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Title:
COMPOSITIONS FOR THE TREATMENT OF HYPERTENSION AND/OR FIBROSIS
Document Type and Number:
WIPO Patent Application WO/2018/053587
Kind Code:
A1
Abstract:
The present invention relates to novel compounds and their use in the prophylactic and/or therapeutic treatment of hypertension and/or fibrosis.

Inventors:
DUGGAN KAREN ANNETTE (AU)
WINKLER DAVID ALAN (AU)
Application Number:
PCT/AU2017/051026
Publication Date:
March 29, 2018
Filing Date:
September 21, 2017
Export Citation:
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Assignee:
VECTUS BIOSYSTEMS LTD (AU)
International Classes:
C07C251/38; A61K31/15; A61K31/341; A61K31/343; A61K31/381; A61K31/40; A61K31/4025; A61K31/4035; A61K31/415; A61K31/4166; A61K31/4192; A61K31/42; A61K31/421; A61K31/423; A61K31/426; A61K31/428; A61K31/435; A61K31/44; A61K31/506; A61P9/12; C07C251/36; C07D207/12; C07D207/273; C07D207/335; C07D209/18; C07D209/34; C07D209/48; C07D213/53; C07D213/68; C07D215/227; C07D231/12; C07D231/56; C07D233/40; C07D235/08; C07D235/10; C07D235/26; C07D239/26; C07D249/18; C07D261/08; C07D261/14; C07D263/06; C07D263/24; C07D263/58; C07D277/28; C07D277/68; C07D307/52
Domestic Patent References:
WO2010026771A12010-03-11
Foreign References:
US9133116B22015-09-15
JP2010248273A2010-11-04
GB2094794A1982-09-22
GB1445979A1976-08-11
US5171354A1992-12-15
JPH06145151A1994-05-24
US4425340A1984-01-10
US20060178527A12006-08-10
US20070173495A12007-07-26
Other References:
PRITHWIRAJ DE ET AL.: "Cul-mediated cross-coupling of aryl halides with oximes: A direct access to O-aryloximes", ORGANIC LETTERS, vol. 9, no. 15, 20 June 2007 (2007-06-20), pages 2767 - 2770, XP055394168, Retrieved from the Internet
BARANOWSKJ, A. ET AL.: "C-Acylation of the azomethine group in some O-substituted aromatic aldoximes. Part II", POLISH JOURNAL OF CHEMISTRY, vol. 66, 1992, pages 1941 - 1951
JIANG, Y ET AL.: "Expedient synthesis of highly substituted pyrroles via tandem rearrangement of alpha-diazo oxime ethers", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 134, no. 9, 14 February 2012 (2012-02-14), pages 4104 - 4107, XP055074776, Retrieved from the Internet
DATABASE CAS 16 September 2011 (2011-09-16), retrieved from STN Database accession no. 1332620-74-2
WANG, G. ET AL.: "A DFT study on formation of bisaryl oxime ether from benzaldehyde and phenoxyamine", CHEMISTRY LETTERS, vol. 37, no. 6, 5 June 2008 (2008-06-05), pages 656 - 657, XP055497786, Retrieved from the Internet
Attorney, Agent or Firm:
SHELSTON IP PTY LTD (AU)
Download PDF:
Claims:
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-

1. A compound of the formula

wherein:

X is:

or

Ri to R9 are independently C, N, O or S;

Rio is independently selected from Ci-6alkyl, halo, C0-6alkyl carboxylic acid, amino, hydroxy and Ci.6alkoxy;

Y is A, CH2-A or CH=A;

A is selected from optionally substituted saturated, partly saturated or unsaturated 5- or 6-membered heterocyclyl; optionally substituted Ci.6alkoxyl amine; optionally substituted Ci.6alkyl amine; optionally substituted C0-6alkyl carboxylic acid; optionally substituted Ci.6alkyl hydroxyl; optionally substituted saturated or unsaturated C0-6alkyl bicyclic heterocyclyl; and optionally substituted saturated or unsaturated Ci.6alkoxyl bicyclic heterocyclyl;

Z is selected from the group consisting of:

and

Rn is independently selected from halo, alkyl, hydroxy, amino and substituted amino; Ri2, Ri4 and R15 are independently C, CH, CH2, O, N, NH or S;

Ri3 is C, CH, CH2, N , NH, C-CF3, CH-CF3 or C=0;

m is 0, 1 , 2, 3, 4 or 5; and

n is 0, 1 , 2, 3 or 4,

or a stereoisomer or pharmaceutically acceptable salt thereof.

2. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 wherein R10 is independently selected from -CH3, -C(0)OH, -F, -NH2, -OH and -OCH3.

3. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R5 to R9 are independently C or N.

4. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the C0-6alkyl carboxylic acid is carboxylic acid.

5. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the saturated, partly saturated or unsaturated 5- or 6- membered heterocyclyl contains one or more of N, S or O, optionally substituted with one or more oxo, Ci_6alkyl, amino, hydroxyl or halo substituents.

6. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the saturated, partly saturated or unsaturated 5- or 6- membered heterocyclyl is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, imidazolidinyl, pyrrolidinyl, pyrrolidinylidene, dihydropyrrolyl, isoxazolyl dihydrooxazolyl, isoxazolidinyl, oxazolidinyl and oxazolyl, optionally substituted with one or more oxo, Ci.6alkyl, amino, hydroxyl or halo substituents.

7. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the Ci.6alkoxyl amine is aminooxymethyl.

8. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the Ci-6alkyl amine is optionally substituted with one or more of Ci-6alkyl, d_6halo alkyl, hydroxyl or halo, preferably mono-, di- or tri-substituted halo alkyl, most preferably tri-fluoro methane.

9. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the Ci-6alkyl hydroxyl is methyl hydroxyl.

10. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the C0-6alkyl bicyclic heterocyclyl is selected from indolyl, isoindolyl, insolinyl and isoindolinyl, optionally substituted with one or more oxo, preferably dioxo.

11. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the Ci.6alkoxyl bicyclic heterocyclyl is selected indolyl, isoindolyl, insolinyl and isoindolinyl, optionally substituted with one or more oxo, and wherein the Ci.6alkoxyl is methoxy or ethoxy.

12. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein A is selected from:

13. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein Rn is halo selected from the group consisting of F, CI, Br and I.

14. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein is substituted amino of the formula -NHR 6 and wherein:

R16 is selected from -CN, -S02(Ri7)aRi8 and -CO(Ri7)aRi8,

a is 0 or 1 ,

Ri7 is selected from -NH- and -0-, and

R18 is selected from -H, -CH3, -CH2CH3, -CH2OH and -CH2CH2OH.

15. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein Rn is substituted amino selected from the group consisting of -NHS02CH3, -NHCOH, -NHCONHCH3, -NHCONHCH2CH3, -NHS02NHCH3,

-NHS02NHCH2CH3, -NHCOCH3, -NHCOOCH3, -NHCOOCH2CH2OH, -NHCONH2 and -NHCN.

16. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl.

17. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is selected from the group consisting of:

-40-

18. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is:

19. A pharmaceutical composition comprising a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18 and a pharmaceutically-acceptable excipient.

20. A method for the therapeutic treatment of hypertension or prehypertension in a subject comprising administering to the subject a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18 or a composition according to claim 19.

21 A method for the prophylactic treatment of fibrosis in a subject comprising administering to the subject a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18 or a composition according to claim 19.

22. A method for the therapeutic treatment of fibrosis in a subject comprising administering to the subject a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18 or a composition according to claim 19.

23. A method for the therapeutic treatment of hypertension and fibrosis in a subject comprising administering to the subject a compound, or a stereoisomer or

pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18 or a composition according to claim 19.

24. A method for the treatment of prehypertension and fibrosis in a subject comprising administering to the subject a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18 or a composition according to claim 19.

25. The method according to any one of claims 21 to 24 wherein the fibrosis selected from myocardial fibrosis, kidney fibrosis, liver fibrosis and lung fibrosis.

26. An alpha helix backbone having the structure:

Description:
COMPOSITIONS FOR THE TREATMENT OF HYPERTENSION AND/OR FIBROSIS

FIELD OF THE INVENTION

[0001] The present application claims priority from Australian Provisional Patent Application No. 2016903799 (filed 21 September 2016), the contents of which are incorporated in their entirety herein.

