ZA200100363B - Substituted phenylamidines with antithrombotic action. - Google Patents
Substituted phenylamidines with antithrombotic action. Download PDFInfo
- Publication number
- ZA200100363B ZA200100363B ZA200100363A ZA200100363A ZA200100363B ZA 200100363 B ZA200100363 B ZA 200100363B ZA 200100363 A ZA200100363 A ZA 200100363A ZA 200100363 A ZA200100363 A ZA 200100363A ZA 200100363 B ZA200100363 B ZA 200100363B
- Authority
- ZA
- South Africa
- Prior art keywords
- phenyl
- general formula
- salts
- denotes
- group
- Prior art date
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- 230000002785 anti-thrombosis Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 47
- 235000002639 sodium chloride Nutrition 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- -1 hexyloxycarbonylamidino Chemical group 0.000 claims description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- AHLUZRHJCUUUOT-UHFFFAOYSA-N ethyl 2-[4-[3-[4-[(e)-n'-hexoxycarbonylcarbamimidoyl]anilino]-3-oxopropyl]piperidin-1-yl]acetate Chemical compound C1=CC(C(/N)=N/C(=O)OCCCCCC)=CC=C1NC(=O)CCC1CCN(CC(=O)OCC)CC1 AHLUZRHJCUUUOT-UHFFFAOYSA-N 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 235000005985 organic acids Nutrition 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
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- 239000011780 sodium chloride Substances 0.000 claims description 3
- 230000002776 aggregation Effects 0.000 claims description 2
- 238000004220 aggregation Methods 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 230000008619 cell matrix interaction Effects 0.000 claims description 2
- AVZFLLFIACKCLY-UHFFFAOYSA-N methyl 2-[4-[3-[4-[(e)-n'-octoxycarbonylcarbamimidoyl]anilino]-3-oxopropyl]piperidin-1-yl]acetate Chemical compound C1=CC(C(/N)=N/C(=O)OCCCCCCCC)=CC=C1NC(=O)CCC1CCN(CC(=O)OC)CC1 AVZFLLFIACKCLY-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
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- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
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- 239000003446 ligand Substances 0.000 description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 6
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- 238000011088 calibration curve Methods 0.000 description 5
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- 239000008101 lactose Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 235000019759 Maize starch Nutrition 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
Boehringer Ingelheim Pharma KG Case 5/1242-FL 55216 Ingelheim Foreign filing text
Substituted phenylamidines, pharmaceutical compositions con- taining these compounds and processes for preparing them _
The scope of protection of WO 96/33970 includes phenylamidines of general formula
RZ
H
0
I il N—C—X——Y——7—— CO-0RS5
R1 3 |, wherein inter alia R' denotes a C,.s-alkyloxycarbonyl group, an aryl-C, ;-alkyloxycarbonyl group or a group of formula 0 0) rb” Ne
No— (HCR®) — o” wherein
RA denotes a hydrogen atom or an alkyl group and
RP denotes an alkyl group or a 3- to 7-membered cycloalkyl group, although no such compound is described in so many words in this published application.
It has now been found that the phenylamidines of general formula
- 2 =
HN
NE — —( y—anco-on, (1),
Rg H wherein
R, denotes a C, ,-alkyloxycarbonyl or phenyl-C, ,-alkyloxycar- bonyl group,
R, denotes a hydrogen atom, a C,,-alkyl, C,,-cycloalkyl, phenyl-C,_,-alkyl or R;-CO-OCHR,-group wherein
R, denotes a C, ,-alkyl, C,,-alkoxy, C,,-cycloalkyl or
C,.,-cycloalkoxy group and
R, denotes a hydrogen atom or a C,,-alkyl group, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, have even more valuable pharmacological properties, preferably antithrombotic effects.
The present invention relates to the compounds of the above general formula I, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceu- tical compositions containing these compounds, their use and processes for preparing them.
Preferred compounds of the above general formula I are those wherein the substituted amidino group is in the 4 position,
particularly those compounds wherein
R, denotes a C, ,,-alkyloxycarbonyl or phenyl-C, ,-alkyloxycar- bonyl group and
R, denotes a hydrogen atom, a C,,-alkyl, C.,-cycloalkyl or phe- nyl-C, ,-alkyl group, the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
R, denotes a C, ,,-alkyloxycarbonyl or phenyl-C, ,-alkyloxycar- bonyl group and
R, denotes a C, ,-alkyl or C,,-cycloalkyl group, the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of the above general for- mula I are those wherein
R, denotes a C,_,,-alkyloxycarbonyl cor benzyloxycarbonyl group and
R, denotes a C, ,-alkyl or C. ,-cycloalkyl group, the tautomers, stereoisomers and salts thereof.
