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1. WO1995032944 - SUCCINYL HYDROXAMIC ACID, N-FORMYL-N-HYDROXY AMINO CARBOXYLIC ACID AND SUCCINIC ACID AMIDE DERIVATIVES AS METALLOPROTEASE INHIBITORS

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

[ EN ]

Claims:

1. A compound of general formula


wherein

X is a -C02H, -N(OH)CHO or -CONHOH group;

Ri is hydrogen; (Cι-C6)alkyl; (C2-C6)alkenyl; phenyl; substituted phenyl; phenyl (C C6)alkyl); substituted phenyl(C C6)alkyl; heterocyclyl; substituted
heterocyclyl; heterocyclyl(CrC6)alkyl; substituted heterocyclyl(CrC6)alkyl; a group BSOpA- wherein n is 0, 1 or 2 and B is hydrogen or a (C C6) alkyl, phenyl, substituted phenyl, heterocyclyl, (C C6)acyl, phenacyl or substituted phenacyl group, and A represents (Cι-Ce)alkyl; amino; protected amino;
acylamino; OH; SH; (CrC6)alkoxy; (CrC6)alkylamino; di-(CrC6)alkylamino; (C C6)alkylthio; aryl (C C6)alkyl; amino(C C6)alkyl; hydroxy(C C6)alkyl, mercapto(CrC6)alkyl or carboxy(CrC6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl- group amidated; lower alkyl substituted by carbamoyl, mono(lower
alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy- lower alkanoylamino;

R2 represents a linear saturated or unsaturated Ci3-C24 hydrocarbon chain, which chain (i) may be interrupted by one or more non-adjacent -O- or -S- atoms or - C(=0)-, -S(→O)-, -S(=0) - or -N(Rx)- groups wherein Rx is hydrogen, methyl or ethyl, provided that the maximum length of the chain is no more than 28 C, 0, S and N atoms, and/or

(ii) may be substituted with one or more groups selected from Ci-Cβ alkyl,
OH, OMe, halogen, NH2, NHCH3, N(CH3 ) , C02H, C02CH3, COCH3, CHO, CONH2, CONHCH3, CON(CH3 )2, CH2OH, NHCOCH3, provided that the maximum length of the chain is no more than 28 C, O, S and N atoms;

R3 is the characterising side chain of a natural or non-natural α amino acid in which any functional groups may be protected, with the proviso that R3 does not represent hydrogen;

R is hydrogen, C Cβ alkyl, (CrC4)perfluoroalkyl or a group D-(C C6 alkyl) wherein D represents hydroxy, (CrC6)alkoxy, (CrCβJalkylthio, acylamino, optionally substituted phenyl or heteroaryl, NH , or mono- or di-(C C6 alkyl amino;

R5 is hydrogen or a (C CδJalkyl group;

or a salt, hydrate or solvate thereof.

2. A compound as claimed in claim 1 wherein the stereochemistry is in general as follows:
C atom carrying the R1 and X group - S,
C atom carrying the R2 group - R,
C atom carrying the R3 group - S.

3. A compound as claimed in claim 1 or claim 2 wherein X is -COOH.

4. A compound as claimed in any one of claims 1 to 3 wherein Ri is methyl, ethyl, hydroxyl, allyl, or thienylsulphanylmethyl, thienylsulphinylmethyl,
thienylsulphonylmethyl or phthaiimidomethyl.

5. A compound as claimed in any one of claims 1 to 3 wherein Ri is hydrogen.

6. A compound as claimed in any of the preceding claims wherein R is a linear saturated or unsaturated Ci3-C2 hydrocarbon chain, which chain (i) may be interrupted by one or more non-adjacent -O- or -S- atoms and/or (ii) may be optionally substituted, and which has a chain length of from 13 to 20, 13 to 18, 13 to 16, 14 to 20, 14 to 18 and 14 to 16, specifically of 13, 14, 15, 16, 17 or 18 C and optional O, S, and N atoms.

7. A compound as claimed in any of claims 1 to 5 wherein R2 is tridecyl, tetradecyl, pentadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, 13-methoxytridecyl, 3-undecoxypropyl, 4-decoxybutyl, 5-nonoxypentyl, 6-octoxyhexyl, 7-heptaoxylheptyl, or 8-hexaoxyoctyl.

