IE871689L - Dihydropyridines - Google Patents

Dihydropyridines

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Publication number
IE871689L
IE871689L IE871689A IE168987A IE871689L IE 871689 L IE871689 L IE 871689L IE 871689 A IE871689 A IE 871689A IE 168987 A IE168987 A IE 168987A IE 871689 L IE871689 L IE 871689L
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alkyl
phenyl
hydroxy
represents hydrogen
substituted
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IE871689A
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IE59546B1 (en
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Boehringer Ingelheim Int
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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
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The carbocyclic and heterocyclic fused dihydropyridines have the formula <IMAGE> and their tautomeric forms have the formula II <IMAGE> in which A represents the fused ring systems <IMAGE> and X represents OR1, NHR2 or NR3R4. [EP0251194A1]

Description

54 6 - 2 - 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 CO-X and the tautomeric forms thereof of formula II, this designation representing the cis and trans forms II* and II" altogether: or cox II' - 3 - wherein X represents 01^; NHR2; NR^R^ and represents hydrogen, C1-4 alkyl; alkoxyalkyl having up to 4 carbon atoms; R2 represents hydrogen; C^_g alkenyl; C^g alkynyl; C^_g cycloalkyl; C^_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-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^_4 alkylamino, di-C^_4 alkylamino (wherein the alkyl groups may be identical or different), C2_j 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; or Cg cycloalkenyl; C2_^ acyl; C^_4 alkylsulphonyl; - 4 - or phenyl (which may in turn be substituted up to three times as described in b)). and independently of each other represent C1_4 alkyl, which may, if desired, be phenyl- substituted, 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 6-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 alkyl, hydroxy or (CH2^p-R5 (wherein P = 0,1) and R^ represents a phenyl radical which is optionally substituted as in b) hereinbefore; wherein Rg represents hydrogen; C^_4 alkyl; or Cj_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 Ry together represent -0-(CH2)n~0- (wherein n = 1,2) Rg represents hydrogen, C-^_4 alkyl R10 represents hydrogen or 2-phenyl-2-ethoxy- carbonylacetyl and compounds of general formula I or II wherein X represents NHR2, R2 represents 3-chlorophenyl or 2-methyl-3- chlorophenyl; and A represents the anellated ring systems $ wherein R represents hydrogen or methoxy; O R,, represents methoxy, hydroxy, amino or o methanesulphonylamino; Ry represents hydrogen, methoxy or hydroxy; Rq represents methyl; R10 represents 2-phenyl-2-ethoxycarbonyl-acetyl; and the salts thereof with physiologically acceptable acids, bases or complexing agents for cardioprotection.
It is preferable to use carbocyclically and hetero-cyclically anellated dihydropyridines of formula and the tautomeric forms thereof of formula in which X represents OR^ NHR2; NR^R4 R^ represents methyl or ethyl R2 represents hydrogen, straight-chained or branched unsubstituted alkyl; allyl; propargyl; cycloalkyl; 3- chlorophenyl; 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, 2,4-dimethoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxy-4-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-3-yl, pyridin-4-yl R^ and R^ independently of each other represent methyl; ethyl; 3-cyanopropyl; benzyl, or 3,4,5-trimethoxvphenethyl or - 8 - Rj and R^ 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 represents the anellated ring systems ^10 wherein Rg represents hydrogen or methoxy Rg represents methoxy, hydroxy, hydrogen, amino or methanesulphonylamino R^ represents hydrogen, methoxy or hydroxy Rg represents methyl R10 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 0CK-CC* dihydro-thieno[3,2-c]pyridines of formula la Preferably, compounds of formula I or II are used wherein A is the group (more particularly those wherein R is hydrogen and R^ and R_, independently of each o o / other, represent hydroxy or methoxy or together represent -0-CH2~0-) and those wherein X is -NHR2 or -NR3R4 (particularly those wherein X is -NHR2, wherein R2 is C1.6 alkyl, preferably alkyl which is unsubstituted or substituted by hydroxy, phenyl [optionally substituted by hydroxy, methoxy or -0-CH2~0~] 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.
