WO1998028311A1 - Pharmaceutical aminophosphonic acid derivatives - Google Patents
Pharmaceutical aminophosphonic acid derivatives Download PDFInfo
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- WO1998028311A1 WO1998028311A1 PCT/EP1997/007192 EP9707192W WO9828311A1 WO 1998028311 A1 WO1998028311 A1 WO 1998028311A1 EP 9707192 W EP9707192 W EP 9707192W WO 9828311 A1 WO9828311 A1 WO 9828311A1
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- Prior art keywords
- aminomethylphosphonate
- compound
- hydroxy
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- diethyl
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- 0 CC1(C)C/N=C/C(C)(*)/C=C/C1 Chemical compound CC1(C)C/N=C/C(C)(*)/C=C/C1 0.000 description 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- 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 plasma and in tissues.
- Lipoprotein(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).
- 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).
- potent hypocholesterolemic agents such as the HMGCoA reductase inhibitors do not affect Lp(a).
- 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).
- ⁇ l is C ⁇ _4)alkyl or C ⁇ _4)alkoxy
- X 2 is C(i_3)alkyl
- X 3 is H
- R.1 and R 2 which may be the same or different, are H, or a straight or branched
- Z is H or methyl; m is O or 1;
- Y is C ⁇ _3)alkyl, C ⁇ _3)alkoxy group, or a halogen atom (F, Cl, Br, I); or a pharmaceutically acceptable salt thereof.
- X* is C(i _3)alkyl or C(i_3)alkoxy.
- Representative examples of X* include methyl, t-butyl, methoxy and ethoxy.
- X 2 is methyl
- X ⁇ is alkoxy and X 2 is alkyl or X* and X 2 is each alkyl.
- Suitable combinations of X and X 2 include methoxy and methyl, ethoxy and methyl, t-butyl and methyl, methyl and methyl, respectively.
- (B) n is a direct bond.
- Rl and R 2 is each a C ⁇ _3)alkyl group, more preferably, a C2 or C3 alkyl group, in particular R! and R 2 is ethyl or isopropyl.
- m is 0.
- Z is hydrogen
- Y is methyl, methoxy or chloro.
- the substituent Y is located on the ring carbon adjacent the pyridyl nitrogen, to give a 2- or 5 -substituent.
- the pyridyl ring is attached by the ring carbon ⁇ - to the nitrogen.
- preferred substituent patterns include both 5-(2-Y-pyridyl) and 3-(2-Y-pyridyl).
- 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 of 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.
- the compounds of the present invention will generally be administered in a standard pharmaceutical composition.
- 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.
- 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.
- parenterally may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
- 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.
- 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 structure (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.
- 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.
- 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.
- 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.
- the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
- a typical suppository formulation comprises a compound of structure (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.
- a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
- 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 pharmaceutically acceptable compounds of the invention will normally be administered to a subject in a daily dosage regimen.
- 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
- compounds of formula (I) in which Z is hydrogen may be prepared by a process which comprises treating an imine of structure (II) :
- Rl, R 2 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.
- 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 include 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-dimethoxy ethane.
- 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 struc
- the condensation may be effected with or without a catalyst in a solvent such as ether, tetrahydrofuran, benzene, toluene or ethanol.
- a catalyst 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 ⁇ l, X 2 , X 3 , B, n , Z, m, Y, R 1 and R 2 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.
- a hydrocarbon solvent such as petroleum ether, benzene, toluene or xylene
- m is an integer from 1 to 5 and Y is as previously described; under reductive amination conditions.
- 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)
- aminophosphonate ester (I) can form salts, for instance with inorganic acids such as HC1, H2SO4 or with organic acids such as oxalic acid, maleic acid, sulfonic acids, etc... All these salts are integral part of this invention.
- Compounds of formula (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 (I) therefore exist in the two enantiomeric forms. The racemic mixtures (50% of each enantiomer), the pure enantiomers and other mixtures thereof form part of the present. Unless otherwise indicated, the physical constants and biological data given for compounds of formula (I) refer to racemates.
