Keto acid salts and amine derivatives, and their use for...

Details Keto acid salts and amine derivatives, and their use for... Keto acid salts and amine derivatives, and their use for...

2000-11-13

2002-08-06

Killos, Paul J. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S564000, C514S574000, C514S562000, C514S553000, C514S424000, C514S319000

Reexamination Certificate

active

06429229

ABSTRACT:

The present invention has for its objects salts of keto acids and of amine derivatives, as well as their use for the preparation of pharmaceutical compositions for the treatment of pathologies in which are involved silent neurons.
The nociceptive message results from the intense activation of the free terminals (nociceptors) of the C and A&dgr; fibers which under physiological conditions take part in the regulation of the function of the organs. These fibers are contained in the cutaneous, muscular and articular tissues as well as in the walls of the viscera.
In the digestive tract as well as in the bladder and the biliary ducts, this nerve structure cohabits with a population of silent neurons (Mayer, E. A.; Gebhart, G. F.; Gastroenterology, 1994, 107, 271-293) whose expression appears only in the presence of an inflammatory or nervous lesion.
This physiopathological mechanism inspired the creation of the model of distension of the colon first irritated with 1% acetic acid, in rat. This model is hence representative of the illnesses of digestive origin and is used particularly for detecting compounds active in the treatment of the irritable intestine syndrome (IIS). IIS is characterized by the presence of abdominal pain. Patients having this pathology have a lowered threshold of digestive sensitivity.
Morphine is active on the model of colic distension whilst the classical analgesics (AINS, aspirin, paracetamol) are inactive in the test. They are on the other hand active in the “writhing test” (model of visceral pain in which the silent neurons are not involved) which is effected by intraperitoneal injection of phenylbenzoquinone or 3% acetic acid in rat or a mouse. Morphine is hence capable of modifying the reactivity of the silent nociceptors, which AINS cannot do.
Similarly, one opinion, described in JP 43-05524 as an analgesic, is active in the “writhing test” at 500 and 1000 mg/kg by intravenous route in mice. It is also active in a somatic pain test in which the silent neurons are not involved (Kawabata, Atsugumi et coll., Eur. J. Pharmacol., 1996, 296 (1), 23-31), at doses between 300 and 1000 mg/kg by subcutaneous route in rat.
By contrast, it is inactive in the model of colic distension in rat at doses of 1 to 20 mg/kg by oral route (Table I). Ornithine is thus not capable of modifying the reactivity of the silent nociceptors at these dosages.
Moreover, J. Goldhill et coll. (Gastroenterology, April 1996, 110 (4), abstract A916) have shown that glutamine is active in the test of colic distension at a dose of 6 mg/kg by rectal route in rat (local administration on the irritated colic mucosa).
Finally, &agr;-ketoglutarate of di-ornithine is used in therapy (French patent 3 533 M) to improve the proteic metabolism of starved subjects. It is also known as a hormonal stimulant (growth hormone and insulin) and stimulating cellular growth.
The present invention follows from the discovery by the inventors, of the fact that salts of the general formula (I):
(X)
n1
,Y,(Z)
n2
  (I)
in which:
X is an amino acid;
Y is a keto acid;
Z is an amino acid or a polyamine,
n
1
and n
2
represent 0 or 1, provided that when n
1
=0 then n
2
=1, and when n
2
=0, n
1
=1,
have the property of increasing the threshold of perception of digestive pain and as a result are capable of modifying the reactivity of the silent nociceptors in an amount at least 1 mg/kg by oral route.
This discovery is the more unexpected, because the keto acids separately tested are inactive. The separately tested amino acids are also inactive or active at higher dosages (see Table I hereafter).
The activity of these salts is not due to the keto acid alone or to the amino acid alone, but to the synergy between these two types of compounds.
Thus, by way of illustration, Table I shows nicely that:
