Cdc25 phosphatase inhibitors
View Patent ↗The invention concerns novel cdc25 phosphatase inhibitors, and in particular cdc25-C, which correspond to the general formula (I) wherein: A represents a carbocyclic aryl radical optionally substituted 1 to 3 times by one or more radicals independently selected among a halogen atom and an alkyl, hydroxy, alkoxy, alkylthio or NR 1 R 2 radical wherein R 1 and R 2 represent a hydrogen atom or an alkyl radical or R 1 and R 2 form together with the nitrogen atom a heterocycle of 4 to 7 members comprising 1 to 2 heteroatoms, the members required to complete the heterocycle being selected independently among the CR 3 R 4 —, —O—, —S and NR 5 -radicals, R 3 and R 4 representing independently each time they are involved a hydrogen atom or an alkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino radical, and R 5 representing independently each time it is involved a hydrogen atom or an alkyl radical, or A represents a phenyl radical substituted by a phenyl radical optionally substituted 1 to 3 times by one or more radicals selected independently among a halogen atom and an alkyl, hydroxy, alkoxy, alkylthio or NR 1 R 2 radical wherein R 1 and R 2 represent a hydrogen atom or an alkyl radical; B represents a —(CH 2 ) i —(CO)— or —NH—CO—(CH 2 ) n or —(CH 2 ) p and i and n being integers from 0 to 2 and p being an integer from 0 to 1; W represents a hydrogen atom or an alkyl radical; X represents a —(CH 2 ) q — or (CH 2 ) j —CO—(CH 2 ) r —, q being an integer from 1 to 4 and j and r being integers from 0 to 6; Y represents in particular a nitrophenyl, aminophenyl, alkylaminophenyl or dialkylaminophenyl radical or the radical (T)
1. A compound of the formula
wherein A is
two of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen 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 one of R 1 , R 3 and R 5 is 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 form a heterocycle with 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, benzyloxycarbonylalkylamino and dialkylamino, and R 10 independently is each time that it occurs hydrogen or alkyl,
A is
R 11 and one of R 13 , R 14 , and R 15 are hydroxy while the other R 13 , R 14 and R 15 as well as R 16 are hydrogen;
B is —(CH 2 ) p — and p is an integer from 0 to 1;
W is selected from the group consisting of hydrogen or alkyl;
X is selected from the group consisting of —(CH 2 ) q —, —(CH 2 ) q —NH— and —CO—(C 2 ) r — [radical], q is an integer from 1 to 6 and r is an integer from 0 to 6;
or B—N(W)—X—Y group 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 —SO 2 —,—NR 23 R 24 , —NH—SO 2 —R 25 R 24 and —O—P(O)(OR 26 )OR 27 ),
R 23 and R 24 independently are hydrogen or alkyl, or R 23 and R 24 together with the nitrogen which carries them form a heterocycle with 5 to 7 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, 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 hydrogen, halogen, alkyl, alkoxy and alkylthio;
when X is —(CH 2 )q—NH— or when B—N(W)—X—Y is
then Y is only —SO 2 —R 30 , R 30 is selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, the aryl or heteroaryl nucleus of which is optionally substituted by at least one 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
the B is —(CH 2 )—.
2. A compound of claim 1 selected from the group consisting of:
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;
and a salt thereof.
3. A pharmeceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable salt thereof.
4. A composition 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 of a phannaceutically acceptable salt of one of the latter.
5. A composition of claim 1 wherein the compound is 5-(4-{[1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino) phenyl]pentanamide or a pharmaceutically acceptable salt thereof.
6. A process for the preparation of a compound of claim 1 of the formula
wherein A, B, W, X, R 20 and R 25 have the definitions of claim 1 , comprising reacting a compound of the formula
with a compound of formula R 25 —SO 2 Cl in an aprotic solvent and in the presence of a base.
7. A process for the preparation of a compound of the formula
A, B, W, q and R 30 have the definitions of claim 1 , comprising reacting a compound of the formula
with a compound of claim 1 of the formula
R 30 —SO 2 Cl (XXV)
in an aprotic solvent and in the presence of a base.
8. A process for the preparation of a compound of claim 1 of the formula
wherein A, B, W, q and R 30 have the definitions of claim 1 , comprising reacting a compound of claim 1 having the formula
with a compound of the formula
R 30 —SO 2 Cl (XXV)
in an aprotic solvent and in the presence of a base.
9. A process for the preparation of a compound of claim 1 of the formula
wherein A, W, X, R 20 , R 26 , and R 27 have the definition of claim 1 , and B is —CO— or —CH 2 — comprising reacting an amine of the formula
and B is —CH 2 —, with an aldehyde of the formula
A—CHO (VI)
in an alcoholic solvent and in the presence of a reducing agent.