- Table 1 lists the physico-chemical data of compounds of structure (I) that were prepared by the methods illustrated.
- the abbreviations used in this application are the following :
- n normal, i is iso, s is secondary and t is tertiary.
- t tertiary.
- TsOH is p-toluenesulfonic acid monohydrate. The temperatures were recorded in degrees Celsius and the melting points are not corrected.
- 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. 10 5 to 1.10 5 viable cells per cm 2 in tissue culture plates in Williams E tissue culture medium containing 10% fetal calf serum. Cells were incubated for 4-6 hours at 37°C in a CO2 incubator (5% CO2) in the presence of 20 ⁇ M 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.
- 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.
- the compounds No. 1 - 23 tested at 20 ⁇ M were found to decrease the Lp(a) secretion in the range from 1 1% to 53 %.
- 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.
Abstract
Aminophosphonates alpha substituted by phenol groups, of formula (I) have lipoprotein(a) lowering activity.
Description
PHARMACEUTICAL AMINOPHOSPHONIC AC ID 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 plasma 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 Xa is H, C(i_g)alkyl, hydro xy or C(i _g)alkoxy; XDis Cπ _g)alkyl or C(i_g)alkoxy; Xc is H, C(i_4)alkyl, or X3O and one of the two other substituents Xa or XD may form an alkylidene dioxy ring having from 1 to 4 carbon atoms; Ra and RD which may be identical or different, are H or Cπ _6)alkyl; B is CH2CH2, CH=CH, or CH2; n is zero or 1; Z is H or a C(i _g)alkyl group; m is 0 or an integer from 1 to 5; X^ is H, or C(i _g)alkyl, C(i_g)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 refinement of the most appropriate combination of substituents on the phenol ring as well as a single small substituent on the pyridyl ring provides compounds with an improved biological profile.
X2 is C(i_3)alkyl;
X3 is H;
R.1 and R2, which may be the same or different, are H, or a straight or branched
C(i_4)alkyl group,
B is CH2, CH2-CH2 or CH=CH; n is zero or 1 ;
Z is H or methyl; m is O or 1;
Y is Cπ _3)alkyl, Cπ _3)alkoxy group, or a halogen atom (F, Cl, Br, I);
or a pharmaceutically acceptable salt thereof.
Preferably, X* is C(i _3)alkyl or C(i_3)alkoxy. Representative examples of X* include methyl, t-butyl, methoxy and ethoxy.
Preferably, X2 is methyl.
Preferably, X^ is alkoxy and X2 is alkyl or X* and X2 is each alkyl.
Suitable combinations of X and X2 include methoxy and methyl, ethoxy and methyl, t-butyl and methyl, methyl and methyl, respectively.
Preferably, (B)n is a direct bond.
Preferably, Rl and R2 is each a Cπ _3)alkyl group, more preferably, a C2 or C3 alkyl group, in particular R! and R2 is ethyl or isopropyl.
Preferably, m is 0.
Preferably, Z is hydrogen.
Preferably, Y is methyl, methoxy or chloro. Preferably, the substituent Y is located on the ring carbon adjacent the pyridyl nitrogen, to give a 2- or 5 -substituent.
Preferably, the pyridyl ring is attached by the ring carbon β- to the nitrogen. It will be appreciated that preferred substituent patterns include both 5-(2-Y-pyridyl) and 3-(2-Y-pyridyl).
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 of 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 structure (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 structure (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 pharmaceutically acceptable 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 structure (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 structure (II) :
x_
(II)
in which χ , X2, X3, B, n, m and Y are as previously defined; with a dialkyl phosphite of structure (III)
H-P0(0R! )(0R2) (III) in which Rl, 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 include 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-dimethoxy ethane. 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 struc
H_N _ < CH2 ) m -L. -L_Y
(V) in which Z, m and Y 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 χl, X2, X3, B, n , Z, m, Y, R1 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 tre
in which m is an integer from 1 to 5 and Y is as previously described; under reductive amination conditions.
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 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 (I) can form salts, for instance with inorganic acids such as HC1, H2SO4 or with organic acids such as oxalic acid, maleic acid, sulfonic acids, etc... All these salts are integral part of this invention.
