GB2163050A - Treating or preventing diseases using 1,4-dihydropyridines - Google Patents

Treating or preventing diseases using 1,4-dihydropyridines Download PDF

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GB2163050A
GB2163050A GB08520486A GB8520486A GB2163050A GB 2163050 A GB2163050 A GB 2163050A GB 08520486 A GB08520486 A GB 08520486A GB 8520486 A GB8520486 A GB 8520486A GB 2163050 A GB2163050 A GB 2163050A
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ethyl
methyl
alkyl
treating
inhibition
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GB8520486D0 (en
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John Leheup Archibald
Terence James Ward
Albert Opalko
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John Wyeth and Brother Ltd
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John Wyeth and Brother Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Description

1 GB 2 163 050 A 1
SPECIFICATION Method of treating or preventing diseases using 1,4dihydropyridines
This invention relates to a method of treatment using 1,4-dihydropyridine derivatives, more particularly to a method for the treatment or prevention of diseases responsive to the inhibition of blood platelet 5 aggregation and/or inhibition of the enzymes thromboxane synthetase and/or phospholipase.
In European Patent Publication No. 100189 there are disclosed compounds having the formula R 1 0OC COOR 2 H 3 C N CH 2-O-Y-X H wherein R is aryl or heteroary]; (I) RI and R 2 are each independently C1_C4 alkyl or 2-methoxyethyl; Y is -(CH2)rr-I -CH2CH(CH3)- or -CH2C(CH3)27-; X is a 5 or 6 membered nitrogen containing aromatic heterocyclic ring which may optionally be substituted by one or more C1-C4 alkyl, phenyl, benzyl, CN,-N(R 3 6 (CH2), ',CO2H, (CH2),,CO2(Cl-C4 alkyl) or (CH2)mCON(R')2 groups wherein each R 3 is independently H or C1_C4 alkyl-and m is 0 or 1:
and n is 1 to 3 when X is linked by a ring carbon atom or 2 or 3 when X is linked by a ring nitrogen atom; which compounds are stated to possess antihypertensive and anti-ischaemic properties.
We have now surprisingly found that compounds of formula I possess both blood platelet and thromboxane synthetase-inhibitory properties and hence may be used in the treatment or prevention of diseases responsive to such properties such as thrombosis, atherosclerosis, peripheral vascular diseases and migraine.
Accordingly in one aspectthis invention provides a method for treating or preventing disorders responsiveto inhibition of blood platelet aggregation orthromboxane synthetase in a mammal which comprises administering to said mammal an effective amount of a compound of formula I as shown above or a pharmaceutically acceptable salt thereof.
This invention also provides use of a compound of formula I as shown above or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of disorders 25 responsive to inhibition of blood platelet aggregation orthromboxane synthetase, e.g. thrombosis, atherosclerosis, peripheral vascular disease or migraine.
Examples of the groups R, R', R 2 X and Y in formula I are given in EP 100189.
In the methods of this invention preferred examples of R are optionally substituted phenyl such as halophenyl (e.g. 2-chlorophenyl, pentafluorophenyl); dihalophenyl (e.g. 2, 3-dichlorophenyl); nitrophenyl 30 (e.g. 2- or 3-nitrophenyl); trifluoromethylphenyl; (e.g. 2trifluoromethylphe-nyl).
Examples of RI and/or RI are methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl.
Examples of X are imidazolyl, (e.g. 1 -imidazolyl) and pyridyl (e.g. 3pyridyl).
Examples of Y are -CH- and -CH2CHr-.
Compounds of formula I were tested for their ability to inhibit blood platelet aggregation by a modification of the procedure of Fantl, Australian J. Exp. Biol. Med. Sci. 45, 355-62 1967.
Since platelet aggregation is the initial step in thrombus formation it is considered that compounds which prevent aggregation or reduce platelet adhesiveness may inhibit the initiation of the atherosclerotic process. The effect of drugs on aggregation is measured in platelet-rich plasma containing a small amount of arachidonic acid which markedly increases aggregation in vitro and maybe a physiological agent for doing so in vivo. The actual test procedure used is described below.
New Zealand White rabbits (2.5-3kg) are anaesthetised with an injection, via the marginal ear vein, of sodium pentobarbitone 30-40 mg/kg. The carotid artery is cannulated and blood (100-150 ml) is withdrawn into 50ml syringes containing 3.8% sodium citrate (Ratio blood: citrate=9: 1).
