Organic compounds -- part of the class 532-570 series – Organic compounds – Hydroxamic acids – chalcogen analogs or salts thereof
Reexamination Certificate
2002-04-11
2003-08-12
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Hydroxamic acids, chalcogen analogs or salts thereof
C562S622000, C562S444000, C562S433000, C560S045000, C564S013000, C514S079000, C514S110000, C514S538000, C514S575000, C514S561000, C514S567000
Reexamination Certificate
active
06605742
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a hitherto unknown class of compounds, namely cyclo azaphospha hydrocarbons, which exhibits 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 cyclo azaphospha hydrocarbon derivatives of general formula I are potent inhibitors of MMP.
Accordingly, the present invention relates to a compound of general formula I
wherein bonds denoted a, b and c independently represents single or double bonds;
m and n are independently 0, 1, 2 or 3, provided that m and n are not both 0;
X is S or O;
R
1
is
wherein E, when present represents a bond, methylene or ethylene optionally substituted with halogen, hydroxy, cyano, nitro, C
1-4
alkyl, haloalkyl, hydroxyalkyl, alkoxy or alkylcarbonyl;
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;
Y represents a bond, O, S, C(O)NR
10
, NR
10
C(O) or NR
10
, wherein R
10
is hydrogen, hydroxy, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, nitro, cyano, hydroxyl, alkoxy, alkylcarbonyl or alkylamino;
R
8
represents a bond, hydrogen, alkanediyl or alkendiyl diradical, one or more ether diradicals (R′—O—R″) or amine diradicals (R′—N—R″), wherein R′ and R″ independently represent alkyl or alkenyl with a C-content from 0 to 3;
R
9
represents hydrogen, hydroxy, halogen, cyano, nitro, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, hydroxyl, alkoxy, alkylcarbonyl or alkylamino; NR
11
R
12
, C(O)NR
11
R
12
, C(O)R
11
R
12
, CO(O)R
11
R
12
, S(O)
2
R
11
, wherein each R
11
and R
12
independently represent hydrogen, halogen, a branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, hydroxyl, alkoxy, alkylcarbonyl or alkylamino;
R
2
represents hydroxamic acid, carboxylic acid, phosphonic acid or a mercaptomethyl group;
R
3
and R
4
each independently represent hydrogen, halogen, cyano, hydroxy, nitro, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, nitro, hydroxy; alkoxy, hydroxy, alkylcarbonyl, alkylamino; or R
3
and R
4
together with the carbon atoms to which they are attached and the connecting nitrogen atom form a heterocyclic ring; each R
5
, R
6
, and R
7
independently represents hydrogen, hydroxy, nitro, cyano, halogen, branched or straight, saturated or unsaturated hydrocarbon radical, optionally substituted with halogen, cyano, nitro, hydroxyl, alkoxy, alkylcarbonyl or alkylamino; or R
4
and R
5
, R
5
and R
6
or R
6
and R
7
, together with the carbon atom to which they are attached form a saturated or unsaturated, optionally substituted cyclic or heterocyclic ring;
and pharmaceutically acceptable salts thereof.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, together with a pharmaceutically acceptable excipient.
In still another aspect, the invention relates to a method of treating or preventing diseases or conditions involving tissue breakdown, inflammation or proliferative disorder comprising administering to a patient in need thereof an effective amount of a compound of formula I.
In a still further aspect, the invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment or profylaxis of diseases or conditions involving tissue breakdown, inflammation or proliferative disorder.
DETAILED DESCRIPTION OF THE INVENTION
The term “halogen” when used herein is intended to indicate members of the seventh main group of the periodic table, i.e. flouro, chloro, bromo and iodo.
The term “alkane” is intended to indicate straight, branched or cyclic compounds, containing carbon and hydrogen, which are saturated. The term includes the subclasses primary, secondary and tertiary alkane, such as methane, ethane, n-propane, iso-butan, tert. butan, cyclohexan, cyclopentan.
The term “alkene” is intended to indicate straight, branched or cyclic compounds, containing carbon and hydrogen, and with at least one double bond. The term includes primary secondary and tertiary alkene, such as ethene, propene, 1-butene, 2-butene, 3,3-dimethyl-1-butene, cyclopropene, cyclohexen e.
The term “alkyl” is intended to indicate a univalent radical derived from straight, branched or cyclic alkane by removing a hydrogen atom from any carbon atom. The term includes the subclasses primary, secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, isopentyl, isohexyl, cycloheptyl, cyclohexyl, cyclopentyl and cyclopropyl.
The term “haloalkyl” is intended to indicate partially or fully halogenated alkyl radicals, such as trifluoromethyl.
The term “hydroxyalkyl” is intended to indicate an alkyl substituted with one or more hydroxy groups, such as 2-hydroxyethyl, 2-hydroxypropyl and 2,4-dihydroxypentyl.
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.
Høyer Thomas
Sørensen Morten Dahl
Kumar Shailendra
LEO Pharma A/S
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