The following are mentioned as examples of particularly preferred compounds: (1) 4-[2-[[4- (octyloxycarbonylamidino)phenyl]amino-carbonyl] - ethyl] -1-[(ethoxycarbonyl)methyl] -piperidine,
(2) 4-[2-[[4- (hexyloxycarbonylamidino)phenyl]amino-carbonyl] - ethyl] -1- [(ethoxycarbonyl) methyl] -piperidine, (3) 4-[2-{[4-(hexyloxycarbonylamidino)phenyl]amino-carbonyl] - 8 ethyl] -1- [ (methoxycarbonyl)methyl] -piperidine and (4) 4-[2-[[4- (cctyloxycarbonylamidino)phenyl]amino-carbonyl] - ethyl] -1-[ (methoxycarbonyl) methyl] -piperidine and the salts thereof.
According to the invention the new compounds of general formula
I are obtained, for example, by the following method: reacting a compound of general formula
HN a), (11),
Re wherein
R, is as hereinbefore defined, with a compound of general for- mula
HO- CO——CH,CH, —( encom (111), wherein
R, is as hereinbefore defined, or a reactive derivative thereof and optionally subsequently converting the group R, into a hydrogen atom.
Examples of reactive derivatives of a compound of general formula IIT include the acid chlorides, acid azides, mixed anhydrides with aliphatic or aromatic carboxylic acids or monocarbonates, imidazolides and esters thereof such as the alkyl, aryl and aralkyl esters, e.g. the methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl or benzyl esters.
The reaction is expediently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, di- methylsulphoxide, benzene, toluene, chlorobenzene, tetrahydro- furan, pyridine, pyridine/methylene chloride, pyridine/dime- thylformamide, benzene/tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chlorxoformate, thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohe- xylcarbodiimide, N,N'-dicyclchexylcarbodiimide/N-hydroxysuc- cinimide, 2-(1H-benzotriazolyl)-1,1,3,3-tetramethyl-uronium salts, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, 2-chloro-l-methylpyridinium iodide or triphenylphosphine/carbon tetrachloride, optionally in the presence of dimethylaminopyri- dine or 1l-hydroxy-benzotriazole and/or a base such as triethyl- amine, N-ethyl-diisopropylamine, pyridine or N-methyl-morpho- line, expediently at temperatures between -10 and 180°C, prefe- : 25 rably at temperatures between 0 and 120°C.
The subsequent conversion of the group R, into a hydrogen atom is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a sui- table solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling tem- perature of the reaction mixture.
Cc
Moreover, the compounds of general formula I obtained may op- tionally be resolved into their enantiomers and/or diastereo- mers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures obtained may be re- solved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemi- stry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereo- mers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in race- mic form, they may subsequently be resolved into the enantio- mers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active sub- stance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Opti- cally active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glu- tamic acid, aspartic acid or guinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-) -menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained may be con- verted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with incrganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I thus obtained con- tain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physioclogi- cally acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. the Examples).
As already mentioned, the new phenylamidines of general formula
I and the salts thereof, particularly the physiologically ac- ceptable salts thereof with inorganic or organic acids or bases, have valuable properties. Thus, when administered oral- ly, the new compounds of general formula I produce high and long-lasting plasma levels compared with the aggregation-inhi- biting compound 4-([2-[(4-amidinophenyl)aminocarbonyl]lethyl] - l-carboxymethyl-piperidine {compound 2A) described in
WO 96/33970. Thus, the new phenylamidines of general formula I and the salts thereof have valuable pharmacological properties, not only an anti-inflammatory effect and an inhibitory effect
. Cs on bone degradation but particularly antithrombotic, antiag- gregatory and tumour- or metastasis-inhibiting effects.
For example, the plasma concentration of compound A after oral administration of the compounds of Examples 1 (compound B) and 1(1) (compound C) of the present invention was measured and compared with the plasma concentration of compound A after oral administration of compound A.
