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WO1987002666A2 - Aminoalcools bi-cycliques a substitution alkoxy et alkylthio - Google Patents

Aminoalcools bi-cycliques a substitution alkoxy et alkylthio Download PDF

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Publication number
WO1987002666A2
WO1987002666A2 PCT/EP1986/000595 EP8600595W WO8702666A2 WO 1987002666 A2 WO1987002666 A2 WO 1987002666A2 EP 8600595 W EP8600595 W EP 8600595W WO 8702666 A2 WO8702666 A2 WO 8702666A2
Authority
WO
WIPO (PCT)
Prior art keywords
threo
naphthyl
methoxy
propanol
alkyl group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1986/000595
Other languages
English (en)
Other versions
WO1987002666A3 (fr
Inventor
Giampaolo Picciola
Mario Riva
Franco Ravenna
Piergiorgio Gentili
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Maggioni Winthrop SpA
Original Assignee
Maggioni Winthrop SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB858526913A external-priority patent/GB8526913D0/en
Priority claimed from GB868615561A external-priority patent/GB8615561D0/en
Application filed by Maggioni Winthrop SpA filed Critical Maggioni Winthrop SpA
Publication of WO1987002666A2 publication Critical patent/WO1987002666A2/fr
Priority to DK314187A priority Critical patent/DK314187A/da
Priority to NO872702A priority patent/NO872702L/no
Priority to KR870700558A priority patent/KR870700609A/ko
Publication of WO1987002666A3 publication Critical patent/WO1987002666A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/22—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

