo-3-(4,4,4-Trifluorobutyloxy)-4-(2-methoxycarbonyl-2-azabicyclo[2. 2.2]octyl-6-oxy)-1,2,5-thiadiazole;
- (.+-.)-exo-3-(2-[Fluorophenoxy]ethylthio)-4-(2-methoxycarbonyl-2-azabicyclo [2.2.2]octyl-6-oxy)-1,2,5-thiadiazole;
- (.+-.)-endo-3-(4-Methylthiobenzyloxy)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1, 2,5-thiadiazole;
- (.+-.)-endo-3-(2-Cyclohexenyloxy)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5- thiadiazole;
- (.+-.)-endo-3-[2-(2-Naphthyl)ethoxy]-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2 ,5-thiadiazole;
- (.+-.)-endo-3-(4-Chloro-.alpha.-cyclopropyl-benzyloxy)-4-(1-azabicyclo[3.2. 1]octyl-6-oxy)-1,2,5-thiadiazole;
- (.+-.)-endo-3-(Cyclopropylmethoxy)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5 -thiadiazole;
- (.+-.)-endo-3-(2-Cyclopropylethoxy)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2, 5-thiadiazole;
- (.+-.)-endo-3-(2-Cyclohexylethoxy)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5 -thiadiazole;
- (.+-.)-endo-3-(4-Cyclohexylbutoxy)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5 -thiadiazole;
- (.+-.)-3-(2-Methylthioethyl)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiad iazole;
- 3-Butylthio-4-hydroxy-1,2,5-thiadiazole;
- and
- (.+-.)-3-(2-[3-{1,2,5-Thiadiazolyloxy}]ethoxy)-4-(1-azabicyclo[2.2.2]octyl- 3-oxy)-1,2,5-thiadiazole.
22 more elements
Dependencies are inferred from the claim text.