US 2014/0228362 A1Published application

Method of Treatment or Prophylaxis

AssigneeSpinifex Pharmaceuticals Pty Ltd

InventorsMaree Therese Smith, Bruce Douglas Wyse

Life of this patent

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Abstract

The present invention is directed to methods and agents that are useful in the prevention and amelioration of signs and symptoms associated with neuropathic conditions. More particularly, the present invention discloses the use of angiotensin II receptor 2 (AT2 receptor) antagonists for the treatment, prophylaxis, reversal and/or symptomatic relief of neuropathic pain, including mechanical hyperalgesia, thermal or mechanical allodynia, diabetic pain and entrapment pain, in vertebrate animals and particularly in human subjects. The AT2 receptor antagonists may be provided alone or in combination with other compounds such as those that are useful in the control of neuropathic conditions.

Claims18

Dependent claims

A method for the treatment of neuropathic pain in a subject comprising administering to the subject in need thereof an effective amount of an AT2 receptor antagonist, wherein the AT2 receptor antagonist is selected from compounds represented by formula (III):

wherein:
R1, R2 and R3 are independently selected from H, phenyl, substituted phenyl, benzyl, substituted benzyl, C1-6 alkyl, and substituted C1-6 alkyl, with the proviso that at least one of R1 or R2 are not hydrogen,
X is selected from CH, nitrogen, sulfur or oxygen with the proviso that when X is sulfur or oxygen, one of R1 or R2 is absent, or is aryl or heteroaryl with the proviso that both R1 and R2 are absent,
V is selected from CH or nitrogen atom,
Y is selected from sulfur, oxygen or N—RN, where RN is selected from H, C1-6 alkyl, substituted C1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C1-4 alkylaryl, substituted C1-4 alkylaryl, OH, or NH2,
R4 is selected from a carboxylate, carboxylic acid, sulfate, phosphate, sulfonamide, phosphonamide, or amide,
G is a five or six membered, homoaromatic or unsaturated, substituted or unsubstituted, heterocyclic ring including but not limited to the following rings systems:
where the symbol ‘*’ indicates the bond shared between the fused rings ‘A’ and ‘G’,
R5 is selected from H, C1-6 alkyl, phenyl, substituted phenyl, substituted C1-6 alkyl, or C1-6 alkoxy,
R6 and R8 are independently selected from H, C1-6 alkyl, substituted C1-6 alkyl C1-6 alkoxy, substituted, C1-6 alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, benzylamino, biphenyl, substituted biphenyl, biphenyloxy, substituted biphenyloxy, naphthyl, substituted naphthyl, provided that one of R6 or R8 is not hydrogen, and
R7 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted naphthylmethylene, or a pharmaceutically compatible salt thereof.

