WO1998028312A1

WO1998028312A1 - Pharmaceutical aminophosphonic acid derivatives

Info

Publication number: WO1998028312A1
Application number: PCT/GB1997/003479
Authority: WO
Inventors: Lan Mong Nguyen; Hieu Trung Phan; Raymond Azoulay; Alexia Christinat; Eric Niesor; Craig Leigh Bentzen; Robert John Ife
Original assignee: Symphar S.A.; Smithkline Beecham Plc
Priority date: 1996-12-20
Filing date: 1997-12-18
Publication date: 1998-07-02
Also published as: GB9626616D0

Abstract

Aminophosphonates alpha substituted by phenol groups, of formula (I), have lipoprotein(a) lowering activity.

Description

PHARMACEUTICAL AMINOPHOSPHONIC ACID DERIVATIVES

The present invention relates to novel aminophosphonate derivatives, processes for their preparations, pharmaceutical compositions containing them and their use in therapy, in particular for lowering lipoprotein(a) in plama and in tissues.

Lipoprotein(a) [Lp(a)] is a LDL-like lipoprotein where its major lipoprotein, apoB-100 is covalently linked to an unusual glycoprotein, apoprotein(a). Due to its structural similarity to plasminogen. apo(a) interfers with the normal physiological thrombosis- hemostasis process. The structural feature of Lp(a), where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombolytic activities.

Elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, cerebral infarction, restenosis following balloon angioplasty and stroke. A recent epidemiologic study has provided the clinical proof of a positive correlation between plasma Lp(a) concentrations and the incidence of heart disease (see for instance: "Elevated Plasma Lipoprotein(a) and Coronary Heart Disease in Men Aged 55 Years and Younger"; A.G. Bostom, L. A. Cupples. J.L. Jenner. J.M. Ordovas. L.J. Seman, P.W.F. Wilson, E.J. Schaefer and W.P. Castelli; Journal of American Medical Association 1996, 276, p. 544-548).

Patients that have Lp(a) levels in excess of 20-30 mg/dl run a significantly increased risk of heart attacks and stroke. An effective therapy for lowering Lp(a) does not exist at present as potent hypocholesterolemic agents such as the HMGCoA reductase inhibitors do not affect Lp(a). Until recently, the only compound shown to lower Lp(a) was niacin. The high doses necessary for activity however entail unacceptable side-effects. There is therefore an unmet therapeutic need for agents that effectively reduce elevated levels of Lp(a).

International application WO97/02037 (Symphar SA; SmithKline Beecham pic, published 23 January 1997), published after the priority date of the present application, describes a group of aminophosphonates alpha substitued by phenol groups of the formula (A):

in which X^a is H, Cπ _g)alkyl, hydroxy or Cπ . g^alkoxy; X^is Cπ _g)alkyl or

Cπ _8)alkoxy; X^c is H, C(i_4)alkyl, or X^O and one of the two other substituents X^a or

X^D may form an alkylidene dioxy ring having from 1 to 4 carbon atoms; R^a and R ³ which may be identical or different, are H or Cπ .^alkyl; B is CH2CH2, CH=CH, or CH2; n is zero or 1 ; Z is H or a C(j _g)alkyl group; m is 0 or an integer from 1 to 5; X^ is H, or Cπ _8)alkyl, Cπ _8)alkoxy or halo; and the pyridyl ring is attached by the ring carbon α- or β- to the nitrogen (2- or 3 -pyridyl). These have Lp(a) lowering activity. Compounds of formula (A) fall within scope of the generic disclosure of EP-A-0 559 079. This is directed towards aminophosphonates alpha substitued by phenol groups which are said to be of use in decreasing plasma cholesterol and blood peroxides. It has now been found that further modification of the substituents on the phenyl ring provides compounds with an improved biological profile.