Definitions

  • R represents a lower straight or branched alkyl group
  • X represents -O- or -S-
  • n is an integer from 1 to 3
  • R 1 represents hydrogen or a lower alkyl group
  • R 2 represents hydrogen or benzyl
  • R represents an alkyl group
  • R 2 and R 3 taken together represents a divalent group selected from: a)
  • A is a group selected from
  • R 4 represent a lower alkyl group ;
  • W represents hydrogen, phenyl, benzyl, alkoxyphenyl, methylphenyl, 2-furoyl, nicotinoyl or a radical
  • -CO-CH CH-Z in which Z represents 2-thienyl or phenyl optionally substituted with 1-3 halogen, lower alkyl or alkoxy groups: and their salts with inorganic acids, organic acids, cationic exchange resins and complexes with cyclodextrins.
  • the compounds in which R 1 does not represent hydrogen, having two structural asymmetry centers, may exist both in the erythro and threo configuration.
  • the chemical process for the preparation of the invention compounds consists in contacting a bromo ketone of the partial formula II with an amine to give the amino ketone of the partial formula III.
  • the amino ketone III may be isolated from the reaction mixture before it is hydrogenated.
  • the intermediate III shows a low degree of stability, it is preferable to hydrogenate it directly in the reaction mixture in which it is formed by reaction of the bromo ketone with the amine.
  • the first step of the process is carried out in the presence of a proton acceptor, such as an alkali metal or earth alkali carbonate or bicarbonate or a tertiary amine.
  • a proton acceptor such as an alkali metal or earth alkali carbonate or bicarbonate or a tertiary amine.
  • a solvent inert to the instant reaction such as a lower alkanol, for instance methanol or ethanol, or a ketone, such as a di-lower alkyl ketone, for instance acetone or methyl ethyl ketone. It is immaterial whether the amine is added to the bromo ketone, both or only one of them being dissolved in the solvent, or vice versa the bromo ketone is added to the amine, still both in solution or only one of them.
  • the appropriate way of conducting the first step will be selected considering the properties of the reactants and their reactivity.
  • the reaction temperature is also adjusted depending on the reactivity of the two reactants, although normally the boiling temperature of the solvent is generally preferred.
  • the second step of the process i.e. the hydrogenation, may be carried out by any conventional hydrogenation procedures apt to convert a ketone into an alcohol.
  • the hydrogenation is best performed by using a metal hydride, preferably a double hydride, such as NaBH 4 , LiAlH 4 etc., by conventional procedures in a solvent inert to the hydrogenation reaction, which in the case of NaBH 4 may be water, or a lower alkanol, such as methanol or ethanol, both in the presence of various amounts of water of under anhydrous conditions, or alternatively, when for instance LiAlH 4 is used, the solvent may be diethyl ether, tetrahydrofuran and the like, at a temperature which may range from 0-5°C to the boiling temperature of the selected solvent.
  • a metal hydride preferably a double hydride, such as NaBH 4 , LiAlH 4 etc.
  • An alternative process for preparing the invention compounds consists in reacting an amino alcohol of the partial formula V with an aldehyde in a solvent, preferably in a lower alkanol such as methanol or ethanol, at a temperature between about 0°C and
  • a hydrogenating agent is then added at portions, the agent being preferably selected from metal hydrides or double cyano hydrides, such as sodium cyano boro hydride or lithium cyano boro hydride, these latter hydrogenating agents being preferred.
  • the compounds of this invention show anti-hypertensive, platelet aggregation inhibiting, hypolipemic, antianoxic, spasmolytic, antithrombotic and Ca ++ antagonizing activity. These activities are shared both by the individual stereoisomeric forms and their mixtures, which therefore may be administered for therapeutical purposes, depending on the actuale convenience, in one or the other steric form or mixture.
  • the anti-hypertensive activity was tested on groups of 5 SH rats (spontaneously hypertensive rats) weighing 200 ⁇ 10 g, fasting for 18 hrs and treated orally with the invention compounds suspended in 2.5% gum arabic.
  • the heart rate was also tested (BP Recorder No. 8006 supplied by Basile, Comerio, Italy).
  • the arterial pressure before the treatment was 210 ⁇ 10 mmHg.
  • Table 1 shows that the compounds are endowed with good anti-hypertensive activity at all tested doses.
  • PHE was administered cumulatively and dose-response curves were obtained (controls). Dose-response curves were similarly obtained after administration of the test drugs (1 mg/kg i.v.). From the two curves the PHE dosis causing a 50 mm Hg increase of the arterial pressure was calculated. The PHE dosis was about 9 times, in comparison with the controls, after administration of MG 38069; 20-25 times after MG 14238, MG 14233 and MG 38065; 34 times after MG 38095.
  • the protection against toxic adrenaline doses was tested as follows. Groups of 10-20 male mice CrI:CD 1(CR) BR were treated orally with vehicle (controls) and with various doses of the compounds. After 2 hrs 14.5 mg/kg of 1-adrenaline was administered intraperitoneally and mortality was recorded after 24 hrs: in controls mortality was 100%. From log dose-% protection curves the
  • Table 2 gives the results obtained with some of the compounds as compared with known drugs having alpha-adrenergic receptor blocking activity.
  • the new compounds show generally the same or higher activity as compared with Tibalosine and Phentolamine; MG 14167 and MG 14233 were comparable with Prazosin.
