Inhibitors of cdc25 phosphatases

1 . 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 R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen and the other three are independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, alkylcarbonyloxy, alkylthio and —NR 6 R 7 , it being understood that:

either R 1 and one of R 2 and R 4 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or R 2 and one of R 3 and R 5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or R 4 and one of R 3 and R 5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or also one of R 1 , R 3 and R 5 is selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 , and B—N(W)—X—Y remainder is attached to A by nitrogen,

R 6 and R 7 are independently each time that they occur a hydrogen or alkyl or R 6 and R 7 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 —CR 8 R 9 —, —O—, —S— and —NR 10 —,

R 8 and R 9 independently are each time that they occur selected from the group consisting of hydrogen, alkyl, alkoxy, benzyloxycarbonylamino and dialkylamino, and R 10 independently is each time that it occurs hydrogen or alkyl,

wherein either R 11 and one of R 13 , R 14 and R 15 are hydroxy while R 13 , R 14 and R 15 as well as R 16 are hydrogen,

or R 12 and R 16 are hydroxy while R 11 , R 13 , R 14 and R 15 are hydrogen;

B is —(CH 2 ) p — and p is an integer from 0 to 1;

W is hydrogen or alkyl;

X is selected from the group consisting of —(CH 2 ) q —, —(CH 2 ) q —NH and —CO—(CH 2 ) 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 R 17 and R 18 are independently hydrogen or alkyl; and:

when X is —(CH 2 ) q — or —CO—(CH 2 ) r —, then Y

is

wherein R 19 is selected from the group consisting of hydrogen, halogen, nitro, alkyl, alkylthio, —NR 21 R 22 , —SO 2 —NR 22 R 24 , —NH—SO 2 —R 25 and —O—P(O)(OR 26 )(OR) 27 , R 21 and R 22 independently are hydrogen or alkyl,

R 23 and R 24 independently are hydrogen or alkyl, or R 23 and R 24 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 —CHR 28 —, —NR 29 —, —O— and —S—, R 28 — and R 29 are independently each time that they occur, hydrogen or alkyl,

R 25 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,

R 26 and R 27 are independently alkyl,

and R 20 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylthio,

when X is —(CH 2 ) q —NH— or when B—N(W)—X—Y is

then Y exclusively is —SO 2 —R 30 wherein R 30 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 —(CH 2 )—;

or a pharmaceutically acceptable salt thereof sufficient to inhibit cdc25 phosphatases.

2 . The method of claim 1 , wherein:

A is

wherein two of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and the other three are independently selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonyloxy, hydroxy, alkoxy and NR 6 R 7 , it being understood that:

either R 1 and one of R 2 and R 4 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or R 2 and one of R 3 and R 5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or R 4 and one of R 3 and R 5 are independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or one of R 1 , R 3 and R 5 is independently selected from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 , and B—N(W)—X—Y remainder is attached to A by nitrogen,

R 6 and R 7 are independently each time that they occur, hydrogen or alkyl or R 6 and R 7 together with the nitrogen atom form a heterocycle with 5 to 7 ring members comprising 1 to 2 heteroatoms, the members necessary to complete the heterocycle being independently selected from the group consisting of —CR 8 R 9 —, —O—, —S—, and —NR 10 —, R 8 and R 9 independently each time that they occur hydrogen or alkyl or alkoxy, and R 10 independently is each time that it occurs hydrogen or alkyl,

or A is

wherein

either R 11 and one of R 13 , R 14 and R 15 is hydroxy while the other R 13 , R 14 and R 15 as well as R 16 are hydrogen,

or R 12 and R 16 are hydroxy while R 11 , R 13 , R 14 and R 15 are hydrogen;

B is —(CH 2 ) p , p is an integer from 0 to 1;

W is hydrogen or alkyl;

X is selected from the group consisting of —(CH 2 ) q —, —(CH 2 ) q —NH— and —CO—(CH 2 ) r , q is an integer from 1 to 4 and r is an integer from 0 to 5;

or B—N(W—X—Y is

wherein B is as defined in claim 1 , t is an integer from 0 to 2, s is an integer from 0 to 1, R 17 and R 18 are independently hydrogen or alkyl;

when X is —(CH 2 ) q — or —CO—(CH 2 ) r —, Y is

wherein R 19 is hydrogen, halogen, nitro, alkyl, alkylthio, —NR 21 R 22 , —SO 2 —NR 23 R 24 , —NH—SO 2 —R 25 and —O—P(O)(OR 26 )(OR 27 ),

