MMP inhibitors

Details MMP inhibitors MMP inhibitors

2003-01-16

2004-08-31

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C558S081000

Reexamination Certificate

active

06784169

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a hitherto unknown class of compounds, namely substituted 1,3,2 oxazaphosphacycloalkane derivatives, which exhibit matrix metalloprotease inhibitory effects, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the manufacture of medicaments.
BACKGROUND OF THE INVENTION
The matrix metalloproteases (MMP) are a family of zinc containing enzymes capable of breaking down many protenaceous compounds in the extracellular matrix, such as collagen, gelatine, fibronectin, laminin and proteoglucan core protein.
There are at least 23 different MMPs classified according to their domain structure and substrate preferences [Lauer-Fields,
Exp.Opin.Ther.Patents
, 10, 1873-1884, 2000]. MMP may be classified into four main groups: Collagenases degrade fibrilar collagen; stromelysin degrade proteoglucans and glucoproteins; gelatinases degrade non-fibrilar and degraded collagen, i.e. gelatine; and finally the membrane bound MMPs [O'Brien,
J.Med.Chem
., 43, 156-166, 2000]. The MMPs share a common multidomain structure, but are glycosylated at different sites and to different extent. All MMPs also share a common zinc-binding motif, HisGluXaaGlyHis, and the differences comprise the presence or absence of structural domains controlling such factors as substrate specificity, inhibitor binding, matrix binding and cell-surface localisation. The nomenclature for MMP is simple as they are named MMP-n, wherein n is an integer starting from 1.
MMP plays an important physiological role in tissue remodelling in normal tissue, e.g. angiogenesis, wound healing, bone resorption, ovulation and embryonic development. In healthy tissue, the activity of MMP is carefully controlled by gene expression, by synthesis of the enzymes in a latent pro-enzyme form, and by co-expression of endogenous tissue inhibitors of MMP (TIMP). Excessive or poorly regulated MMP activity has been implicated in a host of pathological conditions, and there has thus been a large effort to design drugs with MMP inhibitor effects, which could be used to re-establish control of the MMP activity.
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and with structural similarities to the cleavage sites in the natural substrates of MMP. Other known MMP inhibitors have less peptidic structure, and may be classified as pseudopeptides or peptidomimetics, e.g. sulfonamides.
Prior art of MMP inhibitors consists of peptidic structures [WO 95/19965 and WO 95/19956]; linear and cyclic sulfonamide compounds, [WO 97/44315, WO 00/09485 and EP 0979 816] and buturic and pentanoic acid derivatives [WO 97/43237, WO 97/43239 and WO 99/61413].
SUMMARY OF THE INVENTION
It has surprisingly been found that the novel substituted oxazaphosphacycloalkane derivatives of formula I are potent matrix metalloprotease inhibitors. Accordingly, the invention relates to compounds of formula I
n is 0, 1, 2 or 3;
X represents hydroxamic acid (CONHOH), carboxylic acid, phosphonic acid, acetylthiomethyl group or a mercaptomethyl group;
R1 is
wherein E, when present, represents a bond or optionally substituted methylene or ethylene;
s and t are independently 0, 1, 2 or 3;
A and A′ independently represent a bond, or a saturated or unsaturated, optionally substituted cyclic or heterocyclic hydrocarbon di- or triradical;
Z represents a bond, O, S, C(O), C(O)NR7, NR7C(O) or NR7, wherein R7 is hydrogen, hydroxy, branched or straight, saturated or unsaturated, optionally substituted hydrocarbon radical;
R5 represents a bond, alkane or alkene diradical, one or more ether diradicals (R—O—R′) or amine diradicals (R—N—R′), wherein R and R′ independently represent alkane or alkene diradicals with a C-content from 0 to 3;
R6 represents hydrogen, hydroxy, halogen, cyano, nitro, branched or straight, saturated or unsaturated, optionally substituted hydrocarbon radical, unsaturated optionally substituted cyclic or heterocyclic hydrocarbon radical, NR8R9, C(O)NR8R9, C(O)R8, CO(O)R8, S(O)
2
R9, wherein each R8 and R9 independently represent hydrogen, halogen, a branched or straight, saturated or unsaturated, optionally substituted hydrocarbon radical;
R2, R10 and R11 independently represent hydrogen or (C
1-8
)alkyl, (C
2-6
)alkenyl, (C
3-8
)cycloalkyl, aryl(C
0-6
)alkyl or heteroaryl(C
0-6
)alkyl, all of which may optionally be substituted;
R3 and R4 independently represent hydrogen, hydroxy or alkoxy;
provided that if A, A′, Z and R5 are all bonds, and s and t are both 0 (zero), then R6 is different from hydrogen, and that at least one of R3, R4, R10 and R11 is different from hydrogen;
and a pharmaceutically acceptable salt, hydrate or solvate thereof.
The invention also relates to pharmaceutical compositions comprising compounds of formula I, to therapeutical treatments comprising administration to a patient of compounds according to formula I, and to the use of compounds according to formula I in the manufacture of medicaments.
The invention also relates to therapeutic methods involving the administration to a subject in need thereof an effective amount of a compound according to formula I.
Furthermore, the invention also provides compounds useful in the manufacture of compounds of formula I, i.e. compounds according to formula III and VII
wherein R1, R2, R3, R4, R10, R11 and n have the same meaning as indicated above, and wherein R13 represents alkyl.
DETAILED DESCRIPTION OF THE INVENTION
As used in the specification, unless specified to the contrary, the following terms have the meaning indicated:
“Alkyl” refers to a straight or branched alkyl moiety, consisting solely of carbon and hydrogen, containing no unsaturation, Alkyl preferably has 1-12 carbon atoms, such as 1-6 carbon atoms. Examples include methyl, n-propyl, isobutyl, t-butyl, hexyl and dodecyl.
“(C
2
-C
6
)alkenyl” refers to a straight or branched alkenyl moiety having 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. This term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
The term “alkoxy” is intended to indicate a radical of formula OR, wherein R is alkyl as defined above, e.g. methoxy, ethoxy, propoxy, butoxy, etc.
The term “alkoxycarbonyl” is intended to indicate a radical of formula —COOR wherein R is alkyl as defined above, e.g. methoxycarbonyl, ethoxycabonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc.
The term “saturated cyclic hydrocarbon” is intended to indicate cyclic compounds, optionally fused bicyclic rings, containing hydrogen and carbon, which are saturated, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane and decaline.
The term “unsaturated cyclic hydrocarbon” is intended to indicate cyclic compounds, optionally fused bicyclic rings, containing hydrogen and carbon, in which one or more carbon-carbon bond is unsaturated, such as cyclopentene, cyclohexene, cyclohexadiene, cycloheptene, benzene, naphtene and 1,4-dihydronaphtene, indane and indene.
The term “heterocyclic hydrocarbon” is intended to indicate saturated or unsaturated cyclic compounds of hydrogen, carbon, and one or more heteroatoms selected from O, S, N and P, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrrolidine, pyridine, pyrimidine, tetrahydrotiophene, tetrahydrofuran, piperidine, piperazine, phosphalane, phosphorinane and phosporepane.
“Aryl” refers to phenyl or naphtyl.
“Cycloalkyl” means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclopentyl, cyclohexyl, and cyclooctyl.
“Heteroaryl” refers to furanyl, pyridyl, indolyl, thienyl or imidazolyl.
The term halogen refers to members of the seventh main group in the periodic table, i.e. fluorine, chlorine, bromine and iodine.
Unless otherwise specified in the context in which it occurs, the term “substituted” as applied to any moiety herein means substituted with up to f

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