[0002] The present invention relates to novel compounds and their use in the prophylactic and/or therapeutic treatment of cardiovascular disease, and in particular the treatment of prehypertension, hypertension and/or fibrotic conditions.

[0003] The invention has been developed primarily for the prophylactic and/or therapeutic treatment of cardiovascular disease and will be described hereinafter with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of use.

BACKGROUND OF THE INVENTION

[0004] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0005] Hypertension (high blood pressure) affects 26% of the adult population worldwide with an incidence of 30-33% in western countries. The world wide incidence of hypertension is expected to reach 29% by 2025 as a consequence of the

westernisation of India and China. Current studies indicate that fewer than 20% of patients with hypertension attain their recommended blood pressure (BP) target and that to achieve these targets >75% of patients require therapy with multiple antihypertensive agents. Prehypertension (slightly elevated blood pressure) affects 31 % of adults in the US and may develop into hypertension if not treated.

[0006] Hypertension and prehypertension are a major factor in the development of blood vessel damage in a variety of organs, resulting in the replacement of normal functional tissue by scar tissue or fibrosis. Some of the current antihypertensive agents are able to slow the progression of the replacement of functional tissue by fibrosis, but none have been shown to reverse existing fibrosis and restore normal tissue

architecture. There is thus a need for agents which have the efficacy to reduce BP significantly and thus enable a larger proportion of patients to attain BP target with single agent therapy and/or to reverse existing fibrosis and/or restore normal tissue

architecture.

[0007] It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

SUMMARY OF THE INVENTION

[0008] Surprisingly, the present inventors have found that certain compounds have blood pressure lowering and/or anti-fibrotic effects. These effects may be seen in intravenous and/or oral dosing studies.

[0009] According to one aspect, the present invention provides a compound of the formula

wherein:

X is:

or

Ri to R 9 are independently C, N, O or S;

Rio is independently selected from Ci -6 alkyl, halo, C 0 - 6 alkyl carboxylic acid, amino, hydroxy and Ci. 6 alkoxy;

Y is A, CH 2 -A or CH=A;

A is selected from optionally substituted saturated, partly saturated or unsaturated 5- or 6-membered heterocyclyl; optionally substituted d_ 6 alkoxyl amine; optionally substituted C -6 alkyl amine; optionally substituted C 0 . 6 alkyl carboxylic acid; optionally substituted C -6 alkyl hydroxyl; optionally substituted saturated or unsaturated C 0 . 6 alkyl bicyclic heterocyclyl; and optionally substituted saturated or unsaturated d. 6 alkoxyl bicyclic heterocyclyl;

Z is selected from the group consisting of:

Rn is independently selected from halo, alkyl, hydroxy, amino and substituted amino; Ri2, Ri4 and R 15 are independently C, CH, CH 2 , O, N, NH or S;

Ri 3 is C, CH, CH 2 , N, NH, C-CF 3 , CH-CF 3 or C=0;

m is 0, 1 , 2, 3, 4 or 5; and

n is 0, 1 , 2, 3 or 4,

or a stereoisomer or pharmaceutically acceptable salt thereof.

[0010] In one embodiment, R 10 is independently selected from -CH 3 , -C(0)OH, -F, -NH 2 , -OH and -OCH 3 .

[001 1] In one embodiment, R 5 to R 9 are independently C or N.

[0012] In one embodiment, the C 0 - 6 alkyl carboxylic acid is carboxylic acid. [0013] In one embodiment, the saturated, partly saturated or unsaturated 5- or 6- membered heterocyclyl contains one or more of N, S or O, optionally substituted with one or more oxo, d_ 6 alkyl, amino, hydroxyl or halo substituents.

[0014] In one embodiment, the saturated, partly saturated or unsaturated 5- or 6- membered heterocyclyl is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, imidazolidinyl, pyrrolidinyl, pyrrolidinylidene, dihydropyrrolyl, isoxazolyl dihydrooxazolyl, isoxazolidinyl, oxazolidinyl and oxazolyl, optionally substituted with one or more oxo, Ci. 6 alkyl, amino, hydroxyl or halo substituents.

[0015] In one embodiment, the Ci. 6 alkoxyl amine is aminooxymethyl.

[0016] In one embodiment, the Ci -6 alkyl amine is optionally substituted with one or more of Ci -6 alkyl, Ci_ 6 halo alkyl, hydroxyl or halo, preferably mono-, di- or tri-substituted halo alkyl, most preferably tri-fluoro methane.

