IE913372A1 - Antiarrhythmic agents - Google Patents
Antiarrhythmic agentsInfo
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- IE913372A1 IE913372A1 IE337291A IE337291A IE913372A1 IE 913372 A1 IE913372 A1 IE 913372A1 IE 337291 A IE337291 A IE 337291A IE 337291 A IE337291 A IE 337291A IE 913372 A1 IE913372 A1 IE 913372A1
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- acceptable salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/10—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Compounds of formula (I), wherein R is C1-C4 alkyl; R<1> is R<3>SO2NH or R<3>CONH; R<2> is H or OH; R<3> is C1-C4 alkyl, C3-C7 cycloalkyl or NR<4>R<5>; R<4> and R<5> are each independently selected from H and C1-C4 alkyl; "Het" is either (a) 2-, 3- or 4-pyridyl optionally substituted by one or two substituents each independently selected from NH2 and C1-C4 alkyl, or (b) 2-imidazolyl optionally substituted by one or two C1-C4 alkyl groups; and n is 1, 2, or 3; and pharmaceutically acceptable salts thereof, are antiarrhythmic agents.
Description
ANTIARRHYIHMIC AGENTS
This invention relates to antiarrhythmic agents useful in the treatment of cardiac arrhythmias.
The compounds of the invention prolong the duration of the action potential in cardiac muscle and conducting tissue, and thereby increase refractoriness to premature stimuli. Thus, they are Class III antiarrhythmic agents according to the classification of Vaughan Williams (Antiarrhythmic Action, Ε. M. Vaughan Williams, Academic Press, 1980). They are effective in atria, ventricles and conducting tissue both in vitro and in vivo and are therefore useful for the prevention and treatment of a wide variety of ventricular and supraventricular arrhythmias including atrial and ventricular fibrillation. Because they do not alter the speed at which impulses are conducted, they have less prepensity than current drugs (mostly Class I) to precipitate or aggravate arrhythmias, and they also produce fewer neurological side effects. Some of the compounds also have positive inotropic activity and therefore are particularly beneficial in patients with impaired cardiac pump function.
The invention provides compounds of the formula:
R
(I) and their pharmaceutically acceptable salts, —2— wherein R is C^-C alkyl;
R1 is R3SO2NH or R3OONH, . 3 . 4 5 wherein R is C^-C4 alkyl, cycloalkyl or NR R ,
wherein R and R are each independently selected from H and cj“C4 alkyl;
R2 is H or OH;
Het is either (a) 2-, 3- or 4-pyridyl optionally substituted by 1 or 2 substituents each independently selected from NH^ and cy~C4 alkyl, or (b) 2-imidazolyl optionally substituted by 1 or 2 C1~C4 alkyl groups;
and n is 1, 2 or 3;
In the above definition, C3 and C4 alkyl groups may be straight or branched chain.
Ihe compounds of formula (I) may contain one or more asymmetric centres and thus they can exist as enantiomers or diastereoisomers. Ihe invention includes both mixtures and separate individual isomers.
Ihe pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed from pharmaceutically acceptable acids. Examples include the hydrochloride, hydrobrcmide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, succinate, lactate, citrate, tartrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
. 3
Seme of the compounds, e.g. those wherein R is R SC>2NH, may also form metal salts, particularly alkali metal and alkaline
-3earth salts. Examples of the former include the sodium and potassium salts.
A preferred group of compounds of the formula (I) is that
is either (a) 2- or 4-pyridyl optionally substituted by or (b) 1-(C1~C4 alkyl)-2-imidazolyl optionally further substituted by a C^-C alkyl group; and n is 1.
A particularly preferred group of compounds of the formula (I) is that wherein R is methyl; R^ is CH^SO^NH or CH^NHSO^NH;
Het is either (a) 4-amino-2-pyridyl or 4-pyridyl, or (b) 1methyl-2-imidazolyl or l,5-dimethyl-2-imidazolyl; and n is 1.
Ihe compounds of the formula (I) provided by the invention may be prepared by the following methods.
(1) Compounds of the formula (I), wherein Het is either (a) 2-,
3- or 4-pyridyl optionally substituted by 1 or 2 alkyl groups, or (b) 1-(C^-C4 alkyl)-2-imidazolyl optionally further 2 1 substituted ty a C^-C4 alkyl group, R is H, and R, R and n are as defined for formula (I), may be prepared from intermediates of the formula:
(J I) wherein Het is as defined in this method and R and n are as defined for formula (I).
—4—
Ihe conpounds of the formula (I), wherein Het, R and n are as defined for formula (II) and R^ is
a) R3SO2NH, . 4 5 4 wherein R is alkyl, cycloalkyl or NR R , wherein R . 5 .
is H or cj“C4 alkyl and R is alkyl, can be prepared by reacting a compound of the formula (II) with a sulphonyl halide of the formula (C^-C* alkyl or cycloalkyl) S02 (Cl or Br), a sulphonic anhydride of the formula [ (C^-C4 alkyl or c2~Cy cycloalkyl)S02J20 or with a sulphamoyl chloride of the formula
4 . 5
R R NSO2C1, wherein R is H or C^-C4 alkyl and R is alkyl, in the presence of a suitable acid acceptor, e.g. triethylamine or pyridine. Ihe reaction is typically carried out at from 0°C to room temperature in a suitable organic solvent, e.g.
dichloromethane. Preferably, the reaction is carried out using pyridine as both the solvent and the acid acceptor;
b) H2NSO2NH, can be prepared by reacting a compound of the formula (II) with sulphamide at up to, and preferably at, the reflux temperature in a suitable organic solvent, e.g. 1,4-dioxane;
c) R3CONH, .
