IE59546B1 - Use of carbocyclically and heterocyclically anellated dihydropyridines in the preparation of cardioprotective agents and new heterocyclically and carbocyclically anellated dihydropyridines, processes for preparing them and intermediate stages for the preparation thereof - Google Patents
Use of carbocyclically and heterocyclically anellated dihydropyridines in the preparation of cardioprotective agents and new heterocyclically and carbocyclically anellated dihydropyridines, processes for preparing them and intermediate stages for the preparation thereofInfo
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- IE59546B1 IE59546B1 IE168987A IE168987A IE59546B1 IE 59546 B1 IE59546 B1 IE 59546B1 IE 168987 A IE168987 A IE 168987A IE 168987 A IE168987 A IE 168987A IE 59546 B1 IE59546 B1 IE 59546B1
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- Ireland
- Prior art keywords
- alkyl
- hydroxy
- phenyl
- represents hydrogen
- represent
- Prior art date
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Hydrogenated Pyridines (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The carbocyclic and heterocyclic fused dihydropyridines have the formula and their tautomeric forms have the formula II in which A represents the fused ring systems and X represents OR1, NHR2 or NR3R4.
Description
Dihydroisoquinolines of general formula la are known from EP-A 37 934. The compounds mentioned therein have a cardiotonic activity and have the effect of increasing contractility and influencing .
blood pressure. They have been proposed for use * in improving the supply of blood to the tissues * and the oxygen supply to the tissues.
Surprisingly, it has now been found that the substances described by general formulae I and II have an exceptional cardioprotective activity and constitute a completely new type of Ca-antagonistic compounds.
The invention thus relates to the use of carbocyclically and heterocyclically anellated dihydropyridines of formula
and the tautomeric forms thereof of formula II, this designation representing the cis and trans forms II’ and II altogether:
wherein X represents ORp NHR2; NR3R4 and
R1 represents hydrogen, C^_4 alkyl; alkoxyalkyl having up to 4 carbon atoms;
R2 represents hydrogen; C3_g alkenyl; C3_g alkynyl;
C^_g cycloalkyl; C3_g cycloalkenyl; straight-chained or branched C^_g alkyl which may, if desired, be mono- or polysubstituted by the following substituents of groups a) to c), which may be identical or different:
a) halogen; cyano; hydroxy; mercapto; C^_4 alkoxy; C^_4 alkylthio; amino; mono-Cj_4 alkylamino; di-C^_4 alkylamino (whilst the alkyl radicals may be identical or different;
b) phenyl; optionally mono- or polysubstituted, by either identical or different substituents, by the groups halogen, C^_4 alkoxy, hydroxy, mercapto, C^_4 alkylthio, C^_4 alkyl, amino, mono-C^_4 alkylamino, di-C^_4 alkylamino (wherein the alkyl groups may be identical or different), C2_3 acylamino, C2_3 acyloxy and the group -0-(CH2)n~0 (wherein n = 1 or 2) which is vicinally bonded to the phenyl system
c) a 5- or 6-membered saturated or wholly or partially unsaturated monocyclic heterocyclic group with up to 3 heteroatoms selected from the group comprising N, 0, S; and, as a bicyclic heterocyclic group, indole (whilst the above-mentioned heterocyclic groups may be mono- or polysubstituted by C^_4 alkyl; C^g cycloalkyl; Cg or Cg cycloalkenyl; C23 acyl; C^_4 alkylsulphonyl;
or phenyl (which may in turn be substituted up to three times as described in b)).
and R^ independently of each other represent alkyl, which may, if desired, be phenylsubstituted, whilst the phenyl substituent * may in turn be substituted as in b) hereinbefore.
R^ and R^ together with the nitrogen atom to which they are bonded may represent a wholly or partially saturated heterocyclic 5- or 6membered ring (which may also contain up to 2 further heteroatoms selected from the group comprising N, 0, S), whilst the resulting heterocyclic group may be substituted by C^_4 alkyl, hydroxy or (wherein
P = 0,1) and
R5 represents a phenyl radical which is optionally substituted as in b) hereinbefore;
A represents the anellated ring systems
wherein
Rθ represents hydrogen; C^_4 alkyl; or 0χ_4 alkoxy
Rg and Rj which may be identical or different represent hydrogen, hydroxy, C^_4 alkyl, C^_4 alkoxy, amino, methanesulphonylamino or
Rg and Ry together represent -O-(CH2)n~O- (wherein n = 1,2)
Rg represents hydrogen, C^_4 alkyl
R10 represents hydrogen or 2-phenyl-2-ethoxycarbonylacetyl and compounds of general formula I or II wherein
X represents NHR2,
R2 represents 3-chlorophenyl or 2-methyl-3chlorophenyl;
and
A represents the anellated ring systems
wherein
R_ represents hydrogen or methoxy; o
Rg represents methoxy, hydroxy, amino or methanesulphonylamino;
represents represents represents acetyl;
hydrogen, methoxy or hydroxy; methyl;
2-phenyl-2-ethoxycarbonyland the salts thereof with physiologically acceptable acids, bases or complexing agents for cardioprotection.
