DE1543264A1 - Process for the production of new ethers of dibenzocycloheptenols - Google Patents

Description

Koninklijke Pharmaoeutisohe Fabrieken v / h Brocades ^ Stheeman & Pharmacia _f Meppel, The Netherlands _e

"Method of Making New Itherxi of dibenzocycloheptenols "

Priority: 31 ο January 1964 / Great Britain Registration Fr * 4342/64

The invention relates to a calibration method for the production of new, therapeutically effective ethers of dibenzocycloheptenes O ~ cle _f eowie of their acid addition salts and to a process for the preparation of pharmaceutical preparations containing these novel compounds ^ _o

According to the invention, new ethers of the dibenzocycloheptene oils of the general formula 1 (see the formula sheet) are produced in which R ₁ and R _{2 have the} same or different meanings and each represent a hydrogen or halogen atom or a leather alkyl group and R ^ a basic ■ sticlcotoffhaltige group with less than 16 carbon

means 909330 / I486 ■

^ - - ■ t

BATH ORIGINAL

Ge to the appropriate groups represented by the symbol R hear:

a) groups of the Pormal -AB, in which A is a lower alkylene group and B is a (lower alkyl) amino, di (lower alkyl) amino, piperidino _t pyrrolidino, morpholine or thiamorpholino group;

b) groups of formula 2 (see the formula sheet), in which R,

a hydrogen atom or a lower alkyl? cg3? uppe and n1 or 2 represents which groups are bonded to the ether oxygen atom via a carbon atom; and

c) saturated bioyclic heterocyclic groups, such as tropan-3-yi, Nortropan-3 ~ yl, 8-alkylnortropan-3 "yl, 8-aralkyl ~ nortropan-3 ~ yl and quinuclidinyl, and their salts

The terms "lower alkyl * and" lower alkylene include ~ sen, as used here, both straight and branched chains with fewer than 8 carbon atoms.

As regards the salts, the invention includes the acid addition salts, especially the non-toxic acid addition salts » Acids suitable for the preparation of non-toxic acid addition salts are inorganic acids, such as the hydrogen halide acids (z "3, hydrochloric acid and hydrobromic acid)" and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, acetic acid, succinic acid, Hiloheäuro and Embonsäure,

909830 / U85

Me ethers of the general formula 1 and their acid addition salts are therapeutically active compounds, which have local anesthetic, anaigetic and apasraolytic activity o They also have an effect on the central nervous system. Preferred are the compounds in which R ₁ and Rp represent fuel atoms and R, is a (lower alkyl) amino (lower alkylene) or a di (lower alkyl) amino (lower alkylene) group,

The new ethers of general formula 1, as well as their acid addition salts can be produced in a manner known per se. -.

A suitable method consists in combining a ketone of the formula 3 (see the formula sheet), in which R. and R _{2 have the} above meanings, with a compound of the formula R * X, in which R, has the above meanings and X is a halogen atom , preferably a chlorine or bromine atom or a sulfonate group of the formula OSOp-Rct in which R ₁ - is an alkyl or aryl group, is reacted in the presence of a basic condensation agent; as Hatriumasnid, potassium amide, alkali metal alcoholates, such as a Nati'iummethoxyd or -äthoxyd, or an alkali metal hydride _n The reaction is preferably an inert organic LOE jungsnittcls such as benzene, toluene or xylene in the presence of>

BAD OR! C "v ^ v 90983C / U85

Suitable ketones of the general formula 3 »which can be used as reaction components in the above process are, for example: lOjii-dihydro-SH-dibenzo ^ äjd / cyclohepten-10-one; 1-, 2-, 3- and 4-chloro-10,11 ™ dihydro-5H ~ dibenzo / a ^ d / cyolohepten-IO-one; 1-, 2-, 3- and 4-bromo 10,11 »dihydro-SH-dibenza / äjd / cyclohepten-'IO-cn; 1-, 2-, 3- and 4-methyl 10,11-dihydro-5H-dibenzo / a, d7cyolohepten-10-one; 1-, 2-, 3- and 4-ethyl 10, H-dihydro-SH-dibenzo / äid / cyclohepten-IO-oh; 1-, 2-, 3- and 4-isoprtipyl 1QJ ¹ -dihydrg-5H-dibenzo / ä _t d7 oyolohepten-10-one; 1 ", 2-, 3- and 4-tert" butyl 10,11-dihydro-

