EP1397327A2 - DEUTERATED N-SUBSTITUTED AND $g(a)-SUBSTITUTED DIPHENYLALKOXY ACETIC ACID AMINO ALKYL ESTERS AND MEDICAMENTS CONTAINING THESE COMPOUNDS - Google Patents

DEUTERATED N-SUBSTITUTED AND $g(a)-SUBSTITUTED DIPHENYLALKOXY ACETIC ACID AMINO ALKYL ESTERS AND MEDICAMENTS CONTAINING THESE COMPOUNDS

Info

Publication number
EP1397327A2
EP1397327A2 EP02752970A EP02752970A EP1397327A2 EP 1397327 A2 EP1397327 A2 EP 1397327A2 EP 02752970 A EP02752970 A EP 02752970A EP 02752970 A EP02752970 A EP 02752970A EP 1397327 A2 EP1397327 A2 EP 1397327A2
Authority
EP
European Patent Office
Prior art keywords
acetic acid
ester
diphenyl
perdeuteropropyloxy
piperidinyl
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.)
Withdrawn
Application number
EP02752970A
Other languages
German (de)
French (fr)
Inventor
Rudolf-Giesbert Alken
Johann Roither
Wolf-Dietrich Hübner
Werner Hrachowina
Thomas Stabingis
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.)
Turicum Drug Development AG
Original Assignee
Turicum Drug Development AG
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 Turicum Drug Development AG filed Critical Turicum Drug Development AG
Publication of EP1397327A2 publication Critical patent/EP1397327A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/145555—Hetero-N

Definitions

  • the invention relates to deuterated N- and ⁇ -substituted Diphenylalkoxyessigklaklarea inoalkylester and medicaments containing these compounds.
  • Diphenylalkoxyacetic acid amino alkyl ester is propiverin (DD 106643, DD 139212 and DE 2937489). This compound is used to treat detrusor hyperactivity.
  • the object of the present invention is to provide N- and ⁇ -substituted diphenylalkoxyacetic acid aminoalkyl esters which have improved pharmokinetic and / or pharmacodynamic properties compared to the already known compounds.
  • the object is therefore achieved by providing deuterated N- and ⁇ -substituted diphenylalkoxyacetic acid aminoalkyl esters of the general formula I.
  • Ri represents hydrogen, deuterium, an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical
  • R 2 is oxygen, a methyl group or a mono-, di- or trideuteromethyl group and
  • R 3 are, independently of one another, H or deuterium, at least one of the radicals R 1, R 2 or R 3 being, independently of one another, deuterium or containing deuterium, and their physiologically tolerable salts.
  • Ri represents an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical
  • R 2 is a methyl group or a mono-, di- or trideuteromethyl group
  • R 3 are, independently of one another, H or deuterium, at least one of the radicals R 1, R 2 or R 3 being, independently of one another, deuterium or containing deuterium, and their physiologically tolerable salts.
  • R 1 is an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical
  • R 2 is oxygen
  • R 3 is independently H or deuterium, wherein at least one of the radicals R lr R 2 and R 3 are independently deuterium or contains deuterium, as well as their physiologically acceptable salts.
  • N- and ⁇ -substituted diphenylalkoxyacetic acid aminoalkyl esters are particularly preferred:
  • deuterated N- and ⁇ -substituted diphenylalkoxyacetic acid aminoalkyl esters and their physiologically used salts for the production of medicaments for Treatment of hypertonic functional states in the urinary bladder.
  • compositions which contain the deuterated N- and ⁇ -substituted diphenylalkoxyacetic acid aminoalkyl esters and their physiologically tolerable salts for the treatment of hypertonic functional states of the bladder in addition to pharmaceutically acceptable auxiliaries and / or additives.
  • the present invention furthermore relates to pharmaceutical compositions for percutaneous and / or transdermal application of interpreted N- and ⁇ -substituted diphenylalkoxyacetic acid aminoalkyl esters and their physiologically tolerable salts
  • N- and ⁇ -substituted diphenylalkoxyacetic acid aminoalkyl esters are known per se and can be carried out as described in DD 106643.
  • methyl benzilate is transesterified in the presence of a catalytically active strong base with an N-substituted aminol alcohol with simultaneous azeotropic removal of methanol and converted into the ⁇ -chloro compound by reaction with thionyl chloride.
  • the halogen compound is reacted with an alcohol, water or D 2 0 and, after a reaction time of up to 10 hours, gives the desired N- and ⁇ -substituted aminoalkyl diphenylalkoxyacetate in the form of its acid chloride.
  • Typical physiologically compatible inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid.
  • Other acids that can be used are described, for example, in Progress in Pharmaceutical Research, vol. 10, pages 224-225, Birkhauser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977).
  • the acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone such as Acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition.
  • physiologically compatible aqueous solutions of acid addition salts of the compounds used according to the invention can be prepared in an aqueous acid solution.
  • the acid addition salts of the compounds according to the invention can be carried out in a manner known per se, e.g. B. with alkalis or ion exchangers, are converted into the free base.
  • the free base can be reacted with Chen, which are suitable for the formation of therapeutically usable salts, win further salts.
  • These or other salts of the new compound, such as. B. the picrate can also be used to purify the free base by converting the free base into a salt, separating this and in turn releasing the base from the salt.
  • the present invention also relates to pharmaceuticals for oral, rectal, subcutaneous, intravenous or intramuscular application which, in addition to conventional carriers and diluents, contain a compound of the general formula I or its acid addition salt as active ingredient.
  • the medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage.
  • the preferred preparations are in a dosage form which is suitable for oral administration.
  • dosage forms are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.
  • parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • auxiliaries for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the active ingredient used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
  • Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
  • the preparation of the pharmaceuticals according to the invention for percutaneous application is known to the person skilled in the art.
  • the auxiliary agents known per se are The preparation of the pharmaceutical preparations according to the invention and is described in the manuals known to the person skilled in the art, for example Hager's Handbuch (5.) 2, 622-1045; List et al. , Drug form theory, Stuttgart: Wiss. Verlagsges. , 1985; Sucker et al., Pharmaceutical Technology, Stuttgart: Thieme 1991; Ulimann's Encyclopedia (5th) A 19, 241-271; Voigt, Pharmaceutical Technology, Berlin: Ullstein Mosby 1995.
  • the pharmaceuticals thus produced can be used to treat hypertensive functional states in the urinary bladder.
  • Symptoms include uncontrolled urine leakage (enuresis), pathological urination (urge incontinence) and painful bladder cramps (tenesmen).
  • the compounds according to the invention have a number of advantages over the compounds known in the prior art which do not have deuterium.
  • the deuteration changes the metabolism in the organism.
  • the hydroxylation on the phenyl radical is made more difficult, which leads to a reduced first-pass effect. This makes it possible to change the dosage and create longer-lasting preparations, which can also improve compliance in the form of depot preparations.
  • the pharmacodynamics have also changed because the deuterated compounds form completely different hydration shells, so that the distribution in the organism differs significantly from that of the undeuterated compounds. This makes it possible to develop completely new forms of preparation.
  • activated carbon is added and the solution is filtered hot. The solution is then cooled and the product filtered and washed with a little n-propanol and dried.
  • Additional product is obtained from the mother liquor by adding n-hexane and is recrystallized from a small amount of n-propanol with a little activated carbon.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to deuterated N-substituted α,α-diphenyl-α-alkoxy acetic acid amino alkyl esters and to their physiologically compatible salts. The invention also relates to the use of deuterated N-substituted α,α-diphenyl-α-alkoxy acetic acid amino alkyl esters for treating hypertonic functional states in the area of the urinary bladder and for producing medicaments used in the treatment of hypertonic functional states in the area of the urinary bladder. The invention additionally relates to pharmaceutical preparations containing N-substituted α,α-diphenyl-α-alkoxy acetic acid amino alkyl esters and to the physiologically compatible salts thereof for treating hypertonic functional states in the area of the urinary bladder in addition to pharmaceutically compatible adjuvants and/or additives.