8. A compound as claimed in any of claims 1 to 5 wherein R2 is hexadecyl.

9. A compound as claimed any of the preceding claims wherein R3 is

(Cι-C6)alkyl, benzyl, hydroxybenzyl, benzyloxybenzyl, (C-i-CβJalkoxybenzyl, or benzyloxy(Cι-C6)aikyl group; or

the characterising group of a natural α amino acid, in which any functional group may be protected, any amino group may be acylated and any
carboxyl group present may be amidated; or

a group -[Alk]nR6 where Alk is a (d-CβJalkyl or (C2-C6)alkenyl group optionally interrupted by one or more -0-, or -S- atoms or -N(R7)- groups [where R7 is a hydrogen atom or a (CrCβJalkyl group], n is 0 or 1 , and He is an optionally substituted cycloalkyl or cycloalkenyl group; or

a benzyl group substituted in the phenyl ring by a group of formula -OCH2CORe where Re is hydroxyl, amino, (C C6)alkoxy, phenyl(C
Cβjalkoxy, (Ci-Cβjalkylamino, di((CrC6)alkyl)amino, phenyl(d-Cβjalkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid; or

a heterocyclic((CrC6)alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (CrC6)alkoxy, cyano, (CrCβJalkanoyl, trifluoromethyl (CrCεJalkyl, hydroxy, formyl, amino, (Cι-C6)alkylamino, di-(CrC6)alkylamino, mercapto, (Ci-Cβjalkylthio, hydroxy(Cι-Ce)alkyl, mercapto(Cι-C6)alkyl or (CrC6)alkylphenylmethyl; or

a group -CRaRbRc in which:

each of Ra, R and Rc is independently hydrogen, (C-i-CεJalkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, phenyKd-CeJalkyl, (C3-C8)cycloalkyl, the foregoing being subject to the proviso that Ra, Rb and Rc are not all hydrogen; or

Rc is hydrogen, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
phenyl(C C6)alkyl, or (C3-C8)cycloalkyl, and Ra and Rb together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or Ra, Rb and Rc together with the carbon atom to which they are
attached form a tricyclic ring (for example adamantyl); or

Ra and Rb are each independently (Ci-CβJalkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, phenyl(CrC6)alkyl, or a group as defined for Rc below
other than hydrogen, or Ra and Rb together with the carbon atom to
which they are attached form a 3 to 8 membered cycloalkyl or a 3- to 8-membered heterocyclic ring, and Rc is hydrogen, -OH, -SH,
halogen, -CN, -C02H, (C C4)perfluoroalkyl, -CH2OH, -C02(Cr
C6)alkyl, -0(C C6)alkyl, -0(C2-C6)alkenyl, -S(CrC6)alkyl, -SO(Cr
C6)alkyl, -S02(CrC6) alkyl, -S(C2-C6)alkenyl, -SO(C2-C6)alkenyl, - S02(C2-C6)alkenyl or a group -Q-W wherein Q represents a bond or - 0-, -S-, -SO- or -S02- and W represents a phenyl, phenylalkyl, (C3- C8)cycloalkyl, (C3-C8)cycloalkylalkyl, (C -C8)cycloalkenyl, (C - Cβjcycloalkenylalkyl, heteroaryl or heteroarylalkyi group, which group W may optionally be substituted by one or more substituents
independently selected from, hydroxyl, halogen, -CN, -C02H, - C02(CrC6)alkyl, -CONH2, -CONH(CrC6)alkyl, -C0NH(CrC6alkyl)2> - CHO, -CH2OH, (C C4)perfiuoroalkyl, -0(C C6)alkyl, -S(C C6)alkyl, - SO(CrC6)alkyl, -S02(CrC6)alkyl, -N02, -NH2, -NH(C C6)alkyl, - N((C C6)alkyl)2, -NHCO(C C6)alkyl, <C C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, phenyl or
benzyl.

10. A compound as claimed in claim 9 wherein R3 is benzyl, iso-butyl, 1 -benzylthio-1 -methylethyl, or 1 -methylthio-1 -methylethyl, or 1 -mercapto-1 -methylethyl.

