Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines

1. A compound having the general formula (I):

a pharmaceutically acceptable salt thereof or a tautomeric form thereof,

wherein

A represents a cyclic or heterocyclic radical chosen from

said cyclic or heterocyclic radical may be substituted with substituents chosen from halogen selected from F, I, C or Br; (C 1 -C 10 ) alkyl; OR with R representing H, (C 1 -C 10 ) alkyl, CF 3 ; CONHR′ with R′ representing H, (C 1 -C 6 )alkyl-NH 2 , a divalent hydrocarbon radical (—CH 2 —) linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 —), cyclobutyl (C 4 H 7 —), cyclopentyl (C 5 H 9 —), cyclohexyl (C 6 H 11 —), morpholinyl

piperazinyl, piperazinyl salt

phenyl (C 6 H 5 —), benzyl (C 6 H 5 CH—), phenetyl (C 6 H 5 CH 2 CH 2 —), tolyl (C 6 H 4 CH 3 —), xylyl (C 6 H 3 (CH 3 ) 2 —), benzylidene (C 6 H 5 CH═CH—), benzoyl (C 6 H 5 CO), biphenyl (or diphenyl) (C 12 H 9 —), naphtyl (C 10 H 7 —) or tetrazolyl

COOR a , with R a representing H, (C 1 -C 10 )alkyl; NR a R′ a with R a and R′ a representing independently H, (C 1 -C 10 )alkyl; CN; a divalent hydrocarbon radical (—CH 2 —) linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 —), cyclobutyl (C 4 H 7 —), cyclopentyl (C 5 H 9 —), cyclohexyl (C 6 H 11 —), morpholinyl

piperazinyl, piperazinyl salt

phenyl (C 6 H 5 —), benzyl (C 6 H 5 CH—), phenetyl (C 6 H 5 CH 2 CH 2 —), tolyl (C 6 H 4 CH 3 —), xylyl (C 6 H 3 (CH 3 ) 2 —), benzylidene (C 6 H 5 CH═CH—), benzoyl (C 6 H 5 CO), biphenyl (or diphenyl) (C 12 H 9 —), naphtyl (C 10 H 7 —) or tetrazolyl

and n being an integer from 0 to 5;

Y represents H; (C 1 -C 10 )alkyl; (CO)(C 1 -C 10 )alkyl; aryl chosen from phenyl, benzyl, phenetyl, tolyl, xylyl, benzylidene or benzoyl;

X represents O, NH or CO;

when X represents O or NH,

then B 1 and B 2 are each independently H; (C 1 -C 10 )alkyl; CO(C 1 -C 10 )alkyl; CF 3 ; (CH 2 ) m NR a R b ; P(O)(OH) 2 ; (CH 2 ) p OCO(C 1 -C 10 )alkyl; CO(CH 2 ) p NR a R b ; COCH[(CH 2 ) n OH][NR a R b ]; COCH[(CH 2 ) n NR a R b ][NR a R b ]; COCH[(CH 2 ) n NR a R b ][NHCOR a ]; COCH[(C 1 -C 10 )alkyl][NR a R b ]; COCH(R d )NH(R e ); a divalent hydrocarbon radical (—CH—) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, morpholinyl salt, piperazinyl, piperazinyl salt, phenyl, benzyl, phenetyl, tolyl, xylyl, benzylidene, benzoyl, biphenyl, naphtyl or tetrazolyl; sulfonate; carboxylate; one or more amino-acids, selected from Lysine or Serine;

with m being an integer from 2 to 5, p being an integer from 1 to 5, n being an integer from 0 to 5, R a and R b being each independently H, (C 1 -C 10 )alkyl and R d and R e being each independently H, (C 1 -C 10 )alkyl, (CH 2 ) n NR a R b , COCH 3 ,

when at least one X represents CO,

then B 1 and/or B 2 which is linked to said CO represents, independently, (C 1 -C 10 ) alkyl; OR c ; C 6 H 5 ;