It is preferable to use carbocyclically and heterocyclically anellated dihydropyridines of formula
CO-X and the tautomeric forms thereof of formula
Σ in which X represents OR^ NHR2; NR^R^
R^ represents methyl or ethyl
R2 represents hydrogen, straight-chained or branched unsubstituted alkyl;
allyl; propargyl; C^_g cycloalkyl; 3chlorophenyl; 2-methyl-3-chlorophenyl; or alkyl which is monosubstituted by one of the substituents listed below in groups d) to f);
d) cyano, hydroxy, methoxy, dimethylamino
e) phenyl, 3,4-methylenedioxyphenyl, 2,4dimethoxyphenyl, 4-methoxyphenyl, 3,4dimethoxyphenyl, 2-methoxyphenyl, 3-methoxy4-hydroxyphenyl, 3,4,5-1r imethoxyphenyl,
3-hydroxy-4-methoxyphenyl,
f) morpholino, pyridin-2-yl, indol-3-yl, furan-2-yl, thiophen-2-yl, pyridin-3yl, pyridin-4-yl
Rj and independently of each other represent methyl; ethyl; 3-cyanopropyl; benzyl, or 3,4,5-trimethoxvphenethyl or and together with the nitrogen atom to which they are bonded represent morpholine; thiomorpholine; pyrrolidine; piperazine; 4-methylpiperazine;
4-benzylpiperazine; or 4-(2-methoxyphenyl)piperazine;
and
A represents the anellated ring systems
wherein
Rθ represents hydrogen or methoxy
Rg represents methoxy, hydroxy, hydrogen, amino or methanesulphonylamino
R-? represents hydrogen, methoxy or hydroxy
Rg represents methyl represents 2-phenyl-2-ethoxycarbonylacetyl or hydrogen and the salts thereof with physiologically acceptable acids for cardioprotection.
The invention thus relates to dihydroisoquinolines of formula
dihydro-thieno[3,2-c]pyridines of formula
dihydropyrrolo[3,2-c]pyridines of formula
and dihydropyrido[3,4-b]indoles of formula
and the tautomeric forms Ila’, lib', lie' and lid and their E/Z-isomeric forms Ila, lib, lie and lid.
The compounds of formula la - Id are chiral. The invention also includes the two R- and S-enantiomeric forms of the compounds of formula I in which the groups X, Rg, Ry, Rg, Rg and R^g are defined as hereinbefore.
Preferably, compounds of formula I or II are used wherein A is the group D (more particularly those wherein
R_ is hydrogen and R, and R_, independently of each other, represent hydroxy or methoxy or together represent -O-CH2~O-) and those wherein X is -NHR2 or -NRgR4 (particularly those wherein X is -NHR2, wherein R2 is CV6 alkyl, preferably CV4 alkyl which is unsubstituted or substituted by hydroxy, phenyl [optionally substituted by hydroxy, methoxy or -O-CH2~O-] or morpholino).
The substances listed in Tables 1 to 11 which follow are preferably in the tautomeric form I or II.
The preferred tautomeric form is indicated in the structure column by I or II.
The following compounds of formula I in tautomeric form I or II will be specified by name.
Structural type:
Table 1
No. X Structure 1. och3 II 2. oc2h5 II 3. nhch3 I 4. NHC2H5 I 5. NH-(CH2)2-C H3 I 6. NH-(CH2 ) 3-C H3 I 7. NH-(CH2)4-CH3 I 8. NH-CH(CH3)2 I 9. .NH-CH2-CH(CH3)2 I • 10. JJH-(CH2 )2-CH(CH3 ) 2 I 11. NH-C(CH3)3 I 12. NH-CH(CH3)-C2H5 I 13. NH-CH2-CH=CH2 I 14. NH-CH2-C=CH I 15. NH-(CH2)2-0H 11 16. NH-CH2-CH(OH)-CH3 I 17. NH-(CH2)2-OCH3 11 18. NHr(CH2)3-OCH3 11 19- NH-(CH2)2-N(CH3)2 I 20. NH-(CH2)3-N(CH3)2 II 21. NH-(CH_)_-/ 0 I I
No
X
Structure
22.
NH-(CH2 ) 2
23.
nh-(ch2 )2 // ·
24.
.
26.
27.
OCH
OCH
II
I
I
No
X
Structure
. NH-(CH2)2
31. NH-N 0
32. NH-CH
2^0
33.
36. N(CH3)2
37. N(C2H5)2
39. N 0
I
I
I
I
No.
41.
42.
Table 2
Structural type:
Structure
I
I
II
I I
I
I
NO.
Structure
45.
oc2h5
II .
47.
nh-(ch2)2nh-(ch2)20
ΖΎο
NO.
Structure
48. HH-(CH2)2-«^0
II
49. N 0
II
50. N
Table 3
Structural type:
No.
Structure
51.OC2H5 I II 52. NH-(CH2 ) 3-CH3 I 53. NH-{CH2)4-CH3 I 54. NH-CH(CH3)2 I 55. NH-CH2-CH(CH3)2 I 56. NH-CH2-CH=CH2 I 57. hh-(CH2)2hQ I OCH_/ 3 58. nh-(ch2)2-/ Voch3 I
No.
Structure
nh-(ch2)2
Table 4
Structural type:
Table 5
NO. X Structure 69. N(C2H5)2 I I type: H-.CO kA |t Ph^ ^c-x It 0 No. X Structure
70. nhch3 I 71. nhc2h5 '1 72. NH-CH^ I 73.NH(CH2)2~^~^> och3 I 74. N(CH3 )C2H5 I
Table 6
Structural type:
No
Structure
Table 7
Structural type:
Table 8
NO. X Structure 80 oc2h5 II . type:C Ίτ II L. 1 ch3o ll ll Ph^ ^c-x II 0 No. X Structure
81.
oc2h5
Table 9
Structural type:
No.
Structure
82. OC2H5
84,
85.
II nh-(ch2)2·
87. NH-CH2-CH(CH3)2
88. NH-(CH2)3-N(CH3)2
II
89.
Table 10
Structural type:
No.
Structure
90. OC2H5
Table 11 Structural type:
No.
Structure
92.