Compounds of formula (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 (I) therefore exist in the two enantiomeric forms. The racemic mixtures (50% of each enantiomer), the pure enantiomers and other mixtures thereof form part of the present. Unless otherwise indicated, the physical constants and biological data given for compounds of formula (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 chromatographies.
The invention is further described in the following examples which are intended to illustrate the invention without limiting its scope. Table 1 lists the physico-chemical data of compounds of structure (I) that were prepared by the methods illustrated. 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 'nϊ 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-f4-hydroxy-3-methoxy-5-methylphenyP-N-[5-f2- methoxypyridyDj-aminomethylphosphonate
A mixture of 3.5 g (21 mmol) of 4-hydroxy-3-methoxy-5-methylbenzaldehyde and 2.61 g (21 mmol) of 5-amino-2-methoxypyridine dissolved in 40 ml toluene and 2 mg of TsOH contained in a flask connected to a Dean Stark apparatus was refluxed for 5 h. The solution was evaporated to dryness to give 5.74 g (100%) of a brown oil which was directly used for the next step.
Diethyl phosphite (5.2 g, 38 mmol) was added to 3.4 g (12.5 mmol) of the crude imine dissolved in 40 ml toluene and the mixture was refluxed for7 h. The solvent and the excess of diethyl phosphite were evaporated and the residue was purified by column chromatography (Siθ2, 98/2 CHC^/MeOH) and recrystallization (petroleum ether/CH2Cl2) to give 1.58 g (31%) of a tan solid, mp = 111-113°C. MS (m e) = 410 : M+, 272 : M+ -1 - PO3Et2 (100%) NMR (CDC13): δ = 7.51, 6.96 and 6.55 (3m, 1H each): aromatic H, 3-pyridyl
6.8 (m, 2H): aromatic H, substituted phenyl
5.71 (s, 1H) : OH
4.55 and 4.45 (partially overlapped peaks): CH-PO3E 2 and N-H
4.18-3.50 (3m, 4H total): P-O-CH2-CH3
3.84 and 3.81(2s, 6H total): phenyl and pyridyl OCH.3_
2.21 (s, 3H) : phenyl CH_3_
1.31 and 1.14: (2t, 6H, J=7Hz): P-O-CH2-CH3
Example 2 : Diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[5- 2- methoxypyridyl)]-aminomethylphosphonate
As described in Example 1, the imine (3.4 g, 12.5 mmol) obtained by condensing 4- hydroxy-3-methoxy-5-methylbenzaldehyde with 5-amino-2-methoxypyridine was reacted with diisopropyl phosphite (6.22 g, 38 mmol) in 40ml toluene at reflux temperature for 7h to give 2.10 g (38%) of the title compound as a white solid, mp =
158-159°C.
MS (m/e) = 438 : M+, 273 : M+ - PO3iPr2 (100%)
NMR (CDC13): δ = 7.51, 6.96 and 6.55 (3m, 1H each): aromatic H, 3-pyridyl
6.82 and 6.79 (2t, 2H): aromatic H, substituted phenyl
5.68 (s, 1H) : OH
4.7 (m, 1H): N-H
4.5-4.4 (several m, 3H total): CH-PO3iPr2 and P-O-CH-(CH3)2
3.84 and 3.81(2s, 6H total): phenyl and pyridyl OCIT/3
2.21 (s, 3H) : phenyl CH.3_
1.32, 1.28, 1.26 and 0.97: (4d, 12H, J=6Hz): P-O-CH-(CH.3)2
Example 3 : Diethyl α-(3-tert-butyl-4-hydroxy-5-methylphenyl)-N-[5-(2- methoxypyridyl)]-aminornethylphosphonate