(PO)(OH) 2 ; a (CH 2 ) n group linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, morpholinyl salt, piperazinyl, piperazinyl salt, phenyl, benzyl, phenetyl, tolyl, xylyl, benzylidene, benzoyl, biphenyl, naphtyl, tetrazolyl, thiophen, pyrrol, pyrazol, oxazol, thiazol, oxadiazol, thiadiazol, pyrimidine, pyrazine, pyridazine;

with R c being H, (C 1 -C 10 ) alkyl, aryl chosen from phenyl, benzyl, phenetyl, tolyl, xylyl, benzylidene or benzoyl, and n being as defined previously,

B 3 , B 4 , B 5 are each independently H; halogen chosen from F, I, C or Br; (C 1 -C 10 ) alkyl; OR; CONHR′; COOR a ; CN; a divalent hydrocarbon radical (—CH—) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 —), cyclobutyl (C 4 H 7 —), cyclopentyl (C 5 H 9 —), cyclohexyl (C 6 H 11 —), morpholinyl

piperazinyl, piperazinyl salt

phenyl (C 6 H 5 —), benzyl (C 6 H 5 CH 2 —), phenetyl (C 6 H 5 CH 2 CH 2 —), tolyl (C 6 H 4 CH 3 —), xylyl (C 6 H 3 (CH 3 ) 2 —), benzylidene (C 6 H 5 CH═CH—), benzoyl (C 6 H 5 CO), biphenyl (or diphenyl) (C 12 H 9 —), naphtyl (C 10 H 7 —) or tetrazolyl

with R representing H, (C 1 -C 10 ) alkyl, CF 3 ; R′ representing H, (C 1 -C 6 )alkyl-NH 2 , a divalent hydrocarbon radical (—CH 2 —) linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 —), cyclobutyl (C 4 H 7 —), cyclopentyl (C 5 H 9 —), cyclohexyl (C 6 H 11 —), morpholinyl

piperazinyl, piperazinyl salt

phenyl (C 6 H 5 —), benzyl (C 6 H 5 CH—), phenetyl (C 6 H 5 CH 2 CH—), tolyl (C 6 H 4 CH 3 —), xylyl (C 6 H 3 (CH 3 ) 2 —), benzylidene (C 6 H 5 CH═CH—), benzoyl (C 6 H 5 CO), biphenyl (or diphenyl) (C 12 H 9 —), naphtyl (C 10 H 7 —) or tetrazolyl

R a and n being as defined previously,

with the proviso that when X represents O, then B 1 and B 2 do not represent at the same time a (C 1 -C 10 ) alkyl,

and with the proviso that compound (I) is not the 4-(1,2-dihydro-6-(4-hydroxy-3-methoxyphenyl)-2-oxopyrimidin-4-yl)-2-methylbenzoic acid.

2. The compound according to claim 1 , wherein A is a phenyl group having the following formula:

wherein

A 1 , A 2 , A 3 , A 4 , A 5 are each independently H; halogen chosen from F, I, C or Br;

(C 1 -C 10 ) alkyl; OR with R representing H, (C 1 -C 10 ) alkyl, CF 3 ; CONHR′ with R′═H, (C 1 -C 6 )alkyl-NH 2 , a divalent hydrocarbon radical (—CH 2 —) linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 —), cyclobutyl (C 4 H 7 —), cyclopentyl (C 5 H 9 —), cyclohexyl (C 6 H 11 —), morpholinyl

piperazinyl, piperazinyl salt

phenyl (C 6 H 5 —), benzyl (C 6 H 5 CH—), phenetyl (C 6 H 5 CH 2 CH—), tolyl (C 6 H 4 CH 3 —), xylyl (C 6 H 3 (CH 3 ) 2 —), benzylidene (C 6 H 5 CH═CH—), benzoyl (C 6 H 5 CO), biphenyl (or diphenyl) (C 12 H 9 —), naphtyl (C 10 H 7 —) or tetrazolyl

COOR a with R a representing H, (C 1 -C 10 )alkyl; NR a R′ a with R a and R′ a representing independently H, (C 1 -C 10 )alkyl; CN; a divalent hydrocarbon radical (—CH 2 —) linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from cyclopropyl (C 3 H 5 —), cyclobutyl (C 4 H 7 —), cyclopentyl (C 5 H 9 —), cyclohexyl (C 6 H 11 —), morpholinyl

piperazinyl, piperazinyl salt

phenyl (C 6 H 5 —), benzyl (C 6 H 5 CH—), phenetyl (C 6 H 5 CH 2 CH 2 —), tolyl (C 6 H 4 CH 3 —), xylyl (C 6 H 3 (CH 3 ) 2 —), benzylidene (C 6 H 5 CH═CH—), benzoyl (C 6 H 5 CO), biphenyl (or diphenyl) (C 12 H 9 —), naphtyl (C 10 H 7 —) or tetrazolyl

and n being an integer from 0 to 5.