wherein R is C^-C^ alkyl or C3~C? cycloalkyl, can be prepared by acylating a compound of the formula (II) with either an acid halide of the formula (C-L~C4 alkyl or C3~C7 cycloalkyl) 00 (Cl or Br) or with an acid anhydride of the formula [ (C^-C alkyl or
-5C3~C7 cycloalkyl) 00] 20. When an acid halide is employed the reaction is typically carried out at from 0°C to room temperature in a suitable organic solvent, e.g. dichloromethane, and in the presence of a suitable acid acceptor, e.g. triethylamine or pyridine. The reaction may also be carried out using pyridine as both the solvent and the acid acceptor. When an acid anhydride is employed the reaction is typically carried out at up to the reflux temperature, preferably at 100°C, in a suitably compatible organic solvent, e.g. a carboxylic acid of the formula (C^-C alkyl or C3~C7 cycloalkyl) COOH;
d) I^NODNHcan be prepared by reacting a compound of the formula (II) with sodium or potassium cyanate at up to, and preferably at, the reflux temperature in a suitable acidic solvent medium, e.g. aqueous acetic acid;
e) (¢^-^ alkyl) NHCONH, can be prepared by reacting a compound of the formula (II) with a (C^-C4 alkyl) isocyanate. Ihe reaction is preferably carried out at room temperature in a suitable organic solvent, e.g.
dimethylformamide although, if necessary, elevated temperatures may be employed to accelerate the rate of reaction;
or f) alkyl) 2NOONH, —6— can be prepared by reacting a compound of the formula (II) with a carbamoyl chloride of the formula alkyl) 2NCOC1. The reaction is typically carried out at from 0°C to the reflux temperature in a suitable organic solvent, e.g. dichloromethane, and in the presence of a suitable acid acceptor, e.g. triethylamine or pyridine.
l 2 (2) Compounds of the formula (I), wherein Het, R, R , R and n are as defined for formula (I), may be prepared from intermediates of the formula:
CH(CH_, N' 2 n · .R (III)
2 6 wherein R, R , R and n are cis defined for formula (I) and R is either H (IIIA)
(0) q wherein q is 0 or 1, r is 0 or 1 and t is 1 or 2, with the proviso that the sum of r and t is 1 or 2.
-71 2
The compounds of the formula (I), wherein R, R , R and n are as defined for formula (I) and Het is
a) 2- or 4-pyridyl optionally substituted by 1 or 2 C^-C alkyl groups, may be prepared by reacting a compound of the formula (IIIA) with a halopyridine of the formula:
X
(C1_C4 alkY1)k wherein X is 2- or 4- halo, preferably Cl or Br, and k is 0, 1 or 2. The reaction is typically carried out at up to, and preferably at, the reflux temperature in a suitable organic solvent, e.g. n-butanol or amyl alcohol, and in the presence of a suitable acid acceptor, e.g. sodium carbonate or sodium bicarbonate;
b) 2-, 3- or 4- pyridyl substituted by 1 NH2 group and optionally further substituted by 1 NH^ group or by 1 alkyl group, can be prepared by reduction of a compound of the formula (IIIB) using conventional methods. Preferably, the reduction is carried out by catalytic hydrogenation using a suitable catalyst,
e.g. palladium on charcoal, at room temperature and in a suitable inert organic solvent, e.g. ethanol;
or c) 2-imidazolyl optionally substituted by 1 or 2 C^-C* alkyl groups, can be prepared from a compound of the formula
-8(ΙΙΙΑ), e.g. as described in Preparation 4 of the Preparations section, according to Scheme 1:
Scheme 1
CH (CH
I?
I
Nil n
(C -C alkyl)NCS or HCNS
------>
CH(CH-) JMHR' n
'(IV) (ΙΠΑ) r8q
(r b ) ( ΙΛ)
—9— wherein R7 is H or Cj-C4 alkyl, R8 is C^-C^ alkyl, R9 and R10 are each independently H or C-^-C4 alkyl, each R11 is c^_c4 alkyl or the two groups R11 are joined to form a G^-C^ alkylene chain, and Q is preferably halo (preferably iodo), (C1~C4 alkyl)SO^-,
S03~ or dlj——S03-; with the proviso that not
9 10 .
more than two of R , R and R in formula (IA) are C-L-C4 alky}.
In the first step, a compound of the formula (IIIA) is either (a) reacted with a C^-C4 alkyl isothiocyanate in a suitable organic solvent, e.g. methanol or dichloromethane, at about room 7 .
temperature to give a thiourea of the formula (IV) wherein R is
C-j-C alkyl, or (b) reacted with a thiocyanate salt, e.g.
ammonium, sodium or potassium thiocyanate, under acidic conditions 7 .
to give a thiourea of the formula (IV) wherein R is H.
Ihe thiourea (IV) is then S-alkylated, preferably using a C^-C4 alkyl halide (preferably an iodide) or a compound of the formula (Cl-C4 aJJqrlJSo/, so/ or so/.
The S-alky1 derivative (V) can then be converted to an imidazole by two different methods.
In the first method, the S-alky 1 derivative (V) is reacted with the acetal or ketal (VI), e.g. by heating at from 60-130°C and preferably under reflux in a suitable organic solvent (such cis pyridine), to form an intermediate guanidine. Ihe guanidine is then heated in aqueous acid, e.g. aqueous hydrochloric acid, and
-10preferably under reflux, to cyclise it to the product (IA) .
In the second method, the S-alkyl derivative (V) is converted to the imidazole (IB) by reaction with propargylamine in a suitable organic solvent, e.g. pyridine, typically at a temperature of from 60-130°C and preferably under reflux.