Description

Deuterierte N- und α-substituierte Diphenyl- alkoxyessigsäureaminoalkylester sowie diese Verbindungen enthaltende Arzneimittel Deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters and medicaments containing these compounds
Die Erfindung betrifft deuterierte N- und α-substituierte Diphenylalkoxyessigsäurea inoalkylester sowie diese Verbindungen enthaltende Arzneimittel.The invention relates to deuterated N- and α-substituted Diphenylalkoxyessigsäurea inoalkylester and medicaments containing these compounds.
Ein bekannter Vertreter der N- und α-substituiertenA well-known representative of the N- and α-substituted
Diphenylalkoxyessigsäureaminoalkylester ist das Propive- rin (DD 106643, DD 139212 und DE 2937489) . Diese Verbindung wird zur Behandlung von Detrusorhyperaktivität eingesetzt .Diphenylalkoxyacetic acid amino alkyl ester is propiverin (DD 106643, DD 139212 and DE 2937489). This compound is used to treat detrusor hyperactivity.
Aufgabe der vorliegenden Erfindung ist es, N- und α- substituierte Diphenylalkoxyessigsäureaminoalkylester bereitzustellen, die gegenüber den bereits bekannten Verbindungen verbesserte pharmokinetische und/oder pharmako- dynamische Eigenschaften aufweisen.The object of the present invention is to provide N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters which have improved pharmokinetic and / or pharmacodynamic properties compared to the already known compounds.
Überraschenderweise wurde nun gefunden, dass die erfindungsgemäßen deuterierten N- und α-substituierten Diphe- nylalkoxyessigsäureaminoalkylester wesentlich bessere pharmokinetische und/oder pharmakodynamische Eigenschaften aufweisen als die undeuterierten Verbindungen.Surprisingly, it has now been found that the deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters have significantly better pharmokinetic and / or pharmacodynamic properties than the undeuterated compounds.
Erfindungsgemäß wird die Aufgabe also gelöst durch die Bereitstellung deuterierter N- und α-substituierter Diphenylalkoxyessigsäureaminoalkylester der allgemeinen Formel I According to the invention, the object is therefore achieved by providing deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters of the general formula I.
worinwherein
Ri Wasserstoff, Deuterium, einen n-Propylrest oder einen einfach, mehrfach oder einen perdeuterierten n-Propylrest darstellt,Ri represents hydrogen, deuterium, an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical,
R2 Sauerstoff, eine Methylgruppe oder eine Mono-, Di- o- der Trideuteromethylgruppe ist undR 2 is oxygen, a methyl group or a mono-, di- or trideuteromethyl group and
R3 unabhängig voneinander H oder Deuterium sind, wobei mindestens einer der Reste Ri, R2 oder R3 unabhängig voneinander Deuterium ist oder Deuterium enthält, sowie deren physiologisch verträgliche Salze.R 3 are, independently of one another, H or deuterium, at least one of the radicals R 1, R 2 or R 3 being, independently of one another, deuterium or containing deuterium, and their physiologically tolerable salts.
Besonders bevorzugt sind dabei erfindungsgemäße deute- rierte N- und α-substituierte Diphenylalkoxyessigsäurea- minoalkylester worinParticularly preferred here are interpreted N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters in which
Ri einen n-Propylrest oder einen einfach, mehrfach oder einen perdeuterierten n-Propylrest darstellt, R2 eine Methylgruppe oder eine Mono-, Di- oder Trideuteromethylgruppe ist undRi represents an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical, R 2 is a methyl group or a mono-, di- or trideuteromethyl group and
R3 unabhängig voneinander H oder Deuterium sind, wobei mindestens einer der Reste Ri, R2 oder R3 unabhängig voneinander Deuterium ist oder Deuterium enthält, sowie deren physiologisch verträgliche Salze. Weiterhin sind besonders bevorzugt erfindungsgemäße deuterierte N- und α-substituierte Diphenylalkoxyessigsäu- reaminoalkylester, worin Ri einen n-Propylrest oder einen einfach, mehrfach oder einen perdeuterierten n-Propylrest darstellt, R2 Sauerstoff ist,R 3 are, independently of one another, H or deuterium, at least one of the radicals R 1, R 2 or R 3 being, independently of one another, deuterium or containing deuterium, and their physiologically tolerable salts. Furthermore, particularly preferred are deuterated N- and α-substituted diphenylalkoxyacetic acid amino alkyl esters according to the invention, in which R 1 is an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical, R 2 is oxygen,
R3 unabhängig voneinander H oder Deuterium sind, wobei mindestens einer der Reste Rl r R2 oder R3 unabhängig von- einander Deuterium ist oder Deuterium enthält, sowie deren physiologisch verträgliche Salze.R 3 is independently H or deuterium, wherein at least one of the radicals R lr R 2 and R 3 are independently deuterium or contains deuterium, as well as their physiologically acceptable salts.
Erfindungsgemäß besonders bevorzugt sind folgende erfindungsgemäß deuterierte N- und α-substituierte Diphenylal- koxyessigsäureaminoalkylester:According to the invention, the following N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters are particularly preferred:
2, 2-Diphenyl-2- (d-hydroxy) essigsaure- (N-methyl-4- piperidinyl) -ester,2,2-diphenyl-2- (d-hydroxy) acetic acid (N-methyl-4-piperidinyl) ester,
2, 2-Diphenyl-2-hydroxyessigsäure- (N-trideuteromethyl-4- piperidinyl) -ester,2,2-diphenyl-2-hydroxyacetic acid (N-trideuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (d-hydroxy) essigs ure- (N-oxido-4- piperidinyl) -ester,2,2-diphenyl-2- (d-hydroxy) acetic acid (N-oxido-4-piperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2- (d-hydroxy) essigsaure- (N- trideuteromethyl-4-perdeuteropiperidinyl) ester,2,2-bis (pentadeuterophenyl) -2- (d-hydroxy) acetic acid (N-trideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2-hydroxyessigsäure- (N- trideuteromethyl-4-perdeuteropiperidinyl) ester,2,2-bis (pentadeuterophenyl) -2-hydroxyacetic acid (N-trideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) essigsaure- (N-oxido-4- perdeuteropiperidinyl) ester, 2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N-methyl- 4-piperidinyl) ester,2,2-bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) acetic acid (N-oxido-4-perdeuteropiperidinyl) ester, 2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-methyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- trideuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-trideuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- monodeuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-monodeuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- dideuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-dideuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N-oxido- 