8 more elements

wherein
R2 is independently
(a) H,
(b) halo (F, Cl, Br, I), or
(c) C1-C4-alkyl;
R3 is
(a) H, or
(b) halo (F, Cl, Br, I);
R6 is
(a) C1-C10 alkyl,
(b) C3-C10 alkenyl, or
(c) C3-C10 alkynyl;
R7 is
(a) C1-C6-alkyl,
(b) C3-C6-cycloalkyl,
(c) aryl, or
(d) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C1-C4-alkyl, C1-C4-alkoxy or —NO2;
R8 is
(a) H,
(b) halogen (F, Cl, Br, I),
(c) phenyl, or phenyl optionally substituted with halogen (F, Cl, Br, I), C1-C4-alkyl, —OH, C1-C4-alkoxy, —NO2, —NR26R27, —NR26COR11, —NR26CO2R7, —S(O)rR10, —SO2NR26R27, —NR26SO2R10, —CF3,
(d) C1-C6-alkyl, optionally substituted with
i) OR25,
ii) S(O)rR10,
iii) NR23R24,
iv) NR26COR11,
v) NR26CO2R7,
vi) NR26CONR23R24,
viii) OCOR11,
ix) aryl,
(e) C2-C6-alkenyl,
(f) —C1-C4-alkyl-aryl,
(h) C1-C4-alkoxy,
(i) CvF2v+1 where v=1 to 3,
(j) —S(O)rR10,
(k) —S(O)2NR23R24,
(l) —CONR23R24,
(m) —COR7, or
(n) —CO2R12;
R9 is
(a) H,
(b) C1-C5-alkyl,
(c) aryl,
(d) —(C1-C4-alkyl)-aryl, or
(e) heteroaryl;
R10 is
(a) aryl,
(b) C3-C7-cycloalkyl,
(c) C1-C4-perfluoroalkyl,
(d) C1-C4-alkyl, optionally substituted with a substituent selected from the group consisting of aryl, heteroaryl, —OH, —SH, C1-C4-alkoxy, C1-C4-alkylthio, —CF3, halo, —NO2, —CO2R12, —NH2, C1-C4-alkylamino, C1-C4-dialkylamino, —PO3H2, or
(e) heteroaryl;
R11, R11a and R11b are independently
(a) H,
(b)
(c) C3-C6-cycloalkyl,
(d) aryl,
(e) —(C1-C5-alkyl)-aryl, or
(f) heteroaryl;
R12 is
(a) H,
(b) methyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C1-C4-alkyl, C1-C4-alkoxy or —NO2;
R13 is
(a) —CO2H,
(b) —CONHSO2R10,
(c) —CONHSO2NHR9,
(d) —NHCONHSO2R10,
(e) —NHSO2R10,
(f) —NHSO2NHCOR10,
(g) —SO2NHR9,
(h) —SO2NHCOR10,
(i) —SO2NHCONHR9,
(j) —SO2NHCO2R10, or
R16 is
(a) H,
(b) C1-C6-alkyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C1-C4-alkyl, C1-C4-alkoxy or —NO2;
R23 and R24 are, independently
(a) H,
(b) C1-C6-alkyl,
(c) aryl, or
(d) —(C1-C4-alkyl)-aryl, or
(e) R23 and R24 when taken together constitute a pyrrolidine, piperidine or morpholine ring;
R26 and R27 are independently
(a) H,
(b) C1-C4-alkyl,
(c) aryl, or
(d) —CH2-aryl;
R28 is
(a) aryl, or
(b) heteroaryl;
R29 is
(a) —CHO,
(b) —CONH2,
(c) —NHCHO,
(d) —CO—(C1-C6 perfluoroalkyl),
(e) —S(O)r—(C1-C6 perfluoroalkyl),
E is
(a) -(T)y-(B)y—X2—(B)y—R28,
(b) -T-(B)y—R28,
(c) -(T)y-(B)y—X2—B or,
(d) -T-(B)y—R29;
L1 is
(a) —CO2—,
(b) —CONR11a—,
(c) —NR1laCO2—,
(d) —NR11aCONR11b—;
B is C1-C6 alkyl;
X2 is
(a) —CO—,
(b) —O—,
(c) —S(O)r—,
(d) —(C1-C4-alkylene)-,
(e) —NR11aCONR11b—,
(f) —CONR11a—,
(g) —NR11aCO—,
(h) —SO2NR16—,
(i) —NR16SO2—,
(j) —CONR11aSO2—,
(k) —SO2NR11aCO—,
(l) —SO2NR11aCO2—,
(m) —OCONR11aSO2—,
(n) —SO2NR11aCONR11b—,
(o) —NR11aCONR11bSO2—,
(p) —SO2NR11aSO2—,
(q) —CONR11aSO2NR11b, or
(r) —NR11aSO2NR11bCO—;
T is
(a) arylene, or
(b) heteroarylene
n is 0 to 2;
r is 0 to 2;
u is 2 to 5;
y is 0 or 1;
and pharmaceutically compatible salts of these compounds.