- Blood is centrifuged at 200g (1500 r.p.m.) for 10 minutes at 50C. and the platelet rich plasma (PRP) removed. The platelets are then kept at room temperature in a screw topped plastic centrifuge tube forthe duration of the experiment.
A twin channel platelet aggregometer- (HU aggregometer, A. Browne Ltd, Leicester, UK) is used. 1.0 ml aliquots of PRP are prewarmed for 5-10 minutes and stirred continuously at 1100 rpm. Aggregation is induced by addition of 25OpM arachidonic acid, (8p] volume) to the PRP samples. The aggregometer output -50 is set at maximum and the chart recorder sensitivity is altered to give a full scale deflection to this arachidonic acid response.
Control responses are recorded as the maximum deflection obtained after addition of 25OPM arachidonic acid.
PRP samples are preincubated for 1 minute with thetest compounds followed by arachidonic acid 55 2 GB 2 163 050 A 2 addition. The maximum deflection after the addition of arachidonic acid is then recorded. All drugs are screened initially at 10-'M (final concentration), i.e. 10PI of a 1 X 10-2M stock solution of the drug dissolved in distilled water is added to the PRP.
Dazoxiben, a thromboxane synthetase inhibitor (Randall, M. J. et al Research 23 145-162,1981) is used as a positive control and all test components are compared with Dazoxiben. The activity of the test compound is expressed as the ratio IC50 Dazoxiben/1C,0 Test where IC50 is the dose required to inhibit the A.A. induced aggregation by 50%. The greater the ratio the more potent the compound to Dazoxiben.
COMPOUND Inhibition of blood platelet aggregation potency ratio (dazoxiben=l) 1,4-Dihydro-2-methyi-4-(2-nitrophenyi)-6[(3-pyridyimethoxy)methyllpyridine-3,5- ----5 dicarboxylic acid diethyl ester 0.65 1,4-Dihydro-2-methyi-4-(3-nitrophenyi)-6[(3-pyridyl methoxy) methyl] pyridine-3,5-dica rboxylic acid 5-diethyl 3-methyl diester 1,4-Dihydro-2-methyl-4-(3-nitrophenyi)-6-[(3pyridylethoxy)methylpyridine3,5-dicarboxylic acid 5-ethy]-3-methyl diester 0.65 1.68 Compounds possessing thromboxanesynthetase inhibitory activity are useful in the treatment or prevention of diseases responsive to the inhibition of thromboxane synthetase especially cardiovascular 10 disorders such as thrombosis, atherosclerosis, cerebral ischaemic attacks; and angina pectoris; peripheral vascular diseases and migraine.
The compounds of formula I were tested for their ability to inhibit thromboxane production by the following standard test:
a) Generation of thromboxanes Blood (approx. 75 ml) is obtained from an anaesthetised rabbit and centrifuged at 200g for 10 minutes to obtain platelet rich plasma (PRP). An aliquot of PRP is incubated for 10 minutes to obtain platelet rich plasma (PRP). An aliquot of PRP is incubated for 10 minutes at 370C in the presence of vehicle or drug. Platelet aggregation is induced by the addition of adenosine diphosphate and adrenalin. The tubes are incubated for 3 minutes, centrifuged at 10,000 for 3 minutes and a 50 ml aliquot of the supernatant taken for 20 radio-immunoassay of thromboxane B2 (TxB2).
b) Radio-immunoassay of TxB2 The total incubation volume is 150p containing 50VI of 1H-TxB2 (0.005 pCi), 50 ml of sample or authentic TxB2 ranging f rom 5 to 300 pg per tube as -standards and 50pl of rabbit anti-sera to TxB2 (in a concentration which will bind 50% of H-TxB2). After incubation for 1 hour at room temperature the tubes 25 are further incubated for 16-20 hours at40C. 1 ml of dextran-coated charcoal then added to the tubes which are further incubated on ice for 10 minutes. Following the incubation the samples are centrifuged at 10,000g for 10 minutes and 500 ml of the supernatant added to 5 ml of scintillation cocktail. Measurement of the radioactivity in the supernatant quantifies the amount of ['H]-TxB, bound by the antibody. The conc!Bntration of unlabelled TxB2 in he sample is then determined from a linear standard curve.
