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(12) PATENT
(51) Int.C1.6:
A 61K 31/435, C 07D 207/44, 209/00, 221/00, 471/04
(21) Application Number: 1994/ 000025
(22) Filing Date: 15/06/1994
(30) Priority data:
93201771.1 21/06/1993 AT
(86) PCT data
PCT/EP94/01960 15/06/1994
WO 19/950005 05/01/1995
(73) Owner:
JANSSEN PHARMACEUTICA N.V.; of , Turnhoutsweg 30, B¬2340 Beerse, Belgium
(72) Inventor:
FREYNE, Eddy, Jean, Edgard; and RAEYMAEKERS, Alfons, Herman, Margaretha
(74) Agent/address for correspondence:
Daly & Figgis Advocates, 8th Floor Lonrho House, P.O. Box 40034¬100, Nairobi
(54) Title:
POSITIVE INOTROPIC AND LUSITROPIC PYRROLOQUINOLINONE DERIVATIVES (57) Abstract:
The present invention relates to novel positive inotropic and lusitropic compounds of formula (I), the pharmaceutical acceptable acid addition salts thereof and the stereocktemically isomeric forms thereof wherein L is a radical of formula -0- Aik-(NH)p-C(=0)-RL pharmaceutical compositions thereof, methods of preparing said compounds and intermediates in the preparation thereof.
POSITIVE INOTROPIC AND LUSITROPIC PYRROLOQUINOLINONE
DERIVATIVES
5 EP-0,406,958 describes imidazoquinazolinone derivatives having positive inotropic
and lusitropic properties. - GB-2,190,676 and EP-0,426,180 disclose a number of imidazoquinolinones as c-AMP phosphodiesterase inhibitors. VS-5,196,428 describes
imidazoquinolinones having an inhibitory effect on the ADP induced blood platelet aggregation in human platelet-rich plasma.
10 Perkin and Robinson, J. Chem. Soc., 103, 1973 (1913) describe the preparation of
1,3-dihydro-21-1-pyrrolo[2,3-h3quinolin-2-one. However, according to Tanaka et al., J. Het. Chem., 9, 135 (1972) the procedure of Perkin and Robinson did not produce the above pyrroloquinolinone compound, but rather some plain quinoline derivatives.
Vogel et al., Helv. Chim. Acta., 52(7), 1929 (1969) and US-3,974,165 describe the
15 preparation of some partially hydrogenated pyrrolof2,3-biquinolin-2-one derivatives.
The compounds of the present invention differ structurally from the cited art-known compounds by the particular substitution of the pyrroloquinolinone moiety and by their favorable positive isotropic and lusitropic properties.
20
The present invention is concerned with novel 1,3-dihyclro-21-1-pyrrolo[2,3-13]- quinolin-2-one derivatives having the formula
the pharmaceutically acceptable addition salts thereof and the stereochemically isomeric forms thereof, wherein
L is a radical of formula -0-Alk-(NH)p-C(=0)-10, wherein 30 Alk is C1.6alkanediy1;
p is 0 or 1; and
RI, is hydroxy, Ci_galkyloxy or -NR2R3, wherein R2 is hydrogen or Ci_galkyl; and
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under Me PCT.
AT Aurada
AU Australia
BB Barbados
BE Belgium
OP Burt. Pao
I, Bulgaria
BJ Bann
BR Bradt
BY Bolaros
CA Canada
CF Central African Republie
CG Congo
CH S.M..
CI Cnte dleo,
CM Cameroon
CN mina
CS Crectionlovaak
CZ Cm. Republic
DE Germany
DK Dean,
ES SAW.
Ft Flub..
FR Prance
GA Gabon
GB Ulu. MBOWil MR ...tank
GE Georgia MW Malawi
GB Goleta NE Niger
GE Grotto NL Notberlands
HU Hung, NO Norway
IE Deland NZ New Zealand
IT Rely Pt Mani
JP Japan FT Poetugal
KE Kenya RO Romania
KG Kyr... RU Ruwien Fedora/ion
KP Danmark People, Republic SD Sudan
of Korea SE Sweden
Republic of Korea Si Slovenia
lUzekbamn SK Slovakia
Liednenweln SN Senegal
Sri Lulu TB toad
Lusembo, TO Togo
Lat. Ti Tajitiaao
Monaco ST Thradad and Tobago
Rep.. of Moldova VA Ukraine
Madagascar US Milted Stales of America
Mali UZ Width=
Mongolia VN Via Nam
-2-
R3 is C3.7cycloalkyl or piperidinyl, which is optionally substituted with C1.4alkyl, phenylmethyl or C3.7cycloalkylmethyl;
R2 and R3 may also be joined together to form piperazinyl, optionally substituted with C3.7cycloalkyl, C3_7cycloallcylmethyl, Ci.6alkyl optionally substituted with one or two
5 hydroxy groups, 2,2-dimethy1-1,3-dioxolanylmethyl, benzyl, halophenylmethyl,
(cyclopentyloxy)(methoxy)phenylmethyl, dipheny1C1.4alkyl, PYridinYI, pyrimidinyl or
phenyl optionally substituted with Cl4alkyloxy or halo; or ,
R2 and R3 are joined together to form piperidinyl, optionally substituted with imidazolylcarbonyl.
10
In the foregoing definitions halo is generic to fluoro, chlorq, bromo and iodo; the term Ci_.4allcyl defines straight and branched saturated hydrocarbon radicals having from I to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; C1.6alkyl defines C1_4alkyl and
15 the higher homologs thereof such as, for example, pentyl, hexyl and the like;
C3.7cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclotteptyl; Cii6alkanediyldefines straight and branch chained bivalent hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propane¬diyl, 1,4-butanedlyl, l,5-pentanediyl, 1,6-hexanediyl, 1,I-ethanediyl, 1,1-propanediyl,
20 1,2-propanediy1 and the like.