0C2HS
II
In the definitions used in the text the radicals and groups may be identical or different, i.e. if one of the above-mentioned substituents occurs several times in a particular molecule, the meaning in that instance may be freely selected within the scope of the definitions.
The word alkyl indicates C^_g alkyl and alkyl radicals which may in turn be substituted or, as alkyl radicals, form part of a functional group such as alkoxy or alkylthio. The alkyl radicals include the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl and tert-butyl radicals and the various isomeric pentyl and hexyl radicals such as isopentyl, neopentyl, n-pentyl and the n-hexyl radical.
The above definition thus also applies when the alkyl radical itself is substituted and/or is itself part of an alkoxyalkyl, alkoxycarbonyl, alkoxy, alkylthio, alkylsulphonyl, monoalkylamino, alkylmethyl, alkylthiomethyl or dialkylamino group or the alkyl radical is bonded as substituent to an aromatic heterocyclic or carbocyclic system.
The halogens are fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine and to a lesser extent iodine.
C3_g cycloalkyl indicates cyclopropane, cyclobutane, cyclopentane and cyclohexane.
Cg_g cycloalkenes include cyclopentene, cyclohexene and cyclohexadiene, for example.
The C2 and acyl radical indicates the acetyl and propionyl radical.
Cjg alkynes are the isomeric hexynes, pentynes, butynes and propynes, preferably propargyl.
C^_g alkenes are the isomeric hexenes, pentenes, butenes and propenes, preferably allyl.
Examples of unsaturated heterocycles include:
furan, pyran, pyrrole, pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, thiazole, oxazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,4triazine, 1,3,5-triazine, indole.
Examples of 5- or 6-membered, wholly or partially saturated monocyclic heterocycles include:
imidazolidine, pyrazolidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene, 1,4-dioxane, imidazoline, pyrazoline, pyrroline, etc.
The compounds of formula I and II according to the invention are bases and may be converted in the usual way into any desired physiologically acceptable adducts (salts) with inorganic or organic acids and salts and complexing agents.
Acids suitable for salt formation include hydrochloric, hydrobromic, hydriodic, hydrofluoric, sulphuric, phosphoric, nitric, acetic, propionic, butyric, capric, valeric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, p-hydroxybenzoic acid, phthalic, cinnamic, salicylic, ascorbic and methanesulphonic acid and the like.
It has now surprisingly been found that compounds of formula I and II have a cardioprotective activity.
The cardioprotective activity is determined as follows:
+2
As is well known, the myocardiac Ca content is a measurement of hypoxic heart damage or the heart damage caused by toxic doses of catecholamine (Higgins et al., Mol. Cell. Cardiol. 10: 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242: 437 - 449, 1982; Fleckenstein, A.,
VortrSge der Erlanger Physiol. Tagung 1970, Ed. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenalineinduced myocardial calcium uptake is a measurement of the cardioprotective efficacy of calcium antagonists (Fleckenstein loc.cit.), calmodulin inhibitors (Higgins) and other drugs, e.g. Beta-adrenolytics (Arndts, Arzneimittelforschung 25: 1279-1284, 1975).
The cardioprotective activity was determined on conscious rats after subcutaneous or oral administration of the active substance using the method described by Arndts (loc.cit.) and the potency of the test substances was given as the Η^θ value; this value corresponds to the dosage which brings about a 50% inhibition in the myocardial radio-calcium uptake caused by the administration of 30 mg/kg of isoprenaline (s.c.). The new compounds tested were found to be effective in this test. Test results are shown for the following compounds:
A 0.73
B 0.50
24a
Tests were carried out on hearts isolated by the
Langendorff method, according to a slight variation of O. Langendorff, Pflu^ers Arch 61 291 (1985).
Isolated heart, retrograde perfusion via the aorta.
Electrical stimulation (300 pulses/min, pulse duration 1 msec). The pressure developed in the left ventricle was measured using a rubber ballon filled with liquid.
After a 20 min equilibration period, restriction of the perfusion rate which reduces the flow rate by a factor of 100 creates an oxygen deficiency. When the normal flow rate is restored, a large increase in the basic tension is brought about, and, under the control conditions, an irregular heart action is established after 6-7 mins, and after 15-18 mins there is a rapid transition to regular contractions. Compounds with a cardioprotective effect shorten the time before regular contractions occur. The substance under test (dissolved in a degassed perfusion medium) is infused in the perfusion system during the period of oxygen deficiency in the heart.
When the compounds under test were used in the concentrations given below, they caused a significant reduction in the time taken for regular contractions to occur.
Compound Concentration
B 13.3 pg/ml
In vitro tests on the smooth muscle (strips of aorta; C. van Breemen, P. Aarenson, R. Lautzenheiser, K. Meisheri, Chest 78; 157S - 165S (1980); R. Casteels and G. Droogman,
J. Physio. 317: 263 - 279 (1981)) have shown that the substances according to the invention are calcium antagonists with a new mechanism of activity.
On the basis of these findings, compounds of general formula I and II and the salts thereof with acids, bases or complexing agents are valuable active substances for use in pharmaceutical compositions with a cardioprotective activity and may be used, inter alia for the treatment of cardiac infarct and, in ischaemic heart disease, in prevention and treatment.
Suitable forms for administration include, for example, tablets, capsules, suppositories, solutions, syrups, emulsions, aerosols or dispersable powders. Tablets may be made, for example, by mixing the active substance or substances with known excipients, e.g. inert diluants such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc, and/or agents for obtaining delayed release such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.