Accordingly, the present invention provides compounds of formula (I):

in which: χl, X^, which may be the same or different, are H, a straight or branched Cj.g alkyl or C g alkoxy group, OH;

X^ is H, a Cj_4 alkyl group, X^O and one of the two other substituents χl and X^ may form a Cj_4 alkylidene dioxy ring;

may form a 5 or 6-membered alkylidene ring optionally substituted with C1.4 alkyl groups or a 5 or 6-membered alkylidenedioxy ring optionally substituted with Cι _4 alkyl groups, X³ is H, a straight or branched Cj.g alkyl or alkoxy group, OH, F, Cl, Br, I ;

R1 , R2, which may be the same or different, are H, a straight or branched C1. alkyl group;

B is CH₂, CH₂-CH₂ or CH-CH, n is zero or 1 ;

Z is H, a straight or branched Cj.g alkyl group; m is 0 or an integer from 1 to 5; γl, Y^, Y^ and Y^, which may be the same or different, are H. a straight or branched C\. g alkyl or C g alkoxy group, a cyano, trifluoromethyl, nitro, hydroxy, hydroxy methyl, C 1 -C4 alkoxymethyl, amino, C \ .4 alkylamino, C \ .4 dialkylamino group, a halogen atom

(F, Cl, Br, I); or any two adjacent Y¹, Y², γ3 and Y⁴ may form an optionally substituted

C 1 _g alkylidene or C 1 _g alkylidenedioxy ring; or a pharmaceutically acceptable salt thereof.

Suitably, χl is H, hydroxy, C(i _4)alkyl, for instance methyl or t-butyl, or Cπ _3)alkoxy. for instance methoxy.

Suitably, X² is H, hydroxy, Cπ _4)alkyl, for instance methyl or t-butyl, or Cπ _3)alkoxy. for instance methoxy and χ4 is hydroxy, C(i_4)alkyl, for instance methyl or t-butyl, or C(i _3)alkoxy, for instance methoxy, or X² and X^ together form a C4 alkylidene ring optionally substituted, for instance by one or two alkyl groups.

Suitably, X^ is hydrogen, C _3)alkyl, for instance methyl or Cπ _3)alkoxy, for instance methoxy.

Preferably, X^ is hydrogen.

Preferably, (B)_n is a direct bond.

Preferably, R^ and R² is each a C _3)alkyl group, more preferably, a C₂ or C3 alkyl group, in particular R^ and R² is ethyl or isopropyl.

Preferably, Z is hydrogen.

Representative values for γl to Y^ include alkyl, for instance methyl or t-butyl, methoxy or chloro. Preferably, the pyridyl ring is attached to the ring carbon β- to the nitrogen (3- or 5- pyridyl).

Pharmaceutically acceptable salts are well known in the art and include inorganic and organic salts, for instance salts with HC1, H2SO4, oxalic acid, maleic acid, sulfonic acid, etc..

Compounds of formula (I) are found to be effective in decreasing Lp(a) production by primary cultures of Cynomolgus monkey hepatocytes. The Lp(a) of these primates is similar in immunologic properties to human Lp(a) and occurs in an almost identical frequency distribution of plasma concentrations (see "Plasma Lipoprotein(a) Concentration is Controlled by Apolipoprotein(a) Protein Size and the Abundance of Hepatic Apo(a) mRNA in a Cynomolgus Monkey Model", N. Azrolan et al, J. Biol. Chem., 266. 13866-13872, 1991). The compounds of formula (I) are thus potentially useful for decreasing Lp(a) in man and thereby providing a therapeutic benefit.

Accordingly, in a further aspect, the present invention provides a compound of formula (I ) or a pharmaceutically acceptable salt thereof for use in therapy, in particular as an Lp(a) lowering agent. Elevated plasma and tissue levels of lipoprotein(a) is associated accelerated atherosclerosis, abnormal proliferation smooth muscle cells and increased thrombogenesis and expressed in disease states such as, for instance: coronary heart disease, peripheral artery disease : intermittent claudication, thrombosis, restenosis after angioplasty, extracranial carotid atherosclerosis, stroke and atherosclerosis occuring after heart transplant. Compounds of formula (I) may also be useful in treating inflammatory diseases and excessive wound healing.