  • the receptors binding assay for the inhibition of 3 H-Prazosin, 3 H-Clonidine and 3 H-Spiperone binding to rat brain membrane was carried out according to Greenberg et al., Life Sci. 19, 69, 1976 and U'Prichard et al., Molec. Pharmacol. 13, 454, 1977.
  • a moderate affinity toward serotoninergic 2 (5-HT 2 ) receptors is displayed by MG 38069.
  • Platelet aggregation was stimulated with collagen (2-4 mcg/ml) added simultaneously to PRP of control and treated rats. The results were assessed photometrically. Each test was replicated 4 times in groups of 3 animals. Aggregation curves were evaluated in terms of two parameters namely maximum optical density variation (maximum aggregation) and aggregation rate.
  • Table 4 gives the effects recorded after treatment with some of the tested compounds. They show an activity comparable to Ticlopidine and Suloctidil and only slightly lower than Sulfinpyrazone.
  • Sprague Dawley Nos male rats (180-200 g) were treated orally for 4 consecutive days with vehicle (0.5 ml/100 g gum arabic 2.5%, controls) and with 1-3 doses of the tested compounds, and were sacrificed at the 5th day after 18 hrs fasting.
  • Total cholesterol (CHOL), triglycerides (TG), HDL cholesterol (CHOL-HDL) were assayed in serum and the liver was weighed.
  • MG 28451, MG 38065, MG 38068 and MG 28453 cause a significative decrease of serum TG and an increase of CHOL-HDL, and the other compounds are effective in decreasing both CHOL and serum TG.
  • MG 38127 and MG 38105 exert a good activity at very low doses.
  • the activity of the foregoing compounds is higher than with Clofibrate which, as known, causes a significative liver increase.
  • the Probucol activity is moderate and is noted only after prolonged treatment (8 days).
  • the anti-hypoxic activity was determined according to Yasuda et al., Arch. Int. Pharmacodyn. 222, 136, 1978.
  • mice Groups of 10 male mice (21-23 g) were treated orally with vehicle (controls) and the invention compounds. After 45 or 90 minutes the animals were decapitated and the gasping time was determined. Table 6 gives the results obtained after administration of some of the invention compounds which display an activity higher than Suloctidil.
  • the invention compounds also showed a very low acute toxicity per os in male mice.
  • the LD 50 was higher than 1000 mg/kg for MG 14233, MG 28451, MG 38068, MG 38088 and MG 38095, and higher than 2000 mg/kg for MG 14167, MG 14237, MG 14244, MG 38065, MG 38069 and MG 38078.
  • the filtered mother liquor is cooled on ice, 18 per cent hydrochloric acid is added to precipitate additional product as the hydrochloride which is collected, recrystallized from methanol/water and converted into the free base, which is combined with the first crop.
  • Example 2 The compound of Example 2 (8.7 g) is hydrogenated at room temperature in methanol in the presence of Pd/C as the catalyst. After filtering off the catalyst the solution is evaporated to dryness under reduced pressure.
  • ketone (10 g, 23.3 mmole) is dissolved in 200 ml of methanol, then 1.76 g of NaBH 4 (46.5 mmole) dissolved in 10 ml of alkaline water is dropped into the solution heated to reflux. At the end of the addition heating is continued for additional 5 hours, then the mixture is cooled to room temperature and 100 ml of water are added.
  • the filtrate is made acidic by the addition of aqueous 18% HCl and concentrated under reduced pressure.
  • the residue is treated with ethyl acetate and made alkaline with aqueous 5% sodium carbonate.
  • the organic layer is separated and evaporated to dryness under reduced pressure.
  • the erythro isomer was also obtained in a 55% yield by hydrogenating the intermediate propanone, MG 38094 (see above), in the presence of PtO 2 in an acetic acid-methanol mixture at 55° under a pressure of 3 atm. After purification through silicagel using chloroform:methanol 95:5 as the eluent; the erythro form was substantially pure and free from traces of the threo isomer formed during the hydrogenation.
  • 6-Propionyl-2-naphthol and 2-iodopropane give 1-(6-isopropoxy-2- -naphthyl)-1-propanone (m.p. 79-80°C) which is converted into the bromo derivative (MG 14226), m.p. 82-83°C.
  • Example 23 Prepared as in Example 23 starting from 6-acetyl-2-naphthol through the corresponding ethanone (MG 14222 m.p. 54-56°C).
  • the intermediate bromo ketone (MG 14224) has m.p. 91-93°C.
  • the end compound (MG 14237) has m.p. 217-219°C.
  • EXAMPLE 30 2-[ 4-(2-Oxo-3-indolinylidene)-1-piperidinyl]-1-(6-methoxy-2-naphthyl)- propanol.
  • Priority Country GB pean patent
  • GA O.API patent
  • GB European tent
  • HU IT
  • IT European patent
  • JP JP
  • KP KR
  • LU European patent
  • MC MG
  • ML OAPI pat
  • the compounds show anti-hypert sive, platelet aggregation inhibiting, hypolipemic, antianoxic, spasmolytic, antithrombotic, calcium antagonizing and n roleptic activity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Nouveaux aminoalcools bi-cycliques à substitution alkoxy et alkylthio de formule (I). Ces composés présentent une action anti-hypertensive, inhibant l'aggrégation des plaquettes hypolipémiques antianoxiques, spasmolytiques, antithrombotiques, antagonistes du calcium et neuroleptiques.
PCT/EP1986/000595 1985-10-31 1986-10-18 Aminoalcools bi-cycliques a substitution alkoxy et alkylthio Ceased WO1987002666A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
DK314187A DK314187A (da) 1985-10-31 1987-06-19 Bicycliske alkoxy- og alkylthio-substituerede aminoalkoholer
NO872702A NO872702L (no) 1985-10-31 1987-06-26 Bicykliske alkoksy- og alkyl-tio-substituerte aminoalkoholer.
KR870700558A KR870700609A (ko) 1985-10-31 1987-06-29 비사이클릭 알콕시 및 알킬티오-치환된 아미노알콜