. 1 (3) Compounds of the formula (I), wherein R is OH, and R, R , Het” and n are as defined for formula (I), may be prepared from intermediates of the formula:
wherein R, r\ Het and n are cis defined for formula (I), by reaction of (VII) with a reducing agent such as sodium borohydride. The reduction is typically carried out in a suitable solvent, e.g. aqueous ethanol, at from 0°C to reflux temperature.
The intermediates of the formulae (II), (IIIA) , (IIIB) and (VII), required for the preparation of the compounds of the invention of the formula (I), may be prepared by the following methods.
(i) The intermediates of the formula (II), wherein Het, R and n are as previously defined for formula (II), can be prepared by conventional techniques, e.g. as described in Preparation 1 of the Preparations section and cis summarised in Scheme 2:
-11Scheroe 2
Cil2 (C3 > n-lCO2ri
IIN-Ile L (VIII) ( IX)
V
Ile t
-12In the first step, a carboxylic acid of formula (VIII) is coupled with an amine of formula (IX) to afford an amide of formula (X). This may be effected by prior activation of (VIII) , using a conventional peptide coupling reagent such as N,N'dicyclohexylcarbodiimide, or by prior formation of the corresponding acyl halide, e.g. the acyl chloride, using a conventional chlorinating reagent such as thionyl chloride. In the latter case, the coupling is preferably carried out in the presence of an excess of a suitable acid acceptor, e.g. triethylamine. Conversion of the amide (X) to amine (XI), in the second step, can be achieved by use of a typical amide reducing agent such as diborane whilst, in the third step, the nitro group of (XI) may be reduced, for example, by catalytic hydrogenation using a palladium catalyst, to provide the intermediate (II).
.... 12 (ii) The intermediates of the formula (IIIA), wherein R, R , R and n are as previously defined for formula (III), can be prepared by conventional techniques such as those summarised in Scheme 3:
H X(Cil.,) CX λ I)
(IIIA; R =H)
-13Scheroe 3
(CH2* nNW (CH.) X 2 tl (XJ V)
I
IINW (XV)
V
OH R
OH K
I I /11(0)0 NH / ζ n
( 1 I ] Λ ; R =011) (xvi) (XVIII) wherein W is a suitable amine protecting group such as benzyl, and
X is a halogen atom, preferably chlorine or bromine.
-14In the first step an appropriate arene of formula (XII), wherein R1 is as previously defined for the formula (I), is acylated with an Cd-haloacyl halide of formula (XIII) under typical Friedel-Crafts conditions, e.g. in the presence of aluminium chloride, to afford an 1*3-haloketone of formula (XIV) which, in the second step, is used to alkylate a protected amine of the formula (XV) wherein R is as previously defined for the formula (I). The said alkylation is preferably conducted in the presence of an excess of a suitable acid acceptor, e.g.
triethylamine, to furnish the CaJ-aminoketone of formula (XVI).
The latter may then be either fully reduced to the (J-aminoalkane of formula (XVII) or partially reduced to the
U) -aminoalcchol of formula (XVIII). The former reduction may be carried out by classical procedures such as the Clemmensen or
Wolff-Kishner reductions, whilst reduction of the ketone to the corresponding alcohol may be effected with sodium borohydride.
Subsequent removal of the protecting group from either (XVII) or (XVIII) in the final steps may be achieved, for example, by catalytic hydrogenolysis using a palladium catalyst, to afford 2 .
intermediates of the formula (IIIA) wherein R is H or OH respectively.
(iii) The intermediates of the formula (IIIB), wherein R, R1,
R , n, q, r and t are as previously defined for formula (IIIB), can be prepared by conventional techniques, e.q. as described in Preparations 2 and 3 of the Preparations section, by reactinq a compound of the formula (IIIA) with a halopyridine of the formula:
(c -C alkyl) r wherein X is a halogen atom, preferably Cl or Br, and q, r and t are as previously defined for the formula (IIIB). The reaction is typically carried out in the presence of an excess of a suitable acid acceptor, e.g. pyridine, which may also serve as an appropriate solvent.
(iv) The intermediates of the formula (VII), wherein Het, R, R1 and n are as previously defined for formula (VII), can be prepared by conventional techniques such as those summarised in Scheme 4:
—16—
Scheme 4
I?
( (CH ) NH 2 il (XIX) (CH,| N n
Het (VII) wherein W is as previously defined in Scheme 3.
The intermediate of formula (XVI), which may be synthesised as described within Scheme 3, can be deprotected as described for the analogous deprotections of the compounds of formulae (XVII) and (XVIII), in Scheme 3, to provide the O-aminoketone of formula (XIX). Conversion of (XIX) to intermediates of formula (VII) may then be effected by the procedures described in Method 2, by analogy with the conversion of intermediates of formula (IIIA) to compounds of the formula (I).
The invention also includes any novel intermediates disclosed herein, such as those of the formulae (II), (III) and (VII).
All of the above reactions are entirely conventional and
-17appropriate reagents and conditions for their performance, and procedures for isolating the desired products, can readily be established by reference to standard organic chemistry textbooks and to the Examples provided hereafter. Alternatives and variations, in accordance with literature precedent, will also be evident to the person skilled in the art to enable all the compounds defined by formula (I) to be prepared.
Pharmaceutically acceptable salts are readily prepared by, mixing solutions containing equimolar amounts of a free base of the formula (I) and the desired acid. Ihe salt is isolated either after its precipitation from solution or after its recovery by evaporation of the solvent employed.
Ihe biological activity of the compounds of the invention is assessed by measuring the effect of the compounds on atrial refractoriness. In this test guinea pig right hemiatria are mounted in a bath containing physiological salt solution, with one end connected to a force transducer. Ihe tissues are stimulated at 1 Hz using field electrodes. Effective refractory period (ERP) is measured by introducing premature stimuli (S2) after every 8th basic stimulus (sp. ihe S^S2 coupling interval is gradually increased until S2 reproducibly elicits a propagated response.