4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-oxido-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3, 3, 3-trideuteropropyloxy) essigsaure- (N- methyl-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-methyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3, 3, 3-trideuteropropyloxy) essigsaure- (N- trideuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-trideuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsaure- (N- monodeuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-monodeuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsaure- (N- dideuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-dideuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsaure- (N- oxido-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-oxido-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N-methyl- 4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-methyl-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- -,-^ ^o,.,.,.^^^^-! -4-DercieuteroDiperidinyl) ester, 2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- monodeuteromethyl-4-perdeuteropiperidinyl) ester,2,2-Diphenyl-2- (perdeuteropropyloxy) acetic acid- (N- -, - ^ ^ o, . , . , . ^^^^ -! -4- Derc ieutero D iperidinyl) ester, 2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-monodeuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- dideuteromethyl-4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-dideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N-oxido- 4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-oxido-4-perdeuteropiperidinyl) ester,
2,2-Bis (pentadeuterophenyl) -2-2,2-bis (pentadeuterophenyl) -2-
(perdeuteropropyloxy) essigsaure- (N-trideuteromethyl-4- perdeuteropiperidinyl) ester,(perdeuteropropyloxy) acetic acid (N-trideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) essigsaure- (N-oxido-4- perdeuteropiperidinyl) -ester,2,2-bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) acetic acid (N-oxido-4-perdeuteropiperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) essigsaure- (N-methyl-4- piperidinyl) ester und2,2-bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) acetic acid- (N-methyl-4-piperidinyl) ester and
2, 2-Bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) essigsaure- (N-oxido-4- piperidinyl) ester.2,2-bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) acetic acid- (N-oxido-4-piperidinyl) ester.
Bevorzugt ist die Verwendung der erfindungsgemäßen deute- rierten N- und α-substituierten Diphenylalkoxyessigsäu- reaminoalkylester sowie deren physiologisch verträgliche Salze, zur Behandlung hypertoner Funktionszustände im Be- reich der Harnblase.Preference is given to using the interpreted N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters and their physiologically tolerable salts for the treatment of hypertonic functional states in the urinary bladder.
Besonders bevorzugt ist die Verwendung der erfindungsgemäßen deuterierten N- und α-substituierten Diphenylalko- xyessigsäureaminoalkylester sowie deren physiologisch ve»τ"r-rärrl i ehe Salze, zur Herstellung von Arzneimitteln zur Behandlung hypertoner Funktionszustände im Bereich der Harnblase.It is particularly preferred to use the deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters and their physiologically used salts for the production of medicaments for Treatment of hypertonic functional states in the urinary bladder.
Insbesondere bevorzugt sind pharmazeutische Zusammenset- zungen, welche die erfindungsgemäßen deuterierten N- und α-substituierten Diphenylalkoxyessigsäureaminoalkylester sowie deren physiologisch verträgliche Salze zur Behandlung hypertoner Funktionszustände der Harnblase neben pharmazeutisch verträglichen Hilfs- und/oder Zusatzstof- fen enthalten.Particular preference is given to pharmaceutical compositions which contain the deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters and their physiologically tolerable salts for the treatment of hypertonic functional states of the bladder in addition to pharmaceutically acceptable auxiliaries and / or additives.
Ein weiterer Gegenstand der vorliegenden Erfindung sind pharmazeutische Zusammensetzungen zur percutanen und/oder transdermalen Applikation von erfindungsgemäßen deute- rierten N- und α-substituierten Diphenylalkoxyessigsäu- reaminoalkylestern sowie deren physiologisch verträgliche SalzeThe present invention furthermore relates to pharmaceutical compositions for percutaneous and / or transdermal application of interpreted N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters and their physiologically tolerable salts
Die Herstellung der erfindungsgemäßen N- und α- substituierten Diphenylalkoxyessigsäureaminoalkylester ist an sich bekannt und kann wie in DD 106643 beschrieben erfolgen.The production of the N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters is known per se and can be carried out as described in DD 106643.
Dazu wird Benzilsäuremethylester in Gegenwart einer kata- lytisch wirkenden starken Base mit einem N-substituierten Aminolkohol unter gleichzeitiger azeotroper Entfernung von Methanol umgeestert und durch Reaktion mit Thionylch- lorid in die α-Chlorverbindung überführt. Die Halogenverbindung wird mit einem Alkohol Wasser oder D20 zur Reak- tion gebracht und ergibt nach einer Reaktionszeit von bis zu 10 Stunden den gewünschten N- und α-substituierten Diphenylalkoxyessigsäureaminoalkylester in Form seines Säurechlorids .For this purpose, methyl benzilate is transesterified in the presence of a catalytically active strong base with an N-substituted aminol alcohol with simultaneous azeotropic removal of methanol and converted into the α-chloro compound by reaction with thionyl chloride. The halogen compound is reacted with an alcohol, water or D 2 0 and, after a reaction time of up to 10 hours, gives the desired N- and α-substituted aminoalkyl diphenylalkoxyacetate in the form of its acid chloride.
So erfolgt die Herstellung der deuterierten Verbindungen gangsstoffe wie d-Benzilsäuremethylester, deuterierten N- substituierten Aminoal ohlen oder wie in Ausführungsbei- spiel 1 beschrieben durch die Umsetzung der α- Chlorverbindung mit deuteriertem Alkohol.This is how the deuterated compounds are produced Starting materials such as methyl d-benzilate, deuterated N-substituted aminoal or as described in Example 1 by reacting the α-chloro compound with deuterated alcohol.