After the oral administration of 1 mg/kg of the test compounds to Rhesus monkeys, the concentration of compound A in the plasma was measured 4, 8, 12 and 24 hours after the admini- stration of the substance. Tc do this the Rhesus plasma was incubated with a suspension of human thrombocytes in plasma and
H-BIBU 52 (cf. DE-A-4,214,245) as ligand. The free and bound ligand is separated by centrifuging and quantitatively determi- ned by scintillation counting. The concentration of compound A is calculated from the quantity of bound ligand using a cali- bration curve.
For this purpose donor blood is taken from an anticubital vein and anticoagulated with trisodium citrate (final concentration: 13 mmol/l). The blocd is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) is removed. The residual blood is sharply centrifuged off again at 3200 x g and the supernatant platelet-poor plasma (PPP) is removed.
For the calibration curve for calculating the concentration, 5 pul of a solution of compound A is added to 995 ul PPP (final concentration 5000 nmol/l). Further samples of this plasma are diluted with PPP to a final concentration of 2.5 nmol/l.
To 150 ul of plasma sample from Rhesus monkeys or calibration curve plasma are added 10 ul of ’H-BIBU 52 (final concentration 10 nmol/l), 10 pl of '‘C-sucrose (370 Bg) and 80 ul of PRP and the mixture is incubated at ambient temperature for 20 minutes.
Then the samples are centrifuged at 2000 x g for 5 minutes and the supernatant is removed. 100 ul of the supernatant are mixed with 100 pul of NaOH 0.2 mol/l, 15 ul of HCl S mol/l and 2 ml of scintillator and the ’H and *C radioactivity is measured quan- titatively. The pellet is dissolved in 200 pl of NaOH 0.2 mol/l. 180 pl thereof are mixed with 15 pl of HCl 5 mol/l and 2 ml of scintillator and the *H and **C radicactivity is mea- sured. The residual plasma remaining in the pellet is deter- mined from the '“C content and removed. The quantity of bound ligand is determined from the °H content. The quantity of bound ligand is plotted against the concentration of the calibration curve plasma. The concentration of compound A in the Rhesus plasma is calculated from the quantity of bound ligand in the relevant plasma sample compared with the calibration curve.
The following Table contains the results:
Substance conc. of A |conc. of A |conc. of A conc. of A in [nM], in [nM], in [nM], in [nM], 4h 8h 12h 24h
ER EE EE rE
In view of their biological properties the new compounds of general formula I according to the invention and their physio- logically acceptable salts are suitable for fighting or preven- ting diseases in which larger or smaller cell aggregations occur or in which cell-matrix interactions are involved, e.g. in combating or preventing venous and arterial thromboses, cerebrovascular diseases, pulmonary embolisms, cardiac infarct, arteriosclerosis, osteoporosis and tumour metastasis and for treating genetically caused or acquired disorders of cell in- teractions with one another or with solid structures. Moreover, they are suitable for parallel therapy in thrombolysis using fibrinolytics or vascular interventions such as transluminal angioplasty or in the treatment of states of shock, psoriasis, diabetes and inflammation.
For fighting or preventing the abovementioned diseases the dosage is between 0.1 pug and 30 mg/kg of body weight, prefe- rably 1 pg to 15 mg/kg of bedy weight, taken up to 4 times a day. For this, the compounds of formula I prepared according to the invention, optionally in conjunction with other active sub- stances such as thromboxane receptor antagonists and thrombo- xane synthesis inhibitors or combinations thereof, ADP-receptor antagonists, clopidogrel, ticlopidine, serotonin antagonists, o-receptor antagonists, alkylnitrates such as glycerol trini- trate, phosphodiesterase inhibitors, prostacycline and the ana- logues thereof, fibrinolytics such as tPA, prourckinase, uroki- nase, streptokinase, or anticoagulants such as heparin, derma- tane sulphate, activated protein C, vitamin K antagonists, hirudine, inhibitors of thrombin or other activated clotting factors, may be incorporated, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/ polyethyleneglycol, propyleneglycol, stearylalcohol, carboxy- methylcellulose or fatty substances such as hardened fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspen- sions, solutions, sprays or suppositories.
