Nitriloxy derivatives of (R) and (S)-carnitine

Details Nitriloxy derivatives of (R) and (S)-carnitine Nitriloxy derivatives of (R) and (S)-carnitine

2002-04-11

2003-04-15

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrate esters or chalcogen analogues thereof

C562S567000, C560S176000

Reexamination Certificate

active

06548693

ABSTRACT:

FIELD OF THE INVENTION
The invention described herein relates to derivatives of (R) and (S)-carnitine, and particularly nitriloxy derivatives which are useful as intermediate synthesis products and as therapeutic agents.
BACKGROUND OF THE INVENTION
Organ ischaemia is caused by an imbalance between the oxygen requirements of the tissue and oxygen availability from the bloodstream. In the particular case of cardiac ischaemia, this manifests with typical symptoms, known as
angina pectoris.
The causes are multiple and, among them, we should mention the reduced ability of the coronary circulation to supply oxygen, owing, for example, to the presence of atheromatous plaques. One possible consequence of the ischaemia is myocardial infarction.
Myocardial ischaemia may also be asymptomatic and detectable only by means of clinical and instrumental examinations.
The therapy currently available is based mainly on the administration of coronary dilating drugs, which, on account of the specific needs of symptomatological treatment, have to have as rapid an action as possible. Calcium antagonists, &bgr;-adrenergic antagonists and antiaggregant agents should also be mentioned.
Among the drugs still most commonly used today, we should mention the organic nitrates, which by releasing NO at the action site exert a local vasodilatory action.
Amyl nitrite is used by inhalation in cases of angina attack. Nitroglycerine and organic nitrates of higher molecular weight are also used for the prevention of such attacks. Nitroderivatives are associated with a series of important side effects. The most common of these is headache, which may even be very severe. More serious is the fact that these drugs give rise to tolerance and their withdrawal causes a rebound effect. Nitroglycerine is also administered using transdermal release systems, which, however well designed they may be, present problems in their own right, such as those relating to permanence at the application site, controlled delivery of the drug and patient compliance.
Calcium antagonists present the problem of excessive vasodilatation, with consequent dizziness, hypotension, headache, and nausea, and it is by no means easy to establish the appropriate therapeutic regimen.
&bgr;-antagonists have effects on cardiac haemodynamics.
For a more detailed discussion of these aspects, the reader is referred to Goodman & Gilman's The Pharmacological Basis of Therapeutics-9th edition, chapter 32.
To date, no single drug therapy is available for the treatment of ischaemic states, particularly
angina pectoris,
which possesses the desired characteristics in terms of patient compliance, safety of use, lack of side effects and immediacy of action. In particular, no ester of nitric acid is as yet available which combines the characteristics of immediacy of action and a lack of the side effects typical of this class of drugs.
Patent application WO98/56759 describes pentaerythrite derivatives of general formula (O
2
NOCH
2
)
m
C(CH
2
OH)
n
(CH
2
COR
1
)
o
(COR
1
)
p
The multiple meanings of R
1
include nitriloxy derivatives of carnitine, in particular nitriloxy-carnitine chloride, its inner salt and ester with (1-alkoxy-carbonylmethyl-2-trialkylammonium)ethanol. An ester of racemic nitriloxy-carnitine with (1-alkoxycarbonylmethyl-2-trialkyl-ammonium) ethyl alcohol is also envisaged, provided on mixtures containing equimolar amounts of (R) and (S) isomers. The anti-angina activity of these compounds is mentioned in the description. Nitriloxy-carnitine is also prepared as an intermediate. The examples of the compounds are provided on the racemic mixtures. The only example of a preparation, example 17, which uses L-carnitine, envisages reaction with the chloride of 3-nitriloxy-2,2-bis(nitriloxymethyl)propionic acid. The resulting compound (not identified either in physico-chemical or in structural terms) is not included in the claims and is not mentioned in relation to its presumed pharmacological activity. The patent application cited does not provide a general scheme for preparation of the compounds, and thus the compounds effectively described are to be found in the preparation examples. No pharmacological activity data are provided.