Coated tablets may be produced accordingly by coating cores made in the same way as the tablets with substances conventionally used for tablet coatings, e.g. collidone or schellack, gum arabic, talc, titanium dioxide or sugar. In order to obtain delayed release or prevent incompatibilities, the core may also consist of several layers. Similarly the tablet coating may consist of several layers in order to achieve delayed release, whilst the excipients used may be those mentioned for the tablets above.
Syrups containing the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour-improving agent, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents, e.g. condensation products of fatty alcohols with ethylenoxide, or preservatives such as p-hydroxybenzoates.
Injection solutions are produced in the usual way, e.g. by adding preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylene diamine tetraacetic acid and transferring the solution into an injection vial or ampoule.
Capsules containing one or more active substances or combinations of active substances may be produced, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and encapsulating them in gelatine capsules.
Suitable suppositories may be produced, for example, by mixing with carriers intended for this purpose such as neutral fats or polyethylene glycol or derivatives thereof.
The compounds of formula lb, Ic and Id and the tautomeric forms lib’, lib, lie', lie, lid' and lid are new. Numerous compounds of formula la and the tautomeric forms la’ and la” (such as, for example, those wherein X = OR^) are also new.
The invention thus also relates to the new compounds of formula
(I) wherein A and X are as hereinbefore defined, with the proviso that compounds of formula la are only included if X is OR^.
The compounds of formulae I and II may be prepared
a) analogously to the process known from EP-A
37 934 by cyclising a phenyl malonic acid diamide of general formula III wherein A and X are defined as hereinbefore
-h2o
CH2-CH2-NH-CChCHlC6H5)-CO-X I/£ nr in the presence of a condensing agent or
b) starting from carboxylic acids or carboxylic acid halides of formula IV wherein A is defined as hereinbefore and Y represents OH or halogen, by reacting with alcohols or amines of general formula VI wherein X is defined as hereinbefore
in the presence of a suitable condensing agent.
Suitable condensing agents according to the invention include numerous Lewis acids such as phosphorous oxychloride, borontrifluoride, tin tetrachloride or titanium tetrachloride and also strong mineral acids such as sulphuric acid, fluorosulphonic acids, hydrofluoric acid or polyphosphoric acid. They are generally used in an excess. Phosphorus oxychloride is preferred.
The cyclisation reaction may be carried out with or without a solvent present. Any inert solvent is suitable provided that it has sufficient solubility for the reactants and a sufficiently high boiling point. Examples include benzene, alkylbenzenes, chlorobenzenes, decalin, chloroform, methylenechloride, acetonitrile and the like. In an alternative embodiment of the process the condensing agent, e.g. phophorus oxychloride, may itself be used as the solvent.
No special conditions apply with regard to the reaction temperature. The reaction according to the invention may be carried out within a wide temperature range, preferably with heating up to ' about the boiling point of the solvent.
The esterification or amidation reaction b) may in principle be carried out under the same conditions as reaction a). Carbodiimides such as cyclohexvlcarbodiimide or carbonyldiimidazole are additional examples of condensing agents which may be used.
The phenylmalonic acids used as starting compounds for both processes and the dihydropyridinylacetic acids of formula IV are also new compounds and constitute valuable intermediates for the synthesis of the end products I and II.
The invention thus also relates to phenylmalonic acids of formula
CH2-CH2-NH-CO-CHlC6H5)-CO X (HI) wherein A and X are defined as for the new compounds hereinbefore.
The invention also relates to dihydropyridinyl acetic acids of formula
(IV) and the tautomeric forms
wherein Y represents OH or halogen, preferably fluorine, chlorine or bromine and A is defined as hereinbefore.
The phenylmalonic acids of formula III may be prepared analogously to the processes known from EP-A 00 37 934.
Dihydropyridinyl acetic acids of formulae IV or V may be prepared analogously to general process a) by cyclisation of correspondingly substituted phenylmalonic acids.
Example 1 l-[Benzyl-alpha-(4-methyl-piperazin-l-yl-carbonyl]3,4-dihydro-5,6,7-trimethoxy-isoquinoline hydrochloride
37.8 g of alpha-(4-methylpiperazin-l-yl-carbonyl)phenylacetic acid 2-[(3,4,5-trimethoxyphenyl)ethyl]amide are dissolved in 120 ml of acetonitrile and mixed with 18 ml of phosphorusoxychloride. The reaction mixture is heated to reflux temperature for about two hours. It is then concentrated by evaporation, the residue is taken up in 200 ml of methylene chloride and made alkaline by stirring into an ice water/potash solution. After working up in the usual way - extracting with methylene chloride, drying the organic phase over Na2SC>4 evaporating the solvents, etc - the residue is purified over a silica gel column (CH2Cl2/MeOH =
100/1 to 100/2. The free base of the title compound is isolated. In order to prepare the hydrochloride the base is dissolved in the minimum amount of ethanol and mixed with ethanolic hydrochloric acid. The hydrochloride is brought to crystallisation by the dropwise addition of absolute ether and petroleum ether 40:80° (1:1).
16.5 g of the title compound are isolated in the form of crystals, mp. 233°.
The compounds listed as follows may be prepared analogously:
Table 1
Structural type:
No. X Structure Salt form Mp (°C)0CH3 11 Ba se 86 - 1 oc2h5 I I Base177
Table 2 Structural type: CG |« Ph ' 1· ^c-x M 0 No. X Structure Salt form Mp (°C)
I I
Base oc2h5
45.
104 - 106
Table 3
Structural type:
No.
X Structure Salt form Mp (°C)
51. oc2H5
Base
Base
212 - 214 208 - 211
Table 7
Structural type:
No.
X Structure Salt form Mp (°C)
0C2H5
Base 198
Table 8
Structural type:
No.
X Structure Salt form Mp (°C)
81.
