PH26225A - Condensed bis-[3,4-dihydro-1-pyridinyl]methanes and pharmaceutical compositions containing those compounds and method of use thereof - Google Patents

Condensed bis-[3,4-dihydro-1-pyridinyl]methanes and pharmaceutical compositions containing those compounds and method of use thereof Download PDF

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Publication number
PH26225A
PH26225A PH36836A PH36836A PH26225A PH 26225 A PH26225 A PH 26225A PH 36836 A PH36836 A PH 36836A PH 36836 A PH36836 A PH 36836A PH 26225 A PH26225 A PH 26225A
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represent
compound
independently
hydrogen
group
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PH36836A
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Walter Losel
Gerd Schnorrenberg
Otto Roos
Dietrich Arndts
Georg Speck
Ilse Streller
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Walter Losel
Gerd Schnorrenberg
Otto Roos
Dietrich Arndts
Georg Speck
Ilse Streller
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • 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
    • 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
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

The invention relates to new condensed bis-(3,4- dihydro-1l-pyridinyl)methanes, processes for preparing them and pharmaceutical compositions containing these compounds.
The new compounds have the general formula I
Ro Ry - wa 11'm N I
R
NN
R R
1 No 6
Ryn Co) R wherein ’
A and B independently of each other represent a benzo or thieno group; '
Ry represents hydrogen, (Cq_q0) alkyl, phenyl, phenyl = (C,_g)alkyl, (C;_4) alkoxy or -NHCOX (wherein X is (C,_glalkyl);
Rg represents hydrogen, (Cy_4)alkyl or hydroxymethyl;
Ry, Ry, Rg and R, independently of one another represent hydrogen or (Ci_g)alkyl or R, together with Ry and/or Re together with R, and the associated carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring;
Riy and Ryy independently of each other represent (Cy_4) alkyl, halogen (F, Cl, Br, I), hydroxy, (Ci_4)- alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents
Ryq Or Ry, together represent -0-CH,-0- or -0-CH,-CH,-0-;
m and n independently of each other represent 0, 1, 2 or 3, if A or B is a benzo group, and 0, 1 or 2, if A or B is a thieno group; and the pharmaceutically acceptable salts thereof with inorganic and organic acids; an exception is the compound of formula I wherein
Ry Ry Ry, Rg, Re and R, represent hydrogen and
A and B represent the group
CH;0 °
CH,0
Compounds of formula I wherein Rg is hydrogen form tautomers of formulae Ia and Ib
R R
(Ry) (1) ZN Ri1)m CJ N-Rg
Rg N la | Ib
R R N
R 6 1 Re x x (Ry2)n (0) (Ri2)n Co)
R. R 7 . 7 wherein Rg is also hydrogen. The definition of formula I also includes the above-mentioned tautomers.
A compound of general formula I above wherein Ryv
Ry, Ry, Re, Re and Ro represent hydrogen and A and B represent the group
CH40
CH,0
Ce 5 is described by Kober, Jeno in Szegedi Tqnarkepzo
FoRskola Iud. Kozl. 1975, pages 145-153 (see Chen.
Abstr. 87; 1349802). This publication does not contain any information as to the physiological effects of this compound.
It has been found that, surprisingly, the new bis- (3,4~dihydro-1-pyridinyl) -methanes of general formula
I have valuable therapeutic properties both as bases and in the form of their salts.
