Patentamt 0 1 99 393 JEuropaischesEuropean Patent Office Publication number: B1 Office europeen des brevets EUROPEAN PATENT SPECIFICATION 07 C 83/10, C 07 C 123/00, (45) Date of publication of patent specification: 07.12.88 Intel.4: C C 07 C 133/12, C 07 C 135/00, ® Application number: 86200495.9 A 61 K 31/155 ® Date of filing: 24.03.86 Indene and naphthalene derivatives. (§j) Priority: 02.04.85 GB 8508588 Proprietor: AKZON.V. Velperweg 76 NL-6824 BM Arnhem (NL) Date of publication of application: 29.10.86 Bulletin 86/44 Inventor: Logan, Robert Thomas "Leven"1StaikHHI Scotland (GB) Publication of the grant of the patent: Lanark ML11 9PW Lanarkshire 07.12.88 Bulletin 88/49 Inventor: Redpath, James 5 Etive Crescent Bishopbriggs Glasgow Scotland (GB) Gibson Designated Contracting States: Inventor: Roy, Robert BECHDEFRGBITLINLSE 63 Kenshaw Avenue Larkhall ML9 1PW Lanarkshire Scotland (GB) cited: References G.M. et al EP-A-0 030 749 Representative: Hermans, Franciscus FR-A-2 504 526 Postbus 20 US-A-3130 232 NL-5340 BH Oss (NL) US-A-4013 682 CO US-A-4 076 726 CO o CO The file contains technical information filed and o submitted after the application was not included in this specification Note- Within nine months from the publication of the mention of the grant of the European patent, any person may Notice of shall give notice to the European Patent Office of opposition to the European patent granted. opposition be deemed to have been filed until the opposition fee has been Q. be filed in a written reasoned statement. It shall not 99(1 ) convention). LU paid. (Art. European patent Courier Press, Leamington Spa, England. EP 0 199 393 B1 Description The invention relates to compounds of the general formula I "*1 (CH = CH)n-R3 10 wherein R, represents one up to and including four, the same or different substituents selected from alkyl(1 — 6 C), alkoxy(1— 6 C), hydroxy, halogen, NO2, CF3 or the group — NR5R6, whereby two substituents taken together may also represent a methylene-dioxy group, X represents the group 15 R4 -CH-, — CH2— CH2— or — CH=CH— , 20 n has the value 0, 1 or 2, R3 represents one of the moieties: NH / -c: -c; or 25 N-OH N-OH 30 NH -c = n-n-c; \ 35 NI-L and R2< ^4» Rs and R6 represent H or alkyl(1 — 6 C) and pharamaceutically acceptable salts thereof. The compounds according to the invention have a cardiotonic activity and more particularly they show 40 a very potent increase of the force and energy of the heart-musuclar contractions (positive inotropic effect). Compounds differing from the present compounds in at least the degree of saturation of the molecule are disclosed in EP — A — 0 030 749. These prior art compounds are, however, described for their potent platelet aggregation inhibiting properties, an activity that has no relation whatsoever with the cardiotonic activity found with respect to the present compounds. 45 The compounds of the invention may be prepared by any method for the preparation of analogous compounds. A very suitable starting product for the preparation of the compounds I is a compound of the formula II 50 (CH = CH)n-C-OH 55 wherein R1f R2, n and X have the aforementioned meanings. Compounds of the invention in which R3 represents the moiety 60 /@ — C \ N— OH I 65 R5 EP 0 199 393 B1 may for example be prepared by reacting the compound of formula II or an acid halide or anhydride thereof with an hydroxylamine of the formula: R5 HN (Ml) \ OH 10 in which R5 has the aforementioned meaning, or a reactive derivative thereof, in which the hydrogen atom is replaced by a more reactive moiety, such as an alkali metal. Compounds of the invention in which R3 represents a NH 15 /• — c \ N— OH I 20 Rs moiety may, for example be prepared from a nitrile of the general formula IV: I IV 30 in which Rv R2, X and n have the meanings assigned before by reacting the said nitrile in the usual manner with a compound of the formula: H— |M— OH III R5 wherein R5 has the aforementioned meanings, or a reactive derivative thereof, in which hydrogen (at the nitrogen atom) has been replaced by a more reactive moiety, such as an alkali metal. The nitrile of formula IV may be prepared in the usual manner from the corresponding carboxylic acid of formula II by converting the carboxylic acid into the corresponding carboxamide followed by 40 dehydration of the carboxamide. Compounds of the invention, in which R3 represents a — C=N— NH— C(=NH)NH2 moiety, may most conveniently be prepared from an aldehyde of the formula: 45 . ^ k V by condensation of this compound (V) with amino guanidine or a salt thereof. 50 The aldehyde of formula V can be prepared in various manners. For example the aldehyde may be manufactured by reducing the carboxylic acid of formula II in a well known manner. Another convenient synthesis for preparing the aldehyde consists of a mild reduction of the corresponding nitrile of formula II, e.g. with the aid of a metal hydride such as diisobutylaluminiumhydride. The starting product of general formula II may be prepared by known methods. The attached flow 55 sheet shows the preparation of a compound of formula II, wherein n = 0. Chain length extension to n = 1 and n = 2 can be obtained by converting the carboxylic acid II (n = 0) into the corresponding aldehyde (n = 0) and reacting said aldehyde with the appropriate phosphonate ylid using reaction conditions well known in carrying out the Wittig reaction. Appropriate phosphonate ylids are, for example, cyanomethylene triphenylphosphorane, carboxy- 60 methylene triphenylphosphorane and corresponding (alkyl)esters, and 3-cyano propen(2)-ylidene tri- phenylphosphorane. If necessary, the nitrile — obtained through this Wittig reaction — can be converted in to the corresponding amide or carboxylic acid. Preferably most substituents at the benzo-ring (see R,) are already present in one of the starting products. Nevertheless it is very well possible to convert a substituent R-, into another substituent R, after 65 the above mentioned condensation reactions. EP 0 199 393 B1 Thus, one or more hydroxy groups (F^) may be converted into the corresponding alkoxy groups or halogen in the usual manner. Furthermore two hydroxy groups may be converted into one methylene- dioxy group and an alkoxy group may be hydrolysed to the corresponding hydroxy group. The compounds according to the general formula I may be converted into a pharmaceutically 5 acceptable salt. The compounds of formula I which have an alkaline character may be obtained as the free base or as an acid addition salt. If required, however, the free base I can be prepared from the salt, for example by reaction with an alkaline compound or by means of an ion exchanger, whilst the free base I can be converted in a simple manner into an acid addition salt. 10 Pharmaceutically acceptable acid addition salts are derived from acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, lactic acid, citric acid, ascorbic acid, salicylic acid, benzoic acid and methanesulphonic acid. Compounds I having an acidic nature may be converted into a metal salt, preferably an alkali metal salt 15 such as the sodium salt. By the term "alky!(1— 6 C)" as used in the definitions of R1# R4, R5 and R6 is meant a saturated hydro- carbon with 1 to 6 carbon atoms, and preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso- propyl, butyl, isobutyl, tert. butyl, pentyl and isopentyl. An alkoxy(1— 6C) group is an alkyloxy group, in which the term alkyl has a similar meaning as above. 20 By halogen in the definition of R-, is preferably meant iodine, bromine, chlorine and fluorine. The most preferred halogens are chlorine and bromine. The said compounds in accordance with the invention can be administered either orally, locally or parenterally, preferably in a daily dose between 0.01 and 50 mg/kg body weight. For this purpose the compounds are processed in a form suitable for oral, local or parenteral administration, for example a 25 tablet, pill, capsule, solution, suspension, emulsion, paste or spray. The oral form is the most preferred form of administration. The most potent inotropic compounds are found amongst theose compounds of formula I in which at least two substituents Ri are present selected from hydroxy or alkoxy or in which at least one methylene- dioxy group (R,) is present, whereby the dimethoxy or methoxy-hydroxy substitution pattern is most 30 preferred. Preferred compounds of formula I are moreover those compounds I in which X is — CH2— CH2— . The position of the double bond between nitrogen and carbon in some of the moieties defined by R3 of formula i cannot be clearly specified, because an equilibrium will prevail between: 35 NH NH2 "< « >"°\ V .... M OLJ 40 NH NH2 C -C = N-N-C^ < > -C = N-N = H NNH.NH2 NH2NH, The preferred R3 moiety in the compounds of the invention is the N-hydroxy-(carbox)imidamide moiety. so The preferred value of n is 0 or 1. Example 1 A. 2-Bromo-5,6-dimethoxy-indan- 1-one: 5,6-Dimethoxy-indan-1-one (50 g) was dissolved in chloroform (1040 ml) and ethanol (1040 ml) and the 55 solution was stirred and heated to 50°C then treated portionwise over 7 hours with cupric bromide (104 g).