The following Examples are intended to illustrate the invention more fully:
Preparation of the starting compounds:
Example T 4-(hexyloxycarbonylamidino)-aniline 5.1 g of 4-(hexyloxycarbonylamidino) -nitrobenzene are hydro- genated in 100 ml of tetrahydrofuran in the presence of 0.5 g of palladium on activated charcoal at ambient temperature under a hydrogen pressure of 50 psi. Then the catalyst is removed by suction filtering and the filtrate is concentrated by evapora- tion.
Yield: 4.5 g 100 % of theory,
R; value: 0.23 (silica gel; cyclohexane/ethyl acetate = 1:1)
The following compounds are obtained analogously to Example I: (1) 4- (octyloxycarbonylamidino) -aniline
R; value: 0.25 (silica gel; cyclohexane/ethyl acetate = 1:1) (2) 4-(methoxycarbonylamidino) -aniline
R value: 0.35 (silica gel; methylene chloride/methanol = 9:1) (3) 4-(benzyloxycarbonylamidino)-aniline
R, value: 0.35 (silica gel; methylene chloride/methanol/conc. agueous ammonia = 9:1:0.1)
Example IT 4-(hexvloxycarbonylamidino)-nitrobenzene 2.8 ml of hexyl chloroformate in 80 ml of tetrahydrofuran are added dropwise to 3.5 g of 4-nitrobenzamidine-hydrochloride and 7.2 g of potassium carbonate in a mixture of 350 ml tetrahydro- furan and 70 ml water, whilst cooling with ice. After 1 hour's stirring in an ice bath the mixture is left to stand overnight at ambient temperature. The organic phase is separated off,
washed twice with saturated saline solution, dried and concen- trated by evaporation.
Yield: 5.1 g (100 % of theory),
Re value: 0.72 (silica gel; cyclohexane/ethyl acetate = 1:1)
The following compounds are obtained analogously to Example II: (1) 4- (octyloxycarbonylamidino) -nitrocbenzene mass spectrum: M" = 321 (2) 4-(methoxycarbonylamidino) -nitrocbenzene melting point: 183-185°C (3) 4-(benzyloxycarbonylamidino) -nitrobenzene
R; value: 0.88 (silica gel; methylene chloride/methancl/conc. aqueous ammonia = 9:1:0.1)
Example TTT 4-[2-(chlorocarbonyl)ethyl] -1-[(ethoxycarbonyl)methyl] - ir {dine-hvd hi 4
To 1.46 g of 4-(2-carboxyethyl)-1-[(ethoxycarbonyl)methyl] - piperidine in 10 ml of methylene chloride is added 1 wml of saturated ethereal hydrochloric acid. 1.2 g of thionyl chloride . 25 are added and the mixture is stirred for 3 hours at ambient temperature. The reaction mixture is concentrated by evapora- tion and the residue is mixed twice with toluene and again concentrated by evaporation. The crude product is reacted further in Example 1 without purification.
The following compounds are obtained analogously to Example
IIT: (1) 1-[2-(chlorocarbonyl)ethyl]-4-[{(methoxycarbonyl)-methyl] - piperidine-hydrochloride
(2) 4-[2-(chlorocarbonyl)ethyll-1-[(cyclohexyloxycarbonyl) - methyl] -piperidine-hydrochloride (3) 4-[2-(chlorocarbonyl)ethyl]~1-[(isopropoxycarbonyl) - methyl] -piperidine-hydrochloride
Example IV 4-[2- (carboxy) ethyl -1- (ethoxycarbonyllmethy -piperidine 10 g of 4-[2-(benzyloxycarbonyl)ethyl]-1-[(ethoxycarbonyl - methyl] -piperidine are hydrogenated in 150 ml of tetrahydro- furan for 4 hours at ambient temperature under a hydrogen pressure of 50 psi in the presence of 1.3 g of palladium on activated charcoal. The reaction mixture is concentrated by evaporation and crystallised with diethylether and a little acetone.