[0017] In one embodiment, the Ci -6 alkyl hydroxyl is methyl hydroxyl.

[0018] In one embodiment, the C 0 - 6 alkyl bicyclic heterocyclyl is selected from indolyl, isoindolyl, insolinyl and isoindolinyl, optionally substituted with one or more oxo, preferably dioxo.

[0019] In one embodiment, the Ci. 6 alkoxyl bicyclic heterocyclyl is selected indolyl, isoindolyl, insolinyl and isoindolinyl, optionally substituted with one or more oxo, and wherein the Ci. 6 alkoxyl is methoxy or ethoxy.

[0020] In one embodiment, A is selected from:

[0021] In one embodiment, is halo selected from the group consisting of F, CI, Br and I.

[0022] In one embodiment, is substituted amino of the formula -NHR 6 and wherein:

R 16 is selected from -CN, -S0 2 (Ri 7 ) a Ri8 and -CO(Ri 7 ) a Ri 8 ,

a is 0 or 1 ,

Ri 7 is selected from -NH- and -0-, and

R 18 is selected from -H, -CH 3 , -CH 2 CH 3 , -CH 2 OH and -CH 2 CH 2 OH.

[0023] In one embodiment, Rn is substituted amino selected from the group consisting of -NHS0 2 CH 3 , -NHCOH, -NHCONHCH3, -NHCONHCH 2 CH 3 , -NHS0 2 NHCH 3 , -NHS0 2 NHCH 2 CH 3 , -NHCOCH 3 , -NHCOOCH 3, -NHCOOCH 2 CH 2 OH, -NHCONH 2 and

-NHCN.

[0024] In one embodiment, Rn is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl.

[0025] In one embodiment, the compound is selected from the group consisting of:

[0026] In one embodiment, the compound is:

[0027] According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0028] According to another aspect, the present invention relates to a method for the therapeutic treatment of hypertension or prehypertension in a subject comprising administering to the subject a compound according to the present invention.

[0029] According to another aspect, the present invention relates to a method for the therapeutic treatment of fibrosis in a subject comprising administering to the subject a compound according to the present invention.

[0030] According to another aspect, the present invention relates to a method for the prophylactic treatment of fibrosis in a subject comprising administering to the subject a compound according to the present invention.

[0031] According to another aspect, the present invention relates to a method for the therapeutic treatment of hypertension and fibrosis in a subject comprising administering to the subject a compound according to the present invention.

[0032] According to another aspect, the present invention relates to a method for the therapeutic treatment of prehypertension and fibrosis in a subject comprising

administering to the subject a compound according to the present invention. [0033] According to another aspect, the present invention relates to a compound of the present invention for use in the therapeutic treatment of hypertension or

prehypertension.

[0034] According to another aspect, the present invention relates to a compound of the present invention for use in the therapeutic treatment of fibrosis.

[0035] According to another aspect, the present invention relates to a compound of the present invention for use in the prophylactic treatment of fibrosis.

[0036] According to another aspect, the present invention relates to a compound of the present invention for use in the therapeutic treatment of hypertension and fibrosis.

[0037] According to another aspect, the present invention relates to a compound of the present invention for use in the therapeutic treatment of prehypertension and fibrosis.

[0038] According to another aspect, the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of hypertension or prehypertension.

[0039] According to another aspect, the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of fibrosis.

[0040] According to another aspect, the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the prophylactic treatment of fibrosis.

[0041] According to another aspect, the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of hypertension and fibrosis.

[0042] According to another aspect, the present invention relates to use of a compound of the present invention for the manufacture of a medicament for the therapeutic treatment of prehypertension and fibrosis.

[0043] In one embodiment, the fibrosis is myocardial fibrosis.

[0044] In one embodiment, the fibrosis is kidney fibrosis.

[0045] In one embodiment, the fibrosis is liver fibrosis.

[0046] In one embodiment, the fibrosis is lung fibrosis.

[0047] According to another aspect, the present invention relates to an alpha helix backbone having the structure:

[0048] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

BRIEF DESCRIPTION OF THE FIGURES

[0049] Figure 1 : Synthesis scheme for (3E)-3-(3-hydroxyphenoxy)imino-3-phenyl- propanamide (VB0001).