Of the compounds of formula I, the following may be particularly mentioned as being. of especial interest: ~) Compounds of formula T wherein Ry represents hydrogen, (Cy_yq) alkyl, phenyl (C, _c)alkyl or -NHCOX (wherein X is (Cy_5) alkyl);
Riy and Ryo independently of each other represent (Cq_4) alkyl, hydroxy, (Cy.4) alkoxy, methane- sulphonyloxy or methanesulphonamido, or two adjacent substituents Ry, or R;, together represent ~0-CH,-0- or ~0-CH,-CH,-0-; -) Compounds of formula I, wherein Ry represents hydrogen, (Cy_19) alkyl or -NHCOX (wherein
X is (Cy_g)alkyl);
Ry, Ry, Re and R, independently of one another represent hydrogen or R, together with Ry and/or Re together with R, and the associated carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring;
Ry and RH independently of each other represent hydroxy, (Cy_4) alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents
Ryq or Ry, together represent ~0-CH,~0~ or -0-CH,-CH,~0-; -) particularly compounds wherein Ry represents hydrogen, (Cy_g) alkyl or —NHCOCH4 and/or
Rg represents hydrogen, methyl or hydroxymethyl and/or
Ry, Rj, Rg and Ro independently of each other represent hydrogen or R, together with Ry and/or Re together with R, and the associated carbon atom to which they are bound represent a 5-membered carbocyclic ring and/or
Ry1 and R, 5 independently of each other represent hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents
Ryq or Ry, together represent -0-CH,-O-.
Preferred compounds are those of formula TI wherein m and/or n represents 2, particularly those wherein
A and/or B is a benzo group, whilst preferably the two substituents Rey and/or Ry, are in the meta or para position relative to the fusion points of the group A or B, respectively.
Particular mention should be made of compounds wherein Ryy and Ryo are methoxy.
Examples of specific compounds according to the invention are listed in Tables 1 to 3; special mention should be made of 1-(3,4-dihydroxy-6,7-dimethoxy- isoquinolin-1-y1)-1-(3,4-dihydro-6,7-dimethoxy- isoquinolin-l-ylidene)-ethane or a physiologically acceptable salt thereof.
The compounds according to the invention may be prepared in known manner.
In the presence of a condensing agent, an amide of general formula II
R
2 Ry (Ry): ,
R 11
Re
TET Te 0 12'n wherein A, Ry. Ro, Ry, Re, Ro, Ryqr Ryo and m are defined as hereinbefore, Ar represents phenyl or thienyl and n' represents 0, 1, 2 or 3, if Ar is phenyl, and 0, 1 or 2, if Ar is thienyl, and Rg represents hydrogen or (Cy_4) alkyl, may be cyclised to form a corresponding compound (I).
Suitable condensing agents are strong Lewis acids such as phosphorous oxychloride, phosphorous penta- chloride, phosphorous trichloride, phosphorous pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride, and also inorganic acids such as polyphosphoric, sulphuric, fluorosulphonic and hydrofluoric acid, or mixtures of condensing agents such as, for example, a mixture of phosphorous ~ oxychloride and phosphorous pentachloride, or a mixture of phosphorous pentoxide and (C;_4)alkylsulphonic acid, e.g. containing about 10% by weight of P,0g.
If a compound of formula II wherein Rg is hydrogen : is cyclised in the presence of a mixture of phosphorous pentoxide and (Cy_4)alkylsulphonic acid, there is obtained, in addition to the corresponding compound of formula I wherein Rg is hydrogen, the analogous compound of formula I wherein Rg is (Cy_4)alkyl.
Preferably, this variant of the process is carried out with methanesulphonic acid.
Cyclisation may be carried out in the presence or absence of a solvent. Any inert solvent is suitable provided that it has sufficient solubility for the reactants and a sufficiently high boiling point, for example benzene, alkylbenzenes (e.g. toluene, xylene), chlorobenzenes, chloroform, acetonitrile and decalin. In a preferred embodiment of the process, the condensing agent, such as phosphorous oxychloride or a mixture of "Cy .-4)alkylsulphonic acid and phosphorous pentoxide, is used without the addition of solvent.
Cyclisation is preferably effected with phosphorous oxychloride or, in difficult cases, with a mixture of phosphorous pentoxide and (C,_,)alkylsulphonic acid (preferably methanesulphonic acid).
The reaction may be carried out within a wide temperature range, preferably with heating to 50°C up to about the boiling point of the reaction mixture.