R P - 11 - Table 1 Structural type: No. X Structure 1.
OCH 3 ii 2. oc2h5 11 3. nhch3 I 4. nhc2h5 i 5. nh-(ch2)2-ch3 I 6. nh-(ch2 )3-ch3 i 7. nh-(ch2)4-ch3 i 8. nh-ch(ch3)2 i 9. ,nh-ch2-ch(ch3)2 i 10. >jh-(ch2)2-ch(ch3)2 i 11. nh-c(ch3)3 i 12. nh-ch(ch3)-c2h5 i 13. nh-ch--ch=ch2 i 14.
X <_> III <_> 1 CM X o 1 X i 15. nh-(ch2)2-0h 11 16. nh-ch2-ch(0h)-ch3 i 17. nh-(ch2)2-0ch3 11 18. nhr(ch2)3-0ch3 11 19- mh-(ch2)2-n(ch3)2 i ro o • nh-(ch2)3-n(ch3)2 ii 21. nh-(ch2)2-n/ ^0 11 - 12 - No. X Structure 22. nh-(ch2)2 23. NH-f CH2 ) 2 24. NH-(CH2)2^-0CH3 och. 25. NH-(CH2)2 3 I 26. NH-(CH2)2 3 II .27. NH-(CH2)2 II och3 28. NH-(CH2)2 29. NH-(CH2)2 - 13 - No. X Structure U3 30. nh-(ch2)2-n ii 31. NH-N 0 -Q 32. nh-ch2- ii 36. N(C H 3 ) 2 37. n(c2h5)2 i och3 38. n(ch2-ch2-0-och3,2 i OCH 3 39. N 0 - 14 - NO.
Structure 40 M ,s 41. N 0 I I 42. N N - C H 2 A 11 Table 2 43 N N-CH3 44 N N Structural type: OCH. < Ph ^ ^C-X 11 0 NO.
Structure 45 oc2H5 .-/""Co1 1 46. NH-(CH2)2-x .
II I I 47. NH-(CH2)2 11 - 15 - v structure No. A 48. nh-(ch2)2-n 0 11 49.
N 0 II 50. N 0 Table 3 Structural type: No.
Structure 51. 0C2H5 52. NH-(CH2)3-CH3 53. NH-(CH2)4-CH3 54. nh-ch(ch3)2 55. nh-ch2-ch(ch3)2 56. nh-ch2-ch=ch2 I I I I I I I I 57, nh-(ch2)2 •O 58. nh-(ch2 )2 ^°ch3 OCH. o - 16 - No. X Structure 59. «h-(ch2)2-q-och3 i oh 60. NH-(CH2)2/3 61. nh-(ch_),-n 0 i- <- \ / 62. nh 63. nh ^ h3c ci 64. nh-^3 65. nh 66. H Vu~/~\ \_/ y=J och3 6 7. N* \) /ch2-ch2-cn 68. N \ CH ^ / \ 2 \— - 17 - Table 4 Structural type: No.
Structure 69. N(C2H5)2 Table 5 Structural type: No.
Structure 70. NHCH3 I 71. NHC2H5 72. NH -CH.
-O 73. NH(CH2)2 2 .// x) och 3 74. N(CH3)C2H5 - 18 - Table 6 Structural type: och. co x No.
Structure 75. NH-CH. ■-0 76. NH-(CH2)2-Q-0CH3 h3co och3 77. N(CH3)C2H5 78. NH -O I I 79. N N-CH, \ / * 3 - 19 - Table 7 Structural type: H3cso2HN No.
Structure 80 0C2H5 ii Table 8 Structural type: c-x No.
Structure 81. 0C2H5 11 - 20 - Table 9 Structural type: No.