For such therapeutic use, the compounds of the present invention will generally be administered in a standard pharmaceutical composition. Accordingly, in a further aspect, the present invention provides for a pharmaceutical composition comprising a compound of formaula (I) and a pharmaceutically acceptable excipient or carrier. Suitable excipients and carriers are well known in the art and will be selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compositions may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsule, ovules or lozenges either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The choice of form for administration as well as effective dosages will vary depending, inter alia, on the condition being treated. The choice of mode of administration and dosage is within the skill of the art.

The compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions or as solids for example, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agents. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base.

The compounds of the invention will normally be administered to a subject in a daily dosage regimen. For an adult patient this may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.

Compounds of formula (I) may be prepared by processes well known in the art, for instance those previously described in WO 97/02037.

Thus, for instance, compounds of formula (I) in which Z is hydrogen may be prepared by a process which comprises treating an imine of formula (II) :

in which χl, χ2, χ3. χ4_? χ5_{? B? n? m}. γl_; γ2_; γ3_^ γ4 _{are as} previously defined: with a dialkyl phosphite of structure (III)

H-P0(0R1)(0R²) (III) in which R , R2 are as previously defined; or a trialkyl silyl derivative thereof, preferably the trimethyl silyl phosphite, or a metal thereof, for instance the sodium salt, formed in situ by treatment of the compound of structure (III) with a suitable base, for instance sodium hydride, ethoxide or methoxide.

The reaction may be carried out in presence or absence of a catalyst. Suitable catalysts incude an amine such as diethylamine or triethylamine. The reaction may be carried out in presence or in absence of a solvent.

Suitable solvents include petroleum ether, benzene, toluene, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane. Suitable reaction temperatures are in the range of 30 to l40°C.

The imine compound of structure (II) may be obtained by condensing an aldehyde compound of structure (I

in which χ , X², χ3, χ4 _s χ5_^ β ^d _{n are as} previously defined ; with a primary amine of structure (V)

in which Z, m, Ys Y². Y³ and Y⁴ are as previously described; under imine forming conditions.

Suitably, the condensation may be effected with or without a catalyst in a solvent such as ether, tetrahydrofuran, benzene, toluene or ethanol. Suitable catalysts include molecular sieve, an acid such as glacial acetic acid, p-toluenesulfonic acid, thionyl chloride, titanium tetrachloride, boron trifluoride etherate, or a base such as potassium carbonate. The reaction is suitably carried out in the range of 0°C to the boiling point of the solvent being used. For less reactive amines or aldehydes, the reaction may be usefully carried out in a Dean-Stark apparatus.

Novel compounds of structure (I) may also be prepared by a process which comprises treating equimolar amounts of an aldehyde of structure (IV) , an amine of structure (V) ; and a dialkyl phosphite of structure (III), in which X¹, X², X³, X⁴ , χ5, B ,n, Z, m, Y¹. Y², Y³ ,Y⁴ , R! and R² are as previously described, suitably in the presence of p- toluenesulfonic acid as a catalyst, in a hydrocarbon solvent such as petroleum ether, benzene, toluene or xylene, at a temperature between ambient room temperature and the boiling point of the solvent being used, and with concomitant elimination of water, for instance, by using a Dean-Stark apparatus.

Compounds of formula (I) in which m is not zero may also be prepared by a process which comprises treating a compound of formula (VI): o

in which χ , X², X³, X⁴, X^, B and n are as previously defined; with an aldehyde of formula (VII)

in which m is an integer from 1 to 5 and γl, Y², Y³ and Y⁴ are as previously described; under reductive amination condiions.

Suitable such conditions include carrying out the reaction in the presence of sodium cyanoborohydride in an alcoholic solvent, preferably methanol. at a pH between 3 to 6 and at a temperature between 0°C and 25 °C.

A compound of formula (VI) may be obtained according to the process previously described for a compound of structure (I) from an aldehyde of formula (IV), an amine of structure (VIII)

A-NH₂ (VIII) in which A is a protecting group which can be removed by hydrogenolysis, for instance an α substituted benzyl or benzyloxycarbonyl and a phosphite of structure (III). This forms an intermediate which is then subjected to hydrogenolysis according to standard conditions, to give a compound of formula (VI).