0C2«5
II
HCI
183
Table 9
Structural type:
No.
Structure Salt form Mp (°C)
82. 0C2h5
HC1 base
280
159 - 160
84.
85.
H
II
II
I
II
86. N 0
87. NH-CH2-CH(CH3)2 base
- 70 base 156 _ ieo base base
260
186
263
188 base 133 - 135 base
- 102
88. NH-(CH2)3-N(CH3)2
II base
204
89. NH-(CH ) -N 0 base 140 - 143
Table 10
Structural type:
No. X Structure Salt form Mp (°C)OC2H5 ΝΗ-(ΟΗ2)2γ5η] I I base 1042 Table 11 Structural type: ph-ch-cI u EtO2C 0 CHo I ** if if^N ph^^C-X «« 0 No. X Structure Salt form Mp (°C)
92.
0C2H5 base
155
156
Claims (12)
1. Use of carbocyclically and heterocyclically anellated dihydropyridines of formula wherein X represents OR^; NHR 2 ; NR^R^ and R^ represents hydrogen, C^_^ alkyl; alkoxyalkyl having up to 4 carbon atoms; R 2 represents hydrogen; C 3 _g alkenyl; C 3 _g alkynyl; C^_g cycloalkyl; C 3 _g cycloalkenyl; straightchained or branched C^g alkyl which may, if desired, be mono- or polysubstituted by the following substituents of groups a) to c), which may be identical or different: a) halogen; cyano; hydroxy; mercapto; alkoxy; C^_^ alkylthio; amino; mono-C^_^ alkylamino; di-C x _ 4 alkylamino (whilst the alkyl radicals may be identical or different; b) phenyl; optionally mono- or polysubstituted, by either identical or different substituents, by the groups halogen, C^_ 4 alkoxy, hydroxy, mercapto, C^_ 4 alkylthio, C^_ 4 alkyl, amino, mono-C^_ 4 alkylamino, di-C x _ 4 alkylamino (wherein the alkyl groups may be identical or different), C 2 _ 3 acylamino, C 2 _ 3 acyloxy and the group -0-(CH 2 ) n -0 (wherein n = 1 or 2) which is vicinally bonded to the phenyl system c) a 5- or 6-membered saturated or wholly or partially unsaturated monocyclic heterocyclic group with up to 3 heteroatoms selected from the group comprising N, 0, S; and, as a bicyclic heterocyclic group, indole (whilst the above-mentioned heterocyclic groups may be mono- or polysubstituted by C^_ 4 alkyl; C 3 _ g cycloalkyl; C g or C g cycloalkenyl; C 2 _ 3 acyl; C^_ 4 alkylsulphonyl; or phenyl (which may in turn be substituted up to three times as described in b)). and R^ independently of each other represent C^_ 4 alkyl, which may, if desired, be phenylsubstituted, whilst the phenyl substituent may in turn be substituted as in b) hereinbefore. and R 4 together with the nitrogen atom to which they are bonded may represent a wholly or partially saturated heterocyclic 5- or 639 membered ring (which may also contain up to 2 further heteroatoms selected from the group comprising N, 0, S), whilst the resulting heterocyclic group may be substituted by C-^_ 4 alkyl, hydroxy or (CI^lp-Rg (wherein p = 0 or 1) and R 5 represents a phenyl radical which is optionally substituted as in b) hereinbefore; A represents the anellated ring systems wherein Rθ represents hydrogen; C^_ 4 alkyl; or C^_ 4 alkoxy Rg and R 7 which may be identical or different represent hydrogen, hydroxy, C^_ 4 alkyl, alkoxy, amino, methanesulphonylamino or Rg and R 7 together represent -0-(CH 2 ) n -0- (wherein n = 1 or 2) Rg represents hydrogen, C^_ 4 alkyl r represents hydrogen or 2-phenyl-2-ethoxycarbonylacetyl and compounds of general formula I or II wherein X represents NHR^ , R 2 represents 3-chlorophenyl or 2-methyl-3chlorophenyl; and A represents the anellated ring systems wherein Rg represents hydrogen or methoxy; Rg represents methoxy, hydroxy, amino or methanesulphonylamino; R ? represents hydrogen, methoxy or hydroxy; R g represents methyl; R 10 represents 2-phenyl-2-ethoxycarbonylacetyl; and the salts thereof with physiologically acceptable acids, bases or complexing agents for preparing agents for cardioprotection.
2. Use of carbocyclically and heterocyclically anellated dihydropyridines of formula I or II as claimed in claim 1 wherein X represents OR^ NHR 2 ; NR^R^ R^ represents methyl or ethyl R 2 represents hydrogen, straight-chained or branched unsubstituted alkyl; allyl; propargyl; C 3 _ g cycloalkyl; 3chlorophenyl; 2-methyl-3-chlorophenyl; or C^_ 3 alkyl which is monosubstituted by one of the substituents listed below in groups d) to f); d) cyano, hydroxy, methoxy, dimethylamino e) phenyl, 3,4-methylenedioxyphenyl, 2,4dimethoxyphenyl, 4-methoxyphenyl, 3,4dimethoxyphenyl, 2-methoxyphenyl, 3-methoxy 4-hydroxyphenyl, 3,4,5-tr imethoxyphenyl, 3-hydroxy-4-methoxyphenyl, f) morpholino, pyridin-2-yl, indol-3-yl, furan-2-yl, thiophen-2-yl, pyridin-3yl, pyridin-4-yl R 3 and R^ independently of each other represent methyl; ethyl; 3-cyanopropyl; benzyl, or 3,4,5-trimethoxyphenethyl or R 3 and R 4 together with the nitrogen atom to which they are bonded represent morpholine; thiomorpholine; pyrrolidine; piperazine; 4-methylpiperazine; 4-benzylpiperazine; or 4-(2-methoxyphenyl)piperazine; and A represents the anellated ring systems wherein R g represents hydrogen or methoxy Rg represents methoxy, hydroxy, amino or methanesulphonylamino Rj represents hydrogen, methoxy or hydroxy Rg represents methyl R 10 represents 2-phenyl-2-ethoxycarbonylacetyl.
