Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-04-22
2003-02-11
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S075000, C514S120000, C562S008000
Reexamination Certificate
active
06518260
ABSTRACT:
Novel (&agr;-aminophosphino)peptide derivatives, process for their preparation and their therapeutic applications
The perception, transmission and regulation of nociceptive influxes come under the influence of several endogenous neurotransmitters. In 1975, Hugues et al.,
Nature,
258, 577, 1975 revealed the enkephalins, two pentapeptides originally isolated from mammalian brains, which are involved in the transmission of pain influxes. Enkephalins are associated with at least two classes of receptors: the &mgr; and &dgr; opioid sites (Pert,
Sciences,
179, 1011, 1973) whose roles and locations are different. Their antinociceptive properties have been demonstrated by Belluzi et al.,
Nature,
260, 625, 1976. However, the analgesia induced by the administration of exogenous enkephalins is very fleeting, on account of the rapid metabolization of these peptides. Enkephalin analogues made resistant to enzymatic degradation by chemical modifications have been synthesized, but their side effects are similar to those of morphine.
Enkephalins are physiologically degraded by two types of enzymatic activities which metabolize enkephalins in vivo: neutral endopeptidase (EC 3.4.24.11, also known as NEP) which cleaves the Gly
3
-Phe
4
bond, and aminopeptidase N (EC 3.4.11.2, also known as APN) which cleaves the Tyr
1
-Gly
2
bond (review in Roques et al.,
Pharmacol. Rev.,
45, 87-146, 1993).
Prodrugs which possess analgesic and antidepressant activities after intravenous or oral administration (Noble et al.,
J. Pharm. Exp. Ther.,
261, 181, 1992; Baamonde et al.,
Eur. J. Pharmacol.,
216, 157, 1992) are known, these being described in European patent EP 0,487,620 and in Fournié-Zaluski et al.,
J. Med. Chem.,
35, 2473, 1992. However, these compounds do not satisfy the concept of mixed inhibitors, on account of their structure in which an APN inhibitor and an NEP inhibitor are associated by means of a disulphide bridge. These compounds are then reduced by cerebral reductases and each act on their specific target.
According to patent application WO 95/35302 and
Bioorganic
&
Medicinal Chemistry Letters
, Vol. 6, No. 11, pp 1257-1260, 1996, certain phosphinic acid derivatives are known which have, respectively, an inhibitory activity on endothelin conversion enzyme (ECE) and a mixed inhibitory activity on angiotensin conversion enzyme (ACE) and on neutral endopeptidase (NEP). These compounds are useful in the treatment of cardiovascular diseases.
One of the objects of the invention is to provide novel compounds which behave as true mixed inhibitors of APN and of NEP, and which are capable of jointly inhibiting the two enzymatic activities responsible for the degradation of enkephalins and of manifesting their pharmacological properties after intravenous, cutaneous or oral injection.
These compounds have certain properties of morphinic substances, in particular analgesia, beneficial effects on behaviour (antidepressants, sedatives, anxiolytic agents, inhibition removers and promnesic agents), and peripheral effects (antidiarrhoeic, antitussive, hypotensive, anti-inflammatory, etc. effects). Furthermore, one advantage of these compounds is that they have none of the harmful effects of morphinic agents (tolerance, physical and psychic dependency, respiratory depression, intestinal stasis, etc.).