In the above mentioned test the representative compounds of Examples 3 and 4 gave IC50 values of 115 and 72pM respectively. In the same test the antihypertensive agent nifedipine had an IC50>1 OOOPM- IC50 values represent the concentrations of drug which achieve 50% inhibition of TxB2.
Some compounds of formula I have also been found to possess Phospholipase A2(PLA2) inhibitory activity and hence are also indicated for use as antiinflammatory and antiallergic agents. Of particular interest for this activity are compounds of formula I wherein Ar represents an aryl radical having a 2-nitro substituent. For example the compound of Example 1 produced 90% inhibition of PLA2 activity at a concentration of 1 OOVM. PLA2 activity was assayed by a procedure based on Franson, R. C., Chapter 12.
Intracellular Metabolism of Ingested Phospholipids. Liposomes: from Physical Structure to Therapeutic 49 Applications. North-Holland Biomedical Press, 1981, pp 349-380 and involving measuring the hydrolysis 40 of E. coli. membrane phospholipids and the release of free [1___1410 leic acid from the C-2 position of phospholipids by human platelet PLA2.
Accordingly a second aspect of this invention provides a method fortreating or preventing inflammatory or allergic conditions in a mammal which comprises administering to said mammal an effective amount of a compound of formula I wherein Ar is 2-nitrophenyl or a pharmaceutically acceptable 45 saItthereof.
3 GB 2 163 050 A 3 The compounds of formula 1 and intermediates of analogous structure may be prepared by processes described in EP 100189.
The compounds of formula 1 may be conveniently prepared by a process comprising reacting corresponding compounds of formula ' RCHO 5 R I 00C and H C NH 3 2 COOR 2 CH 2 O-Y-X (IV) wherein R, W, R', X and Y have the meanings above.
Another process for preparing compounds of formula 1 involves reacting ammonia with a compound of formula (V) and (V[):
R and R 1 00C IdpI H 3 c "Q 0 COOR 2 0 CH O-Y-X (VI) (V) wherein R, R', R2, Y and X are as defined above.
The above mentioned processes are conveniently carried out by heating in an inert solvent such as ethanol.
When used in the method of this invention the compound of formula 1, or a pharmaceutically acceptable acid addition salt thereof may be administered alone or in the form of a pharmaceutically acceptable composition. Suitable carriers are well known in the art. The particular dosage will depend on the chosen route of administration and standard pharmaceutical practice.
Preferably the composition is in unit dosage form, e.g. tablets or capsules.
Based on the experiments detained hereinabove, the compounds of formula I or pharmaceutically acceptable salts thereof can be administered at a dose level of about 1 to 200 mg/day maybe used for 20 treating humans suffering from or at risk from thrombosis, atherosclerosis, peripheral vascular diseases, migraine or inflammatory or allergic conditions.
The following Examples illustrate the preparation of compounds of formula 1:
15.
EXAMPLE 1
1,4-Dihydro-2-methyl-4-(2-nitrophenyl)-6-[(3pyridylmethoxy)methyllpyridine-3,5-dicarboxylic acid diethYl 25 ester A mixture of ethyl 3-aminocrotonate (1.3 g, 0.01 mol), ethyl 3-oxo-4-(3pyridylmethoxy) butanoic acid (2.4 g 0.01 mol) and 2-nitrobenzaldehyde (1.56 g, 0.01 m) in ethanol (50 ml) was refluxed for 23 hours. The solvent was removed under reduced pressure and the residue treated with diethyl ether and extracted with 2N hydrochloric acid'. The separated aqueous phase was extracted with chloroform and the chloroform 30 phase separated and evaporated. The residue was treated with acetone and left overnight. Solid material which separated was filtered off and discarded. The acetone solution was evaporated, treated with ammonia solution and extracted with chloroform (X3). The combined chloroform extracts were washed with water, dried (MgS04) and evaporated to give an oil. This was dissolved in ethyl acetate and treated 4 GB 2 163 050 A 4 witn maleic acid (1 g). A little of the solvent was evaporated and acetone and diethyl ether added. The maleic salt of the title compound crystallised and was collected (2.6 g) mp 133-135C.
