3-ARYL-3-HYDROXY-2-AMINO-PROPIONIC ACID AMIDES, 3-HETEROARYL-3-HYDROXY-2-AMINO-PROPIONIC ACID AMIDES AND RELATED COMPOUNDS HAVING ANALGESIC AND/OR IMMUNO STIMULANT ACTIVITY
First Claim
Patent Images
1. A compound of the formula where R1 is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R1 and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups, cyano groups, or with one or two alkyl groups having 1 to 6 carbons, or one or two carbons of said rings being attached to an oxygen to form keto groups and said 4, 5, 6 or 7 membered ring optionally being condensed with an aromatic or non-aromatic 5 or 6 membered ring that optionally includes 1 or heteroatoms selected from N, O and S;
- R3 is independently selected from H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons, aryl-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, or hetero-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R3 is CO—
R7, SO2R7 or CO—
O—
R7 where R7 is H, alkyl of 1 to 1 to 20 carbons, alkyl of 1 to 20 carbons substituted with and NH2 group or with an NH—
COalkyl group where the alkyl group has one to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons or heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons;
R4 is H, alkyl of 1 to 6 carbons or CO—
R8 where R8 is alkyl of 1 to 6 carbons;
the wavy lines represent bonds connected to carbons having R or S configuration;
the dashed lines represent a bond or absence of a bond with the proviso that the ring containing the dashed lines is aromatic;
m, n and q are integers independently selected from 0, 1, 2 or 3 with the proviso that the sum of m, n and q is 2 or 3;
s is zero (0) or when X is N then s is zero (0) or 1;
W, X and Y independently represent a CH, CR5, CR6 or a heteroatom selected independently of N, O and S, and R5 and R6 are independently selected from H, halogen, alkyl of 1 to 6 carbons, halogen substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, phenyl, or R5 and R6 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S;
said carbocyclic or heterocyclic ring jointly formed by R5 and R6 being optionally substituted with 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons or a pharmaceutically acceptable salt of said compound with the proviso that Formula 1 does not cover compounds where R4 is H, R1 and R2 jointly with the nitrogen form a pyrrolidino or morpholino ring, the sum of m, n and q is 3, and where none of W, X and Y represent a heteroatom with the further proviso that the formula does not cover the compounds of the formula below
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Accused Products
Abstract
Compounds of Formulas 1 and 2
where the variables have the meaning disclosed in the specification, have analgesic and in some cases immunostimulant activity.
40 Citations
68 Claims
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1. A compound of the formula
where R1 is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R1 and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups, cyano groups, or with one or two alkyl groups having 1 to 6 carbons, or one or two carbons of said rings being attached to an oxygen to form keto groups and said 4, 5, 6 or 7 membered ring optionally being condensed with an aromatic or non-aromatic 5 or 6 membered ring that optionally includes 1 or heteroatoms selected from N, O and S; -
R3 is independently selected from H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons, aryl-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, or hetero-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R3 is CO—
R7, SO2R7 or CO—
O—
R7 where R7 is H, alkyl of 1 to 1 to 20 carbons, alkyl of 1 to 20 carbons substituted with and NH2 group or with an NH—
COalkyl group where the alkyl group has one to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons or heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons;R4 is H, alkyl of 1 to 6 carbons or CO—
R8 where R8 is alkyl of 1 to 6 carbons;the wavy lines represent bonds connected to carbons having R or S configuration; the dashed lines represent a bond or absence of a bond with the proviso that the ring containing the dashed lines is aromatic; m, n and q are integers independently selected from 0, 1, 2 or 3 with the proviso that the sum of m, n and q is 2 or 3; s is zero (0) or when X is N then s is zero (0) or 1; W, X and Y independently represent a CH, CR5, CR6 or a heteroatom selected independently of N, O and S, and R5 and R6 are independently selected from H, halogen, alkyl of 1 to 6 carbons, halogen substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, phenyl, or R5 and R6 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and R6 being optionally substituted with 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons or a pharmaceutically acceptable salt of said compound with the proviso that Formula 1 does not cover compounds where R4 is H, R1 and R2 jointly with the nitrogen form a pyrrolidino or morpholino ring, the sum of m, n and q is 3, and where none of W, X and Y represent a heteroatom with the further proviso that the formula does not cover the compounds of the formula below - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 56, 59)
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19. A compound of the formula
where R1 is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R1 and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups, cyano groups or with one or two alkyl groups having 1 to 6 carbons; -
R3 is H, CO—
R7 or CO—
O—
R7 where R7 is H, alkyl of 1 to 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl, aryl(hydroxy)alkyl, heteroaryl-alkyl or heteroalkyl(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons;R4 is H, alkyl of 1 to 6 carbons, or CO—
R8 where R8 is alkyl of 1 to 6 carbons,R5 and R6 are independently selected from H, halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R5 and R6 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and R6 being optionally substituted with 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, and the wavy lines represent bonds of the alpha or beta configuration, or any pharmaceutically acceptable salt of said compound. - View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 57, 58, 60, 61)
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48. A compound of the formula
where R1 is H or alkyl of 1 to 6 carbons, R2 is alkyl of 1 to 6 carbons or the R1 and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups, cyano groups, or with one or two alkyl groups having 1 to 6 carbons, R3 is H, CO— - R7 or CO—
