Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-21
2003-08-05
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06602905
ABSTRACT:
This invention relates to certain N-acyl homoserine lactones which have use in the treatment or prevention of cardiac tachyarrhythmias, ischaemic heart disease or congestive heart failure. It, further, relates to a method for the treatment or prevention of tachyarrhythmias, ischaemic heart disease or congestive heart failure and to compositions used in the method.
Many anti-arrhythmic agents and compounds for the treatment of ischaemic heart disease or congestive heart failure that are currently used clinically have several unwanted side effects. One such side effect is hypotension. It is a major disadvantage that in slowing down the heart beat, an anti-arrhythmic drug also, for example, reduces the average blood pressure. The present invention is based on the discovery by the inventors that certain N-acyl homoserine lactone compounds can reduce the heart beat without substantially reducing arterial blood pressure.
Previously, certain N-acyl homoserine lactones (AHL) have been shown to exhibit immunosuppressant activity and to inhibit the release of histamine. For instance, WO 95/01175 discloses that compounds having the following formula (A):
wherein n is 2 or 3; Y is O, S or NH; X is O, S or NH; and R
1
is C
1
-C
18
alkyl or acyl which may be substituted have use in the treatment of allergic diseases, such as asthma, hayfever and autoimmune diseases. There is, however, no teaching or suggestion in this document that a defined subgroup of AHL compounds has any activity that could make such compounds useful in the management of tachyarrythmias, ischaemic heart disease or congestive heart failure.
Accordingly, the invention provides a method for the treatment or prevention of cardiac tachyarrhythmias, ischaemic heart disease and congestive heart failure in human and non-human mammals, which method comprises the administration of an effective, non-toxic amount of a compound of the formula (I):
wherein n is 2 or 3; Y is O, S or NH; X is O, S or NH; and R is 3-15C substituted aliphatic acyl group.
In a further aspect, the present invention provides the use of a compound of formula (I) above for the manufacture of a medicament for the treatment or prevention of cardiac tachyarrhythmias, ischaemic heart disease and congestive heart failure.
The group R, in formula I above, is a substituted aliphatic acyl group which, in total, has from 3 to 15 carbon atoms. By “acyl group” we mean a group which has a terminal carbonyl which is attached directly to the nitrogen atom which itself is attached to the lactone ring. By the term “substituted” we mean that the aliphatic acyl group is substituted in or on the carbon chain of the aliphatic group. Preferably, R is a substituted alkyl carbonyl group wherein the substituted alkyl has from 2 to 14 carbon atoms and is substituted at position &bgr; to the carbonyl and, optionally, elsewhere. Preferred substituents at the &bgr; or 3-position are oxo and hydroxy, with the 3-oxo substituent group being more preferred.
The alkyl of the substituted alkylcarbonyl group for R in formula I may be a straight chain group or a branched chain group, either of which may be substituted internally in the carbon chain or on the carbon chain with a heteroatom, e.g., O , S, NH or NR
1
, where R
1
is a hydrocarbyl group. Preferred are straight chain groups in order to minimise the lipophilic nature of the compound. If the alkyl group is branched then preferably it will have secondary branching only at or near to the end of the group remote from the carbonyl group. Although the chain length of such a substituted alkylcarbonyl group may range broadly from 3 to 15 carbon atoms, groups at the higher end of this carbon content range are preferred, i.e., the substituted alkyl group itself preferably contains from 9 to 14 carbon atoms and is more preferably a 11 to 13C group and most preferably an 11 or 1 2C group. Particular examples of an N-acyl group in formula I, thus, include 3-oxododecanoyl and 3-oxoundecanoyl. The compound N-3-oxoundecanoyl-L-homoserine lactone is, we believe, a novel compound and, as such, forms a further aspect of the present invention as do pharmaceutical compositions containing it together with a pharmaceutically acceptable carrier or diluent.
