WO1990009986A1 - Nouveaux composes d'anesthesie locale et leur procede de preparation - Google Patents

Nouveaux composes d'anesthesie locale et leur procede de preparation Download PDF

Info

Publication number
WO1990009986A1
WO1990009986A1 PCT/SE1990/000110 SE9000110W WO9009986A1 WO 1990009986 A1 WO1990009986 A1 WO 1990009986A1 SE 9000110 W SE9000110 W SE 9000110W WO 9009986 A1 WO9009986 A1 WO 9009986A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
compound according
anaesthesia
atoms
Prior art date
Application number
PCT/SE1990/000110
Other languages
English (en)
Inventor
Rune Verner Sandberg
Sven Bengt Arvid ÅKERMAN
Original Assignee
Aktiebolaget Astra
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 Aktiebolaget Astra filed Critical Aktiebolaget Astra
Publication of WO1990009986A1 publication Critical patent/WO1990009986A1/fr

Links

Classifications

    • 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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons

Definitions

  • the present invention is directed to new local anaesthetic compounds, a process for their preparation and their use in the manufacture of pharmaceutical preparations.
  • Tetracaine is one of the most frequently used local
  • anaesthetic agents especially for spinal and topical anaesthesia.
  • This agent has however certain drawbacks. It cannot be given in concentrations higher than approximately 1% because of the risk of toxic effects, and as it sometimes is desirable to have a longer duration of anaesthesia this thus cannot be obtained with tetracaine. Furthermore, tetracaine is easily hydrolyzed in aqueous solution.
  • the new compounds are more stable than tetracaine and can at least if R 1 and R 2 are methyl be autoclaved without any
  • R 1 and R 2 are the same or different and hydrogen or
  • R 3 and R 4 are the same or different and an alkyl group with
  • R 3 and R 4 together form a chain ( CH 2 ) n , wherein n is 4-6; or one of R 3 and R 4 is hydrogen and the other is an alkyl group with 1-4 C atoms.
  • Preferred compounds according to the invention are those, wherein the groups R 1 , R 2 , R 3 and R 4 all are alkyl.
  • Preferred salts according to the invention are pharmaceutically acceptable salts.
  • the hydrochloride is especially preferred, for injection solutions.
  • For topical use is, however, the base preferred.
  • a haloalkylcarbocyclic acid of the formula II was dissolved together with 2,6-dimetylphenol in dichloromethane, whereupon trifluoroacetic anhydride was added.
  • the resulting 4-halobutyrate of the formula III was in the next step, reacted with the appropriate amine to give a compound of the formula I', wherein R 1 is as defined above and R 3 and R 4 are the same or different alkyl groups with 1-3 C atoms or together form an alkylene chain of 4-6 carbon atoms.
  • the obtained compound was dissolved in tetrahydrofuran and added dropwise to i-Pr 2 NLi (lithium diisopropylamide) in tetrahydrofuran. Methyl iodide was added and the mixture was hydrolyzed.
  • the resulting product was a compound of the formula I" wherein R 3 and R 4 are as defined in formula I
  • haloalkylcarbocyclic acids (II) were prepared from the corresponding butyrolactone according to Olah et al
  • the crude acid II (from 250 mmol of a ⁇ -butyrolactone) was dissolved together with 2,6-dimethylphenol (30.5 g, 250 mmol) in dichloromethane, 100 ml, whereupon trifluoroacetic anhydride, 100 ml, was added.
  • the reaction mixture was left at room temperature over night. It was then evaporated, the residue was dissolved in diethyl ether, the ether solution was washed repeatedly with aqueous sodium hydrogene
  • the compounds Nos. 1-5 were prepared as described above.
  • the compounds 11, 13 and 15 can be prepared in the same way.
  • the preparation of compounds Nos. 6-9 are described in detail in the following.
  • the compounds 10, 12 and 14 can be prepared as described for compound 8 or as described for compound 6.
  • reaction mixture was cooled again to -65°C, whereupon another 140 ml of 0.433 M i-Pr 2 NLi in hexane diluted with 150 ml of THF was added, after 45 min followed by another 7.8 g of methyl iodide in 15 ml of THF.
  • This compound was prepared from 7.90 g (30 mmol) of 2,6-dimethyl 4-diethylaminobutyrate and in all 168 ml (72 mmol) of 0.433 M i-Pr 2 NLi in hexane and 9.4 g (66 mmol) of methyl iodide in the same way as described above for the 4-dimethylaminobutyrate ( compound 6).
  • the crude base was distilled before conversion to hydrochloride, yielding 6.21 g, bp 95-102°C at 0.01 mm Hg.
  • the hydrochloride was recrystallized three times from ethyl acetate yielding 3.22 g with mp 140-142°C.
  • the new compound is dissolved in a liquid diluent which is suitable for injection.
  • the preparations used are aqueous solutions which contain between 2.5 and 40.0 mg/ml of the active compound calculated as the hydrochloride salt.
  • topical preparations containing the base form or other suitable forms especially pharmaceutically acceptable salts of the active substance are solutions and disperse systems like emulsions, microemulsions, suspensions, liposome ⁇ , micelles etc.
  • the active compound can also be included in different kinds of films, tapes etc.
  • the compounds according to the invention were tested for spinal anaesthesia in the mouse.
  • the reference compounds lidocaine and tetracaine and the compound of the formula
  • Table 3 shows the acute toxicity (iv LD 50 ) in the mouse.
  • the result of a test for topical anaesthesia in the rabbit is given in Table 4.
  • Each compound was injected in at least four doses to groups of six mice.
  • Table 4 Corneal anaesthesia in the rabbit. Each value is the mean duration (min ⁇ sem) of the block after application of 0.25 ml of the anaesthetic solution to the conjunctival sac for 0.5 min.
  • the best mode of using the invention known at present is to use the compound according to example 8 in the form of its hydrochloride in injection solutions or the corresponding base in topical preparations.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés de la formule (I) et leurs sels pharmaceutiquement acceptables, utilisés comme anesthésiants locaux, ainsi qu'un procédé permettant leur préparation, leurs préparations pharmaceutiques et leur emploi.
PCT/SE1990/000110 1989-02-28 1990-02-19 Nouveaux composes d'anesthesie locale et leur procede de preparation WO1990009986A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8900685A SE8900685D0 (sv) 1989-02-28 1989-02-28 New compounds
SE8900685-2 1989-02-28

