Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-11
2002-08-20
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S438000, C514S465000, C514S643000, C514S657000, C546S334000, C549S078000, C549S434000, C564S305000, C564S315000
Reexamination Certificate
active
06436973
ABSTRACT:
The invention relates to compounds as defined hereinafter, which constitute a class of medicaments having mainly an anti-inflammatory activity and/or acting by inhibiting LTA
4
(leukotriene A
4
) hydrolase, an enzyme which is responsible for the biosynthesis of leukotriene LTB
4
, a major proinflammatory mediator.
It also relates to such compounds useful for forming prodrugs.
It also relates to methods for preparing these compounds.
LTA
4
hydrolase (EC 3.3.2.6.) is an enzyme which is in particular present in the neutrophils and whose sequence has been recently shown (Funck et al., P.N.A.S., 1987, 89: 6677) to be related to that of a zinc metallopeptidase, aminopeptidase M (Malfroy et al., B.B.R.C., 1989, 161: 236). In agreement with the suggestion by Malfroy et al., it has been recognized that LTA
4
possesses a zinc atom which is essential for its catalytic activity, an aminopeptidase-type activity, and is sensitive to the action of certain metallopeptidase inhibitors (Heggstrom et al., B.B.R.C., 1990, 173: 431; Minami et al., B.B.R.C., 1990, 173: 620).
The inhibition of LTA
4
hydrolase is capable of preventing formation of LTB
4
, a mediator responsible for the adhesion of the neutrophils to the endothelial cells and for their chemotaxis. It appears to be involved in the aetiology or the symptomatology of a variety of conditions and inflammatory states such as rheumatoid arthritis, chronic inflammations of the intestine, multiple sclerosis, gout and psoriasis. In these processes, LTB
4
is thought to act in synergy with other metabolites of arachidonic acid which are produced by 5-lipoxygenase or cyclooxygenases whose inhibition is well known to produce anti-inflammatory effects.
Some LTA
4
hydrolase inhibiting compounds have been described, in particular in patent applications WO 94/00420, WO 96/11192, WO 96/10999 and WO 96/27585.
The objective of the present invention is to provide novel compounds capable of inhibiting LTA
4
hydrolase.
The objective of the present invention is also to provide compounds which can be used as medicaments.
To this end, the subject of the invention is compounds of formula (I) as defined below.
Its subject is also pharmaceutical compositions containing at least one such compound.
Its subject is also the use of compounds of formula (I) as defined below, as medicaments which act as inhibitor of the activity of LTA
4
hydrolase, in particular as anti-inflammatory agents.
The subject of the invention is also the use of compounds of formula (I) in the form of prodrugs.
The inventors have demonstrated that the compounds of formula (I), or their salts obtained with therapeutically acceptable inorganic or organic acids or their stereoisomers, possessed an LTA
4
hydrolase inhibiting activity.
The compounds (I) according to the invention have, moreover, good bioavailability.
The present invention describes a series of compounds capable of potently inhibiting LTA
4
hydrolase.
These compounds have, in addition, a biological activity as indicated below, which makes them therapeutically useful.
The compounds according to the invention correspond to the following formula (I):
in which:
X is chosen from the following groups:
i) —NH
2
R
1
and R
2
are independently chosen from the following groups:
i) a hydrogen atom
ii) a lower alkyl group
iii a lower alkyl group substituted with a halogen atom
iv) CF
3
v) a halogen atom;
n
1
varies from 1 to 4
n
2
varies from 0 to 10
R
3
is chosen from the following groups:
i) a hydrogen atom
Y is chosen from the following groups:
i) —O—
ii) —CH
2
—
iii ) —S—
iv) —OCH
2
—
v) —SCH
2
—
vi) —NH—
Ar is chosen from the following groups:
i) a phenyl group which is unsubstituted or which is mono- or polysubstituted with substituents chosen from halogen atoms and CF
3
, lower alkyl, lower alkoxy, NH
2
, NO
2
, CN, OH, CO
2
H, OPh, OCH
2
Ph, SMe, SEt, Ph, CH
2
Ph and NHCOR
7
groups where R
7
is a lower alkyl group,
R
4
and R
5
are independently chosen from the following groups: an unsubstituted phenyl group, a phenyl group which is mono- or polysubstituted with substituents chosen from halogen atoms and CF
3
, NO
2
, CN, OH, lower alkyl and lower alkoxy groups;
R
6
represents a lower alkyl group or a phenyl group.