the comparisons 1 and 2 are inactive whilst the compounds of Examples 1 and 2 (salts between comparisons 1 and 2) are active at 1 mg/kg;
comparison 3 is inactive whilst the compound of Example 6 (salt between comparisons 3 and 2) is also active from 1 mg/kg;
comparison 4 is active at 10 mg/kg whilst the compound of Example 5 (salt between comparisons 1, 2 and 4) is active from 1 mg/kg;
comparison 5 is active only from 20 mg/kg whilst the compounds of Examples 3 (salts of comparisons 1 and 5) and 4 (salts of comparisons 1, 2 and 5) are active from 10 mg/kg.
The present invention has for its object the use of compounds of the following general formula (I):
(X)
n1
,Y,(Z)
n2
  (I)
in which:
n
1
and n
2
are 0 or 1, provided that when n
1
=0 then n
2
=1, and when n
2
=0 then n
1
=1,
X is a natural amino acid, provided that when n
2
0 then X is a basic amino acid such as:
ornithine,
arginine,
lysine,
or, histidine,
Y is a keto acid of the following formula (II):
R—CO—COOH  (II)
 in which R is an alkyl or alcanolic acid group, substituted or not, from about 1 to about 10 carbon atoms, particularly a keto acid of formula (II) in which when R is:
—CH
3
, said keto acid is pyruvic acid,
—CH
2
—CH
3
, said keto acid is &agr;-ketobutyric acid,
—CH(CH
3
)
2
, said keto acid is &agr;-ketoisovaleric acid,
—CH(CH
3
)—CH
2
—CH
3
, said keto acid is &bgr;-methylvaleric &agr;-keto acid,
—CH
2
—CH(CH
3
)
2
, said keto acid is &agr;-keto isocaprilic acid,
—(CH
2
)
2
—COOH, said keto acid is &agr;-keto glutaric acid,
—(CH
2
)
3
—COOH, said keto acid is &agr;-keto adipic acid,
Z represents:
a natural amino acid, particularly an amino acid selected from ornithine, arginine, lysine, histidine or glutamine,
or, a polyamine comprising at least two primary, secondary or tertiary amine functions, spaced by a linear or branched hydrocarbon chain of about 3 to 10 carbon atoms, particularly a polyamine of the following formula (III):
R
1
—HN—(CH
2
)n-NH—R
2
  (III)
 in which:
n represents a whole number comprised between 4 and 5, and
when n=4,
R
1
and R
2
are H,
or, R
1
is H and R
2
is (CH
2
)
3
NH
2
,
or, R
1
and R
2
are (CH
2
)
3
NH
2
,
when n=5,
R
1
and R
2
are H,
or, R
1
is H and R
2
is a group of the formula particularly a polyamine selected from cadaverine, putrescine, spermidine, spermine or agmatine,
for the preparation of a medication adapted for the treatment of human or animal pathologies in which are involved the silent neurons, such as pathologies of the digestive tract, of the bladder and of the biliary ducts.
Of course, the compounds of formula (I) above result from the formation of principally ionic bonds, and in no case of covalent bonds, between the different constituents X, Y or Z. As a result, the order of appearance of the different constituents in formula (I) has no particular significance, and this formula (I) should be understood to comprehend also the compounds of the formula (X)
n1
, Y, (Z)
n2
those of formula (Z)
n2
, Y, (X)
n1
; (X)
n1
, (Z)
n2
, Y; (Z)
n2
, (X)
n1
, Y; Y, (X)
n1
, (Z)
n2
; Y, (Z)
n2
, (X)
n1
.
Preferably, the invention has for its object the above-mentioned use of compounds of formula (I) as defined above, in which Y is a keto acid selected from &agr;-ketoglutaric acid, or &agr;-ketobutyric acid.
The invention has more particularly for its object the above-mentioned use, of compounds of formula (I) in which:
n
1
=1, and n
2
=0 or 1,
X is an amino acid selected from ornithine, arginine or glutamine,
Y is a keto acid selected from &agr;-ketoglutaric acid, or &agr;-ketobutyric acid,
and, when n
2
=1, Z is:
a natural amino acid, particularly ornithine, arginine or glutamine,
or a polyamine of the above formula (III) such as cadaverine, putrescine, spermidine, spermine or agmatine.
Compounds of formula (I) in which n
1
=1, and n
2
=0, particularly preferred for their use in the field of the present invention, are those in which:
X is ornithine and Y is &agr;-ketoglutaric acid, namely mono-ornithine &agr;-ketoglutarate,
X is ornithine and Y is &agr;-ketobutyric acid, namely mono-ornithine &agr;-ketobutyrate,
or those in which:
X is arginine and Y is &agr;

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