US 2006/0235027 A1Published application

Inhibitors of cdc25 phosphatases

AssigneeScras

InventorsGregoire Prevost, Marie-Christine Brezak Pannetier, Marie-Odile Galcera Contour, Christophe Thurieau, Francoise Goubin Gramatica, Bernard Ducommun, Christophe Lanco

Life of this patent

Estimating the term…

Abstract

A method of inhibiting cdc25 phosphatases in warm-blooded animals comprising administering to warm-blooded animals in need thereof an effective amount of a compound of the formula wherein the substituents are defined as in the specification.

Claims12

Dependent claims

A method of inhibiting cdc 25 phosphatases in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula

wherein A is
wherein two of R1, R2, R3, R4, and R5 are hydrogen and the other three are independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, alkylcarbonyloxy, alkylthio and —NR6R7, it being understood that:
either R1 and one of R2 and R4 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7,
or R2 and one of R3 and R5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7,
or R4 and one of R3 and R5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7,
or also one of R1, R3 and R5 is selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7, and B—N(W)—X—Y remainder is attached to A by nitrogen,
R6 and R7 are independently each time that they occur a hydrogen or alkyl or R6 and R7 together with the nitrogen atom form a heterocycle of 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR8R9—, —O—, —S— and —NR10—,
R8 and R9 independently are each time that they occur selected from the group consisting of hydrogen, alkyl, alkoxy, benzyloxycarbonylamino and dialkylamino, and R10 independently is each time that it occurs hydrogen or alkyl,
wherein either R11 and one of R13, R14 and R15 are hydroxy while R13, R14 and R15 as well as R16 are hydrogen,
or R12 and R16 are hydroxy while R11, R13, R14 and R15 are hydrogen;
B is —(CH2)p— and p is an integer from 0 to 1;
W is hydrogen or alkyl;
X is selected from the group consisting of —(CH2)q—, —(CH2)q—NH and —CO—(CH2)r—, q is an integer from 1 to 6 and r is an integer from 0 to 6;
or B—N(W)—X—Y is
wherein B is as defined above, t is an integer from 0 to 2, s is an integer from 0 to 1 and R17 and R18 are independently hydrogen or alkyl;
and:
when X is —(CH2)q— or —CO—(CH2)r—, then Y
is
wherein R19 is selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkylthio, —NR21R22, —SO2—NR22R24, —NH—SO2—R25 and —O—P(O)(OR26)(OR)27, R21 and R22 independently are hydrogen or alkyl,
R23 and R24 independently are hydrogen or alkyl, or R23 and R24 representing together with the nitrogen atom which carries them a heterocycle with 5 to 7 ring members, the additional members are independently selected from the group consisting of —CHR28—, —NR29—, —O— and —S—, R28— and R29 are independently each time that they occur, hydrogen or alkyl,
R25 is selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, the aryl or heteroaryl nucleus of which is optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl,
R26 and R27 are independently alkyl,
and R20 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylthio,
when X is —(CH2)q—NH— or when B—N(W)—X—Y is
then Y exclusively is —SO2—R30 wherein R30 is selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, the aryl or heteroaryl nucleus of which is optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl;
it being understood that when B—N(W)—X—Y is
then B is —(CH2)—;
or a pharmaceutically acceptable salt thereof sufficient to inhibit cdc25 phosphatases.

25 more elements

Pharmaceutical composition characterized in that it comprises, as active ingredient, one of the following compounds:

4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide;
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenyl acetate;
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide;
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide;
diethyl 4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
3,7-dihydroxy-N-[2-(4-aminophenyl)ethyl]-2-naphthamide;
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-naphthamide;
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide;
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)ethyl]-2-naphthamide;
3,7-dihydroxy-N-(2-{4-[(1-naphthylsulphonyl)amino]phenyl}ethyl)-2-naphthamide;
3,7-dihydroxy-N-{2-[4-({[2-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl]ethyl}-2-naphthamide;
N-(2-{4-[(benzylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide;
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl]ethyl}-2-naphthamide;
3,7-dihydroxy-N-[2-(4-{[(4-nitrophenyl)sulphonyl]amino}phenyl)ethyl]-2-naphthamide;
3,7-dihydroxy-N-{2-[4-({[4-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl]ethyl}-2-naphthamide;
3,7-dihydroxy-N-(2-{4-[(thien-2-ylsulphonyl)amino]phenyl}ethyl)-2-naphthamide;
3,7-dihydroxy-N-[2-(4-{[(4-methoxyphenyl)sulphonyl]amino}phenyl)ethyl]-2-naphthamide;
3,7-dihydroxy-N-[2-(4-{[(1-methyl-1H-imidazol-4-yl)sulphonyl]amino}phenyl)ethyl]-2-naphthamide;
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-naphthamide;
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthamide;
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6-diol;
3-{[4-(methylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol;
3-{[4-(butylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol;
or pharmaceutically acceptable salt of one of the latter.