Yield: 5.8 g of (79 % of theory), melting point: 65-67°C
The following compounds are obtained analogously to Example IV: (1) 4-(2-carboxyethyl)-1-[(cyclohexyloxycarbonyl)methyl] -pipe- ridine melting point: 85-88°C (2) 4-(2-carboxyethyl)-1- [(isopropoxycarbonyl)methyl] -piperi- dine
R; value: 0.41 (Reversed Phase silica gel; methanol/5% saline = 6:4) (3) 4-(2-carboxyethyl) -1-[ (methoxycarbonyl)methyl] -piperidine melting point: 82-83°C
Example V 4-[2- (benzyloxycarbonyl) ethyl] -1-[ (ethoxycarbonyl) methyl] - , di 6.35 g of ethyl bromoacetate in 20 ml of acetonitrile are added dropwise, with stirring, to 9.0 g of 4-[2-(benzyloxycarbonyl) - ethyl] -piperidine and 5.2 g of N-ethyl-diiscpropylamine in 70 ml of acetonitrile, in an ice bath, and the mixture is stir- red for 18 hours at ambient temperature. The reaction mixture is concentrated by evaporation and the residue is quickly dis- tributed between tert.butylmethyl ether, ice water and 10 ml of 2N sodium hydroxide solution. The organic phase is separated off, washed with ice water and saturated saline, dried and con- centrated by evaporation.
Yield: 10.05 g of (83 % of theory),
R; value: 0.84 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 95:5:1)
The following compounds are obtained analogously to Example V: (1) 4-[2-(benzyloxycarbonyl)ethyl]-1-[(cyclohexyloxycarbonyl) ~ methyl] -piperidine
R; value: 0.47 (silica gel; methylene chloride/methanol/conc.
E 25 aqueous ammonia = 98:2:0.5). (2) 4-[2-(benzyloxycarbonyl)ethyl]-1-[(isopropoxycarbonyl) -me- thyl] -piperidine mass spectrum: M' = 347 (3) 4-[2-(benzyloxycarbonyl)ethyl]-1-[{(methoxycarbonyl) -me- thyl] -piperidine
R, value: 0.40 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 9:1:0.1)
Example VT 4-[2- (benzyloxycarbonyl)ethyl]l -piperidine 9.7 g of 4-(2-carboxyethyl)piperidine-hydrochloride (melting point: 240-250°C, prepared by hydrogenating 3- (4-pyridyl) - acrylic acid in glacial acetic acid in the presence of platinum oxide and subsequently treating with hydrochloric acid), 30 ml of benzylalcohol, 3 g of p-toluenesulphonic acid and 50 ml of toluene are heated for 75 minutes using a water separator. The reaction mixture is concentrated by evaporation in vacuo, the residue is mixed with 50 ml of ice water and extracted three times with tert.butylmethyl ether. The aqueous phase is made alkaline and extracted with tert.butylmethyl ether. The extract is washed with saline, dried and concentrated by evaporation.
Yield: 9.0 g of (73 % of theory),
R; value: 0.18 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 95:5:1)
Preparation of the end compounds:
Example 1 4-[2-{[4- (octyloxycarbonylamidinophenyl] -aminocarbonyl] ethyl] - 1-[(ethoxycarbonyl)methyll-piperidine 5.7 g of 4-[2-(chlorocarbonyl)ethyl] -1- [(ethoxycarbonyl)methyl- piperidine-hydrochloride in 30 ml of methylene chloride are ad- ded dropwise, within 30 minutes, to S.1 ag of 4- (octyloxycar- bonylamidino) aniline and 100 mg of 4-dimethylaminopyridine in 30 ml of pyridine whilst cooling with ice. After standing over- night at ambient temperature the reaction mixture is concentra- ted by evaporation and the residue is purified by chromatogra- phy over a silica gel column with methylene chloride/methanol/ conc. agueous ammonia (9:1:0.1).