Structure 82. oc2H5 I II 83. NH-(CH2)2 84. nh-(ch2)2 I I ii 85. nh-(ch2)2- i i i 86. N 0 87. nh-ch2-ch(ch )2 i i 88. NH-(CH2)3-N(CH3)2 i i 89. nh-(ch2)2-n 0 11 - 21 - Table 10 Structural type: " " sM "S Ph ^^c-: No. X Structure 90. oc2H5 91. nh- ( ch^ ) 2 ~lj^ ^ I I Table 11 , ch, Structural type: ■ J PH-CH-C t u Et02C 0 t!n Ph C-X 0 No. X Structure 92- 0CjHc II - 22 - 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.
C^_g cycloalkyl indicates cyclopropane, cyclobutane, cyclopentane and cyclohexane.
C^_g cycloalkenes include cyclopentene, cyclohexene and cyclohexadiene, for example.
The C2 and acyl radical indicates the acetyl and propionyl radical. - 23 - C^_g 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, 1,2,4-triazine, 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. - 24 - 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 5 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). 10 Conversely, the inhibition of hypoxic or isoprenaline-induced 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, 15 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 20 (loc.cit.) and the potency of the test substances was given as the H^q 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 25 compounds tested were found to be effective in this test. Test results are shown for the following compounds: 30 Compound A O / \ I O Compound B Ph- eH-C-NH-CH2-CH2-CH2 CH3 II 0 h5Q Value • 2HC1 35 Compound (oral administration) A B 0.73 0.50 40 - 24a - Tests were carried out on hearts isolated by the Langendorff method, according to a slight variation of 0. Langendorff, Pflu^ers Arch 61_ 291 (1985). 5 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 10 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, 15 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 20 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. 25 Compound Concentration B 13.3 pg/ml 30 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 35 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, - 25 - 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, - 26 - 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 - 27 - 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 00 37 934 by cyclising a phenyl malonic acid diamide of general formula III wherein A and X are defined as hereinbefore -h2o CHfCHfNH-COCH(C6Hs)-CO-X i/i - 28 - 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 (do CH-CO-Y IV - HY XH ^ j/jj; VI 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 - 29 - 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 cyclohexylcarbodiimide 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 wherein A and X are defined as for the new compounds hereinbefore. - 30 - The invention also relates to dihydropyridinyl acetic acids of formula .CH-CO-Y (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 Na2S0^ evaporating the solvents, etc - the residue is purified over a silica gel column (CI^C^/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 - 32 - Table 1 ■ i Structural type: No. X Structure Salt form Mp (°C) 1. 0CH3 II Base 86 - 89 2. 0C2H5 11 Base 177 Table 2 Structural type: No. X Structure Salt form Mp (°C) 45. oc2H5 11 Base 104 - 106 - 33 - Table 3 Structural type: 0 No.
Structure Salt form Mp (°C) 51. 0C2H5 I I I Base Base 212 - 214 208 - 211 Table 7 Structural type: 34 - h3cs02hn No.
Structure Salt form Mp (°C) 80 OC2H5 ii Base 198 Table 8 Structural type: No.
Structure Salt form Mp (°C) 81. °c2h5 ii hc1 183 - 35 - Table 9 Structural type: Ph ^C-X it 0 No.
Structure Salt form Mp (°C) 82. 0C2H5 OCH. 83. nh - (CH^ ) 2""^ y—0CH3 I I I 11 hc1 base base 280 159 - 160 64 - 70 84. NH-(CH2)2-h J ii base 156 - 160 35. nh-(ch2)2- U) h i ii base base 260 186 263 188 16. n 0 base 133 - 135 r- mh-ch2-ch(ch3)2 I I base 93 - 102 nh-(ch2)3-n(ch3)2 ii base 204 nh-(ch2)2-n 0 11 base 140 - 143 - 36 - Table 10 Structural type: AQ ~X Ji Ph ^ ^C-X No. X Structure Salt form Mp (°C) 90. oc2h5 91. NH-(CH2)2-|^Svj| I I base 1042 Table 11 Structural type: PH-CH-C i u NO.