Analysis:
1 C25H2 1.H20 requires C, 57.42; H, 5.32;N, 6.93% ^07.C4H40.1 Found: C, 57.42; H, 5.30; N, 6.83%. 5 EXAMPLE 2 1,4-Dihydro-2-methyi-4-(3-nitrophenyi)-6-[(3-pyridyl methoxy) methyl] pyridi ne-3,5-dica rboxyl ic acid 5-e-thyl3-methyl diester Ethyl 3-nitrobenzylideneacetoacetate (2.5 9, 0.01 and ethyl 3-oxo-4-(3pyridyimethoxy)butanoic acid (3.0 g) in ethanol (50 mi) with 0.88 ammonia (1 m]) was refluxed for 1 hour. The solvent was removed under 10 reduced pressure and the residue treated with diethyl ether and 2N hydrochlo-ric acid and separated. The aqueous acid solution was extracted with chloroform (x3). The combined chloroform extracts were evaporated and the residue treated with acetone and leftto stand overnight. Crystalline solid was filtered off and discarded.
The acetone solution was evaporated and the residue dissolved in chloroform and washed with 15 aqueous ammonia solution, dried (M9S04) and evaporated. The residue was dissolved in diethyl ether acidified with ethanolic HCI and a little ethyl acetate was added. The title compound crystallised as the hydrochloride salt and was collected by filtration and dried (1.74 9) m.p. 139-141'C.
Analysis:
- 20 C124H2.,N307MC1 requires C,57.20; N,520; N,834% 20 Found: C,57.50; 1-1,534; N,8.54% EXAMPLE 3
1,4-Dihydro-2-[(l-imidazolyipthoxy)methyll-6-methyl-4-(3nitrophenyl)pyridin e-3,5-dicarboxylic acid 3 ethyl-5-methyl diester Ethyl 3-nitrobenzylideneacetoacetate (5.0 g 0.02 mo, 1) and ethyl 3-oxo-4(l-imidazolylethyloxy) butanoic acid (4.8 g 0.02 mol) in ethanol (50 ml) with 0.88 ammonia (4 ml) was refluxed for 7 hours. The solvent was removed under reduced pressure and the residue treated with diethyl ether and 2N hydrochloric acid and separated. The aqueous acid solution was extracted with chloroform (3x) then the combined organic extracts washed with dilute ammonia solution, dried (MgS04) and evaporated. The residue was purified by chromatography on silica using chloroform, to remove by-products, and then chloroform: methanol (9: 1) to 30 give the title compound.
Treatment of this product in ethyl acetate with ethanolic HCI gave the hydrochloride, hemihydrate of the title compound, mp 199-201C.
Analysis:
C23H26N402.W21H20 requires C, 53.54; H, 5.66; N, 10.86% 35 Found: C,53.48; H,.5.43;N,10.97%.
EXAMPLE 4
1,4-Dihydro-2-methyl-4-(3-nitrophenyi)-6-1(3pyridylethoxy)methyllpyridine-3,5-dicarboxylic acid 5-ethyi-3 methyl diester Methyl 3-nitrobenzylidienacetoacetate (3.0 g), ethyl 3-oxo-4-[2-(pyrid-3- yi)ethyloxylbutanoate (3.0 g) 40 and conc. ammonia (2 mO in ethanol (50 mO were refluxed for 6 hours. The solventwas removed under reduced pressure and the residue treated with ether and 2N hydrochloric acid, then separated. The aqueous acid phase was extracted with chloroform and the combined chloroform extracts washed with dilute ammonia solution, dried (NaS04) and evaporated.
The residue was purified by chromatography on silica using ethyl acetate as eluent to give the crude 45 title compound (2.7 g). This was dissolved in ethyl acetate, treated with ethanolic HCI and evaporated to reduced volume. Treatment with ether gave the title compound as the hydrochlotide hernihydrate, 2.0 g, m.p. 175-177'C.
Analysis:
C2,H27N307MC1.121-120 requires C,56.98; H,5.55; N,7.97 50 Found: C,56.78; H,5.08;N,819%.
GB 2 163 050 A 5

Claims (16)

  1. CLAIMS 1. The use of a compound of formula 1
    R R 1 OCIC COOR 2 1 1 H 3 c N CH 2-0-Y-X H or a pharmaceutically acceptable acid addition salt thereof; wherein R is aryl or heteroaryl; R' and R' are each independently Cl-C4 alkyl or 2-methoxyethyl; Y is -(CH2)rr-I -CH2CH(CH3)- or-CH2C(CH3)=; X is a 5 or 6 membered nitrogen containing aromatic heterocyclic ring optionally substituted by one or more CI-C4 alkyl, phenyl, benzyl, CN, - N(R 3)2, (CH2),nCO2H, (CH2)tnC02(Cl-C4 alkyl) or (CH2)m CON(R3)2 groups wherein each R3 is independently H or Cl-C4 alkyl and m is 0 or 1; and n is 1 to 3 when X is linked by a ring carbon atom or 2 or 3 when X is linked by a ring nitrogen atom, in the preparation of a medicament in ready-to-use form for treating or preventing diseases responsive to inhibition of blood platelet aggregation or thromboxane synthetase in a mammal.