132 more elements

wherein
R2 is independently
(a) H,
(b) halo (F, Cl, Br, I), or
(c) C1-C4-alkyl;
R3 is
(a) H, or
(b) halo (F, Cl, Br, I);
R6 is
(a) C1-C10 alkyl,
(b) C3-C10 alkenyl, or
(c) C3-C10 alkynyl;
R7 is
(a) C1-C6-alkyl,
(b) C3-C6-cycloalkyl,
(c) aryl, or
(d) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C1-C4-alkyl, C1-C4-alkoxy or —NO2;
R8 is
(a) H,
(b) halogen (F, Cl, Br, I),
(c) phenyl, or phenyl optionally substituted with halogen (F, Cl, Br, I), C1-C4-alkyl, —OH, C1-C4-alkoxy, —NO2, —NR26R27, —NR26COR11, —NR26CO2R7, —S(O)rR16, —SO2NR26R27, —NR26SO2R10, —CF3,
(d) C1-C6-alkyl, optionally substituted with
i) OR25,
ii) S(O)rR10,
iii) NR23R24,
iv) NR26COR11,
v) NR26CO2R7,
vi) NR26CONR23R24,
viii) OCOR11,
ix) aryl,
(e) C2-C6-alkenyl,
(f) —C1-C4-alkyl-aryl,
(h) C1-C4-alkoxy,
(i) CvF2v+1 where v=1 to 3,
(j) —S(O)rR10,
(k) —S(O)2NR23R24,
(l) —CONR23R24,
(m) —COR7, or
(n) —CO2R12;
R9 is
(a) H,
(b) C1-C5-alkyl,
(c) aryl
(d) —(C1-C4-alkyl)-aryl, or
(e) heteroaryl;
R10 is
(a) aryl,
(b) C3-C7-cycloalkyl,
(c) C1-C4-perfluoroalkyl,
(d) C1-C4-alkyl, optionally substituted with a substituent selected from the group consisting of aryl, heteroaryl, —OH, —SH, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, —CF3, halo, —NO2, —CO2R12, —NH2, C1-C4-alkylamino, C1-C4-dialkylamino, —PO3H2, or
(e) heteroaryl;
R11, R11a and R11b are independently
(a) H,
(b) C1-C6-alkyl,
(c) C3-C6-cycloalkyl,
(d) aryl,
(e) —(C1-C5-alkyl)-aryl, or
(f) heteroaryl;
R12 is
(a) H,
(b) methyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C1-C4-alkyl, C1-C4-alkoxy or —NO2;
R13 is
(a) —CO2H,
(b) —CONHSO2R10,
(c) —CONHSO2NHR9,
(d) —NHCONHSO2R10,
(e) —NHSO2R10,
(f) —NHSO2NHCOR10,
(g) —SO2NHR9,
(h) —SO2NHCOR10,
(i) —SO2NHCONHR9,
(j) —SO2NHCO2R10, or
R16 is
(a) H,
(b) C1-C6-alkyl, or
(c) benzyl, optionally substituted on the phenyl ring with 1-2 substituents selected from the group consisting of halo, C1-C4-alkyl, C1-C4-alkoxy or —NO2;
R23 and R24 are, independently
(a) H,
(b) C1-C6-alkyl,
(c) aryl, or
(d) —(C1-C4-alkyl)-aryl, or
(e) R23 and R24 when taken together constitute a pyrrolidine, piperidine or morpholine ring;
R26 and R27 are independently
(a) H,
(b) C1-C4-alkyl,
(c) aryl, or
(d) —CH2-aryl;
R28 is
(a) aryl, or
(b) heteroaryl;
R29 is
(a) —CHO,
(b) —CONH2,
(c) —NHCHO,
(d) —CO—(C1-C6 perfluoroalkyl),
(e) —S(O), —(C1-C6 perfluoroalkyl),
G is
(a) -(T)y-(B)y—X2—(B)y—R28,
(b) -T-(B)y—R28,
(c) -(T)y-(B)y—X2—B, or
(d) -T-(B)y—R29;
L2 is —CO—, —NR11aCO— or —O2C—;
B is C1-C6 alkyl;
X2 is
(a) —CO—,
(b) —O—,
(c) —S(O)r—,
(d) —(C2-C4-alkylene)-,
(e) —NR11aCO, —NR11aCONR11b—
(f) —CONR11a—,
(g) —NR11aCO—,
(h) —SO2NR16—,
(i) —NR16SO2—,
(j) —SO2NR11aSO2—,
(k) —SO2NR11aCO2—,
(l) —SO2NR11aCO2—,
(m) —OCONR11aSO2—,
(n) —SO2NR11aCONR11b—,
(o) —NR11aCONR11bSO2—,
(p) —SO2NR11aSO2—,
(q) —CONR11aSO2NR11b—, or
(r) —NR11aSO2NR11bCO—,
T is
(a) arylene, or
(b) heteroarylene
n is 0 to 2;
r is 0 to 2;
y is 0 or 1;
and pharmaceutically compatible salts of these compounds.