Yield: 2.9 g (32 % of theory), melting point: 151-153°C mass spectrum: (M+H)™ = 517
The following compounds are obtained analogously to Example 1: (1) 4-[2-[[4- (hexyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[ (ethoxycarbonyl) methyl] -piperidine melting point: 151-153°C mass spectrum: M' = 489 (2) 4-[2-[[4- (hexyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[(isopropoxycarbonyl)methyl]-piperidine melting point: 161-162°C
R; value: 0.20 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 9:1:0.1) (3) 4-[2-[[4- (octyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1- [(isopropoxycarbonyl) methyl] -piperidine melting point: 151-152°C mass spectrum: M™ = 531 (4) 4-[2-[[4- (hexyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[(cyclohexyloxycarbonyl) methyl] -piperidine melting point: 149-151°C mass spectrum: (M+H)® = 543 (5) 4-[2-[[4- (octyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[(cyclohexyloxycarbonyl) methyl] -piperidine melting point: 157-162°C mass spectrum: (M+H)® = 571 (6) 4-[2-[[4- (hexyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[(methoxycarbonyl) methyl] -piperidine melting point: 153-155°C
Rf value: 0.32 (silica gel; methylene chloride/methanol/conc. agueous ammonia = 9:1:0.1)
(7) 4-[2-[[4- (octyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1- [ (methoxycarbonyl)methyl] -piperidine melting point: 149-150°C mass spectrum: (M+H)®™ = 503 (8) 4-[2-[[4- (methoxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[(ethoxycarbonyl)methyl] -piperidine melting point: 175-177°C mass spectrum: (M+H)" = 419 (9) 4-[2-[[4-(benzyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1- [ (methoxycarbonyl) methyl] -piperidine melting point: 150-152°C
Instead of the carboxylic acid chloride the corresponding car- boxylic acid is used in the presence of N-methyl-morpholine and 2-chloro-l-methylpyridinium iodide in dimethylformamide. (10) 4-[2-[[4- (decyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1- [(ethoxycarbonyl) methyl] -piperidine (11) 4-[2-[[4- (dodecyloxycarbonylamidino) phenyl] aminocar- bonyl] ethyl] -1- [ (ethoxycarbonyl) methyl] -piperidine (12) 4-[2-[[4-(tetradecyloxycarbonylamidino) phenyl] -amino- .. 25 carbonyl] -ethyl] -1- [(ethoxycarbonyl) methyl] -piperidine (13) 4-[2-[[4- (hexadecyloxycarbonylamidino) phenyl] -amino- carbonyl] -ethyl] -1- [(ethoxycarbonyl) methyl] -piperidine (14) 4-[2-[[4- (octadecyloxycarbonylamidino) phenyl] -amino- carbonyl] -ethyl] -1- [ (ethoxycarbonyl)methyl] -piperidine
Example 2 4-[2-[[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] - ethyll-1-[(ethoxycarbonyl)methyl] -piperidine methanesulphonate 1,228 ml of a 1-molar solution of methanesulphonic acid in ace- tone are added dropwise to 600 mg of 4-[2-[[4- (hexyloxycar- bonylamidino) phenyl] aminocarbonyl] -ethyl] -1- [ (ethoxycarbonyl) - methyl] -piperidine in 30 ml of acetone. After standing over- night and triturating with a glass rod a solid is obtained which is suction filtered and washed twice with acetone. The solid is then dried in vacuo at 40°C.
Yield: 560 mg (78 % of theory), melting point: 117-120°C
Calc.: C 655.46 H 7.58 N 9.58 S 5.48
Found: 55.56 7.85 9.72 5.54
The following compound is obtained analogously to Example 2: (1) 4-[2-[[4- (octyloxycarbonylamidino) phenyl] -aminocar- bonyl]ethyl]-1-(ethoxycarbonyl)methyl] -piperidine methane- sulphonate melting point: 125-127°C
Calc. : C 56.84 H 7.90 N 9.14 S 5.23
Found: 56.94 7.88 9.32 5.27
Example 3
Composition: (1) Active substance 50.0 mg (2) Lactose 958.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate — 2.0 mg 215.0 mg
Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
Example 4
Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg (1), (2) and (3) are mixed together and granulated with an agueous solution of (4). (5) is added to the dried granulated ~ 25 material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on cone side.
Diameter of the tablets: 12 mm.
Example 5
Composition: (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg
(3) Powdered lactose 50.0 mg (4) Magnesium stearate — 2.0 mg 160.0 mg
Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatine capsu- les in a capsule filling machine.
Example 6
Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg
Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.
Claims (13)
1. Phenylamidines of general formula HN a) |e e —( —amco-on, (I), Rg H wherein R, denotes a C, ,;-alkyloxycarbonyl or phenyl-C, ,-alkyloxycar- bonyl group, R; denotes a hydrogen atom, a C,-alkyl, C,.,-cycloalkyl, phe- nyl-C, ,-alkyl or R,-CO-OCHR,-group wherein R, denotes a C, ,-alkyl, C, ,-alkoxy, C,,-cycloalkyl or C,. -cyclo- alkoxy group and R; denotes a hydrogen atom or a C,,-alkyl group, the tautomers, stereoisomers and salts thereof.