SH-dibenso / äjd / oyclohepten-IO-cnf'1,3- and 1,7- and 3 | 7-diaethyl 10,

Of the starting materials of formula 3, the ketone, in which R «and IU each represent a hydrogen atom, was already used by NoJo Leonard CoS. _t produced (J. Am. Chenu Soc. 77 # 3078 (1953)) · The other ketones used as starting materials can be produced, for example, by reacting a phthalic anhydride with benzene or a! ^ - substituted benzene under the influence of a Friedel-Crafts catalyst Formation of an o-benzoylbenzoic acid, which in turn is reduced with a reducing agent such as zinc in an ammoniacal medium, with the corresponding o-benzylbenzoic acid being formed. This acid is then esterified with a lower aliphatic alcohol such as methanol. The ester is reduced with a reaction agent such as lithium aluminum hydride to obtain an o-benzylbenzyl alcohol

909830/1485

AD 0RK3 / MAL

The alcohol is converted into the corresponding o-benzylphenyl = acetic acid via the bromide and cyanide Carboxylic acid derivative is then cyclized, either by Condensation by treatment with phosphoric acid at elevated temperature or conversion of the carboxylic acid into the corresponding Acid halide and then cyclization of this halide under the action of aluminum chloride,

"This series of reactions takes place in the reaction sequence 4 (see the formula sheet), in which R-j and Rp have the above meaning to have·

The compounds according to the invention can, if Bie after Above process are prepared in the form of the free bases, in a manner known per se into the corresponding acid addition salts be reacted, e.g. by the fact that the free base is dissolved in an inert organic solvent, a Solution of the desired acid, preferably in the same

Solvent, added and the salt is precipitated

To explain the production of the invention, ether the following examples are given:

SLnVr / jöeung von IU, 4-1 g 10.11 Ifrhydro-5H-dibenzo / a _t <l7cyelo .btrpten-10-one in 60 cm '' of anhydrous toluene is quickly given "<" 93 (' Katriuaiamid and anachlieasend 6 , 65 g / -dimethyl-

909830/1485, _

aminopropyl chloride in 50 carbons of anhydrous toluene to _u The temperature of the mixture rises slightly and the reaction mixture turns red. The mixture is kept at about 50 ° C for 1 hour and then refluxed for a further hour. The mixture is then cooled and decomposed with water. The toluene layer is separated off, washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is dissolved in anhydrous diethyl ether and washed with a solution of

Maleic acid treated in diethyl ether. When a little ethanol is added, the maleate of 3- (5H ~ dibeiizo / ä, d / cyclo ~ hepten-10-yloxy) 3ÜT, il · dimethylpropylamine precipitates, the salt is crystallized from ethanol or acetone; Melting point HS «151 ° C; Yield 48? 6 _O.

Analysis!

Calculated for Ο ₂ 4 ^Η 27 ^ΚΟ 5 ^! ° ^{70 '59} * ^{H 6f64} * ^{N 5 | 42} ^ Found: C 70.67 $ H 6.68 $ N 3.45 *'

Example 2

The procedure is the same as in Example 1, but below Replacement of the dimethylaminopropyl chloride by an equivalent one Amount of ß-dimethylaminoethylochloride, and get that Maleate-des 2- (5H-dibenzo / ayd / cyolohepten-10-yloxy) H, 17-dimethylethylamine in 48% yield. Melting point of Salt to crystal! aa ti on aua ethanol ?. ? 39 - 143 C »

SAD

909830 / U8S ■

Analysis:

Calculated for C ₂₅ H ₂₅ MO ₅ : O 69.85 £ H 6.37 56 H 3.55 % Found: C 69.87 # H 6.40 # N 3.50 <f »

Example 3

The procedure is the same as in Example 1, but replacing the J-dimethylaminopropyl chloride with a equivalent amount of <*> -Tropan-3 ~ ylohlorid and contains the maleate des 3- (5H-Dibeneo / a, <l7eyclohepten-1Q ~ yloxy) tropane in 45 # - iger yield. Melting point of the salt after crystallization from ethanol 184 - 188 ° C.