3. Use of a compound of formula I or II as claimed in claim 1 or 2 wherein A is the group
4. Use of a compound of formula I or II according to one of claims 1 to 3, wherein Rg is hydrogen and Rg and R? independently of each other represent hydroxy or methoxy or together represent -O-CH 2 -O-.
5. Use of a compound as claimed in one of claims 1 or 2 wherein X is -NHR 2 or -NR^R^.
6. Use of a compound as claimed in claim 5 wherein X is -NHR 2 , wherein R 2 is C^_g alkyl.
7. Use of a compound as claimed in claim 6 wherein R 2 is alkyl which is unsubstituted or substituted by hydroxy, phenyl (which may be substituted by hydroxy, methoxy or -O-CH 2 -O-) or morpholino.
8. Dihydroisoquinolines of formula Ia co-x dihydro-thieno[3,2-c]pyridines of formula lb dihydropyrrolo[3,2-c]pyridines of formula and dihydropyrido[3,4-b]indoles of formula and the tautomeric forms thereof, their E/Z-isomeric forms and their enantiomeric forms wherein X represents OR^; NHR 2 ; NR^R^, with the proviso that, in the compounds of formula la, X represents only OR^, and R^ represents hydrogen, C^_ 4 alkyl; C^_ 4 alkoxyalkyl R 2 represents hydrogen; C 3 _g alkenyl; C^_g alkynyl; Cg_g cycloalkyl; C 3 _g cycloalkenyl; straightchained or branched C^_g alkyl which may, if desired, be mono- or polysubstituted by the following substituents of groups a) to c), which may be identical or different: a) halogen; cyano; hydroxy; mercapto; C^_ 4 alkoxy; C^_ 4 alkylthio; amino; mono-C^_ 4 alkylamino; di-C 1 _ 4 alkylamino (whilst the alkyl radicals may be identical or different; b) phenyl; optionally mono- or polysubstituted, by either identical or different substituents, by the groups halogen, C^_ 4 alkoxy, hydroxy, mercapto, C^_ 4 alkylthio, C^_ 4 alkyl, amino, mono-C^_ 4 alkylamino, di-C^_ 4 alkylamino (wherein the alkyl groups may be identical or different), C 2 _ 3 acylamino, C 2 _ 3 acyloxy and the group -O-(CH 2 ) n ~O (wherein n = 1 or 2) which is vicinally bonded to the phenyl system c) a 5- or 6-membered saturated or wholly or partially unsaturated monocyclic heterocyclic group with up to 3 heteroatoms selected from the group comprising N, 0, S; and, as a bicyclic heterocyclic group, indole (whilst the above-mentioned heterocyclic groups may be mono- or polysubstituted by C 1-4 alkyl; C 3 _g cycloalkyl; C 5 or Cg cycloalkenyl; C 2 _ 3 acyl; C^_ 4 alkylsulphonyl; or phenyl (which may in turn be substituted up to three times as described in b)). and r 4 independently of each other represent C-^_ 4 alkyl, which may, if desired, be phenylsubstituted, whilst the phenyl substituent may in turn be substituted as in b) hereinbefore. or R^ and R 4 together with the nitrogen atom to which they are bonded may represent a wholly or partially saturated heterocyclic 5- or 646 membered ring (which may also contain up to 2 further heteroatoms selected from the group comprising N, 0, S), whilst the resulting heterocyclic group may be substituted by C]__ 4 alkyl, hydroxy or (CH 2 )p-R 5 (wherein p = 0 or 1) and Rg represents a phenyl radical which is optionally substituted as in b) hereinbefore; Rg represents hydrogen; C^_ 4 alkyl; or C^_ 4 alkoxy Rg and which may be identical or different represent hydrogen, hydroxy, C^_ 4 alkyl, C^_ 4 alkoxy, amino, methanesulphonylamino or Rg and R.? together represent -0-(CH 2 ) n -0- (wherein n = 1 or 2) R g represents hydrogen, C^_ 4 alkyl R 10 represents hydrogen or 2-phenyl-2-ethoxycarbonylacetyl .
9. Process for preparing compounds of formulae Ia to Id and their tautomeric forms as claimed in claim 8 a) by cyclising a phenylmalonic acid amide of general formula III -h 2 o CH 2 -CH 2 -NH-CO-CH(C 6 H s ]-CO-X -o I ΠΓ in the presence of a Lewis acid as condensing agent or b) starting from carboxylic acids or carboxylic acid halides of formula IV wherein A is defined as hereinbefore and Y represents OH or halogen, by reacting with alcohols or amines of general formula VI wherein X is defined as hereinbefore XH - HY VI in the presence of a suitable carbodiimide or carbonyldiimidazole as condensing agent.
10. Dihydropyridinyl acetic acids of formula (IV) and the tautomeric forms V-_v_ wherein Y represents OH or halogen and A represents the anellated ring systems «9 N- wherein Rg represents hydrogen; C^_ 4 alkyl; or C^_ 4 alkoxy Rg and R^ which may be identical or different represent hydrogen, hydroxy, C^_ 4 alkyl, C-^_ 4 alkoxy, amino, methanesulphonylamino or Rg and R? together represent -0-(CH2) n -0- (wherein n = 1,2) R g represents hydrogen, C^_ 4 alkyl R-^g represents hydrogen or 2-phenyl-2-ethoxycarbonylacetyl and the salts thereof with acids and bases.