A mixture of 3.0 g (15.6 mmol) of 3 -tert-butyl-4-hydroxy-5 -methyl benzaldehyde, 1.94 g (15.6 mmol) of 5-arnino-2-methoxypyridine and 6.5g (47 mmol) diethylphosphite dissolved in 80 ml toluene contained in a flask connected to a Dean Stark apparatus was refluxed for 6 h. The solution was evaporated to dryness to give a brown oil which was purified by column chromatography (Siθ2, 95/5 CH2Cl2/MeOH) to give 2.6 g (38%) of an oil which slowly solidified, mp = 104- 105°C
MS (m/e) = 436 : M+, 299 : M+ - PO3Et2 (100%)
NMR (CDC13): δ = 7.51, 7.0 and 6.56 (3m, 1H each): aromatic H, 3-pyridyl
7.15 and 7.05 (2t, 1H each): aromatic H, substituted phenyl
5.3 (s, 1H) : OH
4.54 (d, J = 23.5 Hz): CH-PO3Et2
4.18-3.60 (3m, 4H total): P-O-CH2-CH3
3.81 (2s, 6H total): pyridyl OCH.3_
2.19 (s, 3H) : phenyl CH3
1.39 (s, 9H) : t-Bu
1.30 and 1.14: (2t, 6H, J=7Hz): P-O-CH2-CH.3_
Example 4 : Diethyl α-G-ethoxy-4-hydroxy-5-methylphenyl")-N-[5-f2- chloropyridyDJ-aminomefhylphosphonate
A mixture of 1.5 g (8.33 mmol) of 3-ethoxy-4-hydroxy-5-methylbenzaldehyde, 1.12 g (8.75 mmol) of 5-amino-2-chloropyridine and 3.45g (25 mmol) diethylphosphite dissolved in 60 ml toluene contained in a flask connected to a Dean Stark apparatus was refluxed for 6 h. The solution was evaporated to dryness to give an oil which was purified by column chromatography (Siθ2, 95/5 CH2Cl2/MeOH) to give 1.6 g
(45%) of a solid, after recrystallisation in a mixture of ethanol and petroleum ether, mp = 170-172°C
MS (m/e) = 430, 428 : M+(C137, Cl35)
NMR (CDCI3): δ = 7.80, 7.02 and 6.82 (3m, 1H each): aromatic H, 3-pyridyl
6.77 (d, J = 2 Hz, 2 H): aromatic H, substituted phenyl
5.80 (s, 1H) : OH
4.90 (m, 1 H) : NH
4.50 (d x d, 1 H): CH-PO3Et2
4.15-3.60 (3m, 4H): P-O-CH2-CH3
4.05 (m, 2 H) : CH3-CH2O-phenyl
2.20 (s, 3H) : phenyl CH^
1.40 (t, 3H) : CH3-CH2O-phenyl, 1.30 and 1.13: (2t, 6H): P-O-CH2-CH3
Example 5: Diisopropyl α-G-ethoxy-4-hydroxy-5-mefhylphenyl)-N-[5-f2- chloropyridyDJ-aminomethylphosphonate
The title compound was obtained in 46% yield (1.74 g) by following the procedure described in example 4 by refluxing a 60 ml toluene mixture of 3-ethoxy-4-hydroxy-
5-methylbenzaldehyde (1.5g, 8.33 mmol), 5-amino-2-chloropyridine (1.12 g, 8.75 mmol) and diisopropylphosphite (4.15 g, 25 mmol) for 6h. Mp = 180-182 °C
(ethanol-petroleum ether)
MS (m e) = 458, 456 : M+(C137, Cl35)
NMR (CDCI3): δ = 7.80, 7.02 and 6.83 (3m, 1H each): aromatic H, 3-pyridyl
6.77 (m, 2 H): aromatic H, substituted phenyl
5.74 (s, 1H) : OH
4.88 (m, 1 H) : NH
4.70 and 4.42 (2m, 2H): P-O-CH(CH3)2
4.47 (d x d, 1 H): CH-PO3iPr2
4.05 (m, 2 H) : CH3-CH2O-phenyl
2.21 (s, 3H) : phenyl CU3_
1.41 (t, 3H) : CH.3-CH2O-phenyl,
1.32, 1.26, 1.25 and 0.94: (4d, 12H): P-O-CH(CH3)2
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 structure (I) in which X2 is Me, X^ and Z are H and n is 0
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 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 - 23 tested at 20μM were found to decrease the Lp(a) secretion in the range from 1 1% to 53 %.