It will be appreciated that the aminophosphonate ester of formula (I) have a basic centre and can form salts, for instance with inorganic acids such as HC1, H2SO4 and with organic acids such as oxalic acid, maleic acid, sulfonic acids, etc... All these salts are integral part of this invention.

Compounds of structure (I) are racemates as they have at least one chiral center which is the carbon atom in position alpha to the phosphonate group. The compounds of formula ( I) therefore exist in the two enantiomeric forms. The racemic mixtures (50% of each enantiomer), the pure enantiomers and other mixtures thereof all form part of the present invention. Mixtures of enantiomers, including racemates, may be resolved into its constituent enantiomers according to procedures well known in the art, including for instance, chiral chromatography. Unless otherwise indicated, the physical constants and biological data given for compounds of structure (I) refer to racemates.

The structure of compounds of formula (I) described in the following Examples was established by their infrared (IR), mass (MS) and nuclear magnetic resonance (NMR) spectra. The purity of the compounds was checked by thin layer, gas liquid or high performance liquid chromatography.

The invention is further described in the following examples which are intended to illustrate the invention without limiting its scope. The abbreviations used in this application are the following :

In the tables, n is normal, i is iso, s is secondary and t is tertiary. In the description of the NMR spectra, respectively 's' is singlet, 'd' is doublet, 'dd' is double doublet, T is triplet and 'm' is multiplet. TsOH is p-toluenesulfonic acid monohydrate. The temperatures were recorded in degrees Celsius and the melting points are not corrected.

Examples

Example 1 : Diethyl α-⁽3-tert-butyl-4-hvdroxy-5.6.7.8-tetrahydronaphthylVN-(3- pyridylVaminomethylphosphonate

A mixture of 35g (0.151mol) of 3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthaldehyde and 14.9 g (0.158mol) of 3-aminopyridine dissolved in 120 ml toluene and a catalytic amount of p-toluenesulfonic acid (ca. 50 mg) contained in a flask connected to a Dean Stark apparatus was refluxed for 4 h. The solution was evaporated to dryness to give a solid which was purified by recrystallisation from a mixture of toluene and ligroin : 35g, mp = 185-186°, IR (KBr) : 1590 cm-¹ : CH=N.

Diethyl phosphite (40.3 g, 0.29 mol) was added to 30 g (0.097mol) of the previously described imine dissolved in 100 ml THF and the mixture was refluxed for 16 h. The solvent was evaporated and the residue was purified by column chromatography (Siθ2, 9/1 CH2Cl2/MeOH). Recrystallisation from a mixture of C^C^/AcOEt gave a white solid, mp = l 75- 176°C.

MS (m/e) = 447 : M+ + 1, 309 : M⁺ - PO₃Et₂, 57 : t-Bu (100%) NMR (CDC1₃): δ = 8.0, 7.94, 7.02 and 6.81 (4m, 1H each): aromatic H. 3-ρyridyl 7.29 (d, J = 2Hz, 1H): aromatic H, substituted tetrahydronaphthyl

5.1 (broad, 1H) : OH

4.93 (d x d, 1H, J=7.5 and 23Hz): CH-PO₃Et 4.74 (m, 1H): N-H 4.18-3.65 (3m, 4H total): P-O-CH₂-CH₃ 2.9, 2.8, 2.6 and 1.8 (4 m): C-C4H.8 1.34 (s, 9H): t-Bu

1.30 and 1.09: (2t, J-7Hz): P-O-CH2-CH3

Example 2 : Diethyl α-(^"3-tert-butyl-5.5-dimethyl-4-hydroxy-5.6.7.8-tetrahydronaphthyl)- N- 3-pyridylVaminomethylphosphonate

A mixture of 2.0g (7.7mmol) of 3-tert-butyl-5,5-dimethyl-4-hydroxy-5, 6,7,8- tetrahydronaphthaldehyde and 0.76 g (8.1 mmol) of 3-aminopyridine dissolved in 20 ml toluene and 5 mg of TsOH contained in a flask connected to a Dean Stark apparatus was refluxed for 16 h. The solution was evaporated to dryness to give 2.85g of an oil which was directly used for the next step.