The reaction time required is between several days and several hours, depending on starting compound II.
The compounds of general formula II defined above are new compounds. They may be prepared by cyclising + the corresponding malonic acid diamide of general : formula III (R ire 2, coh cormich Xe (R 117m iTh2 i 120 111
Ry R,
wherein Ry. Ry, Ry, Res Ro, Ryy and Rio are defined as hereinbefore, Ar represents phenyl or thienyl and m' and n' independently of each other represent 0, 1, 2 or 3, if Ar is phenyl, and 0, 1 or 2, if
Ar is thienyl.
The reaction is carried out as described above for the cyclisation of compound II to form compound
I. If the reaction is carried out with the mixture of phosphorous pentoxide and (Cy_4)alkylsulphonic acid, there is obtained, in addition to the corresponding compound II wherein Rg is hydrogen, the analogous compound II wherein Rg is (Cy_y)alkyl.
The reaction in which compound III is used as starting material may be carried out without isolating the intermediate compound II in situ up to the preparation of compound I. Since the isoquinoline or thienopyridine ring cyclises only with very great difficulty in many compounds, the intermediate compound of general formula II formed during the reaction of cyclisation or the tautomers thereof may be isolated, the base may be liberated and subjected to the second reaction of cyclisation, if necessary or desirable. In this case, phosphorous oxychloride will preferably be used in the first step, with gentle heating.
In the second step, cyclisation is effected with : : phosphorous pentachloride, a mixture of phosphorous oxychloride and phosphorus pentachloride or with a mixture of methanesulphonic acid and P,0;.
The compounds of general formula IIT are substantially known compounds and may be prepared by methods known per se.
Compounds of formula I wherein Re is hydrogen are - optionally N-alkylated. N-alkylation may be carried out, in principle, with any known alkylating agents provided that they have sufficient reactivity, e.g. active alkylesters such as dialkylsulphate, alkylesters of toluenesulphonic acid or alkylesters of fluoromethanesulphonic acid. The reaction is carried out at temperatures up to the boiling point of the reaction mixture (in this case, alkyl represents (Cy_4)alkyl).
The N-hydroxymethylation is carried out under the conditions of aminoalkylation according to Leuckart-
Wallach (Ber. dtsch. Chem. Ges. 18, (1885) 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; 4 (1950) No. 378). Generally, the substance is treated with a 30% formalin solution, for example, in the presence of formic acid at ambient temperature.
The free base of general formula I is converted into the acid addition salts thereof in a manner known per se.
Suitable acids for salt formation include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, acetic, propionic, butyric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, cinnamic, ascorbic and methanesulphonic acid.
The new bis-(3,4-dihydro-l1-pyridinyl) -methanes of general formula I have valuable therapeutic properties, as already mentioned hereinbefore, both as bases and in the form of their salts.
In particular, these substances have a significant cardioprotective activity which was determined as follows:
© 26225
As 1s well known, the myocardial cat level is a measure of hypoxic heart damage or 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.,
Vortrdge der Erlanger Physiol. Tagung 1970, Edit.
Keidel, Springer Verl. Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenalin-induced myocardial calcium uptake is a measure of the cardioprotective efficacy of calcium antagonists (Fleckenstein loc. cit.), of calmodulin inhibitors (Higgins) and other drugs, e.q. beta-adrenolytics (Arndts, Arzneimittel Forsch. 25: 1279-1284, 1975). The cardioprotective activity was determined in 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 He value; this value corresponds to the dose which results in a 50% inhibition of the myocardial radio-calcium uptake caused by administration of 30 mg/kg s.c. of isoprenalin. The new compounds tested were found to be up to 5 times more effective than the known commercial product propranolol.
Compound Heo . —_—- ee.
A 1.25 * oral administration
Cardioprotective compounds such as Verapamil and
Diltiazem improve the contraction of the heart at re-perfusion after an isolated heart has been held under jschaemic ' conditions (Watts et al, Am. J.