Pharmaceutically acceptable addition salts as mentioned hereinabove comprise the
therapeutically active non-toxic addition salt forms which the compounds of formula (I)
are able to form, Said salt forms can conveniently be obtained by treating the base form
25 of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hycirobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,
30 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfarnic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may also be converted into
35 their therapeutically active non-toxic metal or amine addition salt forms by treatment with
appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium,
-3-
sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term addition salt also comprises the hydrates and solvent addition forms which 5 the compounds of formula (1) are able to form. Examples of such forms are e.g. hydrates, aicoholates e.g. ethanolates, and the like.
Pure stereochemically isomeric forms of the compounds of formula (I) may be
obtained by the application of art-known procedures. Diastereoisomers may be separated
10 by physical methods such as selective crystallization and chromatographic techniques,
e.g. counter current distribution, liquid chromatography and the like; and enantiomers may be separated from each other following art-known resolution methods, for example, by the selective crystallization of their diastereomeric salts with chiral acids. Pure
stereochemically isomeric forms may also be derived from the corresponding pure
15 stereochemically isomeric forms of the appropriate starting materials, provided that the reactions occur steneospecifically. As a further alternative, the enantiomers may be separated by liquid chromatography using a chiral stationary phase. Stereochemically isomeric forms of the compounds of formula (1) are obviously intended to be included within the scope of the invention.
20 Further, the compounds of the present invention may exist in different tautomeric
forms and all such tautomeric forms are intended to be included within the scope of the present invention.
Particular compounds of formula (1) are those compounds wherein
25 Lisa radical of formula -0-Alk-C(=0)-R1, wherein
Alk is Ci_6alkanediy1; and
RI is hydroxy, CI4alkyloxy or -NR2R3, wherein
R2 is hydrogen or Ci_olkyl; and
R3 is C3..7cycIoalkyl or piperidinyl, which is optiOnally substituted with C14allcyl or 30 phenylmethyI;
R2 and R3 may also be joined together to form piperazinyl, optionally substituted with C3.7cycloalkyl, C3_7cycloalkylmethyl, Ci.6alkyl, benzyl, diphenylCi_aalkyl, pyridinyl, pyrimidinyl or phenyl optionally substituted with Ci_aalkyloxy or halo; or
R2 and R3 are joined together to form piperidinyl, optionally substituted with
35 imidazolylcarbonyl.
Preferred compounds of formula (1) are those compounds where R1 is -NR2R3.
-4-
More preferred compounds are those preferred compounds wherein R2 and R3 are joined together to form a piperazinyl substituted with C3_7cycloalicylmethyl.
5 Still more preferred compounds, are those more preferred compounds wherein R1 is
4-(cyclohexylmethyl)piperazinyl.
The most preferred compounds of formula (I) are 1-(cyclohexylmethyl)-4-[4[(2,3-clihydro-2-oxo-11-1-pyrrolo[2,3-b]quinolin-6-y1)oxy]-
10 1-oxobutyllpiperazine and 1-(cyclohexylmethyl)-445-[(2,3-dihydro-2-oxo-1H-pyrrolo
[2,3-b]quinolin-6-yl)oxyl-l-oxopentyl]piperazine, the pharmaceutically acceptable addition salts thereof and the stereochemically isomeric forms thereof.
The compounds of formula (I) can be prepared by reacting an intermediate of formula 15 (U) in the presence of a suitable dehydrogenating reagent in a reaction-inert solvent.
H
N N
(I)
The above reaction may conveniently be conducted using, e.g. 4,5-dichloro-3,6-
20 dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile and the like as a dehydrogenating reagent in
tetrahydrofuran, 1,4-dioxane or a mixture of these solvents. Alternatively, the above
reaction may be performed in the presence of a suitable catalyst, e.g. platinum on charcoal, palladium on charcoal, in a suitable solvent, e.g. toluene, diisopropylbenzene, xylene, cumene and the like, optionally upon addition of a catalyst poison, e.g.
25 thiophene, and optionally in the presence of a hydrogen acceptor, e.g. 2,5-climethy1-2,4-
hexadiene, cyclohexene and the like. When using a Catalyst as described above, the reaction of (II) into (I) is preferably conducted at increased temperature and/or pressure.
The compounds of formula (I) may also be prepared by reacting an intermediate of
30 formula (III) in the presence of a suitable catalyst, e.g. bis(triphenylphosphine)-
palladiumRchloride, tetralds(niphenylphosphine)palladium(0), palladium on charcoal
and the like in a suitable solvent, e.g. methylbenzene, acetic acid, propanoic acid, 2-methylpropanoic acid, 2,2-dimethylpropanoic acid and the like.
-5-
Alternatively, the compounds of formula (I) may be prepared by aalkylating the corresponding 6-hydroxypyrroloquinolinone compounds or a protected derivative
5 thereof following art-known procedures.
The compounds of formula (1) can also be converted into each other following art-known procedures of functional group transformation, e.g. (trans)esterification, (trans)amidation, and the like methods.
10 For example, the compounds of formula (I) wherein R1 is hydroxy can be prepared
by hydrolyzing the corresponding compounds wherein R1 is C1_4alkyloxy, following art-known procedures, e.g. in the presence of a base or an acid.
Further, the compounds of formula (I) wherein R1 is -NR2R3 can be prepared by reacting the corresponding carboxylic acid with HNR2R3 in the presence of a suitable
15 reagent capable of forming amides, e.g. diphenyl phosphoryl azide. When using the latter azide compound, the reaction is preferably conducted in the presence of a suitable base, e.g. kj.,N-diethylethanamine, optionally in the presence of a catalytic amount of N,N-dimethy1-4-pyridinamine, M a reaction-inert solvent, e.g. N,N-dimethylformamide, l-methylpyrrolidin-2-one and the like. The latter procedure, when conducted at elevated
20 temperatures (preferably at 180-200°C) may yield a Curtius like rearrangement reaction as described in J. Med. Chem. 1993, 36, 22, 3252, thus yielding compounds of formula (I) wherein p is 1.