Structure Salt form Mp (°C) 92. 0C2H5 11 base 155 - 156

Claims (12)

37 Patent Claims
1. Use of carbocyclically and heterocyclically anellated dihydropyridines of formula r J, co-x and the tautomeric forms thereof of formula 2" JC wherein X represents OR^; NHR2; NR3R4 and R-^ represents hydrogen, C^_4 alkyl; alkoxyalkyl having up to 4 carbon atoms; R2 represents hydrogen; C3_g alkenyl; C3_g alkynyl; C3_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; alkoxy; Cj.-4 alkylthio; amino; mono-C^_^ 38 alkylamino; di-C1_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 alkyl; C^_g cycloalkyl; or Cg cycloalkenyl; C2_^ acyl; C^_4 alkylsulphonyl; or phenyl (which may in turn be substituted up to three times as described in b)). and R4 independently of each other represent C^_4 alkyl, which may, if desired, be phenyl- substituted, whilst the phenyl substituent may in turn be substituted as in b) hereinbefore. or and R4 together with the nitrogen atom to which they are bonded may represent a wholly or partially saturated heterocyclic 5- or 6- and 39 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 (wherein p = 0 or 1) represents a phenyl radical which is optionally substituted as in b) hereinbefore; represents the anellated ring systems wherein Rg represents hydrogen; C^_4 alkyl; or alkoxy Rg and R7 which may be identical or different represent hydrogen, hydroxy, alkyl, C^_4 alkoxy, amino, methanesulphonylamino or Rg and R^ together represent -0-(CH2)n-0- (wherein n = 1 or 2) 40 Rg represents hydrogen, alkyl r represents hydrogen or 2-phenyl-2-ethoxy- carbonylacetyl and compounds of general formula I or II wherein X represents NHR2, R2 represents 3-chlorophenyl or 2-methyl-3- chlorophenyl; and A represents the anellated ring systems wherein R, R 10 represents hydrogen or methoxy; represents methoxy, hydroxy, amino or methanesulphonylamino; represents hydrogen, methoxy or hydroxy; represents methyl; represents 2-phenyl-2-ethoxycarbonyl-acetyl; and the salts thereof with physiologically acceptable acids, bases or complexing agents for preparing agents for cardioprotection. 41
2. Use of carbocyclically and heterocyclically anellated dihydropyridines of formula I or II as claimed in claim 1 wherein X represents OR^ NHR2; NR^R^ R^ represents methyl or ethyl R2 represents hydrogen, straight-chained or branched unsubstituted alkyl; allyl; propargyl; C3_g cycloalkyl; 3-chlorophenyl; 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, 2,4-dimethoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxy-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 3-hydroxy-4-methoxyphenyl, f) morpholino, pyridin-2-yl, indol-3-yl, furan-2-yl, thiophen-2-yl, pyridin-3-yl, pyridin-4-yl R^ and R^ independently of each other represent methyl; ethyl; 3-cyanopropyl; benzyl, or 3,4,5-trimethoxyphenethyl or 42 and R4 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 represents the anellated ring systems wherein Rg represents hydrogen or methoxy Rg represents methoxy, hydroxy, amino or methanesulphonylamino R^ represents hydrogen, methoxy or hydroxy Rg represents methyl R10 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 43
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
5. Use of a compound as claimed in one of claims 1 or 2 wherein X is -NHR2 or -NR^R^.
6. Use of a compound as claimed in claim 5 wherein X is -NHRjt wherein Rj is C^_g alkyl.
7. Use of a compound as claimed in claim 6 wherein R2 is alkyl which is unsubstituted or substituted by hydroxy, phenyl (which may be substituted by hydroxy, methoxy or -0-CH2-0-) or morpholino.