This is defined as the ERP. Ihe test compound is then added to the bath and the concentration of compound required to increase ERP by 25% is determined (ED^) ' a-'-so measured in guinea pig right papillary muscles incubated in physiological saline solution. Muscles are stimulated at one end using bipolar electrodes and the propagated electrogram is recorded at the opposite end via a unipolar surface electrode. ERP is determined
-18as above using the extrastimulus technique. Condition time is obtained from a digital storage oscilloscope by measuring the interval between the stimulus artefact and the peak of the electrogram (i.e. the time required for the impulse to travel along the length of the muscle).
Atrial and ventricular ERPs are also measured in anaesthetised or conscious dogs by the extrastimulus technique whilst the atrium or right ventricle is being paced at a constant rate.
For human use the compounds of the formula (I) can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. They can be administered both to patients suffering from arrhythmias and also, prophylactically, to those likely to develop arrhythmias. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic with blood.
For administration to man in the curative or prophylactic treatment of cardiac conditions such as ventricular and supraventricular arrhythmias, including atrial and ventricular
-19fibrillation, it is expected that oral dosages of the compounds of the invention will be in the range from 1 to 75 mg daily, taken in up to 4 divided doses per day, for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules might contain 1 to 25 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration would be expected to be within the range 0.5 to 10 mg per single dose as required. A severe cardiac arrhythmia is preferably treated by the i.v. route in order to effect a rapid conversion to the normal rhythm. Variations on these dosages may occur depending on the weight and condition of the subject being treated and will be determined by the medical practitioner.
Thus the present invention provides a pharmaceutical composition comprising a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention also provides a method of preventing or reducing cardiac arrhythmias in a human being, which comprises administering to said human being an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition as defined above.
The invention yet further provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular as an antiarrhythmic agent.
The invention also provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or reduction of
-20cardiac arrhythmias.
Ihe preparation of the ocaxpounds of the invention will new be more particularly illustrated by reference to the following experimental Examples, ihe purity of the compounds was routinely monitored by thin layer chromatography (TLC) using Merck Kieselgel 60 F254 Plates· ^H-Nuclear magnetic resonance spectra were recorded using a Nieolet QE-300 spectrometer and were in all cases consistent with the proposed structures.
-21EXAMPLE 1
Ν-Γ4-Γ2-Γ rMethyl(4-pyridyl) 1 aminol ethyll phenyl lmethanesulphonamide
Methanesulphonyl chloride (0.126 g) was added to a stirred solution of the product of Preparation 1 (0.227 g) in pyridine (2.0 ml) at 0°C. The mixture was stirred for 18 hours, evaporated under vacuum and the residue dissolved in the minimum volume of water. Ihe resulting solution was basified with saturated aqueous sodium bicarbonate solution and the resulting solid was filtered off, washed with water and dried. Purification by chromatography on silica gel, using a 9:1 mixture of dichloromethane and methanol as eluent, gave the product as a solid (0.18 g), m.p. 227-228°C (after crystallisation from ethyl acetate-methanol). Found: C,58.91; H,6.33; N,l3.78. requires: C,58.99; H,6.27;
N, 13.76%.
EXAMPLE 2 l-Methyl-3-r4-r2-i Γmethvl (4-pyridyl) 1 aminol ethyll phenyl Isulphamide
Methylsulpharooyl chloride (0.155 g) was added to a stirred solution of 4-amino-N-methyl-N-(4-pyridyl) benzeneethanamine (the product of Preparation 1) (0.227 g) in pyridine (2 ml) and the mixture was stirred for 18 hours at room temperature and then evaporated under vacuum. Ihe residue was treated with a few ml of dilute aqueous ammonia solution and the resulting mixture extracted with ethyl acetate. A small amount of insoluble material was filtered off and the organic layer of the filtrate was separated. Ihe aqueous layer was extracted several times with ethyl acetate and the organic layers were combined, washed with water and dried (Na2SO4). Evaporation under vacuum of the solvent
-22gave a solid which was chrcmatographed on neutral alumina.
Elution with a 20:1 mixture of dichloromethane and methanol, then evaporation under vacuum of the appropriate fractions, gave a gum which crystallised on trituration with ethyl acetate containing a trace of methanol to give the title compound (0.10 g), m.p. 135-137°C (after recrystallisation from ethyl acetate-methanol). Found: C,56.26; H,6.58; N,16.62. requires: C,56.23;
H,6.29; N,17.49%.
EXAMPLE 3
Ν-Γ4-Γ2-Γ rMethvl(4-amino-2-pyridvl) laminolethyllphenyllroethanesulphonamide
A solution of the product of Preparation 2 (110 mg) in ethanol (10 ml) was hydrogenated at 20°C and 60 p.s.i. (4.1 bar) in the presence of 5% palladium on carbon (20 mg). The catalyst was filtered off and the filtrate was evaporated under vacuum to give a gum which crystallised on scratching. The solid was recrystallised from methanol to give the title compound (65 mg), m.p. 194-196°C. Found: C,56.60; H,6.32; N,17.40. Ν O S requires: C,56.23; H,6.29; N,17.49%.
EXAMPLE 4
N-r4-ri-Hydroxy-2-f Γmethyl f 4-amino-2-pyridyl) 1 aminolethyllphenyl]methanesulphonamide
Hydrogenation of the product of Preparation 3 (100 mg) in ethanol (15 ml) according to the method of Example 3 gave the title compound (75 mg), m.p. 159-162°C. Found: C,52.59; H,5.97; N,15.90. c15H20N4O3S; 1/2 requires C,52.15; H,6.13; N,16.22%.