11. A compound as claimed in claim 9 wherein R3 is t-butyl.

12. A compound as claimed any of the preceding claims wherein R is C Cβ alkyl, (d-C )perfluoroalkyl or a group D-(CrC-6 alkyl) wherein D represents hydroxy, (CrC6)alkoxy, (C C6)alkylthio, acylamino, optionally substituted phenyl or heteroaryl.

13. A compound as claimed in claim 12 wherein R is ethyl, n- and iso-propyl, n- , sec--and tert-butyl, hydroxyethyl, hydroxypropyl, 2,2-dimethyl-3-hydroxypropyl, hydroxybutyl, methoxyethyl, ethoxyethyl, methoxypropyl, 2,2-dimethyl-3- methoxypropyl, 2,2-dimethyl-3-ethoxypropyl, 2-ethylthioethyl, 2-acetoxyethyl, N-acetyl-aminoethyl, 3-(2-pyrrolidone)propyl, optionally substituted phenylethyl, phenylpropyl, phenylbutyl or phenylpentyl.

14. A compound as claimed in claim 12 wherein R4 is hydrogen, or methyl.

15. A compound as claimed any of the preceding claims wherein R5 is hydrogen or methyl.

16. A compound selected from the group consisting of

3R-(1 S-Methylcarbamoyl-2-phenyl-ethylcarbamoyl)nonadecanoic acid
(dicyclohexylamine salt)

3R-(1 S-Methylcarbamoyl-2-phenyl-ethylcarbamoyl)-nonadecanoic acid (free acid)

3R-(2,2-Dimethyl-1 S-methylcarbamoyl-propylcarbamoyl)-nonadecanoic acid

3R or S-(2-Mercapto-2-methyl-1 S-methylcarbamoyl-propylcarbamoyl)-nonadecanoic acid

3-(1 S-fe -Butylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-nonadecanoic acid (dicyclohexylamine salt) 3-(2,2-Dimethyl-1 S-isopropylcarbamoyl-propylcarbamoyl)-nonadecanoic acid (dicyclohexylamine salt)

3-(1 S-Dimethylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-nonadecanoic acid (potassium salt)

3-(2-Methyl-1 S-methylcarbamoyl-2-methylsulfanyl-propylcarbamoyl)-nonadecanoic acid

3-(2-Benzylsulfanyl-2-methyl-1 S-methylcarbamoyl-propylcarbamoyl)-nonadecanoic acid

3-(1 S-Methyicarbamoyl-2-phenyl-ethylcarbamoyl)-heptadecanoic acid

3-(1 S-Methylcarbamoyl-2-phenyl-ethylcarbamoyl)-octadecanoic acid

3-(1 S-Carbamoyl-2,2-dimethyl-propylcarbamoyl)-nonadecanoic acid

3-(2,2-Dimethyl-1 S-methylcarbamoyl-propylcarbamoyI)-heptadecanoic acid

3-(2,2-Dimethyl-1 S-methylcarbamoyl-propylcarbamoyl)-octadecanoic acid

2R-Hexadecyl-N4-hydroxy-Ni-(1 S-methylcarbamoyl-2-phenylethyl)-succinamide

Ni-(2,2-Dimethyl-1 S-methylcarbamoyi-propyl)-2R-hexadecyl-N4-hydroxy-succinamide

N -(1 S-fer.-Butylcarbamoyl-2,2-dimethyl-propyl)-2-hexadecyl-N4-hydroxy-succinamide

2-Hexadecyl-N4-hydroxy-Ni(1 S-isopropylcarbamoyl-2,2-dimethyl-propyl)-succinamide Ni-(1 S-Dimethylcarbamoyl-2,2-dimethyl-propyl)-2-hexadecyl-N4-hydroxy-succinamide

N4-Hydroxy-Ni-(1 S-methylcarbamoyl-2-phenyl-ethyl)-2-tetradecyl-succinamide

Ni-(1 S-Carbamoyl-2,2-dimethyl-propyl)-2-hexadecyl-N4-hydroxy-succinamide

2R or S-[(Formyl-hydroxy-amino)-methyl]-octadecanoic acid (2,2-dimethyl-1 S-methylcarbamoyl-propyl)-amide

and salts, solvates or hydrates thereof.