Publications (1)

Publication Number Publication Date
WO1990009986A1 true WO1990009986A1 (fr) 1990-09-07

Family

ID=20375184

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1990/000110 WO1990009986A1 (fr) 1989-02-28 1990-02-19 Nouveaux composes d'anesthesie locale et leur procede de preparation

Country Status (10)

Country Link
CN (1) CN1045260A (fr)
AU (1) AU5187290A (fr)
CA (1) CA2011047A1 (fr)
DD (1) DD292240A5 (fr)
GR (1) GR900100108A (fr)
IL (1) IL93244A0 (fr)
PT (1) PT93273A (fr)
SE (1) SE8900685D0 (fr)
WO (1) WO1990009986A1 (fr)
ZA (1) ZA90811B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8653131B2 (en) 2008-08-22 2014-02-18 Baxter Healthcare S.A. Polymeric benzyl carbonate-derivatives

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1102011A (en) * 1964-05-21 1968-02-07 Richardson Merrell Spa Phenol esters of amino acids
GB1369259A (en) * 1970-12-22 1974-10-23 Astra Pharma Prod Acylxylidide local anaesthetics
GB2124223A (en) * 1982-07-14 1984-02-15 Medichem Sa Substituted acetamides, a process for their preparation and pharmaceutical compositions containing them
DE3804433A1 (de) * 1987-02-13 1988-08-25 Nii Farmakol Akad Med Arylamide von (alpha)-hexamethyleniminocarbonsaeuren und ihre hydrochloride

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4025630A (en) * 1973-09-19 1977-05-24 Abbott Laboratories Anesthesia methods using benzopyrans and esters thereof as pre-anesthesia medication

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1102011A (en) * 1964-05-21 1968-02-07 Richardson Merrell Spa Phenol esters of amino acids
GB1369259A (en) * 1970-12-22 1974-10-23 Astra Pharma Prod Acylxylidide local anaesthetics
GB2124223A (en) * 1982-07-14 1984-02-15 Medichem Sa Substituted acetamides, a process for their preparation and pharmaceutical compositions containing them
DE3804433A1 (de) * 1987-02-13 1988-08-25 Nii Farmakol Akad Med Arylamide von (alpha)-hexamethyleniminocarbonsaeuren und ihre hydrochloride

