GB2415137A

GB2415137A - Lipoic acid derivatives for the treatment of atherosclerosis and arthritis

Info

Publication number: GB2415137A
Application number: GB0413634A
Authority: GB
Inventors: David Sidney Leake
Original assignee: University of Reading
Current assignee: University of Reading
Priority date: 2004-06-18
Filing date: 2004-06-18
Publication date: 2005-12-21
Anticipated expiration: 2024-06-18
Also published as: GB2415137B; GB0413634D0

Abstract

A lipoic acid or an analogue thereof which has been substituted with a basic group which is protonated at a pH of from 4-5 for use in the treatment or prevention of atherosclerosis or arthritis. Suitable analogues include pharmaceutically acceptable salts, esters, amino acid adducts or peptide adducts of lipoic acid, lipoamides or mixtures thereof. The basic group is preferably a nitrogen-containing group, for example an amino group of form -NR2 where R is hydrogen, straight or branched, optionally substituted C1-8 alkyl or C5-8 cycloalkyl, a piperidinyl group, a pyridinyl group or a pyrrolidinyl group. The most preferred compound is 5-[1,2]dithiolan-3-yl-pentanoic acid (2-dimethylaminoethyl) amide, which has been found to be effective at preventing the oxidation of low density lipoprotein (LDL).

Description

IMPROY ORIENTS IN OR RELATING TO ORGANIC I\IATERIAL The present intention

relates to a compound, composition, and a method for use in treating or presenting atherosclerosis or arthritis by inhibiting :' inlralyso.somal oxidation of low density lipoprotein, in particular it relates to a alpha-lipoamide derivative or an analogue thereof.

Atherosclerosis is an arterial disease characterized by lipid deposits in the artery wall. These lipid deposits partly consist of oxidatively modified low density lipoprotein (LDL). Atherosclerosis can result in myocardial infarction if it occurs in the coronary arteries, strokes if it occurs in arteries supplying the brain or peripheral arterial disease if it occurs in the legs.

A vast amount of research has been carried out to determine how to reduce cholesterol concentration and l..DL oxidation. LDL oxidation is presently believed to occur extracellularly \ithin atherosclerotic lesions (Chisolm, G. M. Steinberg, D., "The oxidation modification hypothesis of atherogenesis: an overview" Free Raclic Biol Med 2()()0; 28 () (12) IXI.-1806). This hypothesis of atherosclerosis has led to large- scale clinical trials of antio,xidants in treating cardiovascular disease. To date, most of these trials have sh<:'vn no protective effects (Collins R. Armitage J. Parish S. Sleight P and Peto, R. (9003) I,ancet. 36(), 2.3-.3.3. MRC/BHF Heart Protection Study of antioxidant \itamin supplementation in 2()..36 2. high-risk individuals: a ranclornised placebo-controlled trial; Yusuf, S., Phil. 1)., Dagenais, G., Pogue, J., Bosch, J. and Sleight, P. (()()0) iNevv England Journal of l\Íedicine 34'' 1.1-16(). Vitamin F. supplementation and cardiovascular cents in high risk patients).

3() .\cklitionaliv it is Juno\\ n that oxidisecl LDI. is present in arthritic joints (\\'in arc. P. G., Tatzber, F., Esicrbauer, H., Kus, M. L., Blake, O. R. and 1\1orris, C. J. (199.3) Annals of The Rheumatic Diseases 59, 677-680.

Presence of foam cells containing oxidized low-density-lipoprotein in the sy no; ial-membrane from patients ith rheumatoid-arthritis; Dai, L., Lamb, D. J., Leake, D. S., Kus, M. L., Jones, H. W., Morris, C. J. and Winyard, P. G. (2000) Free Radical Research 32, 479-486. Evidence for oxidised low density lipoprotein in s'novial fluid from rheumatoid arthritis patients; James, M. J. can Reyk, D., Rye, K. A., Dean, R. T., Cleland, L. G., Barter, P. J. and Jessup, W. (1998) Lipids 33, 1 1 15 112 1. Low density lipoprotein of synovial fluid in inflammatory joint disease is mildly oxidized). However it is not known how to prevent this oxidation from taking place.

A solution to these problems has been sought.

According to the invention there is provided a compound which is a lipoic acid or an analogue thereof which has been substituted with a basic group which is protonated at a pH of from PI to 5, preferably about 4.5 for use in the treatment or prevention of atherosclerosis or arthritis.