17. A process for the preparation of a compound as claimed in claim 1 in which X is a hydroxamic acid group (-CONHOH), which process comprises:

(a) causing an acid of general formula (II)


or an activated derivative thereof to react with hydroxylamine, O-protected hydroxylamine, or an N,0-diprotected hydroxylamine, or a salt thereof, R-| , R2. R3, R4. and R5 being as defined in general formula (I) except that any substituents in R1 f R2, R3, R4, and R5 which are potentially reactive with
hydroxylamine, O-protected hydroxylamine, the N,0-diprotected
hydroxylamine or their salts may themselves be protected from such
reaction, then removing any protecting groups from the resultant hydroxamic acid moiety and from any protected substituents in R-i , R2, R3, R4, and R5; or (b) deprotecting a diprotected hydroxamic acid derivative of formula (lib)


in which R1 f R2, R3, R4, and R5 are as defined in general formula (I), R14 is an amino protecting group and R15 is a hydroxyl protecting group.

18. A process as claimed in claim 17 wherein in step (a) an O-protected hydroxylamine is used which is O-benzylhydroxylamine, 0-4-methoxybenzylhydroxylamine, O-trimethylsilylhydroxylamine, or O-tert-butoxycarbonylhydroxylamine, or an 0,N-diprotected hydroxylamine is used which is N,0-bis(benzyl)hydroxylamine, N,0-bis(4-methoxybenzyl)hydroxylamine, N-tert-butoxycarbonyl-O-tert-butyldimethylsilylhydroxylamine, N-tert-butoxycarbonyl-O-tetrahydropyranylhydroxylamine, or N,0-bis(tert-butoxycarbonyl)hydroxylamine, or in step (b) the protecting groups R14 and R15 are selected from benzyl and substituted benzyl (eg 4-methoxybenzyl).

19. A process as claimed in claim 17 wherein in step (a) (in the special case where Ri in compound (I) is hydroxy) the hydroxy group Ri and the adjacent carboxyl group are simultaneously protected as a dioxalone of formula (lla):


wherein the groups R12 and R13 are derived from a dioxalone forming reagent, and the dioxalone ring being is opened by the reaction with hydroxylamine to give the required hydroxamic acid derivative of formula (I).

20. A process for the preparation of a compound as claimed in claim 1 in which X is a carboxylic acid group (-COOH) which process comprises coupling an acid of formula (III) or an activated derivative thereof with an amine of formula (IV)


wherein H-\ R2, R3, R4, and R5 are as defined in general formula (I) except that any substituents in R-i , R2, R3, R4, and R5 which are potentially reactive in the coupling reaction may themselves be protected from such reaction, and Rn represents a hydroxy protecting group, and subsequently removing the protecting group Rn and any protecting groups from Ri R2, R3, R4, and R5.

21. A process as claimed in claim 20 wherein (in the special case where Ri in compound (I) is hydroxy) compound (III) has the formula (V):


wherein R2, R3, R . and R5 are as defined in general formula (I) and the groups R12 and R13 are derived from a dioxalone forming reagent.

22. A process as claimed in claim 19 or claim 21 wherein R12 and R13 are hydrogen, alkyl, phenyl or substituted phenyl.

23. A process for the preparation of a compound as claimed in claim 1 in which X is an N-formyl-N-hydroxyamino (-N(OH)CHO) group, which process comprises deprotecting an N-protected N-formyl-N-hydroxyamino compound of formula (lie):


in which R1 ( R2, R3, R4, and R5 are as defined in general formula (I) and R 6 is a group convertible to a hydroxy group by hydrogenolysis or hydrolysis.

24. A method of management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs in mammals including humans, which method comprises administering to the mammal an effective amount of a compound as claimed in any one of claims 1 to 16.

25. A compound as claimed in any one of claims 1 to 16 for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs.

26. A compound as claimed in any one of claims 1 to 16 for use in human or veterinary medicine in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs.

27. The use of a compound as claimed in any one of claims 1 to 16 in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs.

28. A method as claimed in claim 24, a compound for use as claimed in claim 25 or claim 26, or the use as claimed in claim 27, wherein the diseases or condition referred to is rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration or tumour invasion by secondary metastases.

29 A pharmaceutical or veterinary composition comprising a compound as claimed in any one of claims 1 to 16 together with a pharmaceutically or veterinarily acceptable excipient or carrier.