28 more elements

As a new industrial product, a compound of the general formula (III)

in which
A is (A1)
in which two of R1, R2, R3, R4 and R5 are hydrogen and the other three are selected independently from the group consisting of hydrogen, a halogen, and alkyl, hydroxy, alkoxy, alkylcarbonyloxy, alkylthio or NR6R7, it being understood moreover that:
either R1 and one of R2 and R4 are selected independently from the group consisting of a hydroxy, alkylcarbonyloxy and —NR6R7,
or R2 and one of R3 and R5 are selected independently from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7,
or R4 and one of R3 and R5 are selected independently from the group consisting of a hydroxy, alkylcarbonyloxy and —NR6R7,
or also one of R1, R3 and R5 is selected from the group consisting of a hydroxy, alkylcarbonyloxy and —NR6R7, and B—N(W)—X—Y remainder is attached to A by nitrogen, R6 and R7 being, independently each time that they occur, a hydrogen or alkyl or R6 and R7 forming together with the nitrogen atom form a heterocycle with 4 to 7 members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being selected independently from the group consisting of —CR8R9—, —O—, —S—, and —NR10—, R8 and R9 independently being each time that they occur a hydrogen or alkyl, alkoxy, benzyloxycarbonylamino or dialkylamino, and R10 independently being each time that it occurs a hydrogen or alkyl,
or also A is (A2):
in which:
either R11 and one of R13, R14 and R15 are hydroxy whilst the others from R13, R14 and R15 as well as R16 are hydrogen,
or R12 and R16 are hydroxy whilst R11, R13, R14 and R15 are hydrogen;
B is —CO—, —NH—CO—(CH2)n— or —CH2)p—, n being an integer from 0 to 3 and p being an integer from 0 to 1;
W is hydrogen or alkyl;
X is —(CH2)q—, —(CH2)q—NH— or —CO—(CH2)r, q being an integer from 1 to 6 and r is an integer from 0 to 6;
or also B—N(W—X—Y is such that it represents
in which B is as defined above, t is an integer from 0 to 2, s is an integer from 0 to 1 and R17 and R18 selected independently from a hydrogen and alkyl;
and:
when X is —(CH2)q— or —CO—(CH2)r—, then Y is
in which R19 is —SO2—NR23R24, —NH—SO2—R25 or —O—P(O)(OR26)(OR27),
R23 and R24 independently being hydrogen or alkyl, or R23 and R24 being together with the nitrogen atom which carries them form a heterocycle with 5 to 7 members the additional members of which are selected independently from the group consisting of —CHR28—, —NR29—, —O— and —S—, R28 and R29 being, independently each time that they occur, a hydrogen or alkyl,
R25 being alkyl, haloalkyl or aryl, heteroaryl, aralkyl or heteroaralkyl aryl or heteroaryl nucleus of which is optionally substituted by one or more radicals selected independently from the group consisting of a halogen and alkyl, haloalkyl, hydroxy, alkoxy or nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are selected from alkyl,
R26 and R27 being selected independently from alkyl,
and R20 is hydrogen, a halogen or alkyl, or alkoxy or alkylthio;
when X is a —(CH2)q—NH— or when B—N(W)—X—Y is such that it is
then Y is exclusively —SO2—R30 in which R30 is selected from the group consisting of alkyl haloalkyl or aryl, heteroaryl, aralkyl or heteroaralkyl aryl or heteroaryl nucleus of which is optionally substituted by one or more members selected independently from the group consisting of halogen and alkyl, haloalkyl, hydroxy, alkoxy or nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are selected from alkyl radicals;
it being understood moreover that when B—N(W)—X—Y group is such that it is
then B exclusively is —CO— or —(CH2)—;
or a salt of a compound of general formula (III).