2() As a result of the substitution of lipoic acid or an analogue thereof with a basic group which is protonated at a pH of from "I to 5, the compound according to the invention concentrates within a Iysosome when administered to a human or animal. This is because the compound is protomted in the moderately acidic environment inside a lsosome and is thus trapped, unable to escape.

The compound according to the invention has surprisingly been found to be effective in preventing the oxidation of LDL. This is believed to be because LDL oxidation occurs s ithin a 1 sosome of a cell in an 3() lherosclerotic lesion.

According to the invention there is further provided a formulation including a compound according to the invention in association with a pharmaceutically acceptable diluent or carrier.

According to the incntion there is also provided a formulation according to the invention for use in the treatment or prevention of atherosclerosis or arthritis.

According to the invention there is further provided use of a compound or of a formulation according to the invention in the manufacture of a medicament for use in the treatment or prevention of atherosclerosis or arthritis.

According to the invention there is also provided a method of treating or lo presenting arthritis or atherosclerosis which method comprising administering to a human or animal patient in need of such treatment a therapeutically effective amount of a compound or of a formulation according to the invention. The animal patient is preferably a mammal.

L.ipoic acid exists in 2 isomer forms, i.c. R( + ) lipoic acid and L(-) lipoic acid. Both isomers as well as a racemic mixture thereof can suitably be used in the invention and arc encompassed by the term "lipoic acid".

1,ipoic acid is easily reduced to its disulphide form. Both the reduced and the oxidised form of lipoic acid can suitably be used in the invention and are encompassed by the term "lipoic acid".

A lipoic acid analogue should be understood to mean a substance which either liberates lipoic acid in the body of the subject to whom the analogue is being administered (usual!\ this means that the analogue is 3() converted by metabolic acti; ity into lipoic acid or a lipoic acid metabolite) or is a substance which is structurally related and shows the same physiological functionality. Preferably the lipoic acid analogue is a pharmaceutically acceptable salt of lipoic acid, an ester of lipoic acid, an amino acid adduct of lipoic acid, a peptide adduct of lipoic acid, Iipoamide and/or a mixture thereof. The ester of lipoic acid preferably comprise a straight, branch-chained or cyclic acyl group with no more than 8 carbon atoms, preferably with or less carbon atoms. Examples of an adduct of lipoic acid which could suitably be used as a lipoic acid analogue include an adduct of lipoic acid and Iysine and an adduct of lipoic acid and a Iysine rich peptide.

The compound according to the invention is preferably substituted with one or more nitrogen-containing groups such as a -NR. group (wherein R independently represents a hydrogen atom, a straight, branched chain optionally unsaturated alkN I group containing from I to 8 (preferably from I to 4) carbon atoms or an optionally unsaturated cycloalkyl group containing from 5 to 8 carbon atoms), a piperidinyl group, a pyridinyl group, or a pyrrolidinyl group. Most preferably the compound of the intention is 5-LI.'l dithiolan-8-1-pentanoic acid (-dimethylamino-ethyl) amide.

The formulation may optionally be prepared for administration orally, parcutcrally, to the skin or mucousal membranes or by inhalation.

For oral administration, either solid or fluid unit dosage forms can be prepared. For preparing a solid composition such as a tablet, the compound of the intention is mixed into a formulation with a conventional ingredient such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminiun1 silicate, calcium sulfate, starch, lactose, acacia, mcth\lcellulose, and/or a functional!\ similar material as 3() a pharmaceutically acceptable diluent or carrier. capsule is prepared by mixing the compound of the in\ ention \N ith an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of an appropriate size.

A soft gelatin capsule is prepared by machine encapsulation of a slurry of the compound of the invention ith an acceptable \ egetable oil, light liquid petrolatum or other inert oil. A fluid unit dosage form for oral administration such as a syrup, elixir and suspension can be prepared.

A water soluble form of a compound according to the invention can be dissolved in an aqueous vehicle together with sugar, an aromatic flavoring agent and a preservative to form a syrup. An elixir is prepared by using a hydroalcoholic (e.g., ethanol) vehicle with a suitable sweetener such as sugar and saccharin, together with an aromatic flavoring agent. A suspension can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, and/or methylcellulose.