11. Compound of general formula IV or V according to claim 10 wherein Y is fluorine, chlorine or bromine.
12. Phenylmalonic acids of formula III ch 2 -ch 2 NH-CO-CH (C 6 H s ) - CO-X III wherein X represents OR^; NHR 2 ; NRgR 4 and R^ represents hydrogen, C^_ 4 alkyl; alkoxyalkyl having up to 4 carbon atoms/ R 2 represents hydrogen; C 3 _g alkenyl; C 3_g alkynyl; C 3 _g cycloalkyl; C 3 _ g cycloalkenyl; straight-chained or branched C. c alkyl which may, if desired, be 1-b mono- or polysubstituted by the following substituents of groups a) to c) , which may be identical or different: a) halogen; cyano; hydroxy; mercapto; C^_ 4 alkoxy; C^_ 4 alkylthio; amino; mono-C^_ 4 alkylamino; di-C^_ 4 alkylamino (whilst the alkyl radicals may be identical or different; b) phenyl; optionally mono- or polysubstituted, by either identical or different substituents, by the groups halogen, C^_ 4 alkoxy, hydroxy, mercapto, C^_ 4 alkylthio, C^_ 4 alkyl, amino, mono-C 1 _ 4 alkylamino, di-C 1 _ 4 alkylamino (wherein the alkyl groups may be identical or different), C 2 _ 3 acylamino, C 2 _ 3 acyloxy and the group -0-(CH 2 ) n -0 (wherein n = 1 or 2) which is vicinally bonded to the phenyl system c) a 5- or 6-membered saturated or wholly or partially unsaturated monocyclic heterocyclic group with up to 3 heteroatoms selected from the group comprising N, 0, S; and, as a bicyclic heterocyclic group, indole (whilst the above-mentioned heterocyclic groups may be mono- or polysubstituted by C^_ 4 alkyl; Cg_g cycloalkyl; Cg or Cg cycloalkenyl; C 2 _ 3 acyl; C^_ 4 alkylsulphonyl; or phenyl (which may in turn be substituted up to three times as described in b)) . Rg and R 4 independently of each other represent alkyl, which may, if desired, be phenylsubstituted, whilst the phenyl substituent may in turn be substituted as in b) hereinbefore; or Rg and R^ together with the nitrogen atom to which they are bonded may represent a wholly or partially saturated heterocyclic 5- or 6membered ring (which may also contain up to 2 further heteroatoms selected from the group comprising N, 0, S) , whilst the resulting heterocyclic group may be substituted by C^_ 4 alkyl, hydroxy or (CH 2 ) p -R 5 (wherein p = 0 or 1) and Rg represents a phenyl radical which is optionally substituted as in b) hereinbefore; A represents the anellated ring systems wherein R g represents hydrogen; C^_ 4 alkyl; or C^_ 4 alkoxy Rg and R 7 which may be identical or different represent hydrogen, hydroxy, C^_ 4 alkyl, C^_ 4 alkoxy, amino, methanesulphonylamino with or Rg and R? together represent -O-(CH 2 ) n -O- (wherein n = 1,2) represents hydrogen, ϋ χ _ 4 alkyl represents hydrogen or 2-phenyl-2-ethoxy carbonylacetyl the proviso that in the compounds wherein A represents the ring system
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863621413 DE3621413A1 (en) | 1986-06-26 | 1986-06-26 | USE OF CARBOCYCLIC AND HETEROCYCLICALLY FURNISHED DIHYDROPYRIDINE AS A CARDIOPROTECTIVE AGENT AND NEW HETEROCYCLIC AND CARBOCYCLICALLY FURNISHED DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND ITS ADDITIONAL PRODUCTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE871689L IE871689L (en) | 1987-12-26 |
| IE59546B1 true IE59546B1 (en) | 1994-03-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE168987A IE59546B1 (en) | 1986-06-26 | 1987-06-25 | Use of carbocyclically and heterocyclically anellated dihydropyridines in the preparation of cardioprotective agents and new heterocyclically and carbocyclically anellated dihydropyridines, processes for preparing them and intermediate stages for the preparation thereof |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0251194B1 (en) |
| JP (1) | JPS63258458A (en) |
| KR (2) | KR890000480A (en) |
| AU (1) | AU598558B2 (en) |
| DD (1) | DD264429A5 (en) |
| DE (2) | DE3621413A1 (en) |
| DK (1) | DK323887A (en) |
| ES (1) | ES2053471T3 (en) |
| FI (1) | FI872827A (en) |
| GR (1) | GR3007545T3 (en) |
| HU (1) | HU203752B (en) |
| IE (1) | IE59546B1 (en) |
| IL (1) | IL82995A0 (en) |
| NO (1) | NO872672L (en) |
| PL (1) | PL159840B1 (en) |
| PT (1) | PT85169B (en) |
| YU (1) | YU46216B (en) |
| ZA (1) | ZA874587B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2623810B2 (en) * | 1987-02-17 | 1992-01-24 | Sanofi Sa | ALPHA SALTS- (TETRAHYDRO-4,5,6,7 THIENO (3,2-C) PYRIDYL-5) (2-CHLORO-PHENYL) -THETHYL ACETATE DEXTROGYRE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| IL86131A0 (en) * | 1987-04-24 | 1988-11-15 | Boehringer Ingelheim Kg | Benzo-and thieno-3,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| DE3827727A1 (en) * | 1988-08-16 | 1990-02-22 | Boehringer Ingelheim Kg | ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE OF SUCH CONNECTIONS FOR CARDIRO PROTECTION |
| GB8921304D0 (en) * | 1989-09-20 | 1989-11-08 | Wyeth John & Brother Ltd | New method of treatment and heterocyclic compounds used therein |
| DE4041482A1 (en) * | 1990-12-22 | 1992-06-25 | Boehringer Ingelheim Kg | NEW PHARMACEUTICAL USE OF CARBOCYCLIC AND HETEROCYCLICALLY ANNELATED DIHYDROPYRIDINE |
| CN1056832C (en) * | 1992-06-22 | 2000-09-27 | 贝林格尔·英格海姆公司 | Carbocyclic and heterocyclic annelleted dihydropyridine and application of same in preparation of pharmaceutical |
| WO1994000435A1 (en) * | 1992-06-22 | 1994-01-06 | Boehringer Ingelheim Kg | Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions |
| DE4343683A1 (en) * | 1993-12-21 | 1995-06-22 | Boehringer Ingelheim Kg | Anellated dihydropyridines and their use for the preparation of pharmaceutical preparations |
| FR2724384B1 (en) * | 1994-09-14 | 1999-04-16 | Cemaf | NOVEL 3,4-DIHYDRO BETA-CARBOLINE DERIVATIVES OF MELATONIN AGONISTS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2417512A1 (en) * | 1978-02-17 | 1979-09-14 | Parcor | THIENO (3,2-C) AND THIENO (2,3-C) PYRIDINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
| DE3013906A1 (en) * | 1980-04-11 | 1981-10-15 | C.H. Boehringer Sohn, 6507 Ingelheim | SUBSTITUTED (ALPHA) -AMINOCARBONYL-L-BENZYL-3,4-DIHYDRO-ISOCHINOLINE, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3309596A1 (en) * | 1982-08-05 | 1984-04-05 | Basf Ag, 6700 Ludwigshafen | 2-SUBSTITUTED 1- (3'-AMINOALKYL) -1,2,3,4-TETRAHYDRO-SS-CARBOLINE, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCT |
-
1986
- 1986-06-26 DE DE19863621413 patent/DE3621413A1/en not_active Ceased
-
1987
- 1987-06-24 DD DD87304137A patent/DD264429A5/en not_active IP Right Cessation
- 1987-06-24 ES ES87109110T patent/ES2053471T3/en not_active Expired - Lifetime
- 1987-06-24 PL PL1987266416A patent/PL159840B1/en unknown
- 1987-06-24 EP EP87109110A patent/EP0251194B1/en not_active Expired - Lifetime
- 1987-06-24 DE DE8787109110T patent/DE3785093D1/en not_active Expired - Fee Related
- 1987-06-25 NO NO872672A patent/NO872672L/en unknown
- 1987-06-25 DK DK323887A patent/DK323887A/en not_active Application Discontinuation
- 1987-06-25 YU YU119887A patent/YU46216B/en unknown
- 1987-06-25 IE IE168987A patent/IE59546B1/en not_active IP Right Cessation
- 1987-06-25 PT PT85169A patent/PT85169B/en not_active IP Right Cessation
- 1987-06-25 ZA ZA874587A patent/ZA874587B/en unknown
- 1987-06-25 KR KR1019870006443A patent/KR890000480A/en not_active Application Discontinuation
- 1987-06-25 HU HU872890A patent/HU203752B/en not_active IP Right Cessation
- 1987-06-25 IL IL82995A patent/IL82995A0/en not_active IP Right Cessation
- 1987-06-26 JP JP62159558A patent/JPS63258458A/en active Pending
- 1987-06-26 AU AU74775/87A patent/AU598558B2/en not_active Ceased
- 1987-06-26 FI FI872827A patent/FI872827A/en not_active Application Discontinuation
- 1987-07-01 KR KR1019870006891A patent/KR930006639B1/en not_active IP Right Cessation
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1993
- 1993-04-01 GR GR930400694T patent/GR3007545T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR930006639B1 (en) | 1993-07-22 |
| YU46216B (en) | 1993-05-28 |
| HUT47932A (en) | 1989-04-28 |
| DE3621413A1 (en) | 1988-01-07 |
| PT85169A (en) | 1987-07-01 |
| DK323887D0 (en) | 1987-06-25 |
| DK323887A (en) | 1987-12-27 |
| KR890000480A (en) | 1989-03-14 |
| FI872827A (en) | 1987-12-27 |
| NO872672D0 (en) | 1987-06-25 |
| IL82995A0 (en) | 1987-12-20 |
| YU119887A (en) | 1988-10-31 |
| AU598558B2 (en) | 1990-06-28 |
| ZA874587B (en) | 1989-02-22 |
| ES2053471T3 (en) | 1994-08-01 |
| GR3007545T3 (en) | 1993-08-31 |
| FI872827A0 (en) | 1987-06-26 |
| PL159840B1 (en) | 1993-01-29 |
| PL266416A1 (en) | 1988-09-01 |
| DD264429A5 (en) | 1989-02-01 |
| IE871689L (en) | 1987-12-26 |
| PT85169B (en) | 1990-03-30 |
| AU7477587A (en) | 1988-01-07 |
| NO872672L (en) | 1987-12-28 |
| EP0251194B1 (en) | 1993-03-31 |
| EP0251194A1 (en) | 1988-01-07 |
| DE3785093D1 (en) | 1993-05-06 |
| JPS63258458A (en) | 1988-10-25 |
| HU203752B (en) | 1991-09-30 |
| KR890002144A (en) | 1989-04-08 |
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Legal Events
| Date | Code | Title | Description |
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| MM4A | Patent lapsed |