Diethyl phosphite (2.05 g, 14.9 mmol) was added to 2.5 g (7.4 mmol) of the crude imine dissolved in 20 ml THF and the mixture was refluxed for 7 h. A further amount of diethyl phosphite (4.8 g, 35 mmol) was added and the mixture was refluxed overnight (total reaction time : 17 h). The solvent and the excess of diethyl phosphite were evaporated and the residue was purified by column chromatography (Siθ2, 9/1 CHCl₃/MeOH) to give 2.25g (64%) of a tan solid. MS (m e) = 475 : M⁺ - 1, 337 : M+ - PO₃Et₂, 57 : t-Bu (100%) NMR (CDCI3): δ = 8.14, 7.94, 7.24 and 7.09 (4m, 1H each): aromatic H, 3-pyridyl

7.30 (d, J = 2Hz, 1H): aromatic H, substituted tetrahydronaphthyl 5.5 (broad): OH 5.25 (broad, 1H): N-H 4.94 (d, 1H, J = 22Hz): CH-PO₃Et₂ 4.18-3.5 (4m, 4H total): P-O-CH₂-CH₃

2.85, 2.76, 1.8 and 1.68 (4 m): C-C4H.6 1.46 and 1.44 (2s, 6H total): c-C H6-(CH₃)2 1.34 (s, 9H): t-Bu 1.29 and 1.1 1 : (2t, J=7Hz): P-O-CH2-CH3

Example 3 : Diethyl α-f4-hydroxy-3.5.6-trimethylphenylVN-(^'3-pyridyl)-amino- methylphosphonate

A mixture of 15.3 g (0.09 mol) of 4-hydroxy-3,5,6-trimethylbenzaldehyde and 8.77 g (0.09 mol) of 3-aminopyridine dissolved in 100 ml toluene and 5 mg of TsOH contained in a flask connected to a Dean Stark apparatus was refluxed for 16 h. The solution was evaporated to dryness to give 20.3 g (83%) of a yellow solid which was directly used for the next step.

Diethyl phosphite (34.5 g, 25 mmol) was added to 20 g (8.3 mmol) of the crude imine dissolved in 150 ml THF and the mixture was refluxed for 22 h. At the end of the refluxing period a precipitate which has formed was collected . Recrystallization from a mixture of ligroine and ethanol gave 20.4 g (65%) of a white solid. MS (m/e) = 378 : M⁺, 241 : M+ - PO3Et₂ NMR (CDCI3): δ = 7.96, 7.92. 7.0 and 6.76 (4m. 1H each): aromatic H. 3-pyridyl 7.06 (d, J = 2Hz, 1H): aromatic H. substituted phenyl 5.5 (broad. 1H) : OH

4.99 and 4.90 (partially overlapped peaks): CH-PO3E12 and N-H 4.18-3.50 (3m, 4H total): P-O-CH₂-CH₃ 2.35, 2.18 and 2.12 (3s,9H total) : aromatic Me

1.31 and 1.09: (2t, 6H. J=7Hz): P-O-CH2-CH3

Further compounds of formula (I) were prepared by following procedures anologous to those described in the foregoing examples. The are included in the following Table 1, along with the preceding examples. The left hand column refers to a 'Compound' rather than the Example number, the same compound numbers being then used in the Biological Data section. Table 1: Aminophosphonates of formula (I) (where n is 0, X^J and X are H)

Biological Data

The compounds of formula (I) were assayed for lowering the production of Lp(a) in primary cultures of Cynomolgus hepatocytes.

Assay - Hepatocytes were isolated from livers of adult Cynomolgus monkeys by the two- step collagenase perfusion method according to C. Guguen-Guillouzo and A. Guillouzo "Methods for preparation of adult and fetal hepatocytes" p.1-12 in "Isolated and Cultured Hepatocytes". les editions Inserm Paris and John Libbey Eurotext London (1986).