The present invention therefore provides an (&agr;-aminophosphino)peptide of general formula (I)
in which
R
1
and R
2
each represent a hydrogen atom or alternatively R
1
and R
2
, taken together, form an unsaturated group of formula R′ (R″)C═, in which,
R′ represents a phenyl group monosubstituted in position 2 with a hydroxyl group, or alternatively a phenyl group disubstituted, in position 2, with a hydroxyl group and, in position 4 or 5, either with a halogen atom or with a nitro group, or with a hydroxyl group, or with an alkoxy group —OR
9
,
R″ represents a phenyl group, a phenyl group substituted by 1 to 5 halogen atoms or a heterocyclic aromatic group,
hereinafter, the terms R
9
and R
10
, used for the definition of radicals, each represent an alkyl group of 1 to 6 carbon atoms,
R
3
represents
a hydrogen atom,
an alkyl group or an alkenyl group of 1 to 6 carbon atoms, it being possible for these last two groups to be substituted with:
a hydroxyl group or an alkoxy group —OR
9
,
a phenyl group or a benzyl group,
a sulphanyl group, an alkylsulphanyl group —SR
9
or an alkylsulphanyl group oxidized on the sulphur atom —S(O)R
9
,
an amino group, a group —NHR
9
or —NR
9
R
10
, optionally oxidized on the nitrogen atom, or
a guanidino group H
2
N—C(═NH)—NH—,
a cycloalkyl or cycloalkylmethyl group,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with 1 or 2 of the following substituents:
a halogen atom,
a hydroxyl group, an alkoxy group —OR
9
,
an alkylsulphanyl group —SR
9
or an alkylsulphanyl group oxidized on the sulphur atom,
an amino group or a group —NHR
9
or —NR
9
R
10
optionally oxidized on the nitrogen atom,
a nitro group,
a phenyl group,
an alkyl group of 1 to 4 carbon atoms,
a methyl group substituted with a heterocyclic aromatic or saturated group, it being possible for the hetero atoms to be oxidized in the form of N-oxide or S-oxide,
R
4
represents
a hydrogen atom,
an alkyl or alkenyl group of 1 to 6 carbon atoms,
a cycloalkyl group, a cycloalkylalkyl group,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with 1 or 2 of the following substituents:
an alkyl group of 1 to 6 carbon atoms,
a halogen atom,
a hydroxyl group or an alkoxy group —OR
9
,
a trifluoromethyl group,
a nitro group,
R
5
represents
a hydrogen atom,
an alkyl group or an alkenyl group of 1 to 6 carbon atoms, it being possible for these last two groups to be substituted with:
a hydroxyl group or an alkoxy group —OR
9
,
a phenyl group or a benzyl group,
a sulphanyl group, an alkylsulphanyl group —SR
9
or an alkylsulphanyl group oxidized on the sulphur atom —S(O)R
9
,
an amino group, a group —NHR
9
or —NR
9
R
10
, optionally oxidized on the nitrogen atom, or
a guanidino group H
2
N—C(═NH)—NH—,
a cycloalkyl or cycloalkylmethyl group,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with 1 or 2 of the following substituents:
a halogen atom,
a hydroxyl group, an alkoxy group —OR
9
,
an alkylsulphanyl group —SR
9
or an alkylsulphanyl group oxidized on the sulphur atom,
an amino group or a group —NHR
9
or —NR
9
R
10
optionally oxidized on the nitrogen atom,
a nitro group,
a phenyl group,
an alkyl group of 1 to 4 carbon atoms,
a methyl group substituted with a heterocyclic group, it being possible for the hetero atoms to be oxidized in the form of N-oxide or S-oxide,
R
6
and R
7
represent, independently of each other,
a hydrogen atom,
an alkyl or alkenyl group of 1 to 6 carbon atoms, which can be substituted with:
a hydroxyl group or an alkoxy group —OR
9
,
a sulphanyl group, an alkylsulphanyl group —SR
9
or an alkylsulphanyl group oxidized on the sulphur atom —S(O)R
9
,
an amino group or an alkylamino group —NHR
9
,
a guanidino group H
2
N—C(═NH)—NH—, or
a carboxyl group or an alkyloxycarbonyl group —COOR
9
,
a phenyl group, a benzyl group, which can be substituted on the phenyl group by 1 or 2 of the following substituents:
a halogen atom,
a phenyl group,
a hydroxyl group or an alkoxy group —OR
9
,
an alkylsulphanyl group —SR
9
or an alkylsulphanyl group oxidized on the sulphur atom —S(O)R
9
,
R
6
and R
7
together represent a saturated or unsaturated 5- or 6-membered ring comprising 1 or 2 hetero atoms, taken from among oxygen, sulphur and nitrogen,
R
8
represents,
a hydrogen atom,
an alkyl or alkenyl group of 1 to 6 carbon atoms,
a phenyl group, a benzyl group,
n is equal to 0 or 1,
with the exception of methyl N-[2-[[(aminomethyl) (methoxy)phosphinyl]methyl]-4-methyl-1-oxopentyl]-(1,1′-biphenyl-4-yl)-L-alaninate hydrochloride.
In the context of the invention the terms below have the following meanings:
an alkyl group is a linear or bran
Chen Huixiong
Fournie-Zaluski Marie-Claude
Roques Bernard Pierre
Borin Michael
Institut National de la Sante et de la Recherche Medicale (Inser
Young & Thompson
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