O—
R7 where R7 is H, alkyl of 1 to 1 to 20 carbons, aryl or heteroaryl, cycloalkyl of 3 to 6 carbons, aryl-alkyl aryl(hydroxy)alkyl, heteroaryl-alkyl or heteroaryl(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons;
R4 is H, alkyl of 1 to 6 carbons, or CO—
R8 where R8 is alkyl of 1 to 6 carbons;R5 and R6 are independently selected from H, halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, thioxy of 1 to 3 carbons and phenyl, or R5 and R6 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and R6 being optionally substituted with 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, and the wavy lines represent bonds connected to carbons having R or S of configuration, with the proviso that the claim does not cover compounds where R4 is H, R1 and R2 jointly with the nitrogen form a pyrrolidino or morpholino ring, or any pharmaceutically acceptable salt of said compound. - View Dependent Claims (49)
- R7 or CO—
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50. A compound of the formula
where X is O or S; -
R1 is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R1 and R2 groups together with the nitrogen form a saturated or unsaturated 5 or 6 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups or cyano groups with one or two alkyl groups having 1 to 6 carbons, R3 is H, CO—
R7 or CO—
O—
R7 where R7 is H, alkyl of 1 to 1 to 20 carbons, aryl or heteroaryl, aryl-alkyl, aryl(hydroxy)alkyl, heteroaryl-alkyl or heteroaryl(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons;R4 is H, alkyl of 1 to 6 carbons, or CO—
R8 where R8 is alkyl of 1 to 6 carbons;R5 and R6 are independently selected from H, halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R5 and R6 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and R6 being optionally substituted with 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, and the wavy lines represent bonds connected to carbons having R or S configuration, or any pharmaceutically acceptable salt of said compound with the further proviso that the claim does not cover the compound shown below - View Dependent Claims (51, 52, 53, 54, 55)
or a pharmaceutically acceptable salt of said compound. -
52. A compound in accordance with claim 51 having the formula
or a pharmaceutically acceptable salt of said compound. -
53. A compound in accordance with claim 51 having the formula
or any other pharmaceutically acceptable salt of said compound. -
54. A compound in accordance with claim 53 having the formula
or any other pharmaceutically acceptable salt of said compound. -
55. A compound in accordance with claim 53 having the formula
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62. A compound of the formula
where R1 is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R1 and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen or cyano groups groups or with one or two alkyl groups having 1 to 6 carbons, or one or two carbons of said rings being attached to an oxygen to form keto groups and said 4, 5, 6 or 7 membered ring optionally being condensed with an aromatic or non-aromatic 5 or 6 membered ring that optionally includes 1 or heteroatoms selected from N, O and S; -
R3 is independently selected from H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons, aryl-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons or hetero-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R3 is CO—
R7, SO2R7 or CO—
O—
R7 where R7 is H, alkyl of 1 to 1 to 20 carbons, alkyl of 1 to 20 carbons substituted with and NH2 group or with an NH—
COalkyl group where the alkyl group has one to 6 carbons aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons or heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons;the wavy lines represent bonds connected to carbons having R or S configuration; the dashed lines represent a bond or absence of a bond with the proviso that the ring containing the dashed lines is aromatic; R9 and R10 are one of the combinations selected from the group consisting of (1) R9 is NOR11 and R10 does not exist, (2) R9 is OR11 and R10 is alkyl of 1 to 6 carbons, (3) when the dashed lines between carbons 2 and 3 of the propionic acid moiety represent a bond then R9 is H or alkyl of 1 to 6 carbons and R10 does not exist; R11 is H, alkyl of 1 to 6 carbons or CO—
R12 where R12 is alkyl of 1 to 6 carbons;m, n and q are integers independently selected from 0, 1, 2 or 3 with the proviso that the sum of m, n and q is 2 or 3; s is zero (0) or when X is N then s is zero (0) or 1; W, X and Y independently represent a CH, CR5, CR6 or a heteroatom selected independently of N, O and S, and R5 and R6 are independently selected from H, halogen, alkyl of 1 to 6 carbons, halogen substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, phenyl, or R5 and R6 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and R6 being optionally substituted with 1 to 6 R12 groups where R12 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons or a pharmaceutically acceptable salt of said compound. - View Dependent Claims (63, 64, 65, 66, 67, 68)
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Specification
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Current AssigneeAllergan, Inc. (Canada) (Abbvie Incorporated), Exonhit Therapeutics SA (Eurobio-Scientific SA)
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Original AssigneeAllergan, Inc. (Canada) (Abbvie Incorporated), Exonhit Therapeutics SA (Eurobio-Scientific SA)
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InventorsDonello, John E., Taverne, Thierry, Leblond, Bertrand, Beausoleil, Eric
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/227.800
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CPC Class CodesA61K 31/40 having five-membered rings ...A61K 31/4025 not condensed and containin...A61K 31/4409 only substituted in positio...A61K 31/4439 containing a five-membered ...A61K 31/4545 containing a six-membered r...A61K 31/4709 Non-condensed quinolines an...A61K 31/496 Non-condensed piperazines c...A61K 31/5375 1,4-Oxazines, e.g. morpholineA61K 31/5377 not condensed and containin...A61K 31/541 Non-condensed thiazines con...A61P 25/00 Drugs for disorders of the ...A61P 25/04 Centrally acting analgesics...A61P 29/00 Non-central analgesic, anti...A61P 29/02 without antiinflammatory ef...A61P 37/02 ImmunomodulatorsA61P 37/04 ImmunostimulantsC07D 207/09 Radicals substituted by nit...C07D 213/64 attached in position 2 or 6C07D 265/30 not condensed with other ringsC07D 295/12 substituted by singly or do...View All