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB8526913 1985-10-31
GB858526913A GB8526913D0 (en) 1985-10-31 1985-10-31 Amino-alcohols
GB868615561A GB8615561D0 (en) 1986-06-25 1986-06-25 Aminoalcohols
GB8615561 1986-06-25

Publications (2)

Publication Number Publication Date
WO1987002666A2 true WO1987002666A2 (fr) 1987-05-07
WO1987002666A3 WO1987002666A3 (fr) 1987-08-27

Family

ID=26289964

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1986/000595 Ceased WO1987002666A2 (fr) 1985-10-31 1986-10-18 Aminoalcools bi-cycliques a substitution alkoxy et alkylthio

Country Status (5)

Country Link
KR (1) KR870700609A (fr)
AU (1) AU6541686A (fr)
DK (1) DK314187A (fr)
GR (1) GR862624B (fr)
WO (1) WO1987002666A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003661A1 (fr) * 1995-07-24 1997-02-06 University Of Florida Research Foundation, Incorporated Utilisation de composes phenoliques polycycliques non ×strogeniques pour la fabrication d'un medicament visant a conferer une neuroprotection cellulaire
US5859001A (en) * 1996-01-11 1999-01-12 University Of Florida Research Foundation, Inc. Neuroprotective effects of polycyclic phenolic compounds
US6197833B1 (en) 1995-07-24 2001-03-06 Apollo Biopharmaceutics, Inc. Neuroprotective effects of polycyclic phenolic compounds

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1183847A (fr) * 1981-10-01 1985-03-12 Georges Van Daele N-(3-hydroxy-4-piperidinyl)benzamide; derives
JPS58180481A (ja) * 1982-04-15 1983-10-21 Kyowa Hakko Kogyo Co Ltd 新規なピペリジン誘導体
JPS60100542A (ja) * 1983-11-07 1985-06-04 Otsuka Pharmaceut Factory Inc １，４，５，８−テトラアルコキシナフタレン誘導体

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003661A1 (fr) * 1995-07-24 1997-02-06 University Of Florida Research Foundation, Incorporated Utilisation de composes phenoliques polycycliques non ×strogeniques pour la fabrication d'un medicament visant a conferer une neuroprotection cellulaire
US6197833B1 (en) 1995-07-24 2001-03-06 Apollo Biopharmaceutics, Inc. Neuroprotective effects of polycyclic phenolic compounds
US5859001A (en) * 1996-01-11 1999-01-12 University Of Florida Research Foundation, Inc. Neuroprotective effects of polycyclic phenolic compounds

Also Published As

Publication number Publication date
GR862624B (en) 1987-03-03
WO1987002666A3 (fr) 1987-08-27
AU6541686A (en) 1987-05-19
DK314187D0 (da) 1987-06-19
KR870700609A (ko) 1987-12-30
DK314187A (da) 1987-06-19

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