(&agr;-aminophosphino) peptides derivative and compositions...

Details (&agr;-aminophosphino) peptides derivative and compositions... (&agr;-aminophosphino) peptides derivative and compositions...

2001-02-09

2002-05-21

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C558S170000

Reexamination Certificate

active

06391866

ABSTRACT:

The perception, transmission and regulation of the nociceptive influxes are dependent on several endogenous neuraltransmitters. In 1975, Hugues et al. (
Nature,
258, 577, 1975) have identified enkephalines, two primitively isolated pentapeptides of mammal brains which are implicated in the transmission of painful influx. Enkephalines connect with at least two classes of receptors: the opioid sites a and 6 (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 administration of exogenous enkephalines is very fleeting, because of the rapid metabolism of these peptides. Analogous enkephalines rendered resistant to enzymatic degradation by chemical modifications, have been synthesized, but their secondary effects are analogous to those of morphine.
The enkephalines are physiologically degraded by two types of enzymatic activity which metabolize in vivo the enkephalines: neutral endopeptidase (EC 3.4.24.11, also called NEP) which cuts the Gly
3
Phe
4
bond and aminopeptidase N (EC 5 3.4.11.2, also called APN) which cuts the Tyr
1
-Gly
2
bond (reviewed in Roques et al.,
Pharmacol. Rev.,
45, 87-146, 1993).
There are known prodrugs described in European patent EP 0 487 620 and in Fournié-Zaluski et al.,
J. Med. Chem.,
35, 2473, 1992, which have analgesic and antidepressive activities after intravenous administration or by oral route (Noble et al.,
J. Pharm. Exp. Ther.,
261, 181, 1992; Baamonde et al.,
Eur. J. Pharmacol.,
216, 157, 1992). However, these compounds do not respond to the concept of mixed inhibitors, because of their structure in which an APN inhibitor and an NEP inhibitor are is associated with a disulfide bridge. These compounds are then reduced by cerebral reductases and each act on its particular target.
According to the patent application WO 95/35302 and
Bioorganic and Medicinal Chemistry Letters,
Vol. 6, No. 11, pp. 1257-1260, 1996, there are known certain derivatives of phosphenic acid having respectively an inhibiting activity on the enzyme conversion of endotheline (ECE) and a mixed inhibitory activity of the enzyme of conversion of angiotensin (ACE) and of neutral endopeptidase (NEP). These compounds are useful in the treatment of cardiovascular maladies.
Derivatives of &agr;-aminophosphino peptides are described in the patent application PCT/FR9701884.
One of the objects of the invention is to provide new compounds, which behave as true mixed inhibitors of APN and NEP, capable of conjointly inhibiting the two enzymatic activities responsible for the degradation of the enkephalines and to manifest their pharmacological properties after intravenous or subcutaneous injection, or by oral route (per os).
These compounds have certain properties of the morphine substances, in particular analgesia, the beneficial effects on the behavior (antidepressants, sedatives, anxiolytics, desinhibitors and promnesics), and peripheral effects (antidiuretic, antitussive, hypotensive, anti-inflammatory . . .). Moreover, an advantage of these compounds is that they have no undesirable morphine effects (tolerance, physical and psychic dependence, respiratory depression, intestinal statis . . .).
The compounds can also be used as a treatment for substitution in the toxiconomy of opioides.
The present invention has for its object compounds derived from &agr;-aminophosphino peptides of the general formula
in which
R
1
and R
2
each represent a hydrogen atom or R
1
and R
2
, taken together, form an unsaturated group of the formula R′ (R″)C═, in which
R′ represents a phenyl group in position 2 monosubstituted with a hydroxy group or a disubstituted phenyl group, in position 2, with a hydroxy group and, in position 4 or 5, either by a halogen atom or by a nitro group, or by a hydroxy group, or by an alcoxy group —OR
9
,
R″ represents a phenyl group, a phenyl group substituted with 1 to 5 halogen atoms or an aromatic heterocyclic group, in what follows, the terms R
9
and R
10
, used for the definition of the 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, these two latter groups can be substituted by:
a hydroxy group or an alcoxy group —OR
9
,
a phenyl group or a benzyl group,
a sulfanyl group, an alkylsulfanyl group —SR
9
or an alkylsulfanyl group oxidized at the sulfur atom —S(O)R
9
,
an amino group, an —NHR, group or —NR
9
R
10
group, if desired oxidized at 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 hydroxy group, an alcoxy group —OR
9
,
an alkylsulfanyl group —SR
9
or an alkylsulfanyl group oxidized at the sulfur atom,
an amino group or a —NHR
9
or —NR
9
R
10
group if desired oxidized at the nitrogen atom,
a nitro group,
a phenyl group,
an alkyl group of 1 to 4 carbon atoms,
a methyl group substituted by an aromatic or saturated heterocyclic group, the heteroatoms being possibly oxidized in the form of N-oxide or S-oxide,
R
4
represents
a —CH(X)—O—C(O)—Y group, in which X and Y represent, independently of each other, an R
9
group or a phenyl group,
a —CH
2
CH
2
—S—C(O)—W group, in which W represents an R
9
group or
a phenyl group,
R
5
represents
a hydrogen atom,
an alkyl group or an alkenyl group of 1 to 6 carbon atoms, these two latter groups being possibly substituted with:
a hydroxy group or an alcoxy group —OR
9
,
a phenyl group or a benzyl group,
a sulfanyl group, an alkylsulfanyl group —SR
9
or an alkylsulfanyl group oxidized at the sulfur atom —S(O)R
9
,
an amino group, an —NHR
9
or —NR
9
R
10
group, possibly oxidized at 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 at the phenyl group by 1 or 2 of the following substituents:
a halogen atom,
a hydroxy group, an alcoxy group —OR
9
,
an alkylsulfanyl group —SR
9
or an alkylsulfanyl group oxidized at the sulfur atom,
an amino group or an —NHR
9
or —NR
9
R
10
group which can be oxidized at 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, the hetero atoms can 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 hydroxy or an alcoxy group —OR
9
,
a sulfanyl group, an alkylsulfanyl group —SR
9
or an alkylsulfanyl group oxidized at the sulfur 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 carboxy 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 hydroxy group or an alcoxy group —OR
9
,
an alkylsulfanyl group —SR
9
or an alkylsulfanyl group oxidized at the sulfur atom —S(O)R
9
,
R
6
and R
7
together represent a saturated or unsaturated cyclic compound of 5 or 6 members, comprising 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen,
R
8
represents,
an alkyl or alkenyl group of 1 to 6 carbon atoms,
a phenyl group, a benzyl group,
n is equal to 0 or 1.
Within the scope of the invention, the following terms have the following meanings:
an alkyl group is a hydrocarbon chain, saturated, linear or branched,
an alkenyl group is a linear or branched hydrocarbon chain, comprising an unsaturation,
a cycloalkyl group is a cyclic hydrocarbon chain comprising 3 to 7 carbon atoms,
a cycloalkylalkyl group is a cycloalkyl group connected to an alkyl group, this alkyl group comprising 1 to 6 carbon atoms,
a cycloalkylmethyl group is a cycloalkyl group connected to a methyl gr

Affiliated with

Also associated with

Rating

(&agr;-aminophosphino) peptides derivative and compositions... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with (&agr;-aminophosphino) peptides derivative and compositions..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and (&agr;-aminophosphino) peptides derivative and compositions... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2841267