Physiol. 238, H 909, 1980; Meno et al, Am. J. Physiol. 247, H 380, 1984). The cardioprotective effect of compounds of this invention has been tested in isolated hearts of rats under ischaemic conditions followed by re-perfusion. After one hour under ischaemic conditions (0.15 ml/min) a period of 10 to 15 minutes with irregular heart activity follows. This period is significantly reduced by the administration of cardioprotective compounds.
Compound conc. ug/ml reduction of the period of the arrhythmicphase of 11-13 min to
A 3.3 4.0 min
Compound A: U
CH; 0
C 2N
CH; 0 H
H NN
CHO
OCH
In vitro tests on the smooth muscle (strips of aorta) have shown that the compounds according to the invention are calcium anta- gonists with a new mechanism of activity: .
Calcium antagonists inhibit the transmembranal influx of calcium ions into the cells. This inhibition affects the voltage-dependent (slow) calcium channel in the cell membrane. The detection of transmembranal calcium ion currents on strips of tissue with potassium
2 26225 depolarisation using the method described by van
Breemen clearly indicates a calcium antagonist (van Breemen et al., Chest. 78, 157 s - 165 sg, 1980; van Breemen et al., Am J. Cardiol. 49, 507 - 510, 1982; Casteels et al., Pfllfigers Arch. 392, 139 - 145, 1981; Deth. and van Breemen, J. Membrane Biol. 30, 363 ~ 380, 1977).
In view of these findings, the compounds of general formula I and the acid addition salts thereof may - be considered for use as active substances for pharmaceutical compositions for the treatment of coronary heart disease and acute myocardial infarction.
The invention further relates to pharmaceutical compositions which contain the substances of general formula I and the salts thereof with inorganic or organic acids. The pharmaceutical compositions are suitable for oral or parenteral administration.
They may be administered chiefly in the form of tablets, coated tablets, ampoules and syrup preparations.
The single dose of these preparations is between 1.0 and 200 mg, preferably between 20 and 50 mg per 75 kg of body weight. Depending on the seriousness of the case, 1 to 3 doses will generally be administered per day.
The following Examples are intended to illustrate the invention:
Example 1 1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)- 1-(1,2,3,A-tetrahydro-6,7-dimethoxy—isoquinolin= 1-ylidene)-pentane and 1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)- 1-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl- isoquinolin-l-ylidene) -pentane 4.9 g of n-butylmalonic acid-di-N-[2-(3,4-dimethoxy- phenyl) ethyl] -amide are heated to 100°C for 1 to 2 hours in 20 ml of a methanesulphonic acid/P,0¢ mixture (10% by weight of P,0g). After the reaction has ended (monitored by thin layer chromatography) the reaction mixture is poured onto ice, made alkaline with saturated soda solution and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, evaporated = down in vacuo and the residue is separated on silica gel (eluant: methylene chloride: methanol = 100:5, v:V). The N-H compound is eluted first.
N-H compound: m.p. = 158-159°C (hydrochloride)
N-CH, compound: m.p. = 136-137°C (hydrochloride) ‘ : Example 2 1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-y1)=
L-(3.4-dihydro-6,7-dimethoxy-2-N-methyl-isoguinolin= 1-ylidene) -pentane-hydrochloride © 1 g of the 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin- l-y1)-1-(1,2.,3,4-tetrahydro-6,7-dimethoxy-isoquinolin= 1-ylidene) -pentane prepared in Example 1 is heated to boiling for 6 hours in 2 ml of freshly distilled
1s 26225 dimethylsulphate. After working up in the usual way, the product is chromatographed on silica gel (eluant: CH,Cl,: MeOH = 100:5, V:V), the hydrochloride is formed and crystallised from ethanol/ether.
The product is identical with that prepared in
Example 1.