Alternatively, said carboxylic acid may be converted into a suitable reactive functional derivative thereof such as, for example, an acyl halide or an acid anhydride, before
25 reaction with the amine HNR2R3. Said reactive functional derivatives may be prepared
following art known methods, for example, by reacting the carboxylic acid with a halogenating reagent such as, for example, thionyl chloride and the like. An acid anhydride may be prepared by reacting an acyl halide derivative with a carboxylate salt . The functional derivatives described above are characterized by R1 being halo or
30 Ci_ztalkyloxycarbonyloxy.
The compounds of formula (I) wherein R2 and R3 form a piperazinyl group may be
prepared by debenzylation of the corresponding phenylmethylpiperazine compound
-6-
following art known procedures e.g. hydrogenation. The compounds of formula (I) wherein R2 and R3 form a piperazinyl group may then be N-alkylated following art known N-allcylation procedures, e.g. reductive N-alkylation. The compounds of formula (I) wherein R2 and R3 form a piperazinyl group substituted with 2,3-
5 dihydroxypropyl may be prepared by reacting the corresponding piperazine derivative
substituted with 2,2-dimethyl-1,3-dioxolanylmethyl in the presence of an acid.
In all of the foregoing and in the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to
10 methodologies generally known in the art.
The intermediates of formula (II) can be prepared by cyclizing an intermediate oL formula (III) upon catalytic hydrogenation in the presence of a suitable catalyst, e.g. palladium on charcoal, in a reaction-inert solvent, e.g. 2-methoxyethanol, acetic acid and
15 the like.
Alternatively, the intermediates of formula (II) can be prepared by cyclizing an
intermediate of formula (IV) upon catalytic hydrogenation in the presence of a suitable
20 catalyst, e.g. palladium on charcoal, in a reaction-inert solvent, e.g. ethanol, 2-methoxy-
ethanol and the like.
CH
NO2 (II)
(IV)
25 The intermediates of formula (III) can be prepared upon catalytic hydrogenation of an .
intermediate of formula (IV) in the presence of a suitable catalyst, e.g. platinum on
-7-
charcoal, in a reaction-inert solvent, e.g. 2-methoxyethanol and the like, preferably in the presence of a catalyst poison, e.g. thiophene.
The intermediates of formula (IV) can be prepared by reacting an intermediate of
5 formula (V) with a phosphorus ylide of formula (VI) (Wittig reaction) in a reaction-inert
solvent, e.g. ethanol, and the like.
CHO
NO2 (C6H5)3r
(V) (V1)
10 • The compounds of formula (I), the pharmaceutically acceptable addition salts and
stereochemically isomeric forms thereof as well as the intermediates of formula (II), the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, are potent inhibitors of the phosphodiesterase type III (cardiotonic-sensitive PDE DI) of warm-blooded animals, in particular humans. Inhibition of PDE III leads to an elevation
15 of cAMP in cardiac muscle, which in turn enhances sarcolemmal entry of Cal,- into the
cell, increases the release and reuptake of Ca2+ by the sarcoplasmic reticulum and probably also increases the sensitivity of contractile proteins to Ca2+. As a result an increased contractile force of the heart ensues (positive inotropy) as well as a faster relaxation of the heart (positive lusitropy).
20 Particularly important is the observation that the positive inotropic and lusitropic effects
generally do not coincide with a simultaneous increase of other haemodynamic variables such as heart rate and blood pressure. Concommittant increases of heart rate and/or blood
pressure would indeed put extra strain on the heart and cancel the beneficial positive cardiac inotropy and lusitropy. In vivo experiments with the instant compounds of
25 formula (I) show moderate systemic vasodilation and hence a decrease in blood pressure.
The heart rate generally only increases at high dosei. In all, the instant compounds of formula (I) significantly increase cardiac output by cardiac positive inotropy and lusitropy and without major influence on heart rate and/or blood pressure.
30 Consequently, the compounds of formula (I) and (II) are considered to be valuable
therapeutical drugs for treating warm-blooded animals, particularly humans, suffering from Congestive Heart Failure. Congestive Heart Failure is a pathophysiological state that is defined by the inability of the heart to pump adequate amounts of blood to the peripheral sites of the organism, with consequent failure to meet the metabolic
-8-
requirement of the body. Said condition may result from a heart attack, infection of the beast, chronic hypertension, deficiencies in the operation of the heart valves and other disorders of the heart leading to Congestive Heart Failure.
5 Some of the subject compounds show the advantage of having improved water
solubility when compared to the art compounds.
In view of their useful positive inotropic and lusitropic properties, the subject
compounds may be formulated into various pharmaceutical forms for administration
10 purposes. To prepare the pharmaceutical compositions of this invention, an effective
amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form
15 suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin,
20 lubricants, binders, disintegrating agents and the like in the case of powders, pills,
capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for
25 example, to aid solubility, may be included. Injectable solutions, for example, may be
prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous adrninistratiOn, the carrier optionally comprises a
30 penetration enhancing agent and/or a suitable wettable agent, optionally combined with
suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration
to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g. as a transdermal patch, as a
35 spot-on or as an ointment. Addition salts of the compounds of formula (I) due to their
increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
-9-
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suitable as unitary dosages, each unit
5 containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated. ablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
10
In view of the usefulness of the subject compounds in the treatment of Congestive Heart Failure it is evident that the present invention provides a method of treating warm-blooded animals suffering from Congestive Heart Failure, said method comprising the systemic administration of a pharmaceutically effective amount of a compound of
15 formula (I) or (II) or a pharmaceutically acceptable addition salt thereof or a
stereochemically isomeric form thereof in admixture with a pharmaceutical carrier. In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 4 mg/kg body weight, more preferably from 0.04 mg/kg to 2 mg/kg body weight.