[0050] Figure 2: Synthesis scheme for 0-[3-[tert-butyl(dimethyl)silyl]oxyphenyl] hydroxylamine (compound A).

[0051] Figure 3: Systolic blood pressure in SHR on a 2.2% salt diet with VB0001 (in 20% DMSO) at a dose of 20 pmol/kg/min or vehicle control (20% DMSO) administered intravenously via an osmotic minipump for 4 weeks. * p<0.0005 vs 18 week control.

[0052] Figure 4: Myocardial fibrosis in SHR on a 2.2% salt diet with VB0001 (in 20% DMSO) at a dose of 20 pmol/kg/min or vehicle control (20% DMSO) administered intravenously via an osmotic minipump for 4 weeks. * p<0.0005 vs 18 week control.

DETAILED DESCRIPTION OF THE INVENTION

[0053] The present invention relates to certain compounds that show blood pressure lowering and anti-fibrotic effects in oral dosing studies in an experimental animal model. With respect to anti-fibrotic activity, the compounds of the present invention are effective in preventing fibrosis, slowing down progression of established fibrosis and/or reducing the degree (reversal) of established fibrosis. These are important findings with respect to the range and severity of conditions which can be treated with the compounds of the present invention.

[0054] The compounds of the present invention are represented by the formula:

wherein: X is:

Ri to R 9 are independently C, N, O or S;

R 0 is independently selected from Ci -6 alkyl, halo, C 0 . 6 alkyl carboxylic acid, amino, hydroxy and d_ 6 alkoxy;

Y is A, CH 2 -A or CH=A;

A is selected from optionally substituted saturated, partly saturated or unsaturated 5- or 6-membered heterocyclyl; optionally substituted Ci_ 6 alkoxyl amine; optionally substituted Ci. 6 alkyl amine; optionally substituted C 0 - 6 alkyl carboxylic acid; optionally substituted Ci. 6 alkyl hydroxyl; optionally substituted saturated or unsaturated C 0 - 6 alkyl bicyclic heterocyclyl; and optionally substituted saturated or unsaturated Ci. 6 alkoxyl bicyclic heterocyclyl;

Z is selected from the group consisting of:

and

Rn is independently selected from halo, alkyl, hydroxy, amino and substituted amino; Ri2, Ri4 and R 15 are independently C, CH, CH 2 , O, N, NH or S;

Ri3 is C, CH, CH 2 , N, NH, C-CF 3 , CH-CF 3 or C=0;

m is 0, 1 , 2, 3, 4 or 5; and

n is 0, 1 , 2, 3 or 4,

or a stereoisomer or pharmaceutically acceptable salt thereof.

[0055] The following compounds are specific, but non-limiting, examples of the compounds of the present invention:

[0056] As used herein, the term "halo" designates -F, -CI, -Br or -I; the term "hydroxy" means -OH; the term "amino" means -NH 2 ; and the term "substituted amino" includes - NHW, wherein W is selected from -CN, -S0 2 (X) a Y and -CO(X) a Y, a is 0 or 1 , X is selected from -NH- and -0-, and Y is selected from -H, -CH 3 , -CH 2 CH 3 , -CH 2 OH and - CH 2 CH 2 OH.

[0057] As used herein, the abbreviations Me, Et, Ph, Ms represent methyl, ethyl, phenyl, and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference. [0058] Compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0059] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0060] In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.

[0061] The present invention also contemplates pharmaceutically acceptable salts of the compounds. The term "pharmaceutically acceptable salt" includes both acid and base addition salts and refers to salts which retain the biological effectiveness and properties of the free bases or acids, and which are not biologically or otherwise undesirable. The pharmaceutically acceptable salts are formed with inorganic or organic acids or bases, and can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.

[0062] The term "fibrosis" as used in the context of the present invention includes, but is not limited to, myocardial fibrosis, kidney fibrosis, liver fibrosis and/or lung fibrosis.