-23EXAMPLE 5
Ν-Γ 4-Γ2-Γ (Methyl(l-methvl-2-imidazolvl) 1 amino 1 ethyl ItAienyllmethanesulphonamide
A solution of the product of Preparation 4 (0.44 g), and aminoacetaldehyde diethyl acetal (0.27 g) in pyridine (1.5 ml) was heated at 100°C for 5 hours and then evaporated under vacuum. Ihe residue was dissolved in 2M hydrochloric acid (2.0 ml) and the resulting solution was heated under reflux for 1 hour and then, cooled. It was next basified using saturated aqueous sodium bicarbonate solution and then the mixture was extracted several times with dichlorcmethane. Ihe combined extracts were washed with water, dried (Na2SC>4) and evaporated under vacuum to give an oil which was chromatographed on silica gel. Elution with a 30:1 mixture of dichloromethane and methanol followed by evaporation under vacuum of the appropriate fractions, gave the product (0.133 g), m.p. 117-118°C. Found: c,53.92; H,6.57; N,17.95.
C14H20N4°2S re<3uires: C,54.52; H,6.54; N,18.17%.
EXAMPLE 6
Ν—ί 4—f 2—Γ rMethyl(1.5-dimethvl-2-imidazolyl) 1 amino 1 ethyl lphenyl 1roethanesulphonamide
A solution of the product of Preparation 4 (3.07 g) and prcpargylamine (2.04 g) in pyridine (18 ml) was heated at 100°C for 1 hour and then evaporated under vacuum. The residue was dissolved in dichloromethane and the solution was washed with saturated aqueous sodium bicarbonate solution, then water, and dried (Na2SC>4). Evaporation under vacuum of the solvent gave an oil which was chromatographed on silica gel. Elution with a 19:1
-24mixture of dichloromethane and methanol, followed by evaporation under vacuum of the appropriate fractions, yielded an oil which crystallised on trituration with ether. Recrystallisation of the solid from ethyl acetate gave the product (0.525 g), m.p. 115.5-117°C. Found: C,55.57; H,6.93; N,16.99. C15H22N4O2S requires: C,55.87; H,6.88; N,17.38%.
Ihe following Preparations illustrate the source of the novel starting materials employed in the previous Examples:
REPARATION 1
4-Amino-N-methvl-N-(4-pyridyl)benzeneethananine (i) N-Methvl-N-(4-pyridyl)-4-nitrobenzeneacetamide
Ν,Ν'-dicyclohexylcarbodiimide (10.3 g) was added to a stirred solution of 4-nitrobenzeneacetic acid (9.0 g) in tetrahydrofuran (200 ml) at -15°C and the resulting solution was stirred at this tenperature for 10 minutes. 4-Methylaminopyridine (6.8 g) was then added and the mixture was stirred at room tenperature for 2 hours and then filtered. Ihe filtrate was evaporated under vacuum and the residue dissolved in ethyl acetate. Ihe solution was filtered, washed with saturated, aqueous sodium bicarbonate solution and then water, dried (Na2SO4) and evaporated under vacuum. Ihe residual oil was chromatographed on silica gel using a methanol in ethyl acetate elution gradient (0-2%), and evaporation under vacuum of the appropriate fractions gave the product (3.0g) as an oil which crystallised on scratching, m.p.
71-73°C. Ihe product was used directly in the next stage without further purification.
-25(ii) N-Methyl-N-(4-pyridyl)-4-nitrobenzeneethanamine
A solution of the previous product (2.50 g) in dry tetrahydrofuran (10 ml) was added over 5 minutes to a stirred 1.0 M solution of borane in tetrahydrofuran (40.0 ml) and the resulting solution was heated under reflux for 2 hours and then cooled. Excess 2M hydrochloric acid was added dropwise and the resulting solution was evaporated under vacuum. Ihe residue was dissolved in water and the solution was basified with saturated aqueous sodium bicarbonate solution. This mixture was extracted several times with ether and the combined extracts were washed with water and dried (Na2SC>4). Evaporation under vacuum of the ether solution gave a solid which was purified by chromatography on silica gel, using a 9:1 mixture of dichlorcmethane and methanol as eluent. Evaporation under vacuum of the appropriate fractions gave the product (1.35 g) as an oil which crystallised on scratching, m.p. 100-102°C (after recrystallisation from ethyl acetate-hexane). Found: C,65.26; H,5.92; N,16.18.
requires: C,65.35; H,5.88; N,16.33%.
(iii) 4-Amino-N-methyl-N- (4-pyr idyl) benzeneethanamine
A solution of the product from (ii) (0.34 g) in ethanol (5 ml) was hydrogenated at 50°C and 60 p.s.i. (4.1 bar) in the presence of 10% palladium on carbon (25 mg). The catalyst was filtered off and the filtrate was evaporated under vacuum to give the product (0.28 g), m.p. 113-116°C.
-26PREPARATION 2
Ν-Γ4-Γ2-Γ rMethyl(4-nitro-2-pyridvl) lamirrol ethyl lphenyl 1 methanesulphonamide
A solution of N-[4-[2-(roethylamino)ethyl]phenyl]methanesulphonamide (0.57 g) (see EP 0281254) and 2-chloro-4-nitropyridine (0.39 g) in pyridine (20 ml) was heated under reflux for 6 hours and then evaporated under vacuum. Ihe residue was dissolved in dichlorcmethane and the solution was washed with saturated, aqueous sodium bicarbonate solution and then dried (Na2SO4). Evaporation under vacuum of the solvent gave a solid which was chromatographed on silica gel. Elution with ethyl acetate, followed by evaporation under vacuum of the appropriate fractions, afforded the pure product as an orange solid (0.20 g), m.p. 180-182°C (after crystallisation from ethyl acetate). Found: C,51.47; H,5.23; N,15.79. requires: C,51.41; H,5.18;
N, 15.99%.