It is evident that said effective daily amount may be lowered or increased depending
20 on the response of the treated subject and/or depending on the evaluation of the physiciat,
prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent.
25 The following examples are intended to illustrate and not to limit the scope of the present
invention.
Experimental part
30 A. Preparation of the intermediates
Example 1
a) A mixture of ethyl 5-(3-formyl-4-nitrophenoxy)pentanoate (0.60 mol) and (4,5-di-
hydro-2-hydroxy-5-oxo-111-pyrrol-3-yl)triphenylphosphonium, hydroxide, inner sa!,
35 (0.57 mol ) in ethanol (1500m1) was stirred and refluxed for I hour. The solvent way
removed. The residue was stirred in methylbenzene. The resulting precipi,--
filtered off, washed with methylbenzene, 2,2'-oxybispropane and dried, yield._ (61%) of (E)-ethyl 543-[(2,5-dioxo-3-pyrrolidinylidene)methy11-4-nitrophenoxy]-
-10-
pentanoate; trip. 112.4°C (interns. 1).
In a similar manner there were prepared :
(E)-ethyl 443-[(2,5-dioxo-3-pyrrolidinylidene)methy1]-4-nitrophenoxylbutanoate (interm. 2);
5 (E)-3-[(2-nitrophenyl)methylene]-2,5-pyrroiidinedione; mp. 174.1°C (interns. 3);
ethyl (E)43-[(2,5-dioxo-3-pyrrolidinylidene)methyl]-4-nitrophenoxyjacetate; mp. 147.8°C (interns. 9); and
methyl (E)-6131(2,5-dioxo-3-pyrrolidinylidene)methy11-4-nitrophenoxylhexanoate (interns. 10).
10 b) A mixture of intermediate (1) (0.179mo1) its 2-methoxyethanol (600m1) and
thiophene, 4% solution (4m1) was hydrogenated at 50°C with platinum on activated carbon (5%) (8g) as a catalyst. After uptake of the theoretical amount of hydrogen, the catalyst was filtered off. The precipitate, which was formed overnight, was filtered off, washed with ethyl acetate and 2,2'-oxybispropane and dried in vacuo, yielding 42.7g of
15 product. The filtrate was evaporated and the residue was stirred in ethyl acetate. The precipitate was filtered off, washed with ethyl acetate and 2,2'-oxybispropane and dried in vacuo yielding a second portion of product (13.8g), which was crystallized from methoxyethanol, yielding 8.3g. Total yield : 51g (82.2%) of ethyl (E)-514-amino-3- ((2,5-dioxo-3-pyrrolidinylidene)methyl]phenoxylpentanoate; mp. 183.5°C (interim 4).
20 In a similar manner there was also prepared :
ethyl 414-amino-34(2,5-dioxo-3-pyrrolidinylidene)methyI]phenoxy]butanoate; mp. 176.5°C (interm. 5);
methyl (E)-644-amino-3-[(2,5-dioxo-3-pyrrolidinylidene)methyl]pherimcybexanoate; mp. 178.4°C (interm. 12); and
25 ethyl (E)44-amino-3-[(2,5-dioxo-3-pyrrolidinylidene)methyl]phenoxy]acetate (intern'.
13).
c) Intermediate (5) (0.06mol) in acetic acid (250m1) was hydrogenated at 50°C with palladium on activated carbon (10%) (4g) as a catalyst. After uptake of the theoretical amount of hydrogen, the catalyst was filtered off and washed with acetic acid. The
30 filtrate was evaporated and the residue was boiled up in ethanol. The precipitate was fihrered off, washed with ethanol, 2,2-oxybispropane and dried in vacuo, yielding 15.2g (80%) of ethyl 4-[(2,3,3a,4-tetrahydro-2-oxo-la-pyrrolo[2,3-b]quinofin-6- yl)oxyjbutanoate (intern'. 6).
-1 I-
Example 2
b) A mixture of intermediate (I) (0,007mol) in ethanol (150mI) was hydrogenated at 50°C and at normal pressure with palladium on activated carbon (10%) (2g) as a catalyst.
5 After uptake of the theoretical amount of hydrogen, the catalyst was filtered off and the
filtrate was evaporated. This fraction was stirred in boiling ethyl acetate, filtered off, washed with ethyl acetate and 2,2'-oxybispropane, and dried (vacuum), yielding 1.0g (45%) of ethyl 54(2,3,3a,4-tetrahydro-2-oxo-IH-pyrrolo12,3-biquinolin-6- yl)oxyjpentanoatet mp. 179.7°C (interm. 7);
10 In a similar manner there was prepared :
ethyl 4-[(2,3,3a,4-tetrahydra-2-oxo-1L1-pyrrolo[2,3-b]quinolia-6-ypoxylbutanoate; mp. 177.1°C (interm. 6);
methyl 64(2,3,3a,4-tetrabydro-2-oxo-ILI-pyrrolo[2,3-biquinolin-6-yl)oxyjhexanoate; tap. 199.3*C (interm. 15); and
15 ethyl [(2,3,3a,4-tetrahydro-2-oxo-ILI-pyrrolor2,3-blquinolin-6-y1)oxy]acetate (interm.
16).
Example 3
A solution of intermediate (3) (0.0215mo1) in acetic acid (150m1) was hydrogenated
20 under atmospheric conditions with palladium on activated carbon (10%) (2g) as a
catalyst. After uptake of the theoretical amount of hydrogen, the reaction mixture was stirred and refluxed for 4 hours (1-12 removal). Then, the catalyst was filtered off and the filtrate was evaporated. The residue was washed with 2-propanol (40ml), then dried, yielding 2.53 g (64%) of 1,3-dihydro-2_11-pyrrolo[2,3-b]quinolin-2-one; mp. 261.1°C
25 (intern). 8).