Übliche physiologisch verträgliche anorganische und organische Säuren sind beispielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Schwefelsäure, Oxalsäure, Maleinsäure, Fumarsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Salicylsäure, Adipinsäure und Benzoesäure. Weitere verwendbare Säuren sind beispielweise in Fortschritte der Arzneimittelforschung, Bd. 10, Seiten 224- 225, Birkhäuser Verlag, Basel und Stuttgart, 1966, und Journal of Pharmaceutical Sciences, Bd. 66, Seiten 1-5 (1977) beschrieben.Typical physiologically compatible inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other acids that can be used are described, for example, in Progress in Pharmaceutical Research, vol. 10, pages 224-225, Birkhauser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977).
Die Säureadditionssalze werden in der Regel in an sich bekannter Weise durch Mischen der freien Base oder deren Lösungen mit der entsprechenden Säure oder deren Lösungen in einem organischen Lösungsmittel, beispielsweise einem niederen Alkohol wie Methanol, Ethanol, n-Propanol oder Isopropanol oder einem niederen Keton wie Aceton, Methyl- ethylketon oder Methyl-isobutylketon oder einem Ether wie Diethylether, Tetrahydrofuran oder Dioxan, erhalten. Zur besseren Kristallabscheidung können auch Mischungen der genannten Lösungsmittel verwendet werden. Darüber hinaus können physiologisch verträgliche wässrige Lösungen von Säureadditionssalzen der erfindungsgemäß verwendeten Verbindungen in einer wässrigen Säurelösung hergestellt wer- den.The acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone such as Acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition. In addition, physiologically compatible aqueous solutions of acid addition salts of the compounds used according to the invention can be prepared in an aqueous acid solution.
Die Säureadditionssalze der erfindungsgemäßen Verbindungen können in an sich bekannter Weise, z. B. mit Alkalien oder Ionenaustauschern, in die freie Base überführt wer- den. Von der freien Base lassen sich durch Umsetzung mit chen, die zur Bildung von therapeutisch verwendbaren Salzen geeignet sind, weitere Salze gewinnen. Diese oder auch andere Salze der neuen Verbindung, wie z. B. das Pikrat, können auch zur Reinigung der freien Base dienen, indem man die freie Base in ein Salz überführt, dieses abtrennt und aus dem Salz wiederum die Base freisetzt.The acid addition salts of the compounds according to the invention can be carried out in a manner known per se, e.g. B. with alkalis or ion exchangers, are converted into the free base. The free base can be reacted with Chen, which are suitable for the formation of therapeutically usable salts, win further salts. These or other salts of the new compound, such as. B. the picrate, can also be used to purify the free base by converting the free base into a salt, separating this and in turn releasing the base from the salt.
Gegenstand der vorliegenden Erfindung sind auch Arzneimittel zur oralen, rektalen, subcutanen, intravenösen o- der intramuskulären Applikation, die neben üblichen Träger- und Verdünnungsmitteln eine Verbindung der allgemeinen Formel I oder deren Säureadditionssalz als Wirkstoff enthalten.The present invention also relates to pharmaceuticals for oral, rectal, subcutaneous, intravenous or intramuscular application which, in addition to conventional carriers and diluents, contain a compound of the general formula I or its acid addition salt as active ingredient.
Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Trägerstoffen oder Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutisch- technischen Hilfsstoffen entsprechend der gewünschten Applikationsart mit einer geeigneten Dosierung in bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in einer Darreichungsform, die zur oralen Applikation geeignet ist. Solche Darreichungsformen sind beispielsweise Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösungen oder Suspensionen oder Depotformen.The medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. The preferred preparations are in a dosage form which is suitable for oral administration. Such dosage forms are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.
Selbstverständlich kommen auch parenterale Zubereitungen wie Injektionslösungen in Betracht. Weiterhin seien als Zubereitungen beispielsweise auch Suppositorien genannt.Of course, parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations.
Entsprechende Tabletten können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln wie Dextrose, Zucker, Sorbit, Mannit, Polyvinylpyrrolidon, Sprengmitteln wie Maisstärke oder Alginsäure, Bindemitteln wie Stärke oder Gelantine, Gleitmitteln wie Magnesiumstearat oder wie Carboxylpolymethylen, Carboxylmethylcellulose, Cellu- loseacetatphthalat oder Polyvinylacetat, erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Poly- vinylpyrrolidon oder Schellack, Gummiarabicum, Talk, Ti- tandioxid oder Zucker, hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
Lösungen oder Suspensionen mit dem erfindungsgemäß verwendeten Wirkstoff können zusätzlich geschmacksverbessernde Mittel wie Saccharin, Cyclamat oder Zucker sowie z. B. Aromastoffe wie Vanillin oder Orangenextrakt enthalten. Sie können außerdem Suspendierhilfsstoffe wie Natriumcarboxymethylcellulose oder Konservierungsstoffe wie p-Hydroxybenzoate enthalten. Wirkstoffe enthaltende Kapseln können beispielsweise hergestellt werden, indem man den Wirkstoff mit einem inerten Träger wie Milchzucker oder Sorbit mischt und in Gelatinekapseln einkap- seit.Solutions or suspensions with the active ingredient used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z. B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
Geeignete Suppositorien lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln wie Neutralfetten oder Polyäthylenglykol bzw. deren Derivaten herstellen.Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
Die Herstellung der erfindungsgemäßen Arzneimittel zur percutanen Application ist dem Fachmann bekannt. Bei der Herstellung der erfindungsgemäßen Arzneimittel zur trans- dermalen Applikation werden die an sich bekannten Hilfs- Die Herstellung der erfindungsgemäßen pharmazeutischen Zubereitungen ist an sich bekannt und in den dem Fachmann bekannten Handbüchern beschrieben, beispielsweise Hager' s Handbuch (5.) 2, 622-1045; List et al . , Arzneiformenlehre, Stuttgart: Wiss. Verlagsges. 1985; Sucker et al., Pharmazeutische Technologie, Stuttgart: Thieme 1991; Ulimann' s Enzyklopädie (5.) A 19, 241-271; Voigt, Pharmazeutische Technologie, Berlin: Ullstein Mosby 1995.The preparation of the pharmaceuticals according to the invention for percutaneous application is known to the person skilled in the art. In the manufacture of the pharmaceuticals according to the invention for transdermal application, the auxiliary agents known per se are The preparation of the pharmaceutical preparations according to the invention is known per se and is described in the manuals known to the person skilled in the art, for example Hager's Handbuch (5.) 2, 622-1045; List et al. , Drug form theory, Stuttgart: Wiss. Verlagsges. , 1985; Sucker et al., Pharmaceutical Technology, Stuttgart: Thieme 1991; Ulimann's Encyclopedia (5th) A 19, 241-271; Voigt, Pharmaceutical Technology, Berlin: Ullstein Mosby 1995.