Example 3 1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)- 1-(3,4-dihydro-6,7-dimethoxy—~1-N-hydroxymethyl- isoquinolin-l-ylidene)-ethane-hydrochloride 12 g of 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin- 1-yl)-1-(3,4-dihydro-6,7-dimethoxy-isoquinolin- l-ylidene) —ethane are left to stand for 20 hours at ambient temperature in a mixture consisting of 20 ml of 30% formalin solution and 10 ml of 98% formic acid. The mixture is evaporated to dryness in a water jet vacuum, the reaction product is taken up in CH,Cl,, washed with dilute soda solution and then with water, the organic phase is dried over Na,SO,, the solvent is eliminated in vacuo, the residue is taken up in just sufficient ethanol and precipitated as the hydrochloride by the addition of ethereal hydrochloric acid. M.p. : = 155°C
Example 4 a-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)- 1,2,3,4-tetrahydro-6,7-dimethoxy-1l-benzylidene- isoquinoline . 4.9 g of 1,2,3,4-tetrabydro-6,7-dimethoxy-l-a-2[2- (3, 4-dimethoxyphenyl) —ethyl]-aminocarbonyl] -benzyl-
isoquinoline are heated to boiling for 4 hours in 20 ml of freshly distilled phosphorous oxychloride.
After the reaction has ended (monitored by thin layer chromatography) excess POC1 4 is distilled of £, the residue is distributed between CH,Cl, and dilute soda solution, the organic phase is washed with water, dried over Na,S0, and evaporated down. The residue is chromatographed on silica gel (eluant: CH,C1,:MeOH = 100:10, V:V). The fast- s running yellow fraction yields a-(3,4-dihydro-6,7- dimethoxy-isoquinolin-1-y1)-1,2,3,4-tetrahydro= 6 7-dimethoxy-1l-benzylidene-2-N-phosphono-isoquinoline (m.p. above 270°C (hydrochloride)), whilst the subsequent red zone yields the N-H compound (m.p. 95-100°C) given in the title.
Example 5 (4,5-Dihydro-thieno[2,3-clpyridin-1-y1)-4,5,6,7- tetrahydro-l-methylidene-thieno[2,3-c]oyridine 19 g of malonic acid di-N-[2- (3-thieno) -ethyl]amide are heated to boiling for 3 hours in 25 ml of phosphorous oxychloride. As soon as no further starting material can be detected, the mixture is worked up in the : usual way, the reaction product is purified on
Al,04 neutral, activity stage III (made by Woelm) : (eluant: CH,Cl,) and the hydrochloride is formed. (M.p. = 223-235°C)
Examples of compounds according to the invention are listed in Tables 1-3 which follow.
Table 1 :
R, Rs
Rin (]
N
R
R | 2 1 nN
Ry R, 0! . 12!
R12 wn
Mm
E ~ 2
Lo] —~ a a = om Fn — 2 ~ £2 os © — - oC ~ a = © 3 fu AS — et et ee ~~ e400
Ji = OO oO m mM « Q Aan OU OU OO OO Nn OU om wn ~~ NNN E = OO NN NN NN ~~ NN ~o Ww ~~ oO Oo OO Wn M QO ~N 0 OO OOM NN nN oO LN ODN) 0 NN = EO NN Dn On ° Ma NH AO Mme NO ONO HAN ~~ ~ | 1 1 NN ' 1 Nt ~~ | 1 1 ! 1 ' '