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, 3 and 5 were tested at 25mg/kg/day for 28 days and lowered plasma Lp(a) in the range of 7% to 27% (values measured at Day 14, % change from predose values). Compound 20 was tested at 25mg/kg/day for 28 days and lowered plasma Lp(a) by 20% (value measured at Day28, % change from predose value).
Claims
1. A co
X2 is C(i_3)alkyl;
X3 is H;
R and R2, which may be the same or different, are H, or a straight or branched
C(i_4)alkyl group,
B is CH2, CH2-CH2 or CH=CH; n is zero or 1 ;
Z is H or methyl; m is 0 or 1 ;
Y is C(i _3)alkyl, C(j_3)alkoxy group, or a halogen atom (F, Cl, Br, I); or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 in which χ is Cπ _3)alkyl or Cπ _3)alkoxy.
3. A compound as claimed in claim 1 or 2 in which χ is alkoxy and X2 is alkyl, χ and X2 is each alkyl alkyl or χ and X2 is each alkoxy.
4. A compound as claimed in any one of claims 1 to 3 in which X2 is methyl.
5. A compound as claimed in any one of claims 1 to 4 in which(B)n is a direct bond.
6. A compound as claimed in any one of claims 1 to 5 in which R and R2 is each a C(i_3)alkyl group.
7. A compound as claimed in any one of claims 1 to 6 in which Z is hydrogen.
8. A compound as claimed in any one of claims 1 to 7 in which Y is methyl, methoxy or chloro.
9. A compound as claimed in any one of claims 1 to 8 in which Y is on the ring carbon adjacent to N.
10. A compound as claimed in any one of claims 1 to 10 in which the pyridyl ring is attached by the ring carbon β- to the nitrogen.
11. A compound of structure (I) as defined in claim 1 selected from: diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[5-(2-methoxypyridyl)]- aminomefhylphosphonate, diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[5-(2-methoxypyridyl)]- aminomefhylphosphonate, diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[5-(2-chloropyridyι)]- aminomethylphosphonate, diisopropyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[5-(2-chloropyridyl)]- aminomethylphosphonate, diethyl α-(4-hydroxy-3-methoxy-5-methylphenyl)-N-[3-(2-chloropyridyl)]- aminomethylphosphonate, diisopropyl α-(4-hydroxy-3 -methoxy-5 -methylphenyl)-N- [3 -(2-chloropyridyl)] - aminomethylphosphonate, diethyl α-(3 -tert-buty l-4-hydroxy-5-methy lphenyl)-N- [5 -(2-methylpyridy 1)] - aminomethylphosphonate, diethyl α-(3-tert-butyl-4-hydroxy-5-methylphenyl)-N-[3-(2-methylpyridyl)]- aminomethylphosphonate, diethyl α-(3-tert-butyl-4-hydroxy-5-methylphenyl)-N-[5-(2-methoxypyridyl)]- aminomethylphosphonate, diethyl α-(3-tert-butyl-4-hydroxy-5-methylphenyl)-N-[5-(2-chloropyridyl)]- aminomethylphosphonate, diethyl α-(3-tert-butyl-4-hydroxy-5-methylphenyl)-N-[3-(2-chloropyridyl)]- aminomethylphosphonate, diethyl α-(3,5-dimethyl-4-hydroxyphenyl)-N-[5-(2-methylpyridyl)]- aminomethylphosphonate, diisopropyl α-(3,5-dimethyl-4-hydroxyphenyl)-N-[5-(2-methylpyridyl)]- aminomethylphosphonate, diethyl α-(3,5-dimethyl-4-hydroxyphenyl)-N-[3-(2-methylpyridyl)]- aminomethylphosphonate, diethyl α-(3,5-dimethyl-4-hydroxyphenyl)-N-[5-(2-methoxypyridyl)]- aminomethylphosphonate, diethyl α-(3,5-dimethyl-4-hydroxyphenyl)-N-[5-(2-chloropyridyl)]- aminomethylphosphonate, diethyl α-(3,5-dimethyl-4-hydroxyphenyl)-N-[3-(2-chloropyridyl)]- aminomethylphosphonate, diethyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[5-(2-methoxypyridyl)]- aminomethylphosphonate, diisopropyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[5-(2-methoxypyridyl)]- aminomethylphosphonate, diethyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[5-(2-chloropyridyl)]- aminomethylphosphonate, diisopropyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[5-(2-chloropyridyl)]- aminomethylphosphonate, diethyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[3-(2-chloropyridyl)]- aminomethylphosphonate, diisopropyl α-(3-ethoxy-4-hydroxy-5-methylphenyl)-N-[3-(2-chloropyridyl)]- aminomethylphosphonate.