Die so hergestellten Arzneimittel können zur Behandlung hypertoner Funktionszustände im Bereich der Harnblase. Zu den Symptomen zählen hierbei unkontrollierter Urinabgang (Enuresis) , krankhaft häufiges Wasserlassen (Urge- Inkontinenz) und schmerhafte Blasenkrämpfe (Tenesmen) .The pharmaceuticals thus produced can be used to treat hypertensive functional states in the urinary bladder. Symptoms include uncontrolled urine leakage (enuresis), pathological urination (urge incontinence) and painful bladder cramps (tenesmen).
Die erfindungsgemäßen Verbindungen weisen gegenüber den im Stand der Technik bekannten Verbindungen, welche kein Deuterium tragen eine Reihe von Vorteilen auf. Durch die Deuterierung wird zum einen die Metabolisierung im Organismus verändert. Insbesondere wird die Hydroxylierung am Phenylrest erschwert, was zu einem verminderten First- pass-Effekt führt. Hierdurch ist es möglich, die Dosierung zu verändern und länger wirkende Zubereitungen zu cshaffen, welche auch in Form von Depotzubereitungen die Compliance verbessern können.The compounds according to the invention have a number of advantages over the compounds known in the prior art which do not have deuterium. On the one hand, the deuteration changes the metabolism in the organism. In particular, the hydroxylation on the phenyl radical is made more difficult, which leads to a reduced first-pass effect. This makes it possible to change the dosage and create longer-lasting preparations, which can also improve compliance in the form of depot preparations.
Daneben ist auch die Pharmakodynamik verändert, weil die deuterierten Verbindungen völlig andere Hydrathüllen aus- bilden, so dass die Verteilung im Organismus sich von der der undeuterierten Verbindungen deutlich unterscheidet. Damit ist es möglich, völlig neuartige Zubereitungsformen zu entwickeln.In addition, the pharmacodynamics have also changed because the deuterated compounds form completely different hydration shells, so that the distribution in the organism differs significantly from that of the undeuterated compounds. This makes it possible to develop completely new forms of preparation.
Das folgende Beispiel erläutert die Erfindung:The following example explains the invention:
Beispiel 1example 1
Herstellung von α, α-Diphenyl-d7-propyl-oxyessigsäure-l- methylpiperidyl-4-esterhydrochloridProduction of α, α-diphenyl-d7-propyl-oxyacetic acid-1-methylpiperidyl-4-ester hydrochloride
24,2 g Benzilsäuremethylester, 0,05 g Natrium (in 3 ml24.2 g methyl benzilate, 0.05 g sodium (in 3 ml
Methanol gelöst) und 11,75 g N-Methyl-4-Piperidinol werden in einem Lösemittelgemisch aus 80 ml Toluol und 200 ml Benzol unter Rühren für 4 Stunden auf 110 °C erhitzt. Während dieser Zeit werden ca. 32 ml Methanol-Azeotrop abdestilliert. Nachfolgend werden weitere 65 bis 70 mlDissolved methanol) and 11.75 g of N-methyl-4-piperidinol are heated in a solvent mixture of 80 ml of toluene and 200 ml of benzene at 110 ° C. with stirring for 4 hours. During this time, approximately 32 ml of azeotrope of methanol are distilled off. Subsequently, another 65 to 70 ml
Methanol-Azeotrop abdestilliert und das abgetrennte Lösemittel durch reines Toluol. Es werden 0,1 ml Dimethylfor- mamid zugesetzt und nach Aufheizen der Lösung auf 100 bis 105 °C werden unter Rühren 13,2 g Thionylchlorid inner- halb von einer Stunde hinzugefügt. Es setzt eine S02- /Distilled off methanol azeotrope and the separated solvent by pure toluene. 0.1 ml of dimethylformamide is added and, after the solution has been heated to 100 to 105 ° C., 13.2 g of thionyl chloride are added within one hour with stirring. It sets an S0 2 - /
HCl-Entwicklung ein und die Reaktionstemperatur sinkt auf 90 bis 85 °C ab. Sobald die Auskristallisation von α, α- Diphenyl-α-chloressigsäure-l-methyl-piperidyl-4- esterhydrochlorid beginnt, wird vorsichtig, der Gasent- Wicklung angepasst, bis auf 110 °C aufgeheizt und mit ansteigendem Wasserstrahlvakuum überschüssiges Thionylchlorid und Lösemittel so weit wie möglich entfernt. Unter Rühren werden 15 ml d9-n-Propanol hinzugefügt und das restliche Toluol azeotrop abdestilliert, bis die Innen- temperatur 100 °C erreicht. Der Reaktionsansatz wird für 10 Stunden zum Rückfluss erhitzt, wobei ein Temperaturabfall auf ca. 93 °C eintritt. Nach Entfernen von 50 bis 60 ml Chlorwasserstoff und wasserhaltigen n-Propanol wird Aktivkohle hinzugegeben und die Lösung heiß filtriert. Anschließend wird die Lösung abgekühlt, das Produkt ab- filtriert und mit wenig n-Propanol gewaschen und getrocknet .HCl development on and the reaction temperature drops to 90 to 85 ° C. As soon as the crystallization of α, α-diphenyl-α-chloroacetic acid-l-methyl-piperidyl-4-ester hydrochloride begins, the gas evolution is carefully adjusted, heated to 110 ° C and excess thionyl chloride and solvent with an increasing water jet vacuum removed as possible. 15 ml of d9-n-propanol are added with stirring and the remaining toluene is distilled off azeotropically until the internal temperature reaches 100 ° C. The reaction mixture is heated to reflux for 10 hours, with a temperature drop to about 93 ° C. After removing 50 to 60 ml of hydrogen chloride and water-containing n-propanol, activated carbon is added and the solution is filtered hot. The solution is then cooled and the product filtered and washed with a little n-propanol and dried.
Aus der Mutterlauge wird durch Zugabe von n-Hexan weiteres Produkt erhalten, das mit wenig Aktivkohle aus einer geringen Menge n-Propanol umkristallisiert wird.Additional product is obtained from the mother liquor by adding n-hexane and is recrystallized from a small amount of n-propanol with a little activated carbon.
Ausbeute: 34,52 g; 84 % Schmelzpunkt: 212 - 217 °CYield: 34.52 g; 84% melting point: 212 - 217 ° C
berechnetcalculated
C: 67,22 %, H: 9,07 %, N: 3,41 % gefundenC: 67.22%, H: 9.07%, N: 3.41% found
C: 67,24 %, H: 9,04 %, N: 3,42 % C: 67.24%, H: 9.04%, N: 3.42%