B. Preparation of the final compounds Example 4
aj A solution of intermediate (6) (0.0064mo1) in tetrabydrofuran (80m1) was stirred at
30 70°C (oil bath). 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (2.16g)
was added in one portion and the mixture was stirred for 5 minutes. A second portion of 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (0.00158 mol) was added
and the reaction mixture was stirred for an additional 10 minutes. The solvent was evaporated. The residue was stirred in a mixture of CH2C12/ CH3OH 90/10 and washed
35 with water. Insoluble material was removed by filtration and the filtrate was evaporated.
-12-
The residue was purified by column chromatography over silica gel (eluent: CH2C12/ CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in boiling ethanol (30m1). The precipitate was filtered off, washed with ethanol and 2,2'-oxybispropane and dried (vacuum; 60-70°C), yielding 0.76 g
5 (38.1%) of ethyl 4-[(2,3-dihydro-2-oxo-1H-pyrrolo[2,3-b]quinolin-6-yljoxy]butanoate;
mp. 181.4°C (comp. 1).
In a similar manner there was prepared :
ethyl 5-[(2,3-dihydro-2-oxo-ILI-pyrrolo[2,3-b]quinolin-6-ylloxy]pentanoate; mp. 180.9°C (comp. 2).
10 b) A solution of compound (1) (0.0130mol) in a mixture of sodium hydroxide 1N (0.040 mol) in ethanol (40 ml) was stirred at room temperature until the reaction was complete. Then, HCl 1N (40 ml) was added and the resulting mixture was concentrated under reduced pressure. The residue was stirred in water and the resulting precipitate was filtered off, washed with water and dried (vacuum; 70°C). This fraction was stirred
15 in boiling ethanol, filtered off, washed with ethanol and 2,2'-oxybispropane, then dried
(vacuum 60-70°C), yielding 3.22 g (86.5%) of 4-[(2,3-dihydro-2-oxo-1H-pyrrolo¬[2,3-b]quinolin-6-y1)oxylbutanoic acid; mp.. 260°C (comp. 3).
In a similar manner there,was prepared : 5-[(2,3-clihydro-2-oxo-1H-pyrrolo[2,3-b]quinolin-6-ypoxy]pentanoic acid; mp. > 260°C 20 (comp. 4);
6-[(2,3-dihydro-2-oxo-lli-pyrrolo[2,3-b]quinolin-6-yl)oxy]hexanoic acid (comp. 18); and
[(2,3-dihydro-2-oxo-11-1-pyrrolo[2,3-b]quinolin-6-yl)oxylacetic acid (comp. 19).
25 Example 5
A mixture of intermediate (6) (0.06mol), 2,5-dimethy1-2,4-hexadiene (40g) in methylbenzene (400m1) was heated overnight at 195°C (closed vessel) in the presence of platinum on activated carbon (10%) (3g) as a catalyst and a 4% solution of thiophene (2m1). The mixture was cooled, filtered over dicalite and washed with methylbenzene.
30 The precipitate was stirred in a mixture of dichloromethane and acetic acid (50/50) and
filtered over dicalite. The filtrate was evaporated and the residue was stirred in boiling ethanol, filtered off, washed and dried in vacuo, yielding 14.5g (77%) of ethyl 4-[(2,3- dihydro-2-oxo-1H-pyrrolo[2,3-b]quinolin-6-yl)oxylbutanoate (comp. 1).
In a similar manner was prepared :
35 ethyl 54(2,3-dihydro-2-oxo-1H-pyrrolo[2,3-b]quinolin-6-yljoxylpentanoate (comp. 2);*
methyl 6-[(2,3-dihydro-2-oxo-lli-pyrrolo[2,3-b]quinolin-6-ypoxylhexanoate (comp. 20);
-13-
ethyl [(2,3-dihydro-2-oxo-1H-pyrrolo[2,3-b]quinolin-6-ypoxyjacetate (comp. 21).
)example 6
Diphenyl phosphoryl azide (0.0085mo1) was added to a mixture of compound (3)
5 (0.0059mo1), 1-(cyclohexanylmethyl)piperazine (0.0072mo1), ELT-diethylethanamine
(0.0124 mol) and lia-dimethy1-4-pyridinamine (catalytic quantity) in N,H-dimethyl-
formamide (30 ml), stirred at room temperature. The reaction mixture was stirred overnight at room temperature. Dichloromethane (200m1) was added and the mixture
was washed with water. The organic layer was dried, filtered and the solvent was
10 evaporated. The residue was stired in boiling methanol (20m1). The precipitate was filtered off, washed with methanol and 2,2'-oxybispropane, then dried. This fraction (1.5g) was dissolved in a mixture of methanol/methanol(NH3)/ttichloromethane (5/5/90) and filtered over silica gel column. The desired fractions were collected and the solvent was evaporated. The residue was stirred in boiling methanol (20m1), filtered off,
15 washed with methanol, 2,2'-oxybispropane and dried in vacuo at 60°C, yielding 1.36g (51.2%) of 1-(cyclohexylmethyl)-444-1(2,3-dihydro-2-oxo-lli-pyrrolo[2,3-b]quinolin¬6-ypoxyl-1-oxobutylipiperazine; mp. 227.2°C (comp. 5).