OM WO 0 OO NN ON uy tr OO © &~ ~~ A ~~ ~ 0, ~~ MN 00M NN NNO NY NYDN on = ~N VN HHH AH HN Ms 0 AN HHH HH ~ ol ; FF XT xX XE XD o@;n =m I om mom om ox En x; « o x [ . © .- 0 onoxXr xn no on ono xno In x oom no onmomno on mx orm x . = ~ ’ = o - Oo vu O OO ©O Oo QO OO OO OO OO oO [>] oO ~ © © ® © a 0 © ™ © © © © ! 1 ~” | 1 ao ~ Tor nom XE = OO :moxroxoxmo xm OO O x OO m oO ox; CoE EEeEEEEEEE | © | | © o ~ oo o = Xx oo 0
LO oO Oo oO ©
Qo ~ 2 lol lol = QO O O OO OO O wn oO oO OO O Oo Q QQ o © no ” a © © © © © ” oO oO oc OO OO 0 OO ~ xT XX XX xo om; Lo XxX xr OO x xx xX x 1 tox ' rt x= [=] OOO OO OO OO UO OO Im LU OO LL oO Oo = oO ” ” © © o oa © w = x xx x x = = [=] mom 0 mm DEOL VOD Om Emm mm TE Im ” ol PD =m om mom om mo; =; om = o@x;mom om o&mom om omom : - o x ~ oO oe Xn OX Mmm om Xn xn In ono nm xn nono omni oxomom ~ x o o ~ = = = Oo - - w wn wo own Q nw
LO a 0 om OO = ox a x oo x ~ ! 1x x | o v x oo = © - ox Xr oS sf 0 Om ERED ODD 00 0m OO o 3 - S y = OO OO OO OO © O OO © vn © O © OO OO Oo Oo oO oO od - © mm a © ao © mo © © m ” © ™ ” © 0 © 0 - In On &§n nn mn xX @InoX Im ono; xem mem xm x x v0 [= OL LD LDU LUD LOO LOLOL OO LOLOL OO! Oo
Q Oo © . - cy 56
L Og ~N ~N 0 —~ = x o.c® = Q oO ® oA = \ ~ noni o - OO vl OO OO OO OO O OO OO 0 0 OO OO OO OO © © oo © o Uv) ~~ ~ "a on ® oa m a a @®& eo ao 6 6 6 0 0 1 o ow QO ~ OX OX Xoo XOX XoXo ox oxox oxox oxox = ox LLU OD OO UD LUD LUD UO LD LO LUD OO |]
Table 2 1
S NH
H R
R Salt form Mp)
H4CO X \ cl 218-222
HCO
SS SN
C1 239-235
Table 3 > \ NH
H R
R salt form Mp (°C)
H,CO eS cl 162-172
H,CO
S >N
C | Cl 237-239 2N ae 3 250-253
S
Examples of pharmaceutical applications a) Coated tablets 1 tablet core contains:
Active substance of general formula I 30.0 mg
Lactose 100.0 mg
Corn starch 75.0 mg
Gelatine 3.0 mg
Magnesium stearate 2.0 mg 210.0 mg
Preparation
A mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous gelatine solution through a 1 mm mesh screen, dried at 40°C and rubbed through a screen again. The granules thus obtained are mixed with magnesium stearate and compressed. The resulting cores are coated in the usual way with a coating applied by means of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax. b) Tablets
Active substance of general formula I 30.0 mg
Lactose 100.0 mg
Corn starch 70.0 mg . Soluble starch 7.0 mg
Magnesium stearate 3.0 mg 210.0 mg
Preparation
The active substance and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and intimately mixed with lactose and corn starch. The mixture is then ~ compressed to form tablets weighing 210 mg.
c) Capsules
Active substance according to claim 1 20.0 mg
Lactose 230.0 mg
Corn starch 40.0 mg
Talc 10.0 mg 300.0 mg
Preparation
The active substance, lactose and corn starch are first mixed together in a mixer and then in a grinding machine. The mixture is returned to the mixer, thoroughly combined with the talc and transferred by machine into hard gelatine capsules.
In these Examples, 1-(3,4-dihydroxy-6,7-dimethoxyiso- quinolin-1-yl)-1-(3,4-dihydro-6,7-dimethoxyisoquinolin=- 1-ylidene)-ethane may be used as the active substance, for example.