2. Phenylamidines of general formula I according to claim 1, wherein the substituted amidino group is in the 4 position, the tautomers, stereoisomers and salts thereof.
3. Phenylamidines of general formula I according to claim 2, wherein R, denotes a C, ,,-alkyloxycarbonyl or phenyl-C, ,-alkyloxycar- bonyl group and
R, denotes a hydrogen atom, a C,,-alkyl, C.,-cycloalkyl or phenyl-C, ,-alkyl group, the tautomers, stereoisomers and salts thereof.
4. Phenylamidines of general formula I according to claim 2, wherein RR, denotes a C, ,,-alkyloxycarbonyl or phenyl-C,_.-alkyloxycar- bonyl group and R, denotes a C, ;-alkyl or C,-cycloalkyl group, the tautomers, stereoisomers and salts thereof.
5. Phenylamidines of general formula I according to claim 2, wherein R, denotes a C,. ,,-alkyloxycarbonyl or benzyloxycarbonyl group and R, denotes a C, ,-alkyl- or C, ,-cycloalkyl group, the tautomers, stereoisomers and salts thereof.
6. The following phenylamidines of general formula I according to claim 1: (1) 4-[2-[[4- (octyloxycarbonylamidino) phenyl] -aminocarbo- nyl]ethyl] -1-[(ethoxycarbonyl)methyl] -piperidine, (2) 4-[2-[[4- (hexyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1- [ (ethoxycarbonyl) methyl] -piperidine, (3) 4-[2-[[4- (hexyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl} -1-[(methoxycarbonyl) methyl] -piperidine and
(4) 4-[2-[[4- (octyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[(methoxycarbonyl)methyl] -piperidine and the salts thereof.
7. 4-[2-[[4- (Hexyloxycarbonylamidino) phenyl] -aminocarbonyl] - ethyl] -1-[(ethoxycarbonyl)methyl]-piperidine and the salts thereof.
8. 4-[2-[[4- (octyloxycarbonylamidino) phenyl] -aminocarbenyl] - ethyl] -1-[(ethoxycarbonyl)methyl] -piperidine and the salts thereof.
9. Physiologically acceptable salts of the compounds according to at least one of the claims 1 to 8 with inorganic or organic acids or bases.
10. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 8 or a physiologically accep- table salt according to claim 9 optionally together with one or more inert carriers and/or diluents.
11. Use of a compound according to at least one of claims 1 to 9 for preparing a pharmaceutical composition which is suitable for fighting or preventing diseases in which smaller or larger cell aggregations occur or cell-matrix interactions are invol-
ved.
12. Process for preparing a pharmaceutical composition accor- ding to claim 10, characterised in that a compound according to at least one of claims 1 to 9 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
13. Process for preparing the compounds cf general formula I according to claims 1 to 9, characterised in that a compound of general formula
HN om (11), Rg wherein Ry is defined as in claims 1 to 8, is reacted with a compound of general formula HO- CO—CH,CH, —( —anco-on (III), wherein R, is defined as in claims 1 to 8, or a reactive derivative thereof, and the group R, is optionally subsequently converted into a hydro- gen atom and if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or a compound of general formula I thus obtained is converted into its salts, particularly, for pharmaceutical use, into its phy- siologically acceptable salts.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19833105A DE19833105A1 (en) | 1998-07-23 | 1998-07-23 | New N-amidinophenyl-1-carboxymethyl-4-piperidinepropanamide derivatives useful as antithrombotic, antiaggregatory, antitumor, antimetastatic, antiinflammatory and anti-osteoporosis agents |
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ZA200100363B true ZA200100363B (en) | 2001-07-18 |
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ZA200100363A ZA200100363B (en) | 1998-07-23 | 2001-01-12 | Substituted phenylamidines with antithrombotic action. |
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EP (1) | EP1102746B1 (en) |