[0063] In addition to treatment of established fibrosis, the compounds of the present invention may be used prophylactically in subjects at risk of developing fibrosis. As an example of subjects in the risk category for developing fibrosis are those having hypertension, diabetes, myocarditis, ischaemic heart disease, Conn's Syndrome, pheochromocytoma, genetic predisposition high salt diet and/or receiving drugs used in cancer chemotherapy (such as daunorubicin). The term "prophylactic" as used in the context of the present invention is intended inter alia to encompass treatments used to prevent or slow down the development of fibrosis in the at risk group. Subjects who may be given prophylactic treatment may already have signs of early heart failure on echocardiography.

[0064] The term "hypertension" as used in the context of the present invention indicates an adult blood pressure of above about 139 mmHg systolic and/or above about 89 mmHg diastolic.

[0065] The term "prehypertension" as used in the context of the present invention indicates an adult blood pressure in the range about 120-139 mmHg systolic and/or about 80-89 mmHg diastolic.

[0066] The present invention also contemplates pharmaceutical compositions which include the compounds of the present invention, in conjunction with acceptable pharmaceutical excipients. The term "pharmaceutically acceptable excipient" as used in the context of the present invention means any pharmaceutically acceptable inactive component of the composition. As is well known in the art, excipients include diluents, buffers, binders, lubricants, disintegrants, colorants, antioxidants/preservatives, pH- adjusters, etc. The excipients are selected based on the desired physical aspects of the final form: e.g. obtaining a tablet with desired hardness and friability being rapidly dispersible and easily swallowed etc. The desired release rate of the active substance from the composition after its ingestion also plays a role in the choice of excipients. Pharmaceutical compositions may include any type of dosage form such as tablets, capsules, powders, liquid formulations, delayed or sustained release, patches, snuffs, nasal sprays and the like. The physical form and content of the pharmaceutical compositions contemplated are conventional preparations that can be formulated by those skilled in the pharmaceutical formulation field and are based on well established principles and compositions described in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition, 1995; British Pharmacopoeia 2000 and similar formulation texts and manuals.

[0067] For example, where the compounds or compositions are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups; or for parenteral administration, they may be formulated as injections (intravenous,

intramuscular or subcutaneous), drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, they may be formulated as eyedrops or eye ointments. These formulations can be prepared by conventional means, and, if desired, the active ingredient may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.

[0068] When the compound(s) of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a

pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0069] The dosage of a compound and frequency of administration that should be used can also be easily determined by the practicing physician in order to produce the desired response.

[0070] Although the dosage will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, in general, a daily dosage of from 0.0001 mg to 200 mg of the compound of the present invention may be a suitable effective amount for an adult human patient, and this may be administered in a single dose or in divided doses.

[0071] A "patient" or "subject" to be treated by the subject method can mean either a human or non-human subject.

[0072] An "effective amount" of a subject compound, with respect to a method of treatment, refers to an amount of the therapeutic in a preparation which, when applied as part of a desired dosage regimen provides a benefit according to clinically acceptable standards for the treatment or prophylaxis of a particular disorder.

[0073] The present invention will now be described in more detail with reference to specific but non-limiting examples describing specific compositions and methods of use. It is to be understood, however, that the detailed description of specific procedures, compositions and methods is included solely for the purpose of exemplifying the present invention. It should not be understood in any way as a restriction on the broad description of the inventive concept as set out above.

EXAMPLES

Example 1 - Synthesis of compounds

[0074] The synthetic route used to prepare (E)-3-(3-Hydroxyphenoxyimino)-3- phenylpropanamide (VB0001 ) is shown in Figure 1. Firstly, an aminolysis reaction between ethyl benzoylacetate and ammonia gave β-ketoamide 1 , which was subsequently condensed with aryloxyamine A to afford O-aryloxime ether 2. A final deprotection reaction yielded VB0001 .

[0075] Compound A was not commercially available, and was prepared as shown in Figure 2. 3-(fert-Butyldimethylsilyloxy)phenylboronic acid was cross-coupled [in the presence of a copper(ll) salt] with A/-hydroxyphthalimide to afford A/-aryloxyphthalimide 3. Compound 3 was then converted in situ to aryloxyamine A

[0076] 3-Oxo-3-phenylpropanamide (1). Ethyl benzoylacetate (21.35 g, 1 11.2 mmole) and 25% aqueous ammonia solution (200 ml_) were stirred in a stoppered flask for 1 week. The volume of solvent was reduced to about 50% by rotary evaporation. The solid was collected by filtration giving 3-oxo-3-phenylpropanamide (6.83 g, 38%) as a pale yellow solid. Further 3-oxo-3-phenylpropanamide (7.52 g, 41 %) was obtained by concentrating the mother liquor to dryness and triturating with diethyl ether. The compound was used without further purification. H NMR analysis indicated the product existed as a mixture of tautomers.