PREPARATION 3
Ν- Γ 4- Γ l-Hydroxy-2- Γ Γmethyl (4-nitro-2-pyridyl) 1 aminol ethyl 1 phenyl 1 roethanesulphonamide
A solution of N-[ 4-[l-hydroxy-2-(methylamino) ethyl] phenyl ]methanesulphonamide (J. Med. Chem., 1966, 9, 88) (1.22 g) and 2chloro-4-nitropyridine (0.79 g) in pyridine (50 ml) was heated under reflux for 4 hours and then evaporated under vacuum. A few ml of water were added to the residue and the mixture was extracted several times with dichlorcmethane. The combined extracts were washed with water, dried (Na2SO4) arid evaporated under vacuum to give a gummy solid which was chromatographed on
-27silica gel. Elution with a 50:1 mixture of dichloromethane and methanol, followed by evaporation under vacuum of the appropriate fractions, gave the title compound (0.20 g), m.p. 200-202°C (after crystallisation from ethyl acetate-hexane). Found: C,49.08; H,4.89; N,15.23. C15H N 0 S requires: C,49.17; H,4.95; N,15.29%.
PREPARATION 4 (i) Ν, N1 -Dimethy 1-N- Γ 2 - (4 -methanesulphonvlamino) phenyl 1 ethylthiourea
A solution of methyl isothiocyanate (0.28 g) in acetonitrile (10 ml) was added dropwise to a stirred solution of N-[4-[2methylamino) ethyl]phenylJmethanesulphonamide (1.00 g) (see EP 0281254) in acetonitrile (16 ml) under reflux. The solution was heated further under reflux for 1 hour and then evaporated under vacuum. The residue was purified by chromatography on silica gel, using a 19:1 mixture of dichloromethane and methanol as eluent, to give a gum which, on trituration with a little ethanol, provided the product as a solid (0.80 g), m.p. 156-156.5°C (after crystallisation from ethanol). Found: C,47.77; H,6.41; N,13.85. C12H19N3°2S re(3uires: C,47.81; H,6.35; N,13.94%.
(ii) Ν,Ν'-Dimethy1-N-Γ2-Γ (4-methvlsulphonylamino)phenyl 1 ethyl 1-Smethylisothiouronium iodide
A solution of the previous product (0.30 g) and iodomethane (0.16 g) in ethanol (4 ml) was heated under gentle reflux for 15 hours and then evaporated under vacuum. Ihe residue (0.44 g) was used directly in Examples 5 and 6.
Claims (41)
1 . 3
2. A compound as claimed in claim 1 wherein R is R SC^NH; R 3 is alkyl or NH(C^-< 4 alkyl); Het is either (a) 2- or 4 pyridyl optionally substituted ty NH^ or (b) 1-(0^-0 alkyl)-2imidazolyl optionally further substituted by a ^-< 4 alkyl group; and n is 1.
3. A compound as claimed in claim 2 wherein R is methyl; R 3 is —29— CH^SC^NH or CH^NHSC^NH; and Het is either (a) 4-amino-2-pyridyl or 4-pyridyl, or (b) 1-methy 1-2-imidazolyl or 1,5-dimethy1-2imidazolyl .
4. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, together with a pharmaceutically acceptable diluent or carrier.
5. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, for use in medicine.
6. The use of a compound of formula (I) or of a pharmaceutically acceptable salt thereof, cis claimed in any one of claims 1 to 3, for the manufacture of a medicament for the treatment of cardiac arrhythmias.
7. A compound of formula: UN (ClI 2 [(et (,11) wherein Het is either (a) 2-, 3- or 4-pyridyl optionally subsituted by one or two C^-C^ alkyl groups, or (b) 1-(C^-C 4 alkyl)-2-imidazolyl optionally further substituted by a C 1 ~C 4 alkyl group, and R and n are as defined in claim 1. -308. A compound of formula: CIi(CH ) Ν' ζ n (III) «12 6 wherein R, R , R and n are as defined in claim 1, and R is either H or wherein q is 0 or 1, r is 0 or 1, and t is 1 or 2, with the proviso that the sum of r and t is 1 or 2.
