US 6,498,196 B1Granted

Compounds useful in pain management

OwnerEdward Roberts, Tiechao Li +4inventors

InventorsEdward Roberts, Tiechao Li, Dilip Dixit, Krzysztof Bednarski, Dick Storer, Wuyi Wang

Life of this patent

Estimating the term…

Abstract

The present invention relates to novel thio-aminotetralin compounds of the formula (I) wherein Z, X, R1, R2, R3, R4, R5, and R6 are defined herein. The compounds are useful in pain management.

Claims24

Dependent claims

A compound represented by formula (1)

and pharmaceutically acceptable derivatives thereof;
wherein;
Z is S,
X is —CR7R8— wherein R7 and R8 are independently selected from the group consisting of H, OH, halogen, CN, COOH, CONH2, amino, nitro, SH, C1-6alkyl where one or more of the carbon atoms in said C1-6alkyl may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6 alkenyl where one or more of the carbon atoms in said C2-6 alkenyl may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms in said C2-6alkynyl may optionally be substituted by one or more heteroatoms selected from O, S and N;
and COORc wherein Rc is C1-6alkyl, C2-6alkenyl or C2-6alkynyl;
R1 is selected from the group consisting of H, C1-12alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-12alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-12alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C6-12 aryl, C6-12 aralkyl, C6-12 aryloxy, and C1-2 acyl;
R2 and R3 are independently selected from the group consisting of C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C6-12 aryl, C6-12 aralkyl, and H;
R4 and R5 are independently selected from the group consisting of C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H;
R6 is hydrogen, OH, C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, halogen, CN, COOH, CONH2, amino, nitro, or SH;
with the provisos that:
1) not both R4 and R5 are H;
and
2) at least one of R2 and R3 is H or C1-6alkyl.

10 more elements

A compound selected from the group consisting of:

Trans-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol, (compound #1);
Trans and cis-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol, (compound #2);
Trans-7-Amino-8,8-diethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol, (compound #3);
Trans-7-Amino-8,8-dimethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol, (compound #4);
Trans-7-Amino-6-(3-amino-phenylsulfanyl)-8,8-dimethyl-5,66,7,8-tetrahydro-naphthalen-2-ol, (compound #7);
Trans-7-Amino-8,8-dimethyl-6-(4-methylsulfanyl-phenylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol, (compound #8);
Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol, (compound #9);
Trans-2-(3-Amino-4,4-diethyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-acetamide (compound #10);
Trans-7-Amino-8,8-diethyl-6-(2-hydroxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 12);
Trans-7-Amino-6-(2-amino-ethylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 14);
Trans-7-Amino-8,8-dimethyl-6-propylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 16);
Trans-7-Amino-6-isopropylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 17);
Trans-7-Amino-6-(2-hydroxy-ethylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 18);
Trans-2-(3-Amino-6-hydroxy-4,4dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-acetamide (compound 19);
Trans-7-Dimethylamino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 20);
8,8-dimethyl-trans-7-methylamino-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 21);
Trans-7-Amino-8,8-diethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 22);
8,8-dimethyl-trans-6-phenylsulfanyl-7-propylamino-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 23);
Trans-7-Amino-6-(2-amino-phenylsulfanyl)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 24);
Trans-7-Amino-8,8-dimethyl-6-(2,2,2-trifluoro-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 25);
Trans-4-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-butyric acid ethyl ester (compound 26);
Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 27);
Trans-7-Amino-8,8-dimethyl-6-(3-phenyl-allylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 28);
Trans-7-Amino-6-isobutylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 29);
Trans-7-Amino-8,8-dimethyl-6-(2-phenoxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 30);
Trans-7-Amino-8,8-diethyl-6-(2-phenoxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 31);
(−)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 32);
(+)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 33);
Trans-7-amino-6-(4-bromo-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 34);
Trans-7-amino-8,8-dimethyl-6-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 35);
Trans-7-Amino-6-(4-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 36);
Trans-7-amino-6-(4-amino-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 37);
Trans-7-amino-6-(3-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 38);
Trans-3-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionic acid ethyl ester (compound 39);
Trans-7-amino-8,8-dimethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound 40);
Trans-2-(3-amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionamide (compound 41);
Trans-3-(3-amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionic acid (compound 42);
Trans-2-[3-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionylamino]-3-(4-hydroxy-phenyl)-propionamide (compound 43);
3-trans-(2-ethoxycarbonyl-ethylsulfanyl)-1,1-diethyl-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl (compound 44);
3-trans-(2-carboxy-ethylsulfanyl)-1,1-diethyl-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl (compound 45);
and pharmaceutically acceptable derivatives thereof.

38 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/460,722Filed 14 Dec 1999 · us provisional application
Priority: 22 Dec 1998
Granted: 24 Dec 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 249/14
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07C 323/30
Containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton: having the sulfur atom of…
C07C 323/37
The thio group being a sulfide group: the sulfur atom of the sulfide group being further bound to a carbon atom of a six-membered aromatic ring
C07C 323/52
Having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton being acyclic and saturated

Family

Application60/113,542Us provisional application · filed 22 Dec 1998
US 6,498,196 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The present invention relates to novel thio-aminotetralin compounds of the formula (I) wherein Z, X, R1, R2, R3, R4, R5, and R6 are defined herein. The compounds are useful in pain management.

A compound represented by formula (1)

and pharmaceutically acceptable derivatives thereof;
wherein;
Z is S,
X is —CR7R8— wherein R7 and R8 are independently selected from the group consisting of H, OH, halogen, CN, COOH, CONH2, amino, nitro, SH, C1-6alkyl where one or more of the carbon atoms in said C1-6alkyl may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6 alkenyl where one or more of the carbon atoms in said C2-6 alkenyl may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms in said C2-6alkynyl may optionally be substituted by one or more heteroatoms selected from O, S and N;
and COORc wherein Rc is C1-6alkyl, C2-6alkenyl or C2-6alkynyl;
R1 is selected from the group consisting of H, C1-12alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-12alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-12alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C6-12 aryl, C6-12 aralkyl, C6-12 aryloxy, and C1-2 acyl;
R2 and R3 are independently selected from the group consisting of C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C6-12 aryl, C6-12 aralkyl, and H;
R4 and R5 are independently selected from the group consisting of C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H;
R6 is hydrogen, OH, C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O—C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, halogen, CN, COOH, CONH2, amino, nitro, or SH;
with the provisos that:
1) not both R4 and R5 are H;
and
2) at least one of R2 and R3 is H or C1-6alkyl.

10 more elements

Facts

Application

09/460,722Filed 14 Dec 1999 · us provisional application

Priority

22 Dec 1998

Granted

24 Dec 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 249/14
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07C 323/30
Containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton: having the sulfur atom of…
C07C 323/37
The thio group being a sulfide group: the sulfur atom of the sulfide group being further bound to a carbon atom of a six-membered aromatic ring
C07C 323/52
Having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton being acyclic and saturated