[0077] (E)-3-[3-(tert-butyldimethylsilyloxy)phenoxyimino]-3-phenylp ropanamide (2). A stirred suspension of 2-[3-(tert-butyldimethylsilyloxy)phenoxy]isoindoline-1 ,3-dione (2.6 g, 7.0 mmole) and Ν,Ν-diethylethylene diamine (1.49 ml_, 10.5 mmole) in ethanol (20 ml_) was heated at gentle reflux for 10 min. The reaction mixture was cooled to room temperature, acetic acid (1.2 ml_) and 3-oxo-3-phenylpropanamide (1.13 g, 7.0 mmole) were added and the reaction was stirred for 10 days. Ethanol was removed in vacuo and the residue partitioned between 20% citric acid and diethyl ether. The layers were separated and the aqueous layer extracted twice more with diethyl ether. The combined organic extracts were washed with water, dried and concentrated in vacuo to give a yellow/tan oil (2.69 g). The crude material was preadsorbed onto Celite and

chromatographed on silica by Dry Column Vacuum Chromatography (DCVC) eluting with chloroform to give (E)-3-[3-(tert-butyldimethylsilyloxy)phenoxyimino]-3- phenylpropanamide (1.28 g, 48%)as a yellow oil. 1 H NMR (400 MHz, CDCI3) δ 7.91- 7.84 (m, 2H), 7.47-7.40 (m, 3H), 7.19 (t, J=8.2 Hz, 1 H), 6.92 (dd, J=8.2, 2.3 Hz, 1 H), 6.84 (t, J=2.3 Hz, 1 H), 6.59 (dd, J=8.2, 2.3 Hz, 1 H), 6.1 1 (br s, 1 H), 6.05 (br s, 1 H), 3.95 (s, 2H), 1.01 (s, 9H), 0.24 (s, 6H). 13C NMR (50 MHz, CDCI3) δ 169.3, 159.8, 156.8, 155.2, 134.1 , 130.5, 129.8, 128.8, 126.7, 1 14.8, 107.9, 107.1 , 36.1 , 25.7, 18.2, -4.4. EIMS: m/z 384 [M]+. HRMS calcd for C21 H28N203Si 384.1864, found 384.1864. A small amount of VB0001 also eluted off the silica gel column. This was recrystallised from methanol and water to give VB0001 as a cream solid (0.103 g, 5%). [0078] (£)-3-(3-Hydroxyphenoxyimino)-3-phenylpropanamide (VB0001). To a stirred solution of ( E)-3-[3-(ferf-butyldimethylsilyloxy)phenoxyimino]-3- phenylpropanamide (1.095 g, 2.85 mole) in THF (18 ml_), under a nitrogen atmosphere and cooled in an ice-bath, was added tetrabutylammonium fluoride (1 M in THF) (4 ml_, 4.0 mmol). The colour changed from bright yellow to tan immediately. After 5 min the solvent was removed in vacuo at -26 °C. The residue was partitioned between water (50 ml_) and ethyl acetate (50ml_). The aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were dried and concentrated in vacuo to give a dark tan oil which solidified. The crude material was triturated with methanol to remove the greenish brown 'goo'. The solid was recrystallised from / ' so-propanol and water to give ( E)-3-(3-hydroxyphenoxyimino)-3-phenylpropanamide (0.45 g, 41 %) as a cream solid; mp 162.5-164.4 °C. H NMR (400 MHz, CD 3 OD) δ 7.85-7.80 (m, 2H), 7.46- 7.42 (m, 3H), 7.11 (t, J^8.2 Hz, 1 H), 6.80-6.77 (m, 1 H), 6.75-6.71 (m, 1 H), 6.50-6.45 (m, 1 H), 3.94 (s, 2H). 3 C NMR (50 MHz, CD 3 OD) δ 173.1 , 161.8, 159.6, 156.9, 136.4, 131.0, 130.7, 129.6, 127.9, 110.6, 107.0, 103.1 , 35.4. EIMS: m/z 270 [M] + . H RMS calcd for C 15 H 14 N20 3 270.0999, found 270.1004.