8. 9. A method of treating or preventing cardiac arrhythmias in a human being which comprises administering to said human being an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, or of a pharmaceutical composition as claimed in claim 4. -3110. A process for the preparation of a compound of formula: L CH(Cll_) N z ti ·. (le t (I) wherein R is C^-C 4 alkyl; R 1 is R 3 SO 2 NH or R 3 C0NH; R 2 is H; R 3 is C 1 ~C 4 alkyl, C 3 ~C 7 cycloalkyl or NR 4 R 5 ; 4 5 R and R are each independently selected from H and alkyl; Het” is either (a) 2-, 3- or 4-pyridyl optionally substituted by one or two C^-C^ alkyl groups, or (b) l-(C-^-C 4 alkyl)-2-imidazolyl optionally further substituted by a c 1 _c 4 alkyl group; and n is 1, 2 or 3; and pharmaceutically acceptable salts thereof, which comprises reacting a compound of formula: fie I. (,11) —32— wherein R, Het and n are as previously defined in this claim, with, for a compound of formula (I) when R 3 is a) R 3 SO 2 NH, 3 4 5.4 wherein R is alkyl, C 3~C 7 cycloalkyl or NR R , wherein R 5 . is H or C^-C 4 alkyl and R is C^-C 4 alkyl, as appropriate, a sulphonyl halide of formula (C^-C 4 alkyl or cycloalkyl) SO 2 ~ (C1 or Br), a sulphonic anhydride of formula [ ( C ^“C 4 alkyl or C 3 ~C 7 cycloalkyl)S0 2 ] 2 0 or a sulphamoyl chloride of formula 4 5 . 4 . 5 . R R NSC> 2 C1, wherein R is H or alkyl and R is alkyl, in the presence of an acid acceptor; b) H 2 NSO 2 NH, sulphamide; c) R 3 CONH, wherein R is c 1 _c 4 alkyl or cycloalkyl, either an acid halide of formula (C^-C^ alkyl or c 3 _c 7 cycloalkyl)CO(Cl or Br) in the presence of an acid acceptor, or an acid anhydride of formula [(Cj-Cj alkyl or cycloalkyl)CO] 2 0; d) H 2 NCONH, sodium or potassium cyanate under acidic conditions; -33e) (C-j-C alkyl) NHCONH, a (Cj-Cj alkyl) isocyanate; or f) (C-j-C alkyl) 2 NOONH, a carbamoyl chloride of formula (C^-C^ alkyl) 2 NCOC1; said process being optionally followed by conversion of the required product to a pharmaceutically acceptable salt. 1 . 3
9. 11. A process as claimed in claim 10 wherein R is R SC> 2 NH; is alkyl or NH(C^-C 4 alkyl); Het” is either (a) 2- or 4-pyridyl optionally substituted by one or two alkyl groups, or (b) 1-(C 1 ~C 4 alkyl)-2-imidazolyl substituted by a further C 1~C 4 alkyl group; and n is 1.
10. 12. A process as claimed in claim 11 wherein R is methyl; R 1 is CH 3 SO 2 NH or CH 3 NHSC> 2 NH; and Het is either (a) 4-pyridyl, or (b) 1-methy 1-2-imidazolyl or l,5-dimethyl-2-imidazolyl.
11. 13. A process for the preparation of a compound of formula (I), . 2 . . . . wherein R is H or OH; Het is 2- or 4-pyridyl optionally substituted by one or two C^-C 4 alkyl groups; and R, R 1 and n are as defined in claim 10; and pharmaceutically acceptable salts thereof, which comprises reacting a compound of formula: -34Of (CH , Ν' 2 n (III) 6 12 wherein R is H and R, R , R and n are cis previously defined ,in this claim, with a halopyr idine of formula: X (c i“ c 4 wherein X is 2- or 4-halo and k is 0, 1 or 2, said process being optionally followed by conversion of the required product to a pharmaceutically acceptable salt. . . 1 3
12. 14. A process as claimed in claim 13 wherein R is R SC> 2 NH; R 3 is C^^-C alkyl or NHiCj-C^ alkyl); and n is 1.
13. 15. A process as claimed in claim 14 wherein R is methyl; R 1 is CH^SC^NH or CH^NHSC^NH; and Het is 4-pyridyl. —35—
14. 16. A process for the preparation of a compound of formula (I), 2 . wherein R is H or CH; Het is 2-, 3- or 4-pyridyl substituted by one NH 2 group and optionally further substituted by one NH 2 group or by one C^-C^ alkyl group; and R, R F and n are as defined in claim 10; and pharmaceutically acceptable salts thereof, which comprises reducing a compound of formula (III), wherein R 6 is (O)q wherein q is 0 or 1, r is 0 or 1 and t is 1 or 2, with the proviso that the sum of r and t is 1 or 2, said process being optionally followed by conversion of the required product to a pharmaceutically acceptable salt. 1 3
15. 17. A process as claimed in claim 16 wherein R is R SO 2 NH; R 3 is C 1 ~C 4 alkyl or ΝΗ^-Ό alkyl); and n is 1.
16. 18. A process as claimed in claim 17 wherein R is methyl; R 1 is CH 3 SO 2 NH or CKjNHSC^NH; and Het is 4-amino-2-pyridyl.
17. 19. A process as claimed in any one of claims 16 to 18 in which the reduction is carried out by catalytic hydrogenation.
18. 20. A process for the preparation of a compound of formula: . 2 . 7 9 10 wherein R is H or CH; R , R and R are each independently H or • · 7 9 C^-C^ alkyl, with the proviso that not more than two of R , R and r!° are C^-C alkyl; and R, R^ and n are as defined in claim 10; and pharmaceutically acceptable salts thereof, which comprises reacting a compound of formula: 1' :h (ch. © 7 Θ NHR q SR (V) 7 8 wherein R is H or C^-C^ alkyl, R is C^-C alkyl, Q is a leaving 12 group and R, R , R and n are as previously defined in this claim, with an acetal or ketal of formula: -37h 2 nch-c(or 11 ) 2 wherein either each R 13 is alkyl or both R 13 groups are • · 9 10 joined to form a C 2 -C 3 alkylene chain, and R and R are as previously defined in this claim, to form an intermediate guanidine derivative, followed by hydrolysis thereof using aqueous acid, said process being optionally followed by conversion of the required product to a pharmaceutically acceptable salt. 1 3
19. 21. A process as claimed in claim 20 wherein R is R SO 2 NH; R 3 is C 1 ~C 4 alkyl or NH alkyl); and n is 1.
20. 22. A process as claimed in claim 21 wherein R is methyl; 1 . 7 9 10 R is or CH^NHSZ^NH; and R , R and R are each independently H or methyl, with the proviso that not more than two of R 7 , R 9 and r!° are methyl.
