NZ545087A

NZ545087A - Novel compounds and compositions comprising sterols and/or stanols and cholesterol biosynthesis inhibitors and use thereof in treating or preventing a variety of diseases and conditions

Info

Publication number: NZ545087A
Application number: NZ545087A
Authority: NZ
Inventors: James P Kutney; Haydn P Pritchard; Tatjana Lukic
Original assignee: Forbes Medi Tech Inc
Priority date: 2003-07-09
Filing date: 2004-07-09
Publication date: 2009-10-30
Also published as: NO20060632L; WO2005005453A3; PL379516A1; MXPA06000326A; RU2006103797A; KR20060052792A; CN1832957A; CA2531836A1; BRPI0412439A; JP2007525470A; AU2004255285A1; WO2005005453A2; EP1644399A2

Abstract

Disclosed is a compound comprising a sterol or stanol, including biologically acceptable salts thereof, having one or more of the formulae a-f wherein R is a sterol or stanol moiety, R2 is a cholesterol biosynthesis inhibitor with at least one free and reactive carboxyl group; R3 is a cholesterol biosynthesis inhibitor with at least one free and reactive hydroxyl group; R4 is derived from ascorbic acid, X is either hydrogen or is selected from the group consisting of a biologically acceptable metal, or an alkali earth metal and n = 1-5, including all biologically acceptable salts or solvates thereof; wherein R is linked in formulae b), c), d) or f) via oxygen, R2 is linked in formulae b), c), d) or f) via a carboxyl function, and R3 is linked in formulae b), c), d) or f) via a hydroxyl group.

Claims

1.WE CLAIM: 1. A compound comprising a sterol or stanol, including biologically acceptable salts thereof, having one or more of the following formulae: a) o R2 —(CH2)n —C —O —R b) R2—R , with the proviso that R2 is not linked to R via a linker Y-CO-CH2-CH2-CO-O-, wherein Y is O or NH; c) o o ii ii r2—c— c-o-r d) 0 ii r3— p—o-r 1 ox e) 0 R2—R, —P —0—R 1 ox f) o o r3—p-r4 -p-o-r ix ix wherein R is a sterol or stanol moiety, R2 is a cholesterol biosynthesis inhibitor with at 545087 least one free and reactive carboxyl group; R3 is a cholesterol biosynthesis inhibitor with at least one free and reactive hydroxyl group; R4 is derived from ascorbic acid, X is either hydrogen or is selected from the group consisting of a biologically acceptable metal, or an alkali earth metal and n=1-5, including all biologically acceptable salts or solvates thereof; wherein R is linked in formulae b), c), d) or f) via oxygen, R2 is linked in formulae b), c), d) or f) via a carboxyl function, and R3 is linked in formulae b), c), d) or f) via a hydroxyl group.

2. A compound according to claim 1, having the formulae a), c), d), e) or f) as defined in claim 1.

3. The compound of claim 1 or claim 2 wherein the sterol is selected from the group consisting of sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, and pollinastasterol.

4. The compound of claim 1 or claim 2 wherein the stanol is selected from the group consisting of sitostanol, campestanol, stigmastanol, brassicastano! (including dihydrobrassicastanol), desmostanol, chalinostanol, poriferastanol, clionastanol, ergostanol, coprostanol, codistanol, isofucostanol, fucostanol, clerostanol, nervistanol, lathostanol, stellastanol, spinastanol, chondrillastanol, pepostanol, avenastanol, isoavenastanol, fecostanol, and poflinastastanol.

5. The compound of claim 1 or claim 2 wherein the sterol and stanol are in either a natural or artificially synthesized form.

6. The compound of claim 1 or claim 2 wherein the sterol and stanoi are in any one of their isomeric forms.

7. The compound of claim 1 or claim 2 wherein the R2 and R3 are selected from the group consisting of competitive inhibitors of HMG CoA reductase, HMG CoA synthase, squalene synthase, and squalene epoxidase.