12. A pharmaceutical composition containing a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable excipient or carrier.
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
(ID in which χl , X2, X3, B, n, m and Y are as defined in claim 1 ; with a dialkyl phosphite of formula (III):
H-PO(OR!)(OR2) (III) in which R 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
X
(c) for compounds of formula (I) in which m is not zero, treating a compound of formula (VI)
Priority Applications (1)
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---|---|---|---|
AU57619/98A AU5761998A (en) | 1996-12-20 | 1997-12-17 | Pharmaceutical aminophosphonic acid derivatives |
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Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9626536.8A GB9626536D0 (en) | 1996-12-20 | 1996-12-20 | Novel compounds |
GB9626536.8 | 1996-12-20 |
Publications (1)
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WO1998028311A1 true WO1998028311A1 (en) | 1998-07-02 |
Family
ID=10804784
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/007192 WO1998028311A1 (en) | 1996-12-20 | 1997-12-17 | Pharmaceutical aminophosphonic acid derivatives |
Country Status (6)
Country | Link |
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AR (1) | AR010809A1 (en) |
AU (1) | AU5761998A (en) |
CO (1) | CO4930277A1 (en) |
GB (1) | GB9626536D0 (en) |
WO (1) | WO1998028311A1 (en) |
ZA (1) | ZA9711430B (en) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6303784B1 (en) | 1996-12-20 | 2001-10-16 | Smithkline Beecham P.L.C. | Pharmaceutical aminophosphonic acid derivatives |
WO2002026752A1 (en) * | 2000-09-27 | 2002-04-04 | Ilex Oncology Research S.A. | α-SUBSTITUTED β-AMINOETHYL PHOSPHONATES |
WO2002030904A1 (en) | 2000-10-10 | 2002-04-18 | Smithkline Beecham P.L.C. | Pyridinone derivatives for treatment of atherosclerosis |
WO2003069302A2 (en) * | 2002-02-11 | 2003-08-21 | Ilex Products, Inc. | Alpha-substituted arylalkyl phosphonate derivatives |
US6872711B2 (en) | 2000-10-23 | 2005-03-29 | Ilex Oncology Research S.A. | β-substituted β-aminoethyl phosphonate derivatives |
EP1686119A1 (en) | 2000-02-16 | 2006-08-02 | Smithkline Beecham Plc | Pyrimidine-4-one derivatives as ldl-pla2 inhibitors |
WO2012076435A1 (en) | 2010-12-06 | 2012-06-14 | Glaxo Group Limited | Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by lp - pla2 |
WO2013013503A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | 2,3-dihydroimidazo[1,2-c] pyrimidin-5(1h)-one compounds use as lp-pla2 inhibitors |
WO2013014185A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | Bicyclic pyrimidone compounds |
WO2013030374A1 (en) | 2011-09-01 | 2013-03-07 | Glaxo Group Limited | Novel crystal form |
WO2014114694A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | 2,3-dihydroimidazol[1,2-c]pyrimidin-5(1h)-one based lipoprotein-associated phospholipase a2 (lp-pla2) inhibitors |
WO2014114248A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
WO2014114249A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic pyrimidone compounds as inhibitors of lp-pla2 |
WO2016012916A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
WO2016012917A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
WO2021089032A1 (en) | 2019-11-09 | 2021-05-14 | 上海赛默罗生物科技有限公司 | Tricyclic dihydroimidazopyrimidone derivative, preparation method therefor, pharmaceutical composition and use thereof |
JP2021527337A (en) * | 2018-06-14 | 2021-10-11 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | Process for the generation of electronic components, including self-assembled monolayers |