[0079] 2-[3-( r ferf-butyldimethylsilyloxy)phenoxy]isoindoline-1 ,3-dione (3). N- hydroxyphthalimide (2.23 g, 13.7 mmole), anhydrous copper(ll) acetate (2.75 g, 15.1 mmole), freshly activated 4A molecular sieves (3.5 g) and pyridine (1.24 ml_, 15.4 mmole) in dry dichloromethane (70 ml_) was stirred under a nitrogen atmosphere. After 4 h, 3-(fert-butyldimethylsilyloxy)phenylboronic acid (6.87 g, 27.3 mmole) was added to the dark green reaction mixture, and it was opened to the air and stirred for 17 h at ambient temperature. The emerald-green reaction mixture was poured onto a short silica column and crude 2-[3-(ferf-butyldimethylsilyloxy)phenoxy]isoindoline-1 ,3-dione (4.89 g) was eluted with chloroform, then preadsorbed onto Celite and then

chromatographed on silica by DCVC eluting with a gradient of ethyl acetate in PE (0-20% ethyl acetate) to give 2-[3-(ferf-butyldimethylsilyloxy)phenoxy]isoindoline-1 ,3-dione (3.13 g, 62%) as a cream solid. H NMR (400 MHz, CDCI 3 ) δ 7.95-7.89 (m, 2H), 7.85-7.79 (m, 2H), 7.15 (t, J^8.2 Hz, 1 H), 6.74 (dd, J^8.2, 2.2 Hz, 1 H), 6.68 (t, J=2.4 Hz, 1 H), 6.61 (dd, J^8.2, 2.4 Hz, 1 H), 0.96 (s, 9H), 0.19 (s, 6H). 3 C NMR (50 MHz, CDCI 3 ) δ 162.8, 159.8, 156.9, 134.9, 130.0, 128.8, 123.9, 1 16.3, 107.0, 106.9, 25.6, 18.1 , -4.5. EIMS: m/z 369 [M] + . HRMS calcd for C 20 H 23 NO 4 Si 369.1396, found 369.1380.

Example 2 - in vivo experiments

[0080] Fourteen week old spontaneous hypertensive rats (SHR; Australian Animal Resources Centre, WA) on a 2.2% salt diet (Glenn Forrest Stockfeeders, WA) were randomized to the following treatment group: 14-week control, or VB0001 infusion (20 pmol/kg/min in 20% DMSO) or vehicle control infusion (20% DMSO) for 4 weeks.

VB0001 and vehicle control infusions were via Alzet osmotic minipump, which was inserted under general anaesthesia (Isoflurane 3% in oxygen) at 14 weeks.

[0081] The 14-week control group were anaesthetized using isoflurane (3%) delivered in oxygen, then had blood sampled and hearts and kidneys harvested for quantitation of fibrosis. The remaining groups were weighed and had blood pressure measured by tail cuff plethysmography (ADI Instruments) twice weekly for a further 4 weeks. After 4 weeks treatment, rats were anaesthetized and samples collected as per the 14-week control group. Results are mean + sem for n=5 rats per group.

[0082] For quantitation of fibrosis, tissue slices < 3 mm thick were fixed in 10% buffered formalin for 24 hours, processed and embedded in paraffin. Three μηι transverse sections were stained using Masson's Trichrome. A minimum of 20 random fields at 40x magnification from transverse sections (5 at each of 2 levels) were digitized. The degree of fibrosis was determined as a percent of field area of each digitized image using Image-Pro Plus V.5 (Media Cybernetics, Bethesda, MD, USA), and then averaged to determine the level of fibrosis for each rat.

[0083] Systolic blood pressure in rats treated with VB0001 was reduced compared to 18 week controls (Figure 3), showing that this compound is effective in lowering blood pressure.

[0084] Myocardial fibrosis in rats treated with VB0001 was reduced compared to 18 week controls (Figure 4), showing that this compound reduces the development of myocardial fibrosis.

[0085] Myocardial fibrosis in rats treated with VB0001 was also reduced compared to 14 week controls (Figure 4), showing that this compound reverses established myocardial fibrosis.