127 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/229,746Filed 28 Mar 2014
Priority: AU 200490733224 Dec 2004
Published: 14 Aug 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/517
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 38/08
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides having 5 to 11 amino acids
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application11/315,354Division · filed 23 Dec 2005
Application12/849,727Division · filed 3 Aug 2010
Application13/923,085Continuation · filed 20 Jun 2013
Application14/229,746Division
Application11/315,354Continuation
Application13/923,085Division
US 2006/0223741 A1Published application
US 2011/0318329 A1Published application
US 2013/0296350 A1Published application
US 7,795,275 B2Related patent
US 8,492,382 B2Related patent
US 8,722,675 B2Related patent
US 9,018,207 B2Related patent
US 2014/0228362 A1This patent

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

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Abstract

wherein:
R1, R2 and R3 are independently selected from H, phenyl, substituted phenyl, benzyl, substituted benzyl, C1-6 alkyl, and substituted C1-6 alkyl, with the proviso that at least one of R1 or R2 are not hydrogen,
X is selected from CH, nitrogen, sulfur or oxygen with the proviso that when X is sulfur or oxygen, one of R1 or R2 is absent, or is aryl or heteroaryl with the proviso that both R1 and R2 are absent,
V is selected from CH or nitrogen atom,
Y is selected from sulfur, oxygen or N—RN, where RN is selected from H, C1-6 alkyl, substituted C1-6 alkyl, aryl, substituted aryl, benzyl, substituted benzyl, C1-4 alkylaryl, substituted C1-4 alkylaryl, OH, or NH2,
R4 is selected from a carboxylate, carboxylic acid, sulfate, phosphate, sulfonamide, phosphonamide, or amide,
G is a five or six membered, homoaromatic or unsaturated, substituted or unsubstituted, heterocyclic ring including but not limited to the following rings systems:
where the symbol ‘*’ indicates the bond shared between the fused rings ‘A’ and ‘G’,
R5 is selected from H, C1-6 alkyl, phenyl, substituted phenyl, substituted C1-6 alkyl, or C1-6 alkoxy,
R6 and R8 are independently selected from H, C1-6 alkyl, substituted C1-6 alkyl C1-6 alkoxy, substituted, C1-6 alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, benzylamino, biphenyl, substituted biphenyl, biphenyloxy, substituted biphenyloxy, naphthyl, substituted naphthyl, provided that one of R6 or R8 is not hydrogen, and
R7 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, biphenyl, substituted biphenyl, biphenylmethylene, substituted biphenylmethylene, naphthyl, substituted naphthyl, naphthylmethylene, and substituted naphthylmethylene, or a pharmaceutically compatible salt thereof.

8 more elements

Facts

Application

14/229,746Filed 28 Mar 2014

Priority

AU 200490733224 Dec 2004

Published

14 Aug 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/517
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 38/08
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides having 5 to 11 amino acids
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application11/315,354Division · filed 23 Dec 2005

Application12/849,727Division · filed 3 Aug 2010

Application13/923,085Continuation · filed 20 Jun 2013

Application14/229,746Division

Application11/315,354Continuation

Application13/923,085Division

US 2006/0223741 A1Published application

US 2011/0318329 A1Published application

US 2013/0296350 A1Published application

US 7,795,275 B2Related patent

US 8,492,382 B2Related patent

US 8,722,675 B2Related patent

US 9,018,207 B2Related patent

US 2014/0228362 A1This patent

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