JP (1) | JP3629208B2 (en) |
KR (1) | KR20010072046A (en) |
CN (1) | CN1310708A (en) |
AR (1) | AR019462A1 (en) |
AT (1) | ATE240297T1 (en) |
AU (1) | AU5285399A (en) |
BG (1) | BG105159A (en) |
BR (1) | BR9912321A (en) |
CA (1) | CA2337413A1 (en) |
CO (1) | CO5080745A1 (en) |
DE (2) | DE19833105A1 (en) |
DK (1) | DK1102746T3 (en) |
EA (1) | EA200100106A1 (en) |
EE (1) | EE200100048A (en) |
ES (1) | ES2199587T3 (en) |
HK (1) | HK1038750A1 (en) |
HU (1) | HUP0103327A3 (en) |
ID (1) | ID27205A (en) |
IL (1) | IL140774A0 (en) |
NO (1) | NO20010354D0 (en) |
PL (1) | PL345624A1 (en) |
PT (1) | PT1102746E (en) |
SK (1) | SK1052001A3 (en) |
TR (1) | TR200100182T2 (en) |
TW (1) | TW460461B (en) |
UY (1) | UY25621A1 (en) |
WO (1) | WO2000005207A1 (en) |
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ZA (1) | ZA200100363B (en) |
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DE10002510A1 (en) | 2000-01-21 | 2001-07-26 | Boehringer Ingelheim Pharma | New phenylamidine compounds are useful for the treatment of thrombosis, cerebrovascular disorders, heart infarction, arteriosclerosis, osteoporosis, tumor metastasis, shock and diabetes |
US8399678B2 (en) * | 2009-11-18 | 2013-03-19 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dabigatran etexilate |
EP2522662A1 (en) * | 2011-05-11 | 2012-11-14 | Medichem, S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
CN105330568B (en) * | 2015-11-27 | 2017-05-10 | 山东省医学科学院药物研究所 | Preparation method for p-aminobenzamidine hydrochloride |
CN105732433A (en) * | 2016-04-13 | 2016-07-06 | 山东新华制药股份有限公司 | Refining method of Dabigatran etexilate intermediate condensation compound |
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HUT77309A (en) * | 1994-12-01 | 1998-03-30 | Toyama Chemical Co. Ltd. | Novel 2,3-diketopiperazine derivative or salt thereof, pharmaceutical compositions containing them and their use |
DE19515500A1 (en) * | 1995-04-27 | 1996-10-31 | Thomae Gmbh Dr K | Substituted phenylamidines, pharmaceutical compositions containing these compounds and processes for their preparation |
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1998
- 1998-07-23 DE DE19833105A patent/DE19833105A1/en not_active Withdrawn
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1999
- 1999-07-19 CO CO99045660A patent/CO5080745A1/en unknown
- 1999-07-20 DK DK99938296T patent/DK1102746T3/en active
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- 1999-07-20 WO PCT/EP1999/005161 patent/WO2000005207A1/en not_active Application Discontinuation
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Also Published As
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HUP0103327A2 (en) | 2002-01-28 |
HUP0103327A3 (en) | 2003-11-28 |
ES2199587T3 (en) | 2004-02-16 |
EE200100048A (en) | 2002-06-17 |
AR019462A1 (en) | 2002-02-20 |
BR9912321A (en) | 2001-04-24 |
EP1102746A1 (en) | 2001-05-30 |
NO20010354L (en) | 2001-01-22 |
BG105159A (en) | 2001-07-31 |
PL345624A1 (en) | 2002-01-02 |
JP2002521363A (en) | 2002-07-16 |
PT1102746E (en) | 2003-10-31 |
TR200100182T2 (en) | 2001-07-23 |
HK1038750A1 (en) | 2002-03-28 |
CN1310708A (en) | 2001-08-29 |
KR20010072046A (en) | 2001-07-31 |
UY25621A1 (en) | 2001-12-28 |
DE19833105A1 (en) | 2000-01-27 |
NO20010354D0 (en) | 2001-01-22 |
DK1102746T3 (en) | 2003-09-08 |
TW460461B (en) | 2001-10-21 |
ATE240297T1 (en) | 2003-05-15 |
YU3701A (en) | 2003-01-31 |
EP1102746B1 (en) | 2003-05-14 |
DE59905568D1 (en) | 2003-06-18 |
CA2337413A1 (en) | 2000-02-03 |
EA200100106A1 (en) | 2001-08-27 |
IL140774A0 (en) | 2002-02-10 |
AU5285399A (en) | 2000-02-14 |
SK1052001A3 (en) | 2001-08-06 |
WO2000005207A1 (en) | 2000-02-03 |
JP3629208B2 (en) | 2005-03-16 |
ID27205A (en) | 2001-03-08 |
CO5080745A1 (en) | 2001-09-25 |
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