The action of L-carnitine in the treatment of heart failure is known (U.S. Pat. No. 3,830,931).
Also known is the fact that acetyl L-carnitine enhances the oxidation of glucose and prevents the accumulation of lactate in the concomitant acidosis (Lopaschuk, G. in
Carnitine Today
—C. De Simone and G. Famularo ed.) Lands Bioscience 1997).
Alkanoyl derivatives of L-carnitine are known for different uses in human or animal therapy.
It has now surprisingly been found that enantiomerically enriched nitriloxy derivatives of (R) or (S)-carnitine are endowed with favourable and advantageous pharmacological activities, particularly as therapeutic agents for organ ischaemias, and even more particularly for the treatment of
angina pectoris.
Nitriloxy derivatives of (R) and (S)-carnitine are also useful intermediates for synthesis for the production of chiral 3-4 carbon atom synthons having the (R) or (S) configuration, such as for example 3-hydroxy-&ggr;-butyrolactone, 1,2,4-butantriole, 3-hydroxytetrahydrofurane, 3-hydroxypyrrolidine, 2,3-dihydroxypropylamine, to be used in the industrial synthesis of enantiomerically pure drugs. However, (R) and (S)-carnitine are not actually available at low cost, therefore a process convenient and applicable on a large scale, allowing the stereospecific conversion of (S)-camitine into (R)-carnitine or vice-versa will be economically advantageous and useful.
It has now surprisingly been found that enantiomerically enriched nitriloxy derivatives of (S)-carnitine, according to the present invention, are suitable intermediates for the production of (R)-carnitine its derivatives, and vice-versa.
ABSTRACT OF THE INVENTION
The subject of the invention described herein are carnitine derivatives of general formula (I) in optically active form of absolute configuration (R) or (S)
where
Y is an OR or NR
1
R2 group with
R equal to hydrogen, C
1
-C
10
alkyl or alkyl substituted with C
6
-C
10
(aryl, said aryl optionally carrying one or more C
1
-C
4
alkyls;
R
1
and R
2
, which may be the same or different, are hydrogen, C
1
-C
10
alkyl or alkyl substituted with C
6
-C
10
aryl, said aryl optionally carrying one or more C
1
-C
4
alkyls; or, taken together, form a 5-7 atom heterocyclic ring with the nitrogen atom;
or Y is the residue of an esterified polyalcohol with at least one nitric acid equivalent;
X- is the anion of a pharmaceutically acceptable organic or inorganic acid,
or, if Y is an OH group, the formula (I) product may exist in the form of an inner salt, i.e. with structure (II)
and their enantiomerically enriched mixtures.
Examples of C
1
-C
10
alkyls are methyl, ethyl propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl and all their possible isomers.
Examples of substituted alkyls are benzyl and phenylethyl.
Examples of substituted aryls are tolyl, xylyl and its isomers.
Examples of polyalcohols are glyceryl mono- or dinitrate, isosorbide mononitrate, erythrityl di- o trinitrate, pentaerythrityl mono-, di- or trinitrate.
Examples of anions of organic or inorganic acids are NO
3
−
, Cl
−
, Br
−
, I
−
, HSO
4
−
, (SO
4
2−
)
0.5
, H
2
PO
4
−
, (HPO
4
2−
)
0.5
, (PO
4
3−
)
0.33
, a residue of a hydroxy acid, a residue of a bicarboxylic acid, OSO
2
Z
−
, OCOZ
−
or OCOH
−
with Z equal to C
1
-C
10
alkyl, substituted alkyl, such as, for example, trihalomethyl or benzyl, aryl, such as, for example, phenyl, tolyl, halophenyl or alkoxyphenyl. What is meant by halogen is fluorine, chlorine, bromine and iodine. Preferred examples of anions of organic and inorganic acids are those derived from pharmaceutically acceptable acids, among which, in addition to those exemplified above, we would mention particularly mandelate, orotate, acid aspartate, acid citrate, fumarate and acid fumarate, maleate and acid maleate, mucate, mala

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