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WO1996032369A1 - Nouveaux composes aryloxypropanolamino(phenyl)propanol - Google Patents

Nouveaux composes aryloxypropanolamino(phenyl)propanol Download PDF

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Publication number
WO1996032369A1
WO1996032369A1 PCT/JP1996/001024 JP9601024W WO9632369A1 WO 1996032369 A1 WO1996032369 A1 WO 1996032369A1 JP 9601024 W JP9601024 W JP 9601024W WO 9632369 A1 WO9632369 A1 WO 9632369A1
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WO
WIPO (PCT)
Prior art keywords
group
substituted
atom
compound
formula
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/JP1996/001024
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English (en)
Japanese (ja)
Inventor
Norio Ohno
Kozo Hiratsuka
Noriko TAKENAWA
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.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Tokyo Tanabe Co Ltd
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
Application filed by Tokyo Tanabe Co Ltd filed Critical Tokyo Tanabe Co Ltd
Priority to AU52894/96A priority Critical patent/AU5289496A/en
Publication of WO1996032369A1 publication Critical patent/WO1996032369A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines

Definitions

  • the present invention relates to a novel aryloxypropanol amino (phenyl) propanol compound, a salt thereof, a production method thereof, an intermediate, and a pharmaceutical composition containing the same as an active ingredient.
  • x represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a lower alkyl group
  • R represents a hydrogen atom, an unsubstituted methyl group, or a methyl group substituted with a carboxyl group or an alkoxycarbonyl group.
  • the present inventors have conducted intensive studies to find a compound having higher intestinal motility regulating activity than a known fluorinylethanol aminotetraline compound. As a result, a compound that is essentially different from the known compound, aryloxypropanol amino (phenyl) propanol, is highly expressed in the intestinal tract. Intestinal motility regulating activity, disclosure of the invention
  • A is a CH or nitrogen atom
  • Z 2 represents a hydrogen atom, a halogen atom or a single OZ group
  • z 3 represents, as a substituent, -C) an alkoxy group or a carbonyl group which may be substituted with a hydroxyl group -c 4 ) alkyl Represents a group.
  • an aryloxypropanol amino (phenyl) propanol compound represented by the formula:
  • (C i - ⁇ ) alkyl refers to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. And represents a monovalent group of a saturated linear or branched hydrocarbon containing 1 to 4 carbon atoms.
  • (C i -c 4 ) alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy. And a straight-chain or branched alkoxy group having 1 to 4 carbon atoms.
  • halogen includes the four forms: fluor, black, bromo and iodo, with the first two being preferred.
  • salt of a compound of formula (I) refers to a pharmaceutically acceptable addition salt of an inorganic or organic acid, for example, hydrochloride, hydrobromide, sulfate, hydrogensulfate, phosphoric acid
  • an inorganic or organic acid for example, hydrochloride, hydrobromide, sulfate, hydrogensulfate, phosphoric acid
  • dihydrogen, citrate, maleate, dalconate, methanesulfonate, naphthalenesulfonate, toluenesulfonate, etc. as well as formulas such as picrates and oxalates
  • Acid addition salts which facilitate the separation or crystallization of the compound of (I), or acid addition salts of optically active acids such as camphorsulfonic acid salt, mandelic acid or substituted mandelic acid.
  • salt- refers to a salt with its inorganic base, preferably an alkali metal such as sodium or potassium and calcium.
  • alkali metal such as sodium or potassium and calcium.
  • alkaline earth metals such as magnesium or organic bases such as triethylamine, o
  • the preferred configuration of the chiral carbon of the aryloxypropanol amino moiety is the absolute configuration of (S).
  • X, ⁇ , ⁇ , ⁇ , Compounds of the formula (I) wherein Z j and z 2 are the same as above and the chiral sequence of the aryloxypropanolamino group has the absolute configuration of (S) are therefore preferred in the practice of the invention. It is an example.
  • A is CH
  • E gar CH CH-
  • X and Y is a hydrogen atom
  • gamma is a hydrogen atom
  • zeta 3 is to c 4) is substituted with a carbonyl group substituted by an alkoxy group or a hydroxyl group (c 1 ⁇ as a substituent.)
  • formula is an alkyl group
  • the compound of formula (I) can be prepared by treating a compound of formula (II) with a compound of formula (III).
  • Compound (II) has the general formula ( ⁇ )
  • A, E, X and Y are the same as above, and glycidol in an optically active or racemic mixture, in an ether or aromatic hydrocarbon solvent, preferably in tetrahydrofuran. It can be synthesized by the Mitsunobu reaction using triphenylphosphine and azodicarboxylic acid diester.
  • Some compounds of the formula (III) are readily available as commercial products, but the compounds of the formula (III) used in most of the present invention are not available.
  • the method for synthesizing the compound represented by the formula (III) is described below.
  • the protected compound at the ⁇ -terminal and the C-terminal of tyrosine or its derivative in an optically active or racemic mixture is used as a starting material.
  • ⁇ Carbomate derivatives are preferred as terminal protecting groups, such as benzyloxycarbonyl group, methoxy or nitrobenzene.
  • T-alkoxycarbonyl groups such as benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (BOC) or tert-amiloquinecarbonyl (AOC), which have substituents such as oxycarbonyl; Any of the known groups that can be removed by catalytic hydrogenation or mild acid hydrolysis, but in particular the BOC group is preferred.
  • C-terminal protecting group -C 4) lower alkyl groups are preferred. It is not necessary to protect phenolic hydroxyl groups.
  • the N-terminal and C-terminal protected tyrosine or its derivative obtained here is reduced with lithium borohydride in an ether-based or aromatic hydrocarbon-based solvent, preferably in tetrahedral furan, Alcohol and body.
  • O-alkylation of the alcohol represented by the formula [I] can be achieved by known alkylation.
  • a reaction reagent D-Z 3 D show a good leaving group
  • a basic condensation agent, ⁇ alkyl payment de i.e. Kurori de, Aiodi de or preferably pro Mi de It is performed by.
  • the 0-alkylation reaction is carried out using a polar, non-protonic solvent, for example, esters such as acetone, ethyl acetate, and ethers such as tetrahydrofuran dioxane, but using acetone.
  • esters such as acetone, ethyl acetate, and ethers such as tetrahydrofuran dioxane, but using acetone.
  • Alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, or tertiary aliphatic amines, such as triethylamine, can be used as the basic condensing agent. .
  • Z represents one OZn group
  • Z 3 is the same as above.
  • the protecting group G of the compound represented by the formula is removed. This can be achieved by catalytic hydrogenation or mild acid hydrolysis according to well-known literature methods, especially when the BOC group is an organic solvent containing trifluoroacetic acid or hydrogen chloride, such as hydrogen chloride-ethyl acetate solution or hydrogen chloride monoalcohol.
  • the benzyloxycarbonyl group and the substituted benzyloxycarbonyl group are removed under catalytic conditions by the action of a solution, preferably by catalytic hydrogenation using palladium carbon as a catalyst.
  • the compound ( ⁇ ) is obtained as a free form.
  • the compound of formula (I) may be prepared by known methods, preferably as described above, such as picric acid, oxalic acid or an optically active acid such as mandelic acid, substituted mandelic acid or camphorsulfonic acid.
  • the free base is regenerated by neutralization and converted to other acid addition salts, or
  • an alkali or Al as the metal salt typically sodium or calcium salt Can be converted to one of the earth metal salts.
  • Each of the two sets of enantiomers is then typically separated into the pure isomers by salt formation of the diastereomers, chromatography on chiral columns or any other suitable technique.
  • the compounds of formula (I) and their salts have very interesting pharmacological properties, as evidenced by their activity as intestinal motility modulating agents. In particular, the effect of these compounds in reducing colonic automotility was confirmed in in vitro pharmacological studies.
  • Nonfasted male rats weighing 250-300 g were used as test animals.
  • the colon (about 3 cm below the cecum) was excised and cut into strips to make specimens.
  • test drug is added cumulatively in the organic bath at 10-minute intervals, Using the area under curve (AUC) for 10 minutes as an index, the effective concentration (EC 5 () ) for reducing the contractile activity observed in the control group by 50% was determined.
  • Example 3 of the present invention was identified as a positive control compound [(R, S) -2-[[2- (3-chlorophenyl) 1-2] as a compound described in European Patent No. 211,721.
  • Table 1 shows the results.
  • the present invention relates to, as another embodiment, a gut motility disorder containing one or more of the compounds represented by the formula (I) and pharmaceutically acceptable salts thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition effective for the treatment of
  • a pharmaceutical composition according to the present invention suitable for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration
  • the above-mentioned active ingredient may be a known pharmaceutical composition.
  • a unit dosage form as a mixture with a carrier.
  • Suitable unit dosage forms include tablets, capsules, powders, granules and other oral forms, solutions and suspensions for oral administration, sublingual and salivary gland forms, subcutaneous, muscle, intravenous, There is a rectal form.
  • the daily dose of the active ingredient is in the range from 0.01 to 100 mg / kg body weight.
  • Each unit dosage form can contain from 0.1 to 500 mg of the active ingredient in admixture with a suitable pharmaceutical carrier. This unit dosage form can be administered one to four times a day.
  • the principal active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. Tablets may be coated with saccharose or other suitable material, and their activity may be sustained for a long period of time, or their onset of activity may be delayed to release a predetermined amount of active ingredient continuously May be processed.
  • a capsule form is obtained by mixing the active ingredient with a diluent and a lubricant and filling the mixture in a hard or hard capsule.
  • Liquid compositions for administration by syrup or elixir or drops may contain the active ingredient together with non-nutritive sweeteners and preservatives such as methylparaben, propylparaben, as well as flavoring and suitable coloring agents.
  • the water-dispersible powder or granules may contain a compounding agent such as a dispersing agent or a wetting agent or a suspending agent such as polyvinylpyrrolidone in the active ingredient, or may contain a sweetener or a flavoring agent. Is also good.
  • suppositories are prepared using a binder that melts at intestinal temperature, such as cocoa butter, polyethylene glycol, and the like.
  • aqueous suspensions, isotonic saline solutions, or sterile injectable solutions are used. These include pharmaceutically acceptable dispersing and wetting agents, for example, propylene glycol, butylene glycol.
  • the active ingredient if necessary, may be formulated in microencapsulated or microemulsioned form, together with one or more supporters or additives.
  • the main active ingredient of the formula (I) can be used as a free base or a pharmaceutically acceptable salt thereof, as it is, or as a complex with, for example, dextran, or other active ingredients such as tranquilizers. May be administered in combination with or at the same time as these.
  • -NMR indicates a proton nuclear magnetic resonance spectrum, which was expressed as a chemical shift value from a standard substance TMS (tetramethylsilane) at 5 ppm.
  • TMS tetramethylsilane
  • the parentheses following i H-NMR indicate the measurement solvent, and s in parentheses of 5 ppm or less s indicates a singlet, d indicates a doublet, t indicates a triplet, q indicates a quartet, m indicates a multiplet, br indicates a broad absorber, and J indicates a spin coupling constant (unit: Hz).
  • the desired (2S) -glycidyl aryl ether can be obtained in a yield of 30 to 90% from the fraction eluted with benzene or a mixture of benzene monoethyl acetate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés ayant la formule générale (I) et leurs sels. Ces composés ont un effet régulateur sur la motilité intestinale. L'invention concerne également un procédé pour produire ces composés, leurs intermédiaires ainsi que des compositions médicales contenant ces composés en tant qu'ingrédients actifs. Comme exemple typique de ces composés, on peut citer le (S,S)-4-[2-[(3-phénoxy-2-hydroxy)propyl]amino-3-hydroxy]propylphénoxyacétate d'éthyle.
PCT/JP1996/001024 1995-04-14 1996-04-12 Nouveaux composes aryloxypropanolamino(phenyl)propanol Ceased WO1996032369A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52894/96A AU5289496A (en) 1995-04-14 1996-04-12 Novel aryloxypropanolamino(phenyl)propanol compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/89706 1995-04-14
JP8970695 1995-04-14