21. 23. A process for the preparation of a compound of formula: 2 . 7 . 1 wherein R is H or OH; R is H or C^-C alkyl; and R, R and n are cis defined in claim 10; and pharmaceutically acceptable salts thereof, which comprises reacting a compound of formula (V) with propargylamine, said process being optionally followed by -38conversion of the required product to a pharmaceutically acceptable salt. 1 3
22. 24. A process as claimed in claim 23 wherein R is R SO^NH; 3 . R is C 1 ~C 4 alkyl or NH(C^-C 4 alkyl); and n is 1.
23. 25. A process as claimed in claim 24 wherein R is methyl; R 1 is CH 3 SO 2 NH or CH 3 NHSO 2 NH; and R 7 is H or methyl.
24. 26. A process for the preparation of a compound of formula (I), 2 . . . wherein R is CH; Het is either (a) 2-, 3- or 4-pyridyl optionally substituted by one or two substituents each independently selected from NH 2 and C^-C 4 alkyl, or (b) 2-imidazolyl optionally substituted by one or two C^-C: 4 alkyl groups; and R, R^ and n are as defined in claim 10; and pharmaceutically acceptable salts thereof, which comprises reducing a compound of formula (VII): R wherein R, R 1 , Het and n are as previously defined in this claim, said process being optionally followed by conversion of the required product to a pharmaceutically acceptable salt. 1 . 3
25. 27. A process as claimed in claim 26 wherein R is R SC> 2 NH; R 3 is c i“C 4 alkyl or NH(C^-< 4 alkyl); Het is either (a) 2- or 4-pyridyl optionally substituted by one or two NH 2 groups, or (b) 1-(C^-C 4 alkyl)-2-imidazolyl substituted by a further C ^~C 4 alkyl -39group; and n is 1.
26. 28. A process as claimed in claim 27 wherein R is methyl; R 1 is CH 3 SO 2 NH or CH 3 NHSO 2 NH; and Het·· is either (a) 4-amino-2-pyridyl or 4-pyridyl, or (b) 1-methy 1-2-imidazolyl or l,5-dimethyl-2imidazolyl.
27. 29. A process as claimed in any one of claims 26 to 28 in which the reducing agent is sodium borohydride.
28. 30. A compound of the formula (I) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, which is any one of those specifically hereinbefore mentioned.
29. 31. A pharmaceutical composition according to claim 4, substantially as hereinbefore described.
30. 32. Use according to claim 5, substantially as hereinbefore described.
31. 33. Use according to claim 6, substantially as hereinbefore described
32. 34. A compound of the formula (II) given and defined in claim 7, which is specifically hereinbefore mentioned.
33. 35. A compound of the formula (HI) given and defined in claim 8, which is specifically hereinbefore mentioned.
34. 36. A process for the preparation of a compound of the formula (I) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples and Preparations.
35. 37. A process according to claim 10 for the preparation of a compound of the formula (I) given and defined therein or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.
36. 38. A process according to claim 13 for the preparation of a compound of the formula (I) given and defined therein or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.
37. 39. A process according to claim 16 for the preparation of a compound of the formula (I) given and defined therein or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.
38. 40. A process according to claim 20 for the preparation of a compound of the formula (IA) given and defined therein or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.
39. 41. A process according to claim 23 for the preparation of a compound of the formula (IB) given and defined therein or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.
40. 42. A process according to claim 26 for the preparation of a compound of the formula (I) given and defined therein or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.
41. 43. A compound of the formula (I) given and defined in claim 1 or a pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in a preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909021056A GB9021056D0 (en) | 1990-09-27 | 1990-09-27 | Antiarrhythmic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE913372A1 true IE913372A1 (en) | 1992-04-08 |
Family
ID=10682850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE337291A IE913372A1 (en) | 1990-09-27 | 1991-09-26 | Antiarrhythmic agents |
Country Status (4)
| Country | Link |
|---|---|
| GB (1) | GB9021056D0 (en) |
| IE (1) | IE913372A1 (en) |
| PT (1) | PT99040A (en) |
| WO (1) | WO1992006080A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE1035115T5 (en) | 1999-02-24 | 2015-08-04 | Hoffmann La Roche | 4-phenylpyridine derivatives and their use as NK-1 receptor antagonists |
| US6552033B1 (en) | 2000-05-16 | 2003-04-22 | The Procter & Gamble Co. | Imidazo-containing heterocyclic compounds, their compositions and uses |
| TWI280239B (en) | 2003-07-15 | 2007-05-01 | Hoffmann La Roche | Process for preparation of pyridine derivatives |
| CN103893145A (en) | 2005-09-23 | 2014-07-02 | 弗·哈夫曼-拉罗切有限公司 | Novel dosage formulation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8609331D0 (en) * | 1986-04-16 | 1986-05-21 | Pfizer Ltd | Anti-arrythmia agents |
| US4956382A (en) * | 1987-02-07 | 1990-09-11 | Pfizer Inc. | Sulfonamide anti-arrhythmic agents |
| GB8710494D0 (en) * | 1987-05-02 | 1987-06-03 | Pfizer Ltd | Antiarrhythmic agents |
| GB8819307D0 (en) * | 1988-08-13 | 1988-09-14 | Pfizer Ltd | Antiarrhythmic agents |
-
1990
- 1990-09-27 GB GB909021056A patent/GB9021056D0/en active Pending
-
1991
- 1991-08-29 WO PCT/EP1991/001654 patent/WO1992006080A1/en unknown
- 1991-09-25 PT PT9904091A patent/PT99040A/en not_active Application Discontinuation
- 1991-09-26 IE IE337291A patent/IE913372A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB9021056D0 (en) | 1990-11-07 |
| PT99040A (en) | 1992-08-31 |
| WO1992006080A1 (en) | 1992-04-16 |
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