8. The compound of claim 1 or claim 2 wherein R2 is either atorvastatin or pravastatin.

9. The compound of claim 1 or claim 2 wherein R3 is either simvastatin or lovastatin. 0FF'ce ySfSrT '< SEP to# 49 3uoci oi c\aW 545087 1 having the following formula: AV ^ecomP°' •*<*»** ln91t"mUla'' -vCW HO, r / 12. the coroP00' rt><*d»w' V\avVnQ t^e^ftoWvn9 forrn^3' HO. HO b"M® w .,*-Ar - -s H,C so comP' ,0uomPoun< V\avVr*9 ^oWo^Q ^ocm^a- ■\5. the compo' Df da,rn H4C . „ fnrtn^a- tbefo«°^n9 -* ^ having HaP ,Cfts 51 545087 16. The compound of claim 1 having the following formula: 17. The compound of claim 1 having the following formula: 18. A pharmaceutical composition comprising at least one compound having one or more of the following formulae: a) o r2-~) r2—R , with the proviso that R2 is not linked to R via a linker Y-CO-CH2-CH2-CO-O-, wherein Y is O or NH; c) e) o R2—R4 —p—o-r ! ox 52 545087 O O II u r3—p —fu -p -o-r OX OX wherein R is a sterol or stanof moiety, R2 is a cholesterol biosynthesis inhibitor with at least one free and reactive carboxyl group; R3 is a cholesterol biosynthesis inhibitor with at least one free and reactive hydroxyl group; R4 is derived from ascorbic add, X is either hydrogen or is selected from the group consisting of a biologically acceptable metal, or an alkali earth metal and n=1-5, including all biologically acceptable salts or solvates thereof and a pharmaceutically acceptable carrier therefor; wherein R is linked in formulae b), c), d) or f) via oxygen, R2 is linked in formulae b), c), d) or f) via a carboxyl function, and R3 is linked in formulae b), c), d) or f) via a hydroxyl group. 19. A pharmaceutical composition according to claim 18, wherein the composition comprises a compound having the formulae a), c), d), e) orf) as defined in claim 18. 20. The composition of claim 18 or 19 wherein R2 and R3 are selected from the group consisting of competitive inhibitors of HMG CoA reductase, HMG CoA synthase, squalene synthase, and squalene epoxidase. 21. The composition of claim 18 or 19 wherein R2 is either atorvastatin or provastatin. 22. The composition of claim 18 or 19 wherein R3 is either simvastatin or lovastatin. 23. Use of a non-toxic and therapeutically effective amount of one or more compounds having the following formulae: a) b) r2 r , with the proviso that R2 is not linked to R via a linker Y-C0-CH2-CH2-C0-0-, wherein Y is O or NH; r2 {ch2)n —c —o —r O II 53 c) O O 545087 It JJ Rg —C *—C —*O —R d) o R3 —P —O -R ix e) o r2_a, —p—o—r 6x f) 0 o i! » R3— P— R4-P-0-R 1 1 ox ox wherein R is a sterol or stanol moiety, R2 is a cholesterol biosynthesis inhibitor with at least one free and reactive carboxyl group; R3 is a cholesterol biosynthesis inhibitor with at least one free and reactive hydroxyl group; R4 is derived from ascorbic acid, X is either hydrogen or is selected from the group consisting of a biologically acceptable metal, or an alkali earth metal and n=1-5, including all biologically acceptable salts or solvates thereof; wherein R is linked in formulae b), c), d) or f) via oxygen, R2 is linked in formulae b), c), d) or f) via a carboxyl function, and R3 is linked in formulae b), c), d) or f) via a hydroxyl group; for the manufacture of a pharmaceutical composition for achieving one or more of the following therapeutic goals: a) preventing, treating or alleviating one or more conditions associated with CVD generally and including arteriosclerosis, atherosclerosis, arteriolosclerosis, angina pectoris, and thrombosis; b) reducing and/or eliminating one or more of the risk factors associated with CVD c) preventing, treating or alleviating atherosclerosis; d) preventing, treating or alleviating hypercholesterolemia; e) preventing, treating or alleviating a hyperlipidic condition; f) preventing, treating or alleviating dislipidemia; g) preventing, treating or alleviating hypertension; h) preventing, treating or alleviating coronary artery disease; i) preventing, treating or alleviating coronary plaque development; M SEP ftEC fziy |p n 54 545087 j) preventing, treating or alleviating coronary plaque inflammation; k) lowering serum LDL cholesterol; I) increasing serum HDL cholesterol; m) decreasing serum triglycerides levels; n) decreasing cholesterol biosynthesis; o) preventing, reducing, eliminating or ameliorating a dislipidemic condition or disorder; p) preventing, reducing, eliminating or ameliorating hypercholesterolemia or hypoalphalipoproteinemia, q) preventing, reducing, eliminating, stabilizing or ameliorating the development of atherosclerotic lesions or plaque; r) preventing, reducing, eliminating, or ameliorating the development of inflammation associated with the development of cardiovascular disease and coronary artery disease; s) preventing, reducing, eliminating or ameliorating any condition, disease or disorder which has as its basis or which is exacerbated by a deficiency in plasma HDL, or by an excess of either LDL, VLDL, Lp(a), beta-VLDL, IDL or remnant lipoproteins; t) decreasing the risk of a stroke; u) inhibition of isoprenoid synthesis; v) preventing, treating or alleviating Alzheimer's disease; w) preventing, treating or alleviating dementia; x) preventing, treating or alleviating osteoporosis; y) preventing, reducing, eliminating or ameliorating injuries due to oxidative stress; z) enhancing and/or preserving the stability of HDL from oxidation; aa)enhancing and/or preserving the stability of LDL, VLDL or IDL from oxidation bb)enhancing and/or preserving the stability of triglyceride (TG) from oxidation; cc) exhibiting anti-coagulatant properties; dd)exhibiting anti-proliferative properties; ee)exhibiting immunomodulatory properties; ff) exhibiting angiogenic properties; gg)preventing, treating or alleviating tumour growth; hh)increasing bone mass and/or bone turnover; and ii) enhancing any of the non-lipid related, pleiotropic effects administration of statins, in particular at the cellular and molecular level. INIfu© 0/r$eVftfi«ry u s& 2009 / V£ 55 545087 24. A use according to claim 23, wherein the compound has the formula a), c), d), e) or f) as defined in claim 23. 