A slow or exiended-rclease delivery system, including a biopolymer (a biological-based system), a system employing a liposome and a polymeric delivery system, can be utilized with the composition described herein to SO provide a continuous or long term source of the compound of the invention. Such a slow release system is applicable to a formulation for oral or parenteral use.

The single dose of the compound according to the invention may, for

example, be:

(i) in an <oral medicinal form: from l()Omg to.1g, preferably from '()Omg to Ig: () (ii) in a parenteral medicinal form (for example intravenous or intramuscular): Irorn l()Orng to I2g, preferably from 2()()mg to fig; (iii) in a medicinal form for inhalation (e.g. a solution or aerosol): from IOOmg to 2g, preferably from 200mg to Ig; and (iv) in a medicinal form for rectal or vaginal application: from 1OOmg to 2g, preferably from 200mg to Ig.

The doses according to (i) to (iv) may, for example, be administered I to 6 times, preferably I to times daily or, however, as a permanent infusion, for example with the aid of an infusioniate, i.e., with an infusion apparatus for accurate hourly dosage of an active substance in solution.

The daily dose of a compound according to the invention in humans should, for example, be from 70 lo 80 mg per kg weight; the single dose, for example, from 16 to 20 mg per kg body weight, this dose appropriately being given 4 times daily. A pharmaceutical formulation according to the invention therefore preferably contains from I to 1.5g of the compound according to the inventions a dose of this type preferably 2() being given 4 times each day.

The recommended treatment is, for example, .3 times daily' from I to tablets with a content of from 5() mg to 2 g of active ingredient per tablet, or, for example, in intravenous injection from I to 4 times daily, one '5 ampoule/infusion bottle of from I to 5()0 ml content with from 20() mg to 6 g of active ingredient. In the case of oral administration the minimum daily dose is for example 3()0 ma; the maximum daily dose, given orally, gcnerallv should not exceed I' g.

3() The close amounts mentioned refer' in each case, to the lipoic acid cleri\atiNe itself. Should the compound of the intention be used in the form of an analoguc having a higher molecular weight, the quoted closages/dosage ranges should be increased in accordance with this higher weight. The formulation of the invention may preferably also contain an additional vitamin.

For example the preferred daily dose of the compound of the invention is preferably 80 mg for the parenteral form of application and 200 mg for the oral form dosed once or twice daily. In particular, the daily dose for the parenteral form of application is 100 mg or 200 mg for the oral form.

The pharmaceutical compositions are preferably administered orally but may also be administered parenterally (intravenously, intraarticularly, intramuscularly, subcutaneously, intradermally), or delivered or applied in the form of a solution, suspension, gel, lotion, ointment or other suitable delivery vehicle topically, directly to the skin, intraorally, In sublingually, as an inhalation, or per rectum, or per \agina directly applied or as a suppository.

A pharmaceutical formulation according to the invention may for example be formulated in the form of a tablet, capsule, pill or coated tablet, 2() granulate, pellet, plaster, solution or emulsion, the active ingredient in each case optionally being combined with appropriate auxiliary and/or carrier substances. [n the case of a solution. it should contain for example ().n to '()'3o by weight, preferably I to 10C/c by \\eight of the compound of the invention.

Where the formulation according to the invention is in the form of an aerosol, it preferably comprises an aqueous solution or.suspension, a nonaqueous suspension (e.g. using a fluorocarbon propellant), a liposomal preparation <' r a solid particle containing the compound according to the 0 intention. Optionally an aqueous solution or.suspcnsion is prepared by formulation an aqueous solution or suspension of the compound according to the invention with a conventional pharmaceutically acceptable carrier and/or stabilizer, e.g. a nonionic.surfactant (c.g. a Tween or Pluronic surfactant or polyethylene glycol), a protein (such as serum albumin, a sorbitan ester, oleic acid and/or lecithin), an amino acid (e.g. glycine), a buffer, salt, sugar or sugar alcohol. The aerosol is preferably prepared from an isotonic solution.

Should a lotion be used, the compound of the invention is preferably used in the form of a salt.