In a similar manner there were prepared :
H
0
0—(CHs),—(NH),—C—(NH)„,—X Y—R
20
Comp. No. n p m X Y R physical data / salts (mp. in 'C)
z z z z z C.)z z Z1 cyclohexylmethyl 194.7
phenylmethyl 234.0
1-butyl 198.4
phenylmethyl 221.8
...._ 0-1 o o z cyclohexyl .2HC1.1/21-120
1H-imidazol-2-ylcarbonyl 255.0
2-pyridinyl 249.1
2-pyrimidinyl 260
phenylmethyl 206.8
-14-
Comp. No. n p m X Y R physical data / salts (mp. in °C)
23 Izzzzzzzzz z z I diphenylmethyl 230.0
24 1-butyl 178.9
25 cycloheptyl • 192.8
26 cyclohexylmethyl 193.2
27 4-methoxyphenyl 218.6
28 cyclohexyhnethyl 244.7
29 .1. 0 z cyclohexylmethyl 170.5
30 cyclohexylmethyl 220.6
31 (4-chlorophenyl)methyl 234.6
32 C113 cii,
X
0 0
—012—\--1 209.0
33 cyclohexylmethyl 209.7
and 4-[(2,3-dihydro-2-oxo-1H-pyrrolo[2,3-b]quinolin-6-ypoxy]-N-methyl-N-(1- methyl-4-piperidinyl)butanamide; sup. 212.4°C (comp. 8).
5 b) Compound (6) (0.0033 mol) was stirred in boiling ethanol (20 ml). This mixture
was acidified with HC1/2-propanol. The mixture was cooled. The precipitate was filtered off, washed with ethanol, 2,2'-oxybispropane and dried (vacuum), yielding 1.40
g (84.7%) of 1-(cyclohexylmethyl)-445-[(2,3-dihydro-2-oxo-111-pyrrolo[2,3-b]- quinolin-6-yi)oxy]-1-oxopentyl]piperazine monohydrochloride; mp. 271.8°C (comp.
10 15).
In a similar manner there was prepared: 1-(cyclohexylmethyl)-444-[(2,3,-dihydro-2-oxo-1LI-pyrrolo[2,3-b]quinolin-6-yfloxy]-
1-oxobutyl]piperazine dihydrochloride ethanolate(1:1); mp. 204.8°C (comp. 16).
15 example 7
Thionyl chloride (0.00803mol) was added dropwise to a suspension of compound (3) (0.0073mol) in Nli-dinaethylformamide (25m1). The mixture was stirred for 5 minutes.
Then, N-methyl-cyclohexanamine (0.0438mo1) was added in one portion and the reaction mixture was further stirred at room temperature. The solvent was evaporated.
20 The residue was taken up in CH2C12/CH3OH (90/10) and washed with water. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:
-15-
CHC13/(CH301-1/NH3)/ tetrahydrofuran 90/5/5). The eluent of the desired fraction was
evaporated and the residue (0.4g) was crystallized from ethanol. The precipitate was filtered off, washed with a small amount of ethanol, 2,2'-oxybispropane and dried (vacuum; 60°C), yielding 0.150g (5.3%) of 1V-cyclohexy1-4-[(2,3-dihydro-2-oxo-1H-
5 pyrrolo[2,3-b]quinolin-6-yl)oxy]-LI-methylbutanamide hemihydrate; mp. 203.9°C
(comp. 17).
Example 8
a) A mixture of compound 10 (0.0078 mol) in 2-methoxyethanol (250 ml) was
10 hydrogenated at 50 °C with palladium on activated carbon, palladium content 10% (1 g) as a catalyst. After uptake of H5 (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in boiling ethyl acetate, filtered off, washed with ethyl acetate and dried (vacuum), yielding 2.4 g (87%) of 114-[(2,3-dihydro-2- oxo-lff-pyrrolo[2,3-b]quinolin-6-yl)oxy]-1-oxobutyllpiperazine (comp. 35).
15 b) A mixture of compound 35 (0.0067 mol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (0.0091 mol) in 2-methoxyethanol (150 ml) was hydrogenated at 50 °C
with palladium on activated carbon, palladium content 10% (2 g) as a catalyst in the presence of thiophene, 4ceo solution (1 ml). After uptake of 1-12 (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column
20 chromatography over silica gel (eluent: C112C12/C11301-1 94/6). The pure fractions were
collected and the solvent was evaporated. The residue was stirred in boiling ethanol. The
precipitate was filtered off, washed with ethanol and DIPE, then dried (vacuum), yielding 0.62 g (16.6%) 14[3-(cyclopentyloxy)-4-rnethoxyphenyI]methyl]-4-14-[(2,3- dihydro-2-oxo-1LI-pyrrolo[2,3-b]quinolin-6-yl)oxyl-l-oxobutylipiperazine; mp.
25 194.1*C (comp. 36).
ExartIple9_
A mixture of compound 32 (0.0085 mol) in acetic acid (95 ml) was stirred for 10 hours
at 60 °C. The solvent was evaporated. The residue was stirred in water and this mixture
30 was alkalized with an aqueous ammonia solution. The water layer was separated and extracted with CH2C12/C113014 90/10. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: CH2C12/(CH301-1/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was stirred in
35 DIPE, filtered off, washed and vacuum dried, yielding 1.05 g (28.2%) (±)-444-[(2,3-
dihydro-2-oxo-1E-pyrrolo[2,3-b]quinolin-6-yl)oxy3-1-oxobuty1)-13-hydroxy-l-piperazinepropanol hemihydrate; mp. 219.7'C (comp. 37).
-16-
C. Pharmacological examples
The positive isotropic and lusitropic effect of the instant compounds was assessed by an in vitro assay system to detect inhibiting effect on the phosphodiesterase type III and in an in vivo experiment in closed-chest anaestetized dogs by monitoring cardiac and
5 haemodynamic effects of an intravenous bolus injection of the instant compounds.
Example 10 : Inhibition of Phosphodiesterase type III (POE HD.
Phosphodiesterase activity was measured in an incubation medium (200 ttl) containing 40 mM Tris, 5 mM MgC12, 3.75 mM 2-mercaptoethanol, [3H]cAMP and [3H]cGMP
10 (310 mCi/mmol) at pH 7.1. For every preparation, time- and concentration-dependent changes in cyclic nucleotide hydrolysis were measured. From these data, a protein concentration was chosen that showed a linear increase in phosphodiesterase activity during an incubation period of 10 min at 37°C. The enzymati6 activity was started by addition of substrate and stopped 10 min later after the tubes were transferred to a
15 waterbath at 100°C for 40 sec. After the tubes had been cooled to mom temperature, alkaline phosphatase (0.25 g/ml) was added and the mixture was left at 37°C for 20 min.
