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1. WO2004006927 - SULPHONYLPIPERIDINE DERIVATIVES CONTAINING AN ALKENYL OR ALKYNLY MOIETY FOR USE AS MATRIX METALLOPROTEINASE INHIBITORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS:
What we claim is :- 1. A compound of formula (1):



formula (1)
whe rreeiinn ZZ iiss sseelleecctteedd ffrroomm --CCOONNRR1155OOHH and -N(OH)CHO;
R is hydrogen or C1- alkyl;
wherein R1 is hydrogen or a group selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyl, C5- cycloalkenyl, aryl, heteroaryl and heterocyclyl where the group is optionally substituted by one or more substituents independently selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cι-4alkyl, C2-4alkenyl, C2,4alkynyl, C3_6cycloalkyl
1*7 1*7

(optionally substituted by one or more R ), aryl (optionally substituted by one or more R ), heteroaryl (optionally substituted by one or more R17), heterocyclyl, Cι- alkoxycarbonyl, -OR5, -SR2, -SOR2, -SO2R2, -COR2, -CO2R5, -CONR5R6, -NR16COR5, -SO2NR5R6 and -NR16SO2R2;
R16 is hydrogen or C1-3alkyl;
R17 is selected from halo, C1-6alkyl, C3-6cycloalkyl and C1-6alkoxy;
R2 is group selected from C1-6alkyl, C3-6cycloalkyl, C5- cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylC1- alkyl and heteroarylC1- alkyl where the group is optionally substituted by one or more halo;
R5 is hydrogen or a group selected from C1-6alkyl, C3-6cycloalkyl, Cs- cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylC1- alkyl and heteroarylCι. alkyl where the group is optionally substituted by one or more halo;
R6 is hydrogen, Cι-6alkyl or C3-6cycloalkyl;
or R5 and R6 together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring;
wherein R8 is hydrogen or a group selected from Ci-ealkyl, C3- cycloalkyl and heterocyclyl where the group is optionally substituted by one or more substituents independently selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy and Cχ-4alkyl;

or R1 and R8 together form a carbocyclic or saturated heterocyclic 3- to 6-membered ring; wherein R and R are independently hydrogen, C1-6alkyl, C3-6cycloalkyl, C5- cycloalkenyl, heterocyclyl, aryl or heteroaryl;
wherein n is 0 or 1;
wherein m is 0 or 1 ;
wherein D is hydrogen, C1- alkyl, C3-6cycloalkyl or fluoro;
wherein X is -(CR9R10)-Q-(CRπR12)u- where u is 0 or 1;
Q is O, S, SO or SO2;
R9, R10, Ruand R12 are independently selected from hydrogen, C -4alkyl and C3-6cycloalkyl; wherein B is C2-4alkenyl or C - alkynyl, each being optionally independently substituted by a group selected from Cι-4alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl whereby the group is optionally substituted by one or more halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, -CONHR13, -CONHR13R14, -SO R13, -SO2NHR13, -SO2NR13R14, - NHSO2 R13, C1-4alkyl and C1-4alkoxy;
R13 and R14 are independently hydrogen, C1-4alkyl or C3-5cycloalkyl;
or R13 and R14 together with the nitrogen to which they are attached form a heterocyclic 4 to

7-membered ring.
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

2. A compound according to claim 1 wherein X is -(CH2)-O- or -(CH2)-O-(CH2)- .

3. A compound according to claim 1 or 2 wherein B is C2-4alkenyl or C2-4alkynyl, each being optionally independently substituted by C1-4alkyl, C3-6cycloa kyl, aryl, heteroaryl or heterocycloalkyl.

4. A compound according to any one of claims 1 to 3 wherein R1 is hydrogen, C1-6alkyl or aryl where C1-6alkyl or aryl are optionally substituted by one or more substituents independently selected from C1-4alkyl, aryl (optionally substituted by R17) and heteroaryl (optionally substituted by R17) and wherein R17 is halo or C1-4alkyl.

5. A compound according to any one of claims 1 to 4 for use as a medicament,

6. The use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament in the treatment of a disease condition mediated by one or more
metalloproteinase enzymes.

7. The use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament in the treatment of a disease condition mediated TNFα.

8. A method of treating autoimmune disease, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound according to claim 1.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4; and a pharmaceutically-acceptable diluent or carrier.

10. A process for preparing a compound according to claim 1 comprising, when Z is -N(OH)CHO, the step of:
a) converting a hydroxylamine of formula (2) into a compound of formula (1);


formula (2) formula (1)
or when Z is -CONR15OH, the step of:
b) converting an acid of formula (14) into a compound of formula (1);



formula (14) formula (1)
and thereafter if necessary:
i) converting a compound of formula (1) into another compound of formula (1);
ii) removing any protecting groups;
5 iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.

11. Ethyl 4-(pyrimidin-2-yl)butanoate.


10 12. A process comprising the reaction of a 2-halopyrimidine, 2-tosylpyrimidine, 2- pyrimidinyl triflate or 2-pyrimidinyl mesylate with 4-ethoxy-4-oxo-butylzinc bromide or 4- ethoxy-4-oxo-butylzinc iodide in the presence of a catalyst;



wherein X is halo, triflate or mesylate and Y is bromide or iodide.
15
13. A process according to claim 11 wherein the catalyst is generated from
bis(acetonitrile) palladium (II) dichloride and triphenylphosphine.

14. The use of bis(acetonitrile) palladium (H) dichloride and triphenylphosphine in a 20 Negishi coupling reaction.