Claims

Patentansprüche claims
1. Deuterierte N- und α-substituierte Diphenylalkoxyes- sigsäureaminoalkylester der allgemeinen Formel I1. Deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters of the general formula I
worinwherein
Ri Wasserstoff, Deuterium, einen n-Propylrest oder einen einfach, mehrfach oder einen perdeuterierten n- Propylrest darstellt,Ri represents hydrogen, deuterium, an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical,
R2 Sauerstoff, eine Methylgruppe oder eine Mono-, Dioder Trideuteromethylgruppe ist undR2 is oxygen, a methyl group or a mono-, di- or trideuteromethyl group and
R3 unabhängig voneinander H oder Deuterium sind, wobei mindestens einer der Reste Ri, R2 oder R3 unabhängig voneinander Deuterium ist oder Deuterium enthält,R3 are independently of one another H or deuterium, where at least one of the radicals R 1, R 2 or R3 is independently of one another deuterium or contains deuterium,
sowie deren physiologisch verträgliche Salze.as well as their physiologically acceptable salts.
2. Deuterierte N- und α-substituierte Diphenylalkoxyes- maß Anspruch 1,2. Deuterated N- and α-substituted diphenylalkoxyes- measured claim 1,
worinwherein
Ri einen n-Propylrest oder einen einfach, mehrfach oder einen perdeuterierten n-Propylrest darstellt,Ri represents an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical,
R2 eine Methylgruppe oder eine Mono-, Di- oder Tri- deuteromethylgruppe ist undR2 is a methyl group or a mono-, di- or tri-deuteromethyl group and
R3 unabhängig voneinander H oder Deuterium sind, wobei mindestens einer der Reste Ri, R2 oder R3 unabhängig voneinander Deuterium ist oder Deuterium enthält,R3 are independently of one another H or deuterium, where at least one of the radicals R 1, R 2 or R3 is independently of one another deuterium or contains deuterium,
sowie deren physiologisch verträgliche Salze.as well as their physiologically acceptable salts.
3. Deuterierte N- und α-substituierte Diphenylalkoxyes- sigsäureaminoalkylester der allgemeinen Formel I gemäß Anspruch 1,3. Deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters of the general formula I according to claim 1,
Ri einen n-Propylrest oder einen einfach, mehrfach oder einen perdeuterierten n-Propylrest darstellt,Ri represents an n-propyl radical or a single, multiple or a perdeuterated n-propyl radical,
R2 Sauerstoff ist,R2 is oxygen
R3 unabhängig voneinander H oder Deuterium sind, wobei mindestens einer der Reste Ri, R2 oder R3 unabhängig voneinander Deuterium ist oder Deuterium enthält,R3 are independently of one another H or deuterium, where at least one of the radicals R 1, R 2 or R3 is independently of one another deuterium or contains deuterium,
sowie deren physiologisch verträgliche Salze.as well as their physiologically acceptable salts.
4. Deuterierte N- und α-substituierte Diphenylalkoxyes- sigsäureaminoalkylester gemäß Anspruch 1, nämlich:4. Deuterated N- and α-substituted diphenylalkoxyacetic acid aminoalkyl esters according to claim 1, namely:
2, 2-Diphenyl-2- (d-hydroxy) essigsaure- (N-methyl-4- piperidinyl) -ester, 2, 2-Diphenyl-2-hydroxyessigsäure- (N-trideuteromethyl- 4-piperidinyl) -ester,2,2-diphenyl-2- (d-hydroxy) acetic acid (N-methyl-4-piperidinyl) ester, 2,2-diphenyl-2-hydroxyacetic acid (N-trideuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (d-hydroxy) essigs ure- (N-oxido-4- piperidinyl) -ester,2,2-diphenyl-2- (d-hydroxy) acetic acid (N-oxido-4-piperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2- (d-hydroxy) essigsäure- (N-trideuteromethyl-4-perdeuteropiperidinyl) ester,2,2-bis (pentadeuterophenyl) -2- (d-hydroxy) acetic acid (N-trideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2-hydroxyessigsäure- (N- trideuteromethyl-4-perdeuteropiperidinyl) ester,2,2-bis (pentadeuterophenyl) -2-hydroxyacetic acid (N-trideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) essigsaure- (N-oxido-4- perdeuteropiperidinyl) ester,2,2-bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) acetic acid (N-oxido-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- methyl-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-methyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- trideutero ethyl-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-trideutero ethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- monodeuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-monodeuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- dideuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-dideuteromethyl-4-piperidinyl) ester,
2,2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- oxido-4-piperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-oxido-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsäure- (N-methyl-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-methyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsaure- 2 , 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsaure- (N-monodeuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid 2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-monodeuteromethyl-4-piperidinyl) ester,
2, 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsäure- (N-dideuteromethyl-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-dideuteromethyl-4-piperidinyl) ester,
2 , 2-Diphenyl-2- (3,3, 3-trideuteropropyloxy) essigsäure- (N-oxido-4-piperidinyl) ester,2,2-diphenyl-2- (3,3,3-trideuteropropyloxy) acetic acid (N-oxido-4-piperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- methyl-4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-methyl-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- trideuteromethyl-4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-trideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- monodeuteromethyl-4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-monodeuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- dideuteromethyl-4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-dideuteromethyl-4-perdeuteropiperidinyl) ester,
2, 2-Diphenyl-2- (perdeuteropropyloxy) essigsaure- (N- oxido-4-perdeuteropiperidinyl) ester,2,2-diphenyl-2- (perdeuteropropyloxy) acetic acid (N-oxido-4-perdeuteropiperidinyl) ester,
2 , 2-Bis (pentadeuterophenyl) -2-2,2-bis (pentadeuterophenyl) -2-
(perdeuteropropyloxy) essigsaure- (N-trideuteromethyl-(perdeuteropropyloxy) acetic acid- (N-trideuteromethyl-
4-perdeuteropiperidinyl) ester,4-perdeuteropiperidinyl) ester,
2, 2-Bis (pentadeuterophenyl) -2-2,2-bis (pentadeuterophenyl) -2-
(perdeuteropropyloxy) essigsaure- (N-oxido-4- perdeuteropiperidinyl) -ester,(perdeuteropropyloxy) acetic acid (N-oxido-4-perdeuteropiperidinyl) ester,
2 , 2-Bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) essigsaure- (N-methyl-4- 2,2-Bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) essigsaure- (N-oxido-4- piperidinyl) ester.2,2-bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) acetic acid- (N-methyl-4- 2,2-bis (pentadeuterophenyl) -2- (perdeuteropropyloxy) acetic acid- (N-oxido-4-piperidinyl) ester.
5. Verwendung der deuterierten N- und α-substituierten Diphenylalkoxyessigsäureaminoalkylester gemäß einem der Ansprüche 1 bis 4 sowie deren physiologisch verträglicher Salze, zur Behandlung hypertoner Funk i- onszustände im Bereich der Harnblase.5. Use of the deuterated N- and α-substituted Diphenylalkoxyessigsäureaminoalkylester according to one of claims 1 to 4 and their physiologically compatible salts, for the treatment of hypertonic func tion states in the urinary bladder.
6. Verwendung der deuterierten N- und α-substituierten Diphenylalkoxyessigsäureaminoalkylester gemäß einem der Ansprüche 1 bis 4 sowie deren physiologisch ver- träglicher Salze, zur Herstellung von Arzneimitteln zur Behandlung hypertoner Funktionszustände im Bereich der Harnblase.6. Use of the deuterated N- and α-substituted Diphenylalkoxyessigsäureaminoalkylester according to one of claims 1 to 4 and their physiologically tolerable salts, for the manufacture of medicaments for the treatment of hypertonic functional states in the urinary bladder.
7. Pharmazeutische Zusammensetzung enthaltend deuterier- te N- und α-substituierte Dip enylalkoxyessigsäurea- minoalkylester gemäß einem der Ansprüche 1 bis 4 sowie deren physiologisch verträgliche Salze zur Behandlung hypertoner Funktionszustände der Harnblase neben pharmazeutisch verträglichen Hilfs- und/oder Zusatzstoffen.7. Pharmaceutical composition containing deuterated N- and α-substituted Dip enylalkoxyessigsäureaminoalkylester according to one of claims 1 to 4 and their physiologically tolerable salts for the treatment of hypertonic functional states of the bladder in addition to pharmaceutically acceptable auxiliaries and / or additives.
8. Pharmazeutische Zusammensetzung zur percutanen und/oder transdermalen Applikation von deuterierten N- und α-substituierten Diphenylalkoxyessigsäureami- noalkylestern gemäß einem der Ansprüche 1 bis 4 sowie deren physiologisch verträgliche Salze. 8. Pharmaceutical composition for percutaneous and / or transdermal application of deuterated N- and α-substituted diphenylalkoxyacetic acid amino alkyl esters according to one of claims 1 to 4 and their physiologically tolerable salts.
EP02752970A 2001-06-17 2002-06-17 DEUTERATED N-SUBSTITUTED AND $g(a)-SUBSTITUTED DIPHENYLALKOXY ACETIC ACID AMINO ALKYL ESTERS AND MEDICAMENTS CONTAINING THESE COMPOUNDS Withdrawn EP1397327A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10129832A DE10129832A1 (en) 2001-06-17 2001-06-17 Deuterated N- and alpha-substituted diphenylalkoxyacetic acid amino alkyl esters and medicaments containing these compounds
DE10129832 2001-06-17
PCT/DE2002/002260 WO2002102743A2 (en) 2001-06-17 2002-06-17 DEUTERATED N-SUBSTITUTED AND α-SUBSTITUTED DIPHENYLALKOXY ACETIC ACID AMINO ALKYL ESTERS AND MEDICAMENTS CONTAINING THESE COMPOUNDS