The expression lower alkyl group is understood to mean an alkyl group having a linear or branched chain containing form 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl and their branched isomers.
The expression lower alkoxy group is understood to mean an alkoxy group containing a linear or branched chain having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and their branched isomers.
The halogen atoms are preferably chosen from chlorine and fluorine.
When a bond is drawn through a bond in a ring, this indicates that the bond may be linked to any available atom in this ring.
The invention also comprises the isomers of the compounds of formula (I), including the diastereoisomeric and enantiomeric forms.
The invention also extends to the therapeutically acceptable salts of these compounds, as well as to the salts of their isomers, including the diastereoisomeric and enantiomeric forms.
The expression therapeutically acceptable salts is understood to mean a salt which does not adversely affect either the chemical structure or the pharmacological properties of the compounds of the present invention. Such salts include inorganic or organic anions such as hydrochloride, hydrobromide, acetate, trifluoroacetate, maleate, fumarate, oxalate and the like, which are well known in the art. These salts are prepared in a conventional manner by neutralizing the compounds of formula (I) with the desired acid.
Among the compounds of formula (I) which is cited above, those for which X represents NH
2
and/or R
3
represents a hydrogen atom are preferred.
In this group, the compounds of formula (I) in which X is NH
2
and R
3
is a hydrogen atom are more particularly preferred.
The compounds of formula (I) for which R
1
represents a hydrogen atom also constitute a particularly preferred subgroup according to the invention.
The compounds of formula (I) with R
1
different from hydrogen represent another subgroup according to the invention.
A subfamily among the abovementioned compounds is formed by the compounds for which n
1
is equal to 1.
Another subfamily consists of the compounds for which n
1
is different from 1.
In accordance with the invention, R
2
preferably represents a hydrogen atom.
Another subgroup of compounds according to the invention is formed by the compounds where R
2
is different from a hydrogen atom. In this case, R
2
preferably represents a methyl group.
A subclass of compounds according to the invention also consists of those for which n
2
is equal to zero. Among these compounds, Y preferably represents —O—, —S—, —OCH
2
—, —SCH
2
— or —NH—.
Another subclass is formed by the compounds for which n
2
varies from 1 to 4, preferably from 2 to 4, and in a more particularly preferred manner by the compounds where n
2
is equal to 3.
Another class of compounds according to the invention is defined by those where n
2
is greater than 4.
From the point of view of the symbol Y, the compounds for which the latter represents an oxygen atom are particularly preferred according to the invention.
Other subfamilies may be defined according to whether Y represents —CH
2
—, a sulphur atom, a group —CH
2
— or —SCH
2
— or alternatively a unit —NH—.
Ar is preferably chosen from a phenyl group which is unsubstituted or substituted, more preferably monosubstituted, with one of the abovementioned substituents.
When Ar symbolizes a substituted phenyl group, the substituent(s) are preferably chosen from halogen atoms, CF
3
, lower alkyl, O(lower alkyl), NO
2
, CN, CO
2
H, OPh, OCH
2
Ph, Ph and CH
2
Ph groups, the halogen atoms as well as the lower alkyl and O(lower alkyl) groups being more particularly preferred.
The compounds for which Ar is a phenyl group which is mono- or polysubstituted with —OPh, —OCH
2
Ph, —Ph or —CH
2
Ph constitute another subfamily according
Chamard Olivier
Danvy Denis
Duhamel Lucette
Duhamel Pierre
Gros Claude
Bioprojet
Davis Zinna Northington
Larson & Taylor PLC
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