3. The compound of formula (I) according to claim 2 , wherein:

A 1 , A 2 , A 4 , B 4 , B 5 and Y represent H.

4. The compound of formula (I) according to claim 3 , wherein:

A 3 , A 5 and B 3 are each independently H; a halogen chosen from F, I or Cl; an alkyl radical chosen from methyl, ethyl or isopropyl; an OR group chosen from OH, OCH 3 , OC 2 H 5 or OCF 3 ; COOH; CN; a cyclic or heterocyclic compound chosen from cyclohexyl, morpholinyl, piperazinyl, piperazinyl salt or tetrazolyl;

when X represents O or NH,

then B 1 and B 2 are each independently H; methyl, ethyl; COCH 3 ; COCH(CH 3 ) 2 ; CF 3 ; CH 2 —CH 2 —NH 2 , CH 2 —CH 2 —NH 3 + Cl − ; P(O)(OH) 2 , P(O)(ONa) 2 ; CH 2 OCOCH 3 ; COCH[(CH 2 )OH][NH 3 + Cl − ]; COCH[(CH 2 ) 4 NH 3 + Cl − ][NH 3 + Cl − ]; SO 3 —Na + ; COCH[(CH 2 ) 4 NH 3 + Cl − ][NHCOCH 3 ]; COCH[(CH(CH 3 ) 2 ][NH 3 + Cl − ]; a hydrocarbon radical

(—CH 2 —) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from

n being as defined previously,

when at least one X represents CO,

then B 1 and/or B 2 which is linked to said CO represents, independently, methyl, ethyl; OH, OCH 3 , OC 6 H 5 ; C 6 H 5 ; (PO)(OH) 2 ; a hydrocarbon radical (—CH 2 —) n linked covalently to a cyclic or heterocyclic compound, saturated or unsaturated, chosen from

n being as defined previously.

5. The compound according to claim 1 , wherein X represents O, B 1 represents a (C 1 -C 10 ) alkyl and B 2 represents H.

6. The compound according to claim 4 , which is selected from the group comprising compounds of formula (I) wherein:

A 1 =A 2 =A 4 =B 4 ═B 5 ═Y═H, and

X═O, A 5 =B 3 ═H, A 3 =Cl, B 1 ═CH 3 , B 2 ═H (1),

X═O, A 5 =B 3 ═H, A 3 =OCH 3 , B 1 ═CH 3 , B 2 ═H (2),

X═O, A 5 =B 3 ═H, A 3 =OH, B 1 ═CH 3 , B 2 ═H (3),

X═O, A 5 =B 3 ═H, A 3 =CH(CH 3 ) 2 , B 1 ═CH 3 , B 2 ═H (4),

X═O, A 5 =B 3 ═H, A 3 =F, B 1 ═CH 3 , B 2 ═H (5),

X═O, A 5 =B 3 ═H, A 3 =I, B 1 ═CH 3 , B 2 ═H (6),

X═O, A 5 =Cl, A 3 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (7),

X═O, A 5 =A 3 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (8),

X═O, A 5 =A 3 =OCH 3 , B 3 ═H, B 1 ═CH 3 , B 2 ═H (11),

X═O, A 3 =OCF 3 , A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (12),

X═O, A 3 =OCH 2 CH 3 , A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (13),

X═O, A 5 =OCH 3 , A 3 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (14),

X═O, A 3 =CN, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (15),

X═O, A 3 =cyclohexyl, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (16),

X═O, A 3 =Cl, A 5 =H, B 3 ═OCH 3 , B 1 ═CH 3 , B 2 ═H (17),

X═O, A 3 =tetrazolyl, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (18),

X═O, A 3 =morpholinyl, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (19),

X═O, A 3 =piperazinyl salt

A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (21),

X═O, A 3 =COOH, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (22),

X═O, A 3 =methyl-piperazinyl

A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═H (24),

and their mixtures.