25. The use of claim 23 or 24 wherein R2 and R3 are selected from the group consisting of competitive inhibitors of HMG CoA reductase, HMG CoA synthase, squalene synthase, and squalene epoxidase. 26. The use of claim 23 or 24 wherein R2 is either atorvastatin or pravastatin. 27. The use of claim 23 or 24 wherein R3 is either simvastatin or lovastatin. 28. A method of achieving one or more of the following therapeutic goals in a non-human animal: a) preventing, treating or alleviating one or more conditions associated with CVD generally and including arteriosclerosis, atherosclerosis, arteriolosclerosis, angina pectoris, and thrombosis; b) reducing and/or eliminating one or more of the risk factors associated with CVD c) preventing, treating or alleviating atherosclerosis; d) preventing, treating or alleviating hypercholesterolemia; e) preventing, treating or alleviating a hyperlipidic condition; f) preventing, treating or alleviating dislipidemia; g) preventing, treating or alleviating hypertension; h) preventing, treating or alleviating coronary artery disease; i) preventing, treating or alleviating coronary plaque development; j) preventing, treating or alleviating coronary plaque inflammation; k) lowering serum LDL cholesterol; I) increasing serum HDL cholesterol; m) decreasing serum triglycerides levels; n) decreasing cholesterol biosynthesis; o) preventing, reducing, eliminating or ameliorating a dislipidemic condition or disorder; p) preventing, reducing, eliminating or ameliorating hypercholesterolemia or hypoalphalipoproteinemia, q) preventing, reducing, eliminating, stabilizing or ameliorating the development of atherosclerotic lesions or plaque; r) preventing, reducing, eliminating, or ameliorating the development of inflammation associated with the development of cardiovascular disease and coronary artery disease; 56 545087 s) preventing, reducing, eliminating or ameliorating any condition, disease or disorder which has as its basis or which is exacerbated by a deficiency in plasma HDL, or by an excess of either LDL, VLDL, Lp(a), beta-VLDL. IDL or remnant lipoproteins; t) decreasing the risk of a stroke; u) inhibition of isoprenoid synthesis; v) preventing, treating or alleviating Alzheimer's disease; w) preventing, treating or alleviating dementia; x) preventing, treating or alleviating osteoporosis; y) preventing, reducing, eliminating or ameliorating injuries due to Oxidative stress; z) enhancing and/or preserving the stability of HDL from oxidation; aa)enhancing and/or preserving the stability of LDL, VLDL or IDL from oxidation bb)enhancing and/or preserving the stability of triglyceride (TG) from oxidation; cc) exhibiting anti-coagulatant properties; dd)exhibiting anti-proliferative properties; ee)exhibiting immunomodulatory properties; ff) exhibiting angiogenic properties; gg)preventing, treating or alleviating tumour growth; hh)increasing bone mass and/or bone turnover; and ii) enhancing any of the non-lipid related, pleiotropic effects achieved by the= administration of statins, in particular at the cellular and molecular level which comprises administering to a non-human animal, a non-toxic and therapeutically effective amount of one or more compounds having the following formulae: o m r2—(ch2)n —c—o-r b) R2—R , with the proviso that R2 is not linked to R via a linker Y-C0-CH2-CH2-C0-0-, wherein Y is O or NH; c) o o 11 U r2 —c —c -o-r 0 II r3—p—o-r 1 ox 57 e) 545087 o R2 —R< —P—O—R ix f) O o r3 —p —r4 -p —o —r ox ox wherein R is a sterol or stanol moiety, R2 is a cholesterol biosynthesis inhibitor with at least one free and reactive carboxyl group; R3 is a cholesterol biosynthesis inhibitor with at least one free and reactive hydroxyl group; R4 is derived from ascorbic acid, X is either hydrogen or is selected from the group consisting of a biologically acceptable metal, or an alkali earth metal and n=1-5, including all biologically acceptable salts or solvates thereof; wherein R is linked in formulae b), c), d) or f) via oxygen, R2 is linked in formulae b), c), d) orf) via a carboxyl function, and R3is linked in formulae b), c), d) orf) via a hydroxyl group. 29. A method according to claim 28, wherein the compound has the formula a), c), d), e) or f) as defined in claim 28. 30. The method of claim 28 or 29 wherein R2 and R3 are selected from the group consisting of competitive inhibitors of HMG CoA reductase, HMG CoA synthase, squalene synthase, and squalene epoxidase. 31. The method of claim 28 or 29 wherein R2 is either atorvastatin or pravastatin. 32. The method of claim 28 or 29 wherein R3 is either simvastatin or lovastatin. 33. A compound according to claim 1, substantially as herein described or exemplified. 34. A pharmaceutical composition according to claim 18, substantially as herein described or exemplified. 35. A use according to claim 23, substantially as herein described or exemplified. 36. A method according to claim 28, substantially as herein described or exemplified. 58