The viability of cells was determined by Trypan blue staining. The cells were then seeded at a density from 0.7. 10⁵ to 1.10⁵ viable cells per cm² in tissue culture plates in Williams E tissue culture medium containing 10% fetal calf serum. Cells were incubated for 4-6 hours and 24 hours at 37°C in a CO2 incubator (5% CO2) in the presence of 20μM of the test compounds dissolved in ethanol. Four to six wells were used for each compound. Nicotinic acid and steroid hormones were used as references to validate the assay system since they are known to decrease Lp(a) in man. Control cells were incubated in the presence of ethanol only.

Results

Lp(a) concentration - The amount of Lp(a) secreted in culture medium was directly assayed by ELISA using a commercially available kit. Cells were washed and lysed as described by A.L. White et al, Journal of Lipid Research vol 34. p. 509-517, (1993) and the cellular content of Lp(a) was assayed as described above. Changes in Lp(a) concentration in culture medium are given as the percentage of value measured for the control plates at 24h.

The compounds No. 1 , 2, 3, 4 and 7 tested at 20μM were found to decrease the Lp(a) secretion in the range from 19% to 22%.

In vivo Results

Study Protocol - Male cynomolgus monkeys weighing between 3 and 7 kg were divided into groups of 3 to 4 animals each. Prior to treatment their plasma Lp(a) levels were followed over a two-month period to ascertain a constant baseline value. The Lp(a) values measured at Day -7 and Day -1 were comparable and served as predose values. Test compounds were given orally in gelatin capsules by gavage at the dose of 25 mg/kg/day for 4 weeks and Lp(a) was measured at weekly intervals (Day 7, 14, 21 and 28). At the end of the dosing period, animals were maintained for a treatment free period of 4 weeks, whereupon their plasma Lp(a) levels returned to pretreatment levels. This control provided proof that the decrease in Lp(a) measured was caused by the pharmacological activity of the test compounds.

Results - At Days -7 . -1, 7, 14, 21 and 28, after an overnight fast blood samples were collected on EDTA and Lp(a) was measured by the highly sensitive and specific ELISA test. Results (mean of 3-4 values of each group ) were expressed as %> of predose values.

Selected compounds of formula (I) were tested under the experimental conditions to investigate their pharmacological activity in vivo.

Compounds No 1 and 7 were tested at 25mg/kg/day for 4 weeks and lowered plasma Lp(a) in the range of 35%> to 40%) (value measured at Day 28. % change from predose).

Compound No 2 was tested at 25mg/kg/day for 4 weeks and lowered plasma Lp(a) by 22

% (value measured at Day 14. %> change from predose).

Claims

1. A compound of formula (I)

in which: χl, X², which may be the same or different, are H. a straight or branched C_]_ alkyl or

Cι _8 alkoxy group, OH; X^ is H. a Cj_4 alkyl group, X^O and one of the two other substituents χl and X² may form a C i .4 alkylidene dioxy ring; X⁴ is a straight or branched C\.g alkyl or alkoxy group, OH. F. Cl. Br. I; or X⁴ and X² may form a 5 or 6-membered alkylidene ring optionally substituted with C]_4 alkyl groups or a 5 or 6-membered alkylidenedioxy ring optionally substituted with Cj_4 alkyl groups, χ5 is H, a straight or branched C\_g alkyl or alkoxy group, OH. F, Cl. Br, I ; RI , R², which may be the same or different, are H. a straight or branched C\ ._β alkyl group;

B is CH , CH₂-CH₂ or CH=CH. n is zero or 1 ;

Z is H. a straight or branched C j_g alkyl group: m is 0 or an integer from 1 to 5; γl , Y², Y^ and Y⁴. which may be the same or different, are H. a straight or branched C \_ g alkyl or C\.g alkoxy group, a cyano. trifluoromethyl, nitro, hydroxy, hydroxymethyl,

C1-C4 alkoxymethyl. amino, Cι _4 alkylamino. Cj_4 dialkylamino group, a halogen atom

(F, Cl. Br, I); or any two adjacent γl, Y², Y^ and Y⁴ may form an optionally substituted C\.β alkylidene or C 1.5 alkylidenedioxy ring; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 in which χl is H, hydroxy, Cπ _4)alkyl or Cπ _3)alkoxy.