It is preferred, in the present invention, that n is 2 and both Y and X are oxygen. It should be noted that the compounds having the formula I above possess a chiral centre in the ring carbon atom attached to the RNH-group. The present invention relates to the use of both L-and D-isomers separately, as well as to the use of racemic mixtures.
The compounds of the formula I have been found to reduce substantially the heart rate in normal rats with little or no effect on the mean arterial pressure. A reduction from a normal heart rate in a rat of about 350 beats per minute by as much as 100 beats per minute has been shown by the inventors. The compounds of the formula I therefore have potential as agents for treating tachyarrhythmias, ischaemic heart disease and congestive heart failure in humans. Obviously, an amount effective to treat tachyarrhythmia, ischaemic heart disease and congestive heart failure hereinbefore described will depend upon several factors such as the efficacy of the active compound used, the nature and severity of the disorder being treated, the age and body weight of the patient being treated and the nature of any concurrent treatment, if any. A typical dose of the active compound is, in most cases, less than 10 mg per kg of body weight of the patient. Pharmaceutical compositions containing the active compound described herein may be administered in a number of ways as will be apparent to one of ordinary skill. Administration may, typically, be by parenteral route or by a formulation to be taken orally. The active compound when it is to be administered by a parenteral route will preferably be administered by intravenous injection or intravenous infusion. Thus, for such administration, fluid unit dose forms are prepared. containing a compound of the formula I and a sterile vehicle. The dose form will normally be prepared by dissolving the active compound in the vehicle, for example acetonitrile/dextrose or, preferably, a sterile saline solution and subjecting the solution to sterilisation before being filled into a suitable vial or ampoule and then sealing. It may further be advantageous to incorporate, into the vehicle, various additives such as a local anaesthetic, preservatives, buffer, stabilizer or pH adjuster. In the case of chronic treatment of tachyarrhythmias, however, the active compound will preferably be administered as an oral formulation, typically in the form of tablets, pills or capsules. Such formulations may include other suitable additives which are known in the art, such as binders, diluents and flavouring agents.
REFERENCES:
patent: 0 925 786 (1999-06-01), None
patent: WO 92 18614 (1992-10-01), None
patent: WO 95 01175 (1995-01-01), None
patent: WO 96 40746 (1996-12-01), None
Robson N.D.: “Bacterial N-Acyl-Homoserine-Lactone-Dependent Signalling and Its Potential Biotechnological Applications”;TIBTECH, vol. 15, 1997, pp. 458-464;.
Zhu Jun et al.: “Analogs of the Autoinducer 3-Oxooctanoyl-Homoserine Lactone Strongly Inhibit Activity of the TraR Protein of Agrobacterium Tumefaciens”;Journal of Bacteriology, vol. 180. No. 20, Oct. 1998, pp. 5398-5405.
Parsek M. et al.: “Acyl Homoserine-Lactone Quorum-Sensing Signal Generation”;Proceedings of the National Academy of Sciences of USA, National Academy of Science. Washington, US, vol. 96, Apr. 1999, pp. 4360-4365.
Lawrence R. N. et al.: “The Pseudomonas Aeruginosa Quorum-Sensing Signal Molecule, N-(3-oxododecanoyl)-L-Homoserine Lactone, Inhibits Porcine Arterial Smooth Muscle Contraction”;British Journal of Pharmacology, vol. 128, No. 4, Oct. 1999, pp. 845-848.
Gardiner, S. M. (1) et al.: “N-(3-oxododecanyl)-L-Homoserine Lactone Causes Bradycadia in Conscious Rats”;British Journal of Pharmacology, Jan. 2000, vol. 129, No. Proceedings Supplements, pp. 47P. Print. Meeting Info.: Meeting of the British Pharmacology Soci
Bennett Terence
Bycroft Barrie Walsham
Gardiner Sheila Margaret
Pritchard David Idris
Williams Paul
Bozicevic, Field & Francis
Field Bret E.
Owens Amelia A.
The University of Nottingham
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