Claims (4)

Patent Claims
1. Compound of general formula I So " 5 ve “5 Vv oa) SE g Ry 2 “4 N SEN RR "1 Rg Ce on Ryn Co) R 7 wherein A and B. independently of each other represent a benzo or thieno group; Ry represents hydrogen, (C, jo2'ky! phenyl, or ~NHCOX (wherein X is (Cy_glaltkyl; Re represents hydrogen, (Cy.4 alkyl or hydroxy- methyl; Ry» R 4 Re and R, independently of - one another reprsent hydrogen or R, together with Ra and/or Re together with R, and the associated carbon ] atom to which they are bound reprsent a 5- or 6-membered carbocyclic ring; : Ri is (Cia )-alkoxy, i or methanesulphonamido, or two adjacent substituents R11 together represent —0-CH,-0- or ~0-CH,~CH,-0-; Rio is hydroxy, (Cy _4)-alkoxy or or two adjacent substituents Riz together : represent -OCH, -O- or -0-CH, -CH,-0~; m and n independently of each other represent o, 1 2 or 3. if Aor B is a benzo group, and o, 1 or and the pharmaceutically acceptable salts thereof with inorganic and organic acids; an exception is the compound of formula 1 wherein Ry , R, . R 4 , Rg , Re , and Rs represent hydrogen and A and B represent the group CH,0 C140
2. Compound as claimed in claim 1, wherein Ry represents hydrogen, (c, grate! or -NHCOCH , ; and/or wherein Rg represents hydrogen, methyl or hydroxymethyl; } and/or wherein Ro , R, , Re and R, independently of each other represent hydrogen OF R, together with Ra and/or Re together with R, and the associated carbon atom to ‘which they are bound represent a 5-membered carbocyclic ring; and/or wherein Ryy 2nd Rip 2are defined as in claim #t, or two adjacent substituents Ry or R,, together represent -0-CHp-0-3 and/or wherein m and/or n represents 2. f BAD ORIGINAL PN
3. Compound as claimed in claim 1, wherein if A and B Co is a benzo group the two substituents R11 and R12
Co. mnt divaly., tO
- 3 p.
4. Compound as claimed in claim 1, which is CH40 AN CH,0 N ~N (7 CH40 OCH, or a physiologically acceptable salt thereof. - §,Pharmaceutical preparation containing as active 14) substance compounds of general formula I R Ry Ryn (Cn N Rr 19 1 N R Ry 6 oe] wherein A and B independently of each other represent a benzo or thieno group; ‘ R, represents hydrogen, (Cr.1glalkyl, phenyl, or [ _NHCOX (wherein X is (Cq_glalkyl); LP ORIGINAL 4) - 2 . Rg represents hydrogen, (C 1-4 alkyl or represent hydrogen or Ro, together with Rj and/or Re together with R and the associated carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring; R11 and Ryo are defined as in claim 1; m and n independently of each other represent O, 1, 2 or 3, if A or B is a benzo group, and 0, 1 or 2, if A or B is a thieno group; and the pharmaceutically acceptable salts thereof with inorganic and organic acids.
: 6 Method of treating of coronary heart disease and acute myocardial infarction which comprises administering to a subject in need of such treatment a cardioprotective amount of a compound of general formula I or salt thereof as defined in claim 1.
PH36836A 1987-04-24 1988-04-22 Condensed bis-[3,4-dihydro-1-pyridinyl]methanes and pharmaceutical compositions containing those compounds and method of use thereof PH26225A (en)

Applications Claiming Priority (1)

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DE19873713743 DE3713743A1 (en) 1987-04-24 1987-04-24 Fused bis(3,4-dihydro-1-pyridinyl)methanes, process for their preparation and medicaments containing these compounds

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PH26225A true PH26225A (en) 1992-04-01

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DE (1) DE3713743A1 (en)
MX (1) MX11218A (en)
PH (1) PH26225A (en)
PL (1) PL161234B1 (en)
ZA (1) ZA882845B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2361390A1 (en) * 1973-12-10 1975-06-19 Merck Patent Gmbh ISOCHINOLINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION

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