8. Dihydroisoquinolines of formula j^s^CH-CO-X dihydro-thieno[3,2-c]pyridines of formula lb (QrCH-C0-x dihydropyrrolo[3,2-c]pyridines of formula 44 h-co-x Ic and dihydropyrido[3,4-b]indoles of formula r» ch-co-x id u and the tautomeric forms thereof, their E/Z-isomeric forms and their enantiomeric forms wherein X represents OR^; NHR2; NR^R^, with the proviso that, in the compounds of formula la, X represents only OR^, and R^ represents hydrogen, alkyl; alkoxyalkyl Rj represents hydrogen; C^_g alkenyl; C^_g alkynyl; C^_g cycloalkyl; C^_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; alkoxy; alkylthio; amino; mono-C^_4 45 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; C3_g cycloalkyl; or Cg cycloalkenyl; C2_3 acyl; C^_4 alkylsulphonyl; or phenyl (which may in turn be substituted up to three times as described in b)). R3 and independently of each other represent C^_4 alkyl, which may, if desired, be phenyl- substituted, whilst the phenyl substituent may in turn be substituted as in b) hereinbefore. or R3 and R4 together with the nitrogen atom to which they are bonded may represent a wholly or partially saturated heterocyclic 5- or 6- 46 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 alkyl, hydroxy or (C^Jp-Rg (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 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 or 2) Rg represents hydrogen, C^_4 alkyl R10 represents hydrogen or 2-phenyl-2-ethoxy- carbonylacetyl . 47
9. Process for preparing compounds of formulae la to Id and their tautomeric forms as claimed in claim 8 a) by cyclising a phenylmalonic acid amide of general formula III iasi] -h20 •ch2-ch2-nh-co-ch(c6hs)-co-x —i nr 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 VI in the presence of a suitable carbodiimide or carbonyldiimidazole as condensing agent. 48
10. Dihydropyridinyl acetic acids of formula IV (IV) and the tautomeric forms V' wherein Y represents OH or halogen and A represents the anellated ring systems *9 to 49 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 R7 together represent -0-(CH2)n-0- (wherein n = 1,2) Rg represents hydrogen, C^_4 alkyl R^g represents hydrogen or 2-phenyl-2-ethoxy- carbonylacetyl 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 CH2- CH2 NH-COCH (C6Hs ) - CO-X III wherein X represents OR^; NHR2; NR^R4 and R^ represents hydrogen, C^_4 alkyl; alkoxyalkyl having up to 4 carbon atomsj R2 represents hydrogen; C3_g alkenyl; C^_g alkynyl; C3_g cycloalkyl; C3_g cycloalkenyl; straight-chained or branched C1_g alkyl which may, if desired, be 50 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^_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^_4 alkylamino, di-C^_4 alkylamino (wherein the alkyl groups may be identical or different), C2_^ 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; Cg_g cycloalkyl; or Cg cycloalkenyl; C2_3 acyl; C^_4 alkylsulphonyl; or phenyl (which may in turn be substituted up to three times as described in b)) . and R4 independently of each other represent C^_4 alkyl, which may, if desired, be phenyl- substituted, whilst the phenyl substituent may in turn be substituted as in b) hereinbefore; 51 or and R^ together with the nitrogen atom to which they are bonded may represent a wholly or partially saturated heterocyclic 5- or 6-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 alkyl, hydroxy or (wherein p = 0 or 1) and R^ represents a phenyl radical which is optionally substituted as in b) hereinbefore; A represents the anellated ring systems wherein Rg represents hydrogen; alkyl; or alkoxy Rg and R7 which may be identical or different represent hydrogen, hydroxy, alkyl, alkoxy, amino, methanesulphonylamino 52 or Rg and R^ together represent -0-(CH2)n~0- (wherein n = 1,2) Rg represents hydrogen, c^-4 R^q represents hydrogen or 2-phenyl-2-ethoxy- carbonylacetyl with the proviso that in the compounds wherein A represents the ring system X represents only OR^. ?
IE168987A 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 IE59546B1 (en)

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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
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