3. A compound as claimed in claim 1 or 2 in which X² is H, hydroxy, Cπ _4)alkyl or Cπ _3)alkoxy and X⁴ is hydroxy, Cπ _4)alkyl. or Cπ _3)alkoxy. or X² and X⁴ together form a C4 alkylidene ring optionally substituted, by one or two alkyl groups.

4. A compound as claimed in any one of claims 1 to 3 in which X^ is hydrogen. Cπ „3)alkyl or Cπ _3)alkoxy.

5. A compound as claimed in any one of claims 1 to 4 in which X^ is hydrogen.

6. A compound as claimed in any one of claims 1 to 5 in which(B)_n is a direct bond.

7. A compound as claimed in any one of claims 1 to 6 in which R* and R² is each a Cπ . 3)alkyl group.

8. A compound as claimed in any one of claims 1 to 7 in which Z is hydrogen.

9. A compound as claimed in any one of claims 1 to 8 in which the pyridyl ring is attached to the ring carbon β- to the nitrogen (3- or 5-pyridyl).

10. A compound of structure (I) as defined in claim 1 selected from: diethyl α-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-N-(3-pyridyl)- aminomethylphosphonate, dimethyl α-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-N-(3-pyridyl)- aminomethylphosphonate, diisopropyl α-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-N-(3-pyridyl)- aminomethylphosphonate, diethyl -(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-N-(2-pyridyl)- aminomethylphosphonate, diethyl α-(3-tert-butyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-N-(4-pyridyl)- aminomethylphosphonate, diethyl α-(3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydronaphthyl)-N-(3- pyridyl)-aminomethylphosphonate, and diethyl α-(4-hydroxy-3 ,5 ,6-trimethylphenyl)-N-(3 -pyridyl)-amino-methylphosphonate: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable excipient thereof.

12. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

13. The use of a compound of formula (I) as defined in claim 1. or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in decreasing plasma and tissue lipoprotein(a) levels.

14 A use of a compound of formula (I) as claimed in claim 13, for the manufacture of a medicament for the treatment of thrombosis by decreasing plasma lipoprotein(a) levels.

15. A use of a compound of formula (I) as claimed in claim 13. for the manufacture of a medicament for the treatment of restenosis following angioplasty by decreasing plasma lipoprotein(a) levels.

16. A use of a compound of formula (I) as claimed in claim 13. for the manufacture of a medicament for the treatment of atherosclerosis by decreasing plasma lipoprotein(a) levels.

17. A method of treating a disease associated with elevated plasma and tissue lipoprotein(a) levels which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined in claim 1. or a pharmaceutically acceptable salt thereof.

18. A process for preparing a compound of formula (I) as defined in claim 1 which process comprises:

(a) for compounds of formula (I) in which Z is hydrogen, treating an imine of formula (II) :

in which X¹, X², X³, X⁴, X⁵, B, n, m. Y¹, Y², Y³, Y⁴ are defined in claim 1 ; with a dialkyl phosphite of formula (III):

H-PO(OR^J)(OR²) (III) in which RI and R² are as defined in claim 1 ; or a trialkyl silyl or metal derivative thereof;

(b) reacting together equimolar amounts of an aldehyde of formula (IV):

1 5

X X

in which χl, X², X³. X⁴ , X^. B and n are as defined in claim 1 ; an amine of formula (V):

1 2

Y Y

in which Z, m, γl , Y², Y³ and Y⁴ are as previously defined: and a dialkyl phosphite of formula (III); or (c) for compounds of formula (I) in which m is not zero, treating a compound of formula

in which χl, X², X³, X⁴, X^, B and n are as defined in claim 1. with an aldehyde of formula (VII): ¹ Y²

in which m is an integer from 1 to 5 and γl, Y², Y³ and Y⁴ are as defined in claim 1 ; under reductive amination conditions.