Publications (1)

Publication Number Publication Date
EP1397327A2 true EP1397327A2 (en) 2004-03-17

Family

ID=7688891

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02752970A Withdrawn EP1397327A2 (en) 2001-06-17 2002-06-17 DEUTERATED N-SUBSTITUTED AND $g(a)-SUBSTITUTED DIPHENYLALKOXY ACETIC ACID AMINO ALKYL ESTERS AND MEDICAMENTS CONTAINING THESE COMPOUNDS

Country Status (16)

Country Link
US (1) US20040242887A1 (en)
EP (1) EP1397327A2 (en)
JP (1) JP2004534802A (en)
KR (1) KR20040020926A (en)
CN (1) CN1516684A (en)
CA (1) CA2451638A1 (en)
CZ (1) CZ20033365A3 (en)
DE (1) DE10129832A1 (en)
HU (1) HUP0400213A3 (en)
IL (1) IL159410A0 (en)
IS (1) IS7061A (en)
NO (1) NO20035599D0 (en)
NZ (1) NZ530352A (en)
PL (1) PL367218A1 (en)
RU (1) RU2004101229A (en)
WO (1) WO2002102743A2 (en)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080146573A1 (en) * 2006-12-04 2008-06-19 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted oxzolidinones
US20090209608A1 (en) * 2007-08-29 2009-08-20 Protia, Llc Deuterium-enriched asenapine
US20090062185A1 (en) * 2007-08-29 2009-03-05 Protia, Llc Deuterium-enriched anidulafungin
US20090069219A1 (en) * 2007-09-09 2009-03-12 Protia, Llc Deuterium-enriched telavancin
US20090076158A1 (en) * 2007-09-13 2009-03-19 Protia, Llc Deuterium-enriched bicalutamide
US20090075870A1 (en) * 2007-09-17 2009-03-19 Protia, Llc Deuterium-enriched caspofungin
US20090082419A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched tegaserod
AR075584A1 (en) 2009-02-27 2011-04-20 Intermune Inc THERAPEUTIC COMPOSITIONS THAT INCLUDE beta-D-2'-DESOXI-2'-FLUORO-2'-C-METHYLYCTIDINE AND A CARDIEX ISOINDOL ACID DERIVATIVE AND ITS USES. COMPOUND.
WO2010138889A1 (en) * 2009-05-28 2010-12-02 Concert Pharmaceuticals, Inc. Peptides for the treatment of hcv infections
US20110129444A1 (en) * 2009-09-28 2011-06-02 Intermune, Inc Novel macrocyclic inhibitors of hepatitis c virus replication
CN102584592B (en) * 2011-12-28 2014-10-15 李进 Deuterated pyrethroid compound and preparation method and application thereof
PT2810936T (en) * 2012-01-30 2018-02-16 Taiho Pharmaceutical Co Ltd Novel acetic acid ester compound or salt thereof
BR112015002832B1 (en) * 2012-08-09 2022-08-16 Chase Pharmaceuticals Corporation PHARMACEUTICAL COMPOSITION AND USE OF A 1-ALKYL-1-METHYL-4-[(2,2-DIPHENYL-2-PROPOXY) ACETOXY]PIPERIDINIUM HALIDE
JP6045691B2 (en) * 2013-05-30 2016-12-14 大鵬薬品工業株式会社 Novel fluorinated benzyl ester compound or salt thereof
CN107445798B (en) * 2016-06-01 2020-11-03 中国农业大学 Synthetic method of alpha, alpha-dideuteroalcohol compound
CN116078377B (en) * 2023-03-06 2023-06-27 泽升科技(广州)有限公司 Production process for preparing deuterated benzene by using supported catalyst