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8653131B2 (en) 2008-08-22 2014-02-18 Baxter Healthcare S.A. Polymeric benzyl carbonate-derivatives
US8962549B2 (en) 2008-08-22 2015-02-24 Baxter International Inc. Polymeric benzyl carbonate-derivatives

Also Published As

Publication number Publication date
AU5187290A (en) 1990-09-26
DD292240A5 (de) 1991-07-25
IL93244A0 (en) 1990-11-29
CA2011047A1 (fr) 1990-08-31
ZA90811B (en) 1990-11-28
GR900100108A (el) 1991-06-28
PT93273A (pt) 1990-08-31
CN1045260A (zh) 1990-09-12
SE8900685D0 (sv) 1989-02-28

Similar Documents

Publication Publication Date Title
US4302465A (en) Therapeutically active, substituted piperidines and pyrrolidines therapeutic compositions thereof and methods of use thereof
DE2334404C2 (de) Alkylthiophenyl-2-n-octylaminoalkohole und deren Salze, Verfahren zu deren Herstellung und pharmazeutische Zubereitung
EP0600949B1 (fr) Nouveaux derives 3,5-di-tert.butyl-4-hydroxyphenyles, leur procede de fabrication et medicaments les renfermant
FR2522325A1 (fr) Nouveaux derives aryliques de la piperazine, de l'homopiperazine et de n,n'-dialkyl diamino-1,2 ethane, leur procede de preparation et leur application en therapeutique
CH621329A5 (fr)
EP0014951A2 (fr) Dérivés hétérocycliques d'oxypropanolamine, procédé pour leur préparation et médicaments contenant ces composés
AT368130B (de) Verfahren zur herstellung von neuen 9-aminoalkyl- fluorenen und von deren salzen
EP0133935B1 (fr) Dérivés d'acides p-oxybenzoiques, procédés pour leur préparation et leur utilisation pour la préparation de médicaments ayant une activité hypolipémique
IL123916A (en) History [(-3 Alkoxy - Paneoxy) - Ethyl] dialkylamine and their use as local anesthetics
DE1518452C3 (de) 4 substituierte 2 Benzhydryl 2 butanol Derivate und Verfahren zu ihrer Herstellung
EP0065295A1 (fr) Dérivés de la tryptamine et de la thiényloxypropanolamine, procédé pour leur préparation, compositions pharmaceutiques les contenant et préparation de celles-ci
EP0009777B1 (fr) N-(carboxy)phényl amides de l'acide rétinoique et 7,8-déhydro-rétinoique, procédé de préparation et compositions pharmaceutiques les contenant
EP0005821B1 (fr) Dérivés d'indanamine, procédé pour leur préparation et médicaments les contenant
WO1990009986A1 (fr) Nouveaux composes d'anesthesie locale et leur procede de preparation
DE3002545A1 (de) 5-amino-tetrazol-derivate von retinsaeuren, ihre herstellung und diese enthaltende pharmazeutische zubereitungen
EP0009776B1 (fr) N-monohydroxypropylamides, N-dihydroxypropylamides et leurs acetonoides de l'acide all-E et 13-Z rétinoique, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1992016496A1 (fr) Acides amines n-[[4,5-dihydroxy- et 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene-yl]carbonyle] utiles dans la therapie des pathologies osteoarticulaires
DE2462967C2 (de) Derivate des 3-Amino-5-methyl-2-phenyl-pyrrols, deren Salze und diese enthaltende pharmazeutische Zubereitung
US4313956A (en) Novel sypathomimetic amine prodrugs
US3096244A (en) Substituted butyric acid amide and analgesia
EP0003298B1 (fr) Dérivés de 4-hydroxy-2-benzimidazoline-thione, leur procédé de préparation et compositions pharmaceutiques les contenant
US4275068A (en) Lipid lowering alkylene glycols and ester derivatives thereof
DE3014738C2 (fr)
DD144764A5 (de) Verfahren zur herstellung von r-n-(2-phenyl-2-hydroxyethyl)-3-phenylpropylaminen
US2851393A (en) Beta-diethylamino butyric acid anilide, nontoxic salts thereof and aqueous local anesthetic solutions therewith

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CA CH DE DK ES FI GB HU JP KP KR LK LU MC MG MW NL NO RO SD SE SU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB IT LU NL SE

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA