Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the instant invention refers to the activity and use of compounds having a prostaglandin-like structure as well as pha maceutical compositions thereof, having platelet antiaggregati antithrombotic activity.
• the above formu la (I) includes all possible stereoisomers, all possible com ⁇ binations of two or more such stereoisomers, of enanthiomers o mixtures of enanthiomers in any proportion.
• the instant invention relates to pros compounds of the above cited formula (I), useful for prepari pharmaceutical compositions having antiplatelet, antithrombo -
• the expression “pharmaceutically accept able cationic salts” refers to the alkali and alkaline-earth metal salts such as, e.g. sodium; potassium, calcium, magne.- sium, or salts of aluminum, ammonium, zinc and of organic amines, including the amino acids such as, e.g. lysine,argi- nine, phenylalaline and proline, triethanol amine, inner sal and salts of basic resins.
• the expression “pharmaceutically accept able anionic salts” refers to salts obtained by the addition of hydrochloric, hydrobromic, nitric, phosphoric, sulfuric, benzenesulfonic, benzoic, citric, laurylsulfonic, fumaric,oxali maleic, ethanesulfonic, tartaric, ascorbic, p-toluenesulfonic, salicylic and succinic acid.
• the salt may include more than one mole of base per mole of acid.
• the salts obtained from one mole of acid per mole of the inventive compound are preferr.
• the present invention refers to pharmaceutical c positions containing a compound of formula (I) or a pharmaceuti cally acceptable anionic or cationic salt thereof.
• the preparation of some of the compounds of formula (I) h already been described in IT 1,190,400 of October 4,1985 and IT 1,205,183 filed on June 25,1987.
• Y 1 - CH NH , CONH , COOR' and R' a linear or branche H(C 1 -C 4 )alkyl.
• inert polar solvents such as, e.g. tetrahydrofuran, ethyl ether, butyl ether, dioxane, dimethylformamide.
• the acetal of the 1,5-dicarbonyl compound(XI) .prepared by gnard condensation, can be cyclized by acid catalyzed,intramole lar crotonic condensation, in a suitable solvent, yielding the desired compound of formula (II).
• the compounds of formula (IX) may be prepared according t methods known from the literature, for example by monohalogenati of the 1,4-butanediol (V) performed as described by Suk-Ku-Kang i Synthesis,1161 (1985) ,oxydation of the aldehyde (VII) of the 6 ⁇ -halobutanol (VI) with a catalytic process employing sodium h chlorite as the oxydizing agent and the free radical 2,2,6,6-tet methyl-piperidinyl-1-oxyl as the catalyst, as described by
• inert solvents are generally used such as, e.g. tetrahydro furan, dimethyl-formamide, ethyl ether, butyl ether.
• the compounds of formula (IV) can be prepared from the c responding cycloalkanones (III) by using per se known reaction such as e.g. reductive aminations with ammonia, hydrogen and m catalysts, in alcoholic solvents, at a temperature of from 30° 100°C and at a pressure of from 1 to 20 atms according to reac scheme I, or according to methods known from the technical lit ture, according to scheme III: SCHEME III
• bases such as.e. N NaaO0HH,,KK0H, K CO , which are capable of hydrolizing the carbalc group.
• the compounds of formula (I) prepared according to the p Dates of the instant invention when not otherwise specified, generally consist of mixtures of the stereoisomers in ratios d pending on the route of synthesis, on the reagents used and th experimental conditions.
• the desired enanthiomer pairs can be prepared by separat the stereoisomeric mixtures by methods known to the man skille in the art.
• each enanthiomer p of the compounds of formula (I) is furthermore possible to prepare each enanthiomer p of the compounds of formula (I) by chromatographically separat the mixture of the stereoisomer alcohols (XII) prepared by red tion with stereoselective reducing agents as described by CH.Brown, S.Kirishnamurthy in J.Am.Chem.Soc. 7159 (1972), or reduction with reducing agents having a low steric demand
• reaction mixture (prepared according to reaction scheme II) in tetrahydrofur (1600 ml) keeping the temperature at 20-25°C, at the end of which the reaction mixture is kept under stirring for furth 60 min.
• the reaction mixture is cooled to -45°C and added w the monochloride of 8-carbomethoxy-octanoic acid (prepared cording to the method disclosed in IT patent application 19 A/84 of January 5,1984), keeping the temperature between -4 and -45°C.
• the reaction mixture is stirred for 5 hrs at -15° at the end of which a 15% solution of sodium chloride(120 ml and ethyl ether (120 ml) is added thereto.
• reaction mixture is extracted with methylene chloride (2 x 300 ml), and the organic phase is washed to neutrality with a 10% brine solution.
• This derivative is prepared according to the process disclosed IT Pat.Appln. 19043 A/84 filed on January 5,1984, by reacting 2-(6'-carbomethoxy-hexyl)-2-cyclohexene-l-one) (41 g) with brom hexane (52 g) and Cul (3.3 g); 48.3 g of the title compound is obtained.
• reaction mixture is refluxed under stirring to compl tion of the reaction. Then it is cooled, acidified to pH 2, ex tracted with methylene chloride (250 ml) and washed with water to neutrality. The reaction mixture is anhydrated and the solv is distilled off; 68 g of the title compound is obtained.
• the compound of example 4(68 g) is reacted with methanol (1000 ammonia (200 g), PtO (3 g), at a temperature of from 40 - 60° in an autoclave, and left for 3 days under hydrogen pressure, yielding 42 g of a solid white compound.
• Analytical data: ffl.p. 166°-168°C
• This derivative is prepared in an analogous manner to that de ⁇ scribed in example 3, using as the starting material 2-(6'-car bomethoxy-hexyl)-2-cyclopentene-l-one (67 g); yield : 78 g of the title compound.
• R,S-cis-2-(6'-carbomethoxy-hexyl)-cis-3-n-hexyl-cyclohexanol a) 2-(6'-carboxyhexyl)--3-n-hexyl-cyclohexanol (125 g) is re ⁇ acted with a IN lithium-tri-sec-butylboronhydride solution THF (800 ml) according to the method described by H.C.Brow et al in J.Am.Chem.Soc.
• reaction mixture is refluxed 90 min, cooled and the me anol is concentrated under reduced pressure; the reaction mixture is then added with water (600 ml) and ethyl ether (400 ml).
• the organic phase is washed with a 20% brine, anhydrated o and the solvent is distilled off under reduced p fres yielding a yellow oil (124.3 g) consisting of a mixture of R,S-cis-2-(6'-carbomethoxyhexyl)-cis-3-n-hexyl-cyclohexano and of R,S-cis-2-(6'-carbomethoxyhexyl)-trans-3-n-hexyl-cy hexanol.
• a solution of R , S-cis-2- ( 6 ' -carbomethoxyhexyl ) -cis-3-hexyl cyclohexanol (70 g) in methylene chloride (350 ml) is added with triethyla ine (51.7 ml) and methanesulfonyl chloride (34.3 g) is added dropwise.at a temperature of from 0° to 5° the reaction mixture is reacted 30 min at the same temperatu and at the end it is poured into water (600 ml).
• reaction mixture is cooled and extracted wit ethyl ether (500 ml).
• the organic phase is then washed with 20% brine, anhydrated over Na SO , and the solvent is distil off under reduced pressure, yielding 96 g of an orange oil.
• the material is purified by silica gel chromatography, eluti with 95:5 hexane:ethyl acetate.
• reaction mixture is then shaken 5 hours under hydrogen a phere, then the catalyst is filtered off and the solvent is distilled off under reduced pressure; the residue is chromat graphed on silica gel using an 80:20:0.5 hexane:acetone:ammon mixture as the eluent.
• PRP platelet-rich plasma
• rat PRP 500,000 platelets/mm adding a compound of formula (I) or a pharmacologically ac ⁇ ceptable salt thereof so that its plasma concentration be 10 Mincubating 9 min at room temperature; whereupon as ag gating agent ADP (3 ,uM) is added * and the percent inhibitio of the platelet aggregation is measured using the turbidim ric method of Born and Cross (Table 1)-.
• test is carried out as described sub 1) (inhibition of platelet aggregation by added ADP), using collagen (3 mcg/ as the aggregating agent (Table 1).
• test is carried out as described sub 1) (inhibition of platelet aggregation by added ADP), using arachidonic acid (200,uM) as the aggregating agent (Table 1).
• the test is carried out as described sub 1) (inhibition of platelet aggregation by added ADP), using thrombin (0.1 U/ as the aggregating agent.
• the transmittance measurements h been effected with a Chromo-Log or Elvi 840 aggregometer.
• R,S-trans-2-(6'-carboxyhexyl)-cis-3-n- hexyl-cyclohexylamine (IBI-P-05006 C) ⁇ 10 100 100 45,
• Table 2 illustrates the percent inhibition of platelet functiono with rat PRP, determined under the same conditions and at the
• the compounds subject of the insta invention show an antiplatelet, antithrombotic activity which is surprisingly higher(more than 10 times)over that of the compounds disclosed in IT 1,060,366 filed on August 7,1984.
• the compounds of the instant invention are preferably adminis ⁇ tered as pharmaceutical compositions in admixture with one or more pharmacologically acceptable diluents and/or carriers.
• pharmaceutically acceptable diluents and/or carriers refers to substances such as e.g. starch and derivatives thereof (e. g. maize starch, STA RX 150Cr-, which is a registered tradenam of Colacon Ltd., Orpington, Kent, rice starch,carboxymethyl starch); cellulose and derivatives thereof (e.g.
• inventive compounds are administered orally (e.g. as tablets, capsules, granules, syr ups) or parenterally (i.v.
• the inventive compounds can be administered ora ly to an adult at a daily dose of from 1 to 2000 mg, preferab of from 10 to 1000 mg, per single dose, or in doses subdivide over a period of 24 hours.

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• Medicinal Chemistry (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1989
  • 1989-09-12 JP JP1509780A patent/JPH03502103A/ja active Pending
  • 1989-09-12 AU AU43138/89A patent/AU628400B2/en not_active Expired - Fee Related
  • 1989-09-12 WO PCT/IT1989/000061 patent/WO1990003170A2/en not_active Application Discontinuation
  • 1989-09-12 EP EP89910462A patent/EP0425584A1/en not_active Withdrawn
• 1990
  • 1990-05-18 DK DK124390A patent/DK124390A/da not_active Application Discontinuation

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