The invention is illustrated by way of example with reference to the Figure of the accompanying drawings which shows a graph illustrating the effect of a compound according to the invention (referred to as "IMP") on the production of 7-ketocholesterol ("ok") in J774 cells; the graph is presented in the form of a bar chart with samples taken at different time intervals; for each time interval, the bars show (from left to right) the baseline data for cells without the compound of the invention, the data for cells \ith l,<'M of the compound of the invention, and the data for cells faith lO,uM of the compound of the invention. ()

The invention will now be illustrated with reference to the following Example which is not intended to limit the scope of the invention.

EXA\IPI,E I 2 The ability of the amine derivative alpha-lipoamide, namely.-[1.21 dithiolan-.3-vl-penlanoic acid (-dimethylamino-ethyl)-amide (alpha-lipoic acid-plus {LAPI; pKa = 8.()) to inhibit intralysosomal oxidation of low clensiv lipoprotein (I,DL) \as measured.

() LAP as so nthesisecl as described in Sen, C. K.; Tirosh, O.; Ro\, S.; Kohavashi, M. S.; Packer. L.. A posili\ely charged alpha-lipoic acid analogue with increased cellular uptake and more potent immunomodulator activity. Bioe/em. Birlts. Rev. Conn7un. 247; 22.3- 928; 1998.

Mouse J774 macrophages-like cells (obtained from the Life Sciences Division of King's College London, London, UK) were incubated with aeetylated LDL (prepared as described by Basu et a/. (1976) Proe. Natl. Aead. Sei. U.S.A. 73, 3178-3182) (50 jug protein /ml) for 24 hours.

Aeetylated LDL was used because cells incubated with LDL modified by such a non-oxidative process have a rapid uptake of LDL. The cells were then incubated in the absence of LDL (chase incubation) in Ham's F-10 medium containing 20o (v/v) lipoprotein-deficient serum for 48 hours with or without addition of the amine derivative (final concentration I and 10,/M). 7-Ketocholesterol was measured by HPLC at the beginning and throughout the chase incubation.

Figure I shows that LDI, was oxidised in the cells over the 48 hour chase incubation period, as indicated by the increase in the levels of 7ketochclesterol (7K). The production of 7-ketocholesterol was completely prevented by both concentrations of the amine derivative (referred to as LAP in Figure 1) (* P < 0.05, # P < 0.02, compared to the appropriate baseline). This dale shoves that LAP will be useful in the treatment of conditions involving the oxidation of L,DL in cells such as atherosclerosis and rheumatoid arthritis. A.)

Claims

1. A compound which is a lipoic acid or an analogue thereof which has been substituted with a basic group which is protonated at a pH of from to 5, preferably about 4.5 for use in the treatment or prevention of atherosclerosis or arthritis.

2. A compound as defined in claim I wherein the lipoic acid analogue is a pharmaceutically acceptable salt of lipoic acid, an ester of lipoic acid, an amino acid adduct of lipoic acid, a peptide adduct of lipoic acid, lipoamide and/or a mixture thereof.

3. A compound as defined in claim 2 wherein the ester of lipoic acid preferably comprise a straight, branch-chained or cyclic acyl group with no more than 8 carbon atoms, preferably with PI or less carbon atoms.

1. A compound as defined in any one of the preceding claims wherein the basic group is a nitrogen-containing group.

2() hi. A compound as defined in any one of the preceding claims wherein the basic group is a -NR. group (wherein R independently represents a hydrogen atom, a straight, branched chain optionally unsaturated alk;yl group containing from I to 8 (preferably from I to 1) carbon atoms or an optionally unsaturated cycloalkyl group containing from.' to 8 carbon 2. atoms), a piperidinyl group' a pyriclinyl group, or a pvrrolidinvl group.

6. A compound as defined in any one of the preceding claims which is a-ll, 2l dithiolan-3-1-pentanoic acid (2-dimethvlamino-ethvl) amide

7. A pharmaceutical formulation including a compound as defined in any one of the preceding claims in association with a pharmaceutically acceptable diluent or carrier.

8. A formulation as defined in claim 7 for use in the treatment or prevention of atherosclerosis or arthritis.

9. Use of a compound as defined in any one of claims I to 6 or of a formulation as defined in claim 7 or claim in the manufacture of a mcdicament for use in the treatment or prevention of atherosclerosis or arthritis.

10. A method of treating or preventing arthritis or atherosclerosis which method comprising administering to a human or animal patient in need of such treatment a therapeutically effective amount of a compound as defined in any one of claims I to 6 or of a formulation as defined in claim 7 or claim S.