The mixture was subsequently applied to a 1-ml DEAE-Sephadex A-25 column and washed twice with 3 ml of 20 mM Tris-HO at pH 7.4. The 311-labeled reaction products in the eluate were quantified by liquid scintillation counting.
20 The inhibiting effect of the present compounds on canine heart phosphodiesterase POE III was measured at different concentrations of the instant compounds. The IC50 values
were calculated graphically from the thus obtained inhibition values. Table 1 shows available IC50 values of the present compounds on canine heart PDE
25 Table 1
Comp. No. Canine heart POE III
IC50 (10-6 M)
*-4 (NS VI , ,0 N 00 WI ,0 r,
■••■ ..1 o 0.29
0.062
0.33
0.018
0.0024
0.058
0.30
0.0018
0.027
0.0076
-17-
Example 111
Positive inotropy and lusitropy. blood rffessure and heart rate in dogs.
The test compound was dissolved in an aqueous glucose solution in a concentration of
5 Img.m1-1. The experiments were performed on 3 Beagle dogs of either sex and varying
age, ranging in body weight from 11 to 18 kg (median 13 kg). The animals were intravenously anaesthetized with a mixture of 0.015 mg.kg-1 scopolamine and 0.05 mg.kg•I lofentanil. The animals were intubated with a cuffed endotracheal tube. Intermittent positive pressure ventilation was performed with a mixture of pressurized air
10 and oxygen (60/40), using a volume-controlled ventilator (Siemens Edema). In the control period the CO2 concentration in the expired air (ET CO2), as determined with a capnograph (Gould Godart), was kept at 5 vol% by adjustment of the respiratory volume (resp. rate --- 20 bteaths.min-1). A continous intravenous infusion of 0.5 mg.kg-l.h-1 of etomidate was started immediately after induction. Body temperature was monitored with
15 a thermistor positioned in the pulmonary artery. To prevent blood clotting heparin, 1000
i.v., was administered.
The electrocardiogram (ECG) was derived from limb leads (standard lead 2). Left ventricular (LVP) and ascending aortic blood pressure (AoP) were measured by retrograde catheterisation via the femoral arteries with high fidelity cathetertip
20 micromanometers (Honeywell). The other femoral vein was cannulated for injection of saline at room temperature into the right atrium and for injection of the test compound. Peak ascending aortic blood flow velocity was measured through the right carotid artery with an electomagnetic catheter-tip probe connected to a square wave electomagnetic flow meter (Janssen Scientific Instruments). The following variables -inter alia- were
25 calculated on-line, usually at 1 min intervals: heart rate (BR), diastolic (AoPd) aortic
blood pressure, left ventricular end-diastolic pressure (LVEI)P), the maximum positive
and maximum negative rate of change of isovolumic LVP (LV dp/dt max and min, respectively), the maximum positive first derivative divided by the actually developed pressure in the left ventricle (LV dp/dtmax/Pd). The time constant (T) of relaxation was
30 measured with the use of an exponential analysis that also estimated the asymptote.
After a stabilization period, the animals were treated by intravenous bolus injection of the test compound at 30 min. interval in cumulative doses of 0.0005, 0.001, 0.004, 0.016, 0.064, 0.125 and 0.25 mg/kg.
The test compounds have positive inotropic properties as indicated by the pronounced
35 and significant increase in the variables related to cardiac performance (LV dp/dtmax,LV. dp/dt../Pd). The test compounds have positive lusitropic properties, as evidenced by the significant decrease in the time constant of relaxation. Upon administration of the test
-18-
compounds, systemic and pulmonary peripheral vascular resistance decrease significantly. This indicates that the test compounds have also additional systemic and pulmonary vasochlatory properties. This unloading of the heart occurs without altering heart rate, but with concomitant increase in cardiac output. These positive inotropic and
5 lusitropic, and vasodilator), effects of the compounds are long-lasting, since the changes
in the variables last for more than 30 min after the bolus injection.
Table 2 shows the changes in haemodynamic variables measured 5 minutes after cumulative intravenous bolus administration of.some of the present compounds in Beagle dogs. The variable AoPd (diastolic aortic blood pressure) shows the decrease in blood
10 pressure (vasodilation), HR the influence of the present compounds on the heart rate, LV cip/dtmax (the maximum positive rate of change of isovolumic left ventricular pressure) shows the positive inotropic effect.
Table 2
15 Calculated dose ( in mg/kg iv.) producing a 30% increase in cardiac contractility (LV
dp/dt max), a 30% increase in heart rate (HR), a 15% reduction in diastolic sonic blood pressure (AoPD) and a 15% reduction of total systemic vascular resistance (TSR) relative to premedication values at 5 min after the iv. administration to anaesthetized, closed-chest dogs (n=3 for each compound).
20
Co. No. HR AoPD LV dp/dtm. TSR
15 5 0.028
0.033 0.015
> 0.25 0.002
0.008 0.003
0.079
D. Composition examples
"Active ingredient " (A.I.) as used throughout these examples relates to a compound of formula (I) or (II), a pharmaceutically acceptable addition salt thereof or a
25 stereochemically isomeric form thereof.
Examole 12 : ORAL DROPS
500 Grams of the A.I. was dissolved in 0.51 of 2-hydroxypropanoic acid and 1.5 1 of the polyethylene glycol at 60-80°C. After cooling to 30-40°C there were added 35 1 of polyethylene glycol and the mixture was stirred well. Then there was added a solution of
30 1750 grams of sodium saccharin in 2.51 of purified water and while stirring there were added 2.5 1 of cocoa flavor and polyethylene glycol q.s. to a volume of 501, providing an oral drop solution comprising 10 mg/ml of A.L. The resulting solution was filled into suitable containers.