R 21 and R 22 independently are hydrogen or alkyl,

R 23 and R 24 independently are hydrogen or alkyl, or R 23 and R 24 together with the nitrogen atom which carries them form a heterocycle with 5 to 6 ring members, the additional members of which are independently selected from the group consisting of —CHR 28 —, NR 29 —, —O— and

—S—, R 28 and R 29 are independently each time that they occur, hydrogen or alkyl,

R 25 is alkyl or aryl optionally substituted by at least one member selected from the groups consisting of halogen, alkyl, haloalkyl, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl,

R 26 and R 27 are independently alkyl,

and R 20 is hydrogen or alkyl or alkoxy,

when X is a —(CH 2 ) q —NH— or B—N(W)—X—Y is

then Y is —SO 2 —R 30 , R 30 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, alkoxy and nitro, except for the optional nitrogen atoms of the heteroaryl nucleus for which the optional substituents are alkyl.

3 . The method of claim 1 , wherein the compound is selected from the group consisting of:

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-(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;

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 wherein Y is not (T) and the condition to be treated is selected from the group consisting of prostate cancer, pancreatic cancer, breast cancer, lymphoma and head and neck cancer.

5 . The method of claim 1 wherein Y is (T), and the condition being treated is spontaneous alopecia, alopecia induced by exogenous products, or radiation-induced alopecia.

6 - 8 . (canceled)

9 . 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.

10 . Pharmaceutical composition comprising, as active ingredient, 5-(4-{[1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino)phenyl]pentanamide or one of its pharmaceutically acceptable salts.

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

in which

A is (A1)

in which two of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and the other three are selected independently from the group consisting of hydrogen, a halogen, and alkyl, hydroxy, alkoxy, alkylcarbonyloxy, alkylthio or NR 6 R 7 , it being understood moreover that:

either R 1 and one of R 2 and R 4 are selected independently from the group consisting of a hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or R 2 and one of R 3 and R 5 are selected independently from the group consisting of hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or R 4 and one of R 3 and R 5 are selected independently from the group consisting of a hydroxy, alkylcarbonyloxy and —NR 6 R 7 ,

or also one of R 1 , R 3 and R 5 is selected from the group consisting of a hydroxy, alkylcarbonyloxy and —NR 6 R 7 , and B—N(W)—X—Y remainder is attached to A by nitrogen, R 6 and R 7 being, independently each time that they occur, a hydrogen or alkyl or R 6 and R 7 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 —CR 8 R 9 —, —O—, —S—, and —NR 10 —, R 8 and R 9 independently being each time that they occur a hydrogen or alkyl, alkoxy, benzyloxycarbonylamino or dialkylamino, and R 10 independently being each time that it occurs a hydrogen or alkyl,

or also A is (A2):

in which:

either R 11 and one of R 13 , R 14 and R 15 are hydroxy whilst the others from R 13 , R 14 and R 15 as well as R 16 are hydrogen,

or R 12 and R 16 are hydroxy whilst R 11 , R 13 , R 14 and R 15 are hydrogen;

B is —CO—, —NH—CO—(CH 2 ) n — or —CH 2 ) 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 —(CH 2 ) q —, —(CH 2 ) q —NH— or —CO—(CH 2 ) 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 R 17 and R 18 selected independently from a hydrogen and alkyl; and:

when X is —(CH 2 ) q — or —CO—(CH 2 ) r —, then Y is

in which R 19 is —SO 2 —NR 23 R 24 , —NH—SO 2 —R 25 or —O—P(O)(OR 26 )(OR 27 ),

R 23 and R 24 independently being hydrogen or alkyl, or R 23 and R 24 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 —CHR 28 —, —NR 29 —, —O— and —S—, R 28 and R 29 being, independently each time that they occur, a hydrogen or alkyl,

R 25 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,

R 26 and R 27 being selected independently from alkyl,

and R 20 is hydrogen, a halogen or alkyl, or alkoxy or alkylthio;

when X is a —(CH 2 ) q —NH— or when B—N(W)—X—Y is such that it is

then Y is exclusively —SO 2 —R 30 in which R 30 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 —(CH 2 )—;

or a salt of a compound of general formula (III).

12 . (canceled)

13 . As a new industrial product, a compound chosen from the following compounds of general formula (I) of the claim:

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;

and the salts of the latter.

14 - 17 . (canceled)