7. The compound of formula (I) according to claim 4 , wherein:

A 1 =A 2 =A 5 =B 3 ═B 4 ═B 5 ═Y═H, and

X═O, A 4 =CH 3 , A 3 =OH, B 1 ═CH 3 , B 2 ═H (59).

8. The compound according to claim 4 , which is selected from the group comprising compounds of formula (I) wherein:

A 1 =A 2 =A 4 =B 4 ═B 5 ═Y═H, and

X═O, A 5 =B 3 ═H, A 3 =Cl, B 1 ═CF 3 , B 2 ═H (9),

X═O, A 5 =B 3 ═H, A 3 =Cl, B 1 ═H, B 2 ═CH 3 (10),

X═O, A 3 =Cl, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═PO(ONa) 2 (20),

X═O, A 3 =C, A 5 =B 3 ═H, B 1 ═CH 2 CH 2 NH 3 + Cl − , B 2 ═H (23),

X═O, A 3 =Cl, A 5 =B 3 ═H, B 1

B 2 ═H (25),

X linked to B 1 represents O and X linked to B 2 represents NH, A 3 =Cl, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═COCH 3 (26),

X linked to B 1 represents O and X linked to B 2 represents CO, A 3 =C, A 5 =B 3 ═H, B 1 ═CH 3 , B 2 ═OH (27),

and their mixtures.

9. The compound of general formula (I) according to claim 6 , which is more particularly selected from the group comprising compounds (1), (2), (3), (5), (7), (8), (9) and their mixture.

10. The compound of general formula (I) according to claim 1 , which is selected from the group comprising compounds of formula (I) wherein:

X═O, B 3 ═B 4 ═B 5 ═Y═H, B 1 ═CH 3 , B 2 ═H, and

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

A represents

and their mixtures.

11. A method of inhibiting the biological activity of CXCL12 in a subject comprising administering to the subject a compound of general formula (I) according to claim 1 .

12. The method according to claim 11 wherein the method is for the prevention and/or treatment of a disease in the subject chosen from the group comprising inflammation and inflammatory diseases, immune and auto-immune diseases, pain-related diseases, genetic diseases and/or cancer.

13. The method according to claim 12 , wherein the disease is chosen in the group comprising asthma, atopic dermatitis, allergic rhinitis, atopic conjunctivitis, rhinoconjunctivitis, chronic obstructive pulmonary disease (COPD), lupus, Sjögren syndrome, hyperalgesia/pain, pulmonary hypertension (PH), obliterative bronchiolitis, chronic lung allograft diseases, rhumatoid arthritis, inflammatory bowel disease, WHIM syndrome (Warts, Hypogammaglobulinemia, Immunodeficiency and Myelokathexis syndrome), hypereosinophilic syndromes, eosinophilic bronchiolitis, Churg-Strauss syndrome, and eosinophilic granulomatosis with polyangeiitis.

14. A pharmaceutical composition comprising at least a compound of formula (I) according to claim 1 , and optionally a pharmaceutically acceptable excipient or carrier.

15. The pharmaceutical composition according to claim 14 , comprising a pharmaceutically acceptable excipient or carrier.

16. A method for the prevention and/or treatment of a disease in a subject chosen from the group comprising asthma, atopic dermatitis, allergic rhinitis, atopic conjunctivitis, rhinoconjunctivitis, chronic obstructive pulmonary disease (COPD), lupus, Sjögren syndrome, hyperalgesia/pain, pulmonary hypertension (PH), obliterative bronchiolitis, chronic lung allograft diseases, rhumatoid arthritis, inflammatory bowel disease, WHIM syndrome (Warts, Hypogammaglobulinemia, Immunodeficiency and Myelokathexis syndrome), hypereosinophilic syndromes, eosinophilic bronchiolitis, Churg-Strauss syndrome, and eosinophilic granulomatosis with polyangeiitis comprising administering the pharmaceutical composition of claim 14 to the subject.