  2. 2. The use as claimed in Claim 1 wherein X is an imidazolyl or pyridyl ring optionally substituted by 1 to 3 alkyl groups of 1 to 4 carbon atoms.
  3. 3. The use as claimed in Claim 1 wherein X is 1 -imiclazolyl or 3-pyridyl.
  4. 4. The use as claimed in any one of Claims 1 to 3 wherein Y is -CH= or CH2CH2.
  5. 5. The use as claimed in any one of Claims 1 to 4 wherein R' and R' are each selected from methyl or ethyl:
    (I)
  6. 6. The use as claimed in any one of Claims 1 to 5, wherein R is optionally substituted phenyl.
  7. 7. The use as claimed in any one of Claims 1 to 5 wherein R is 2- or 3nitrophenyl; 2-chlorophenyl; 2,3 clichlorophenyl; 2-trifluoromethylphenyl or pentafluorophenyl.
  8. 8. The use of 1,4-dihyd ro-2-m ethyl-4-(2-n itro phenyl)-6-[(3-pyridyl methoxy) m ethyl] pyrid ine-3,5 clicarboxylic acid diethyl ester or a pharmaceutically acceptable salt thereof in the preparation of a medicament in ready-to-use form for treating or preventing diseases responsive to inhibition of blood 25 platelet aggregation or thromboxane synthetase in a mammal.
  9. 9. The use of 1,4-d ihyd ro-2-methyl-4-(3-n itrophenyl)-6-[(3-pyridyl meth oxy)m ethyl] pyrid i ne-3,5 clicarboxylic acid 5-ethyl 3-methyl cliester or a pharmaceutically acceptable saItthereof in the preparation of a medicament in ready-to-use form for treating or preventing diseases responsive to inhibition of blood platelet aggregation or thromboxane synthetase in a mammal.
  10. 10. The use of 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-[(3pyridylethoxy)methyllpyridine-3,5- clicarboxylic acid 5-ethyl 3-methyl cliester or a pharmaceutically acceptable salt thereof in the preparation of a medicament in ready-to-use form for treating or preventing diseases responsive to inhibition of blood platelet aggregation or thromboxane synthetase in a mammal.
  11. 11. The use of 1,4-dihydro-2-[(l -im idazolyl eth oxy) m ethyl 1-6-methyl4-(3-n itroph enyl) pyrid in e-3,5- 35 dicarboxylic acid 3-ethyl 5-methyl cliester or a pharmaceutically acceptable salt thereof in the preparation of a medicament in ready-to-use form for treating or preventing diseases responsive to inhibition of blood platelet aggregation or thromboxane synthetase in a mammal.
  12. 12. The use of a compound of formula [a R 1 OOC COOR 2 H 3 c N M5-0-Y-X H or a pharmaceutically acceptable acid addition salt thereof, wherein R is 2-nitrophenyl; R1 and R2 are each independently CI-C4 alkyl or 2-methoxyethyl; Y is -(CH2)rC-f -CH2CH(CH3)- or-CH2C(CH3)9-; X is a 5 or 6 membered nitrogen containing aromatic heterocyclic ring which may optionally be 45 substituted by one or more Cl-C4 alkyl, phenyl, benzyl, CN, -N(R')21 (CH2)tnCO2H, (CH2)tnCO2(Cl-C4 alkyl) or (CHA, CON(R')2 groups wherein each R 3 is independently H or Cl-C4 alkyl and rn is 0 or 1; and (fa) 40 ---AM 6 GB 2 163 050 A 6 n is 1 to 3 when X is linked by a ring carbon atom or 2 or 3 when X is linked by a ring nitrogen atom; in the preparation of a medicament in ready-to-use form for treating or preventing diseases responsive to inhibition of phosphoiipase in a mammal.
  13. 13. The use as claimed in Claim 12 wherein R' and R' are independently methyl or ethyl.
  14. 14. The use as claimed in Claim 12 or Claim 13 wherein X is imidazolyl or pyridyl and Y is -CH,- or 5 -CH,CH,
  15. 15. The use as claimed in any one of Claims 12 to 14 wherein X is 1 Amidazolyl or 3-pyridyl.
  16. 16. The use of 1,4-clihyd ro-2-methy]-4-(2-nitroph enyi)-6-[(3-pyridyl methoxy) methyl] pyridi ne-3,5 dicarboxylic acid diethyl ester or a pharmaceutically acceptable acid addition salt thereof in the preparation of a medicament in ready-to-use form for treating or preventing diseases responsive to inhibition of 10 phospholipase in mammals.
    Printed for Her Majesty's Stationery Office by Courier Press, Leamington Spa. 211986. Demand No. 8817443.
    Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.
GB8520486A 1984-08-17 1985-08-15 Method of treating or preventing diseases using 1,4-dihydropyridines Expired GB2163050B (en)

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US4968703A (en) * 1986-08-08 1990-11-06 Glaxo Group Limited Pharmaceutical compositions for the treatment of occlusive vascular diseases
US5380747A (en) * 1992-10-30 1995-01-10 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5807884A (en) * 1992-10-30 1998-09-15 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5783596A (en) * 1992-10-30 1998-07-21 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5792787A (en) * 1995-06-07 1998-08-11 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases

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GB2105989A (en) * 1981-07-30 1983-04-07 Bayer Ag Dihydropyridines with a positive inotropic action new compounds their use in medicaments and processes for their preparation
EP0100189A2 (en) * 1982-07-22 1984-02-08 Pfizer Limited Dihydropyridine anti-ischaemic and antihypertensive agents

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1670825A1 (en) * 1967-03-20 1971-03-11 Bayer Ag Process for the preparation of 1,4-dihydropyridine derivatives
GB1552911A (en) * 1975-07-02 1979-09-19 Fujisawa Pharmaceutical Co 1,4 dihydropyridine derivatives and the preparation thereof
US4154822A (en) * 1976-08-02 1979-05-15 The University Of Chicago Polysaccharide for enhancement of cardiac output
DE2658183A1 (en) * 1976-12-22 1978-07-06 Bayer Ag 2-POSITION SUBSTITUTED 1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS A MEDICINAL PRODUCT
DE2844595A1 (en) * 1978-10-13 1980-04-30 Bayer Ag 2-Acylamino:alkyl-di:hydro-pyridine derivs. - useful as cardiovascular agents acting as coronary dilators, hypotensives, antiarrhythmics, vascular spasmolytics and hypolipaemics
CS228917B2 (en) * 1981-03-14 1984-05-14 Pfizer Method of preparing substituted derivatives of 1,4-dihydropyridine
DE3207982A1 (en) * 1982-03-05 1983-09-08 Bayer Ag, 5090 Leverkusen NEW 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF IN MEDICINAL PRODUCTS
DK161312C (en) * 1982-03-11 1991-12-09 Pfizer CHANGES FOR THE PREPARATION FOR THE PREPARATION OF 2-Amino-CO-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-4-Methyl-2-D-Hydroxy
PH19166A (en) * 1982-09-04 1986-01-16 Pfizer Dihydropyridined,pharmaceutical compositions and method of use
GB8306666D0 (en) * 1983-03-10 1983-04-13 Pfizer Ltd Therapeutic agents
EP0125803A3 (en) * 1983-04-27 1987-01-21 FISONS plc Pharmaceutically active dihydropyridines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2105989A (en) * 1981-07-30 1983-04-07 Bayer Ag Dihydropyridines with a positive inotropic action new compounds their use in medicaments and processes for their preparation
EP0100189A2 (en) * 1982-07-22 1984-02-08 Pfizer Limited Dihydropyridine anti-ischaemic and antihypertensive agents

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ZA855910B (en) 1987-03-25
US4694012A (en) 1987-09-15
GB2167745B (en) 1987-09-03
GB2167745A (en) 1986-06-04
GB2163050B (en) 1989-03-22
DD236093A5 (en) 1986-05-28
GB8421039D0 (en) 1984-09-19
US4900750A (en) 1990-02-13
MX5840A (en) 1993-11-01
GB8520486D0 (en) 1985-09-18

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