-19-
Example 13 : ORAL SOLUTION
9 Grains of methyl 4-hydroxybenzoam and 1 gram of propyl 4-hydroxybenzoate were
dissolved in 41 of boiling purified water. In 31 of this solution were dissolved first 10
grams of 2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. The latter
5 solution was combined with the remaining part of the former solution and 121 1,2,3- propanetriol and 31 of sorbitol 70% solution were added thereto. 40 Grams of sodium saccharin were dissolved in 051 of water and 2 ml of raspberry and 2 ml of gooseberry, essence were added. The latter solution was combined with the former, water was added q.s. to a volume of 201 providing an oral solution comprising 5 mg of the active ingre-
10 dient per teaspoonful (5 ml). The resulting solution was filled in suitable containers.
Example 14 : CAPSULES
20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56 grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 grams magnesium stearate were vigorously
15 stirred together. The resulting mixture was subsequently filled into 1000 suitable
hardened gelatin capsules, comprising each 20 mg of the active ingredient.
Example 15 : FILM-COATED TABLETS
Preparation of tablet core'
20 A mixture of 100 grams of the A.I., 570 grams lactose and 200 grams starch was mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10
grams polyvinylpyrrolidone (Kollidon-K 90 ®) in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 grams microcrystalline cellulose (Avicel ®) and 15 grams hydrogenated vegetable oil (Sterotex
25 ®). The whole was mixed well and compressed into tablets, giving 10.000 tablets, each
containing 10 mg of the active ingredient.
Coatigi
To a solution of 10 grams methyl cellulose (Methocel 60 MO) in 75 ml of denaturated ethanol there was added a solution of 5 grams of ethyl cellulose (Ethocel 22 cps ao) in
30 150 ml of dichloromethane. Then there were added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 25 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-21096) and the whole was
35 homogenated. The tablet cores were coated with the thus obtained mixture in a coating
apparatus.
-20-
Example 16 : INJECTABLE SOLUTION
1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl 4-hydroxybenzoate were dissolved in about 0.51 of boiling water for injection. After cooling to about 50°C there were added while stirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams
5 of the Ai. The solution was cooled to room temperature and supplemented with water for injection q.s. ad 1 1, giving a solution comprising 4 mg/ml of A.L. The solution was sterilized by filtration (U.S.P. XVII p. 811) and filled in sterile containers.
-21-
Claims
1. A compound having the formula
H
N
(1)
5
a pharmaceutically acceptable addition salt thereof or a stereochemically isomeric form thereof, wherein
10 L is a radical of formula -0-Alk-(NH),-C(=0)-R1, wherein
Alk is C1_6alkanediy1;
p is 0 or 1; and
R1 is hydroxy, Ci_olkyloxy or -NR2R3, wherein
R2 is hydrogen or C1.,alkyl; and
15 R3 is C3_rycycloallcyl or piperidinyl, which is optionally substituted with Cmalkyi or
phenylmethyl or C3.7cycloallcylmethyl;
R2 and R3 may also be joined together to form piperazinyl, optionally substituted with C3_7cycloallcyl, C3_7cycloalkylmethyl, C1_6alkyl optionally substituted with one or two hydroxy groups, 2,2-dimethyl-l,3-dioxolanylmethyl, benzyl, halophenylmethyl,
20 (cyclopentyloxy)(methoxy)phenylmethyl, diphenylC1. alkyl, pyridinyl, pyrimidinyl or
phenyl optionally substituted with Cmalkyloxy or halo; or
R2 and R3 are joined together to form piperidinyl, optionally substituted with imidazolylcarbonyl.
25 2. A compound according to claim I wherein RI is -NR2R3.
3. A compound according to claim 2 wherin R2 and are joined together to form a piperazinyl substituted with C3_7cycloalkylmethyl.
30 4. A compound according to claim 3 wherein the compound is 1-(cyclohexylmethyl)- 444-[(2,3-dihydro-2-oxo-lil-pyrrolo[2,3-b]quinolin-6-ypoxyl-l-oxobutyllpiperazine or 1-(cyclohexylmethyl)-445-[(2,3-dihydro-2-oxo-lli-pyrrolo[2,3-blquinolin-6-y1) oxy)-1-oxopentyl]piperazine, a pharmaceutically acceptable addition salt thereof or a stereochemically isomeric form thereof.
35
-22-
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient an effective positive isotropic and lusitropic amount of a compound as claimed in any of claims i to 4.
5 6. A process for preparing a composition as claimed in claim 5 characterized in that a
therapeutically effective amount of a compound of formula (I) as claimed in any of claims 1 to 4 is intimately mixed with a pharmaceutically acceptable carrier.
7. A compound as claimed in any of claims 1 to 4 for use as a medicine.
10
8. A process for preparing a compound as claimed in any of claims 1 to 4, characterized by
a) reacting an intermediate of formula (II) in the presence of a dehydrogenating reagent 15 in a reaction-inert solvent
(1)
b) reacting an intermediate of formula (III) in the presence of a suitable catalyst in a 20 reaction-inert solvent
and, if desired, converting the compounds of formula (I) into each other following art-
25 known functional group transformation reactions, and further, if desired, converting the
compounds of formula (I) into a salt form by treatment with a pharmaceutically acceptable acid or base, or conversely, converting the salt form into the free base or the free acid by treatment with alkali, respectively an acid; and/or preparing stereochemically isomeric forms thereof.
-23-
9. A compound having the formula
an addition salt thereof or a stereochemically isomeric form thereof, wherein Lis as defined for the compounds of formula (I) in claim I.
10. A compound having the formula 0
an addition salt thereof or a stereochemically isomeric form thereof wherein L is as defined for the compounds of formula (I) in claim 1 and Z is nitro or amino.