Publications (1)

Publication Number Publication Date
WO1996032369A1 true WO1996032369A1 (fr) 1996-10-17

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AU (1) AU5289496A (fr)
WO (1) WO1996032369A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062705A3 (fr) * 2000-02-28 2003-01-16 Fujisawa Pharmaceutical Co Derive d'aminoalcool

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0710827A (ja) * 1993-02-09 1995-01-13 Merck & Co Inc 糖尿病及び肥満の治療のための選択的β３作働薬としての置換フェニルスルホンアミド
WO1995004047A1 (fr) * 1993-07-31 1995-02-09 Smithkline Beecham Plc Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0710827A (ja) * 1993-02-09 1995-01-13 Merck & Co Inc 糖尿病及び肥満の治療のための選択的β３作働薬としての置換フェニルスルホンアミド
WO1995004047A1 (fr) * 1993-07-31 1995-02-09 Smithkline Beecham Plc Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIOORG. MED. CHEM., 3(7), (1995), OLLMANN IAN R. et al., pages 969-995. *
COLLECT. CZECH. CHEM. COMMUN., 33(12), (1968), FRIC IVO et al., pages 4008-4026. *
JAPANESE JOURNAL OF CLINICAL PHARMACOLOGY, 20(3), (September 1989), KOUICHI SUGIMOTO et al., p. 551-564. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062705A3 (fr) * 2000-02-28 2003-01-16 Fujisawa Pharmaceutical Co Derive d'aminoalcool

Also Published As

Publication number Publication date
AU5289496A (en) 1996-10-30

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