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/410,659Filed 25 Apr 2006
Priority: FR 00/0990028 Jul 2000
Published: 19 Oct 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification36 codes

C07D 295/26
With hetero atoms directly attached to ring nitrogen atoms: sulfur atoms
A61K 31/137
Having aromatic rings , e.g. ketamine, nortriptyline: arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
A61K 31/165
Amides, e.g. hydroxamic acids: having aromatic rings, e.g. colchicine, atenolol, progabide
A61K 31/18
Amides, e.g. hydroxamic acids: sulfonamides

Family

Application10/343,171Division · filed 27 Jan 2003
Application11/410,659Division · filed 25 Apr 2006
US 2004/0034103 A1Published application
US 7,196,084 B2Related patent
US 2006/0235027 A1This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A method of inhibiting cdc 25 phosphatases in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula

wherein A is
wherein two of R1, R2, R3, R4, and R5 are hydrogen and the other three are independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, alkylcarbonyloxy, alkylthio and —NR6R7, it being understood that:
either R1 and one of R2 and R4 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7,
or R2 and one of R3 and R5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7,
or R4 and one of R3 and R5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7,
or also one of R1, R3 and R5 is selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR6R7, and B—N(W)—X—Y remainder is attached to A by nitrogen,
R6 and R7 are independently each time that they occur a hydrogen or alkyl or R6 and R7 together with the nitrogen atom form a heterocycle of 4 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR8R9—, —O—, —S— and —NR10—,
R8 and R9 independently are each time that they occur selected from the group consisting of hydrogen, alkyl, alkoxy, benzyloxycarbonylamino and dialkylamino, and R10 independently is each time that it occurs hydrogen or alkyl,
wherein either R11 and one of R13, R14 and R15 are hydroxy while R13, R14 and R15 as well as R16 are hydrogen,
or R12 and R16 are hydroxy while R11, R13, R14 and R15 are hydrogen;
B is —(CH2)p— and p is an integer from 0 to 1;
W is hydrogen or alkyl;
X is selected from the group consisting of —(CH2)q—, —(CH2)q—NH and —CO—(CH2)r—, q is an integer from 1 to 6 and r is an integer from 0 to 6;
or B—N(W)—X—Y is
wherein B is as defined above, t is an integer from 0 to 2, s is an integer from 0 to 1 and R17 and R18 are independently hydrogen or alkyl;
and:
when X is —(CH2)q— or —CO—(CH2)r—, then Y
is
wherein R19 is selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkylthio, —NR21R22, —SO2—NR22R24, —NH—SO2—R25 and —O—P(O)(OR26)(OR)27, R21 and R22 independently are hydrogen or alkyl,
R23 and R24 independently are hydrogen or alkyl, or R23 and R24 representing together with the nitrogen atom which carries them a heterocycle with 5 to 7 ring members, the additional members are independently selected from the group consisting of —CHR28—, —NR29—, —O— and —S—, R28— and R29 are independently each time that they occur, hydrogen or alkyl,
R25 is selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, the aryl or heteroaryl nucleus of which is optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl,
R26 and R27 are independently alkyl,
and R20 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylthio,
when X is —(CH2)q—NH— or when B—N(W)—X—Y is
then Y exclusively is —SO2—R30 wherein R30 is selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, the aryl or heteroaryl nucleus of which is optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxy, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl;
it being understood that when B—N(W)—X—Y is
then B is —(CH2)—;
or a pharmaceutically acceptable salt thereof sufficient to inhibit cdc25 phosphatases.

25 more elements

Facts

Application

11/410,659Filed 25 Apr 2006

Priority

FR 00/0990028 Jul 2000

Published

19 Oct 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification36 codes

C07D 295/26
With hetero atoms directly attached to ring nitrogen atoms: sulfur atoms
A61K 31/137
Having aromatic rings , e.g. ketamine, nortriptyline: arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
A61K 31/165
Amides, e.g. hydroxamic acids: having aromatic rings, e.g. colchicine, atenolol, progabide
A61K 31/18
Amides, e.g. hydroxamic acids: sulfonamides