WO2022233302A1 (en) | 2021-05-07 | 2022-11-10 | 上海赛默罗生物科技有限公司 | Pyrimidinone derivative and preparation method therefor, pharmaceutical composition, and use |
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- 1997-12-17 WO PCT/EP1997/007192 patent/WO1998028311A1/en active Application Filing
- 1997-12-17 AU AU57619/98A patent/AU5761998A/en not_active Abandoned
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EP0559079A1 (en) * | 1992-03-05 | 1993-09-08 | Symphar S.A. | Substituted aminophosphonate derivatives, process for their preparation and pharmaceutical compositions containing them |
EP0703239A1 (en) * | 1994-09-19 | 1996-03-27 | Hoechst Aktiengesellschaft | Aminomethylphosphonic and aminomethylphosphinic acids derivatives and their use in the treatment of degenerative articular diseases |
WO1997002037A1 (en) * | 1995-06-30 | 1997-01-23 | Symphar S.A. | Compounds and pharmaceutical compositions containing them |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
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US6303784B1 (en) | 1996-12-20 | 2001-10-16 | Smithkline Beecham P.L.C. | Pharmaceutical aminophosphonic acid derivatives |
EP1686119A1 (en) | 2000-02-16 | 2006-08-02 | Smithkline Beecham Plc | Pyrimidine-4-one derivatives as ldl-pla2 inhibitors |
WO2002026752A1 (en) * | 2000-09-27 | 2002-04-04 | Ilex Oncology Research S.A. | α-SUBSTITUTED β-AMINOETHYL PHOSPHONATES |
US6706698B2 (en) | 2000-09-27 | 2004-03-16 | Ilex Products, Inc. | α-Substituted β-aminoethyl phosphonate derivatives |
KR100722586B1 (en) * | 2000-09-27 | 2007-05-28 | 일렉스 프로덕츠, 인코포레이티드 | ?-substituted ?-aminoethyl phosphonates |
WO2002030904A1 (en) | 2000-10-10 | 2002-04-18 | Smithkline Beecham P.L.C. | Pyridinone derivatives for treatment of atherosclerosis |
EP2258688A1 (en) | 2000-10-10 | 2010-12-08 | SmithKline Beecham Limited | Pyridinone derivatives for treatment of atherosclerosis |
US6872711B2 (en) | 2000-10-23 | 2005-03-29 | Ilex Oncology Research S.A. | β-substituted β-aminoethyl phosphonate derivatives |
WO2003069302A2 (en) * | 2002-02-11 | 2003-08-21 | Ilex Products, Inc. | Alpha-substituted arylalkyl phosphonate derivatives |
WO2003069302A3 (en) * | 2002-02-11 | 2003-11-27 | Ilex Products Inc | Alpha-substituted arylalkyl phosphonate derivatives |
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WO2013013503A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | 2,3-dihydroimidazo[1,2-c] pyrimidin-5(1h)-one compounds use as lp-pla2 inhibitors |
WO2013014185A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | Bicyclic pyrimidone compounds |
WO2013030374A1 (en) | 2011-09-01 | 2013-03-07 | Glaxo Group Limited | Novel crystal form |
WO2014114694A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | 2,3-dihydroimidazol[1,2-c]pyrimidin-5(1h)-one based lipoprotein-associated phospholipase a2 (lp-pla2) inhibitors |
WO2014114248A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
WO2014114249A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic pyrimidone compounds as inhibitors of lp-pla2 |
WO2016012916A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
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Also Published As
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AR010809A1 (en) | 2000-07-12 |
ZA9711430B (en) | 1999-06-21 |
GB9626536D0 (en) | 1997-02-05 |
AU5761998A (en) | 1998-07-17 |
CO4930277A1 (en) | 2000-06-27 |
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