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD106642A1 (en) * 1973-03-02 1974-06-20
DD139212A1 (en) * 1978-10-09 1979-12-19 Christian Starke PROCESS FOR THE PREPARATION OF A NEW MEDICAMENT FROM ALPHA, ALPHA-DIPHENYL-ALPHA-ALKOXY ACETIC ACID 1-METHYLPIPERIDYL-4-ESTER DERIVATIVES
JPS6439873A (en) * 1987-08-05 1989-02-10 Sharp Kk Synchronizing signal generating circuit
ES2122246T3 (en) * 1993-01-28 1998-12-16 Univ Iowa Res Found SEVOFLURANE DEUTERATED AS AN INHALATION ANESTHETIC.
DE4343838C2 (en) * 1993-12-22 1998-07-09 Lohmann Therapie Syst Lts Deuterated drug in transdermal application and process for its manufacture

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02102743A2 *

Also Published As

Publication number Publication date
CN1516684A (en) 2004-07-28
US20040242887A1 (en) 2004-12-02
HUP0400213A2 (en) 2004-07-28
HUP0400213A3 (en) 2005-08-29
WO2002102743A9 (en) 2004-03-11
PL367218A1 (en) 2005-02-21
CZ20033365A3 (en) 2004-09-15
IL159410A0 (en) 2004-06-01
RU2004101229A (en) 2005-06-27
CA2451638A1 (en) 2002-12-27
IS7061A (en) 2003-11-28
JP2004534802A (en) 2004-11-18
KR20040020926A (en) 2004-03-09
WO2002102743A3 (en) 2003-03-13
DE10129832A1 (en) 2003-07-10
NO20035599D0 (en) 2003-12-16
NZ530352A (en) 2004-12-24
WO2002102743A2 (en) 2002-12-27

Similar Documents

Publication Publication Date Title
EP1397327A2 (en) DEUTERATED N-SUBSTITUTED AND $g(a)-SUBSTITUTED DIPHENYLALKOXY ACETIC ACID AMINO ALKYL ESTERS AND MEDICAMENTS CONTAINING THESE COMPOUNDS
EP1456179A1 (en) Deuterated substituted pyrazolylbenzylsulfonamides and medicaments comprising said compounds
EP1778691A1 (en) Hydrates and polymorphs of 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamide, methods for the production thereof, and use thereof as medicaments
DE2540633A1 (en) NEW QUARTERLY N-BETA-SUBSTITUTED BENZILIC ACID-N-ALKYL-NORTROPINESTER AND PROCESS FOR THE PREPARATION
EP1456192A1 (en) Deuterated substituted dihydrofuranones and medicaments containing these compounds
DE10123129A1 (en) Deuterated 3-piperidinopropiophenones and medicinal products containing these compounds
DE2354002A1 (en) NEW N- (METHOXYMETHYL-FURYLMETHYL) 6,7-BENZOMORPHANES AND MORPHINANES, THEIR ACID-ADDITION SALTS, THEIR USE AS A MEDICINAL PRODUCTS AND METHOD FOR THE PREPARATION
EP0074014B1 (en) 2-(2'-hydroxy-3'-(1,1,-dimethyl propylamino)-propoxy)-beta propiophenone, its addition salts, process for its preparation and medicaments
WO2000051602A1 (en) Utilization of polycyclic 2-amino-thiazole systems in the production of medicaments for prophylaxis or treatment of obesity
EP0132811A1 (en) 1-Substituted 4-hydroxymethyl-pyrrolidinones, processes for their preparation, pharmaceutical composition and intermediate
DD300105A5 (en) New R (-) 3-quinuliclidinol derivatives
PL140992B1 (en) Process for preparing novel derivatives of piperidinedione
EP0056866A2 (en) Phenylpiperazine derivatives of heterylphenols and hetarylanilines, their preparation and their pharmaceutical compositions
WO2003039439A2 (en) Deuterated pyrazolopyrimidinones and drugs containing said compounds
DE10261807A1 (en) Deuterated catecholamine derivatives and medicinal products containing these compounds
WO2000011002A1 (en) 9-dialkylamino purinone derivatives
WO1993020814A1 (en) Immuno-activating and hence anti-viral effect of 4-[3-(subst.-amino)-2-hydroxypropoxy]-1,2,5-thiadiazole compounds
AT349480B (en) METHOD FOR PRODUCING NEW MORPHOLINE DERIVATIVES, THEIR N-OXIDES AND SALTS
DE2222931C3 (en) Piperidinoalkylphenthiazines, processes for the production thereof and pharmaceutical compositions containing them
DE3316155C2 (en)
DE2854341C2 (en)
EP1615631A2 (en) Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases
EP0462150B1 (en) Novel aryloxy alkyl amines, their production and medicaments containing them
DE3242922A1 (en) PHENYLPROPANOLAMINE, THEIR PRODUCTION AND USE
DE10214228A1 (en) Deuterated substituted indoles and medicinal products containing these compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031229

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: STABINGIS, THOMAS

Inventor name: HRACHOWINA, WERNER

Inventor name: HUEBNER, WOLF-DIETRICH

Inventor name: ROITHER, JOHANN

Inventor name: ALKEN, RUDOLF-GIESBERT

17Q First examination report despatched

Effective date: 20050106

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050518