Analysis:

Calculated for C ₂₇ H ₃₉ NO ₅ : G 72.45 # H 6.53 ^ £ i 3.13 5 ^ Found -: C 72.56 # H 6.46 i »M > _f 35 %

If that is applied after the procedure <example 1 T'-dimethylaminopropyl chloride d \ iroh / "- diethylaminopr'apyl bromide, 1-methyl] 4-chloropiperidine, 1-methyl 3 "-bromopiperidine, 1-Xthyl 3-ferorapyrrolidine, ß-piporidinoethyl chloride or If quinuclidinyl bronze is substituted, one obtains the series naoh den ^ -Tiiäthylarainopropyl-, 1-Kethyl 4-piperidyl-, t-methyl 3-piperidyl, t-iithyl 3-pyrrolidyl, S-pipsridinoethyl and ohinuolidinyl ether,

If the Ί0, ii-Piyy 10-Cu of Example ^{1 is} replaced by an R ^ - and / or R _o -substituted

909830 ^1/1485

909830 ^1/1485

BATH ORIGINAL

10, H-DihydrO "5H - dibenzo / ä, d / oyclohepten-10-one, one obtains the corresponding 3- (R ₁ - and Rjj-substituted-5H-dibenzo / ä, d / oyclohepten-10-yloxy ) N, N-diiae thy! Propylamine

The invention also includes pharmaceutical preparations as Active ingredient at least one of the therapeutically active compounds of general formula 1 or a non-toxic one Contain addition salts of these compounds as well as a pharmaceutically acceptable carrier »

The preparations may have any of the forms are applied _t usually for administration of therapeutically active substances, but preferably the molds are selected which are suitable for oral administration of compounds that have the most important effect a spaamolytisohe and analgesic activity, as well as the soft itself suitable for the parenteral administration of compounds, the most important effect of which is a local anesthetic effect

Among the forms suitable for oral administration, tablets, pills and capsules containing the active ingredient are preferred. The tablets and pills can be mixed in the usual manner with one or more pharmaceutically acceptable diluents or excipients, 3, .- E ₀ lactoae or starch, among which auoh Substances lubricating kind, ^ ₀ B ₀ Oalciumstearat or Magnes3.umeter.rat, composed of v .-. Rf.en. To an un- "pleasant taste in the mouth by the loltal-anesthetics

909830 / U85

To avoid the effect of the compounds, the tablets can be provided with a coating that is stable when the tablet passes through the dog and throat, capsules made of absorbable material such as gelatine can contain the active ingredient yourself or with a solid or liquid diluent mixed, contained »

For parenteral administration, the active ingredient can be in .ein sterile, aqueous or non-aqueous solution, suspension or

Emulsion in sterile water or in an organic fluid, like this normaliter used for injectable preparations is, ZoB ", propylene glycol, Polyäthylengl ^ col, or in a vegetable oil such as olive oil can be absorbed »The active ingredient can also be absorbed in a sterile solid mixture which can be made suitable for parenteral administration by placing in water or in another sterile injectable medium and that is dissolved immediately before use.

For external use, the active ingredient can be made into an ointment, Paste or cream according to standard pharmaceutical practice are processed"

The dosages of the drugs that are abraichen to ver ~ a patient depends on the activity of the ether, the desired effect s and the wines of administration "

BATH 909830 / Ί.485

Claims (1)

- · ίο - Claims 1. A process for the preparation of new xethers of dibenzocyclohepten-10-ols, characterized in that ethers of the formula> 1 (see the formula sheet) or acid addition salts thereof are prepared in a manner known per se, in which R ₁ and H _{2 are the} same or different Have meaning and each represent a hydrogen or halogen atom or a lower alkyl group and R, a basic stick «· means a group containing less than 16 carbon atoms» 2. The method according to claims 1, characterized in that one Xther of the formula 1 (see the formula sheet) or acid additionaaalse produces the same in which R, a) a group of the formula -AB ₁ in which A is a lower alkylene group and B is a (lower alkyl) amino, di (lower alkyl) amino, piperidino, pyrrolidino, morpho-uno or thiamorpholino group; * b) a group of formula 2 (see the formula sheet), in the Rj is a hydrogen atom or a lower alkyl group and η represents 1 or 2, the former group having a carbon atom on the ether oxygen atom is bound; or q) a saturated bicyolic heterocyclic nitrogen-containing Group represents 90983G / Uß5 Method according to claim 1 or 2, characterized by that one ether of the formula 1 (see the Pormelblatt) or Acid addition salts of the same, in which R, a Tropan-3-yl "» Nortropan-3-yl-t e-Alkyl-nortropan - ^ - yl-f represents e-aralkylnortropan - ^ - yl or quinuelidinyl, Method according to claim 1 or 2, characterized in that ethers of the formula 1 (see d $ .s formula sheet) or acid addition salts thereof are prepared in which R ₁ and Hp represent hydrogen atoms and R is a (lower alkyl) amino (lower alkyl) Alkyl en) - = or a di (lower alkyl) amino (lower alkylene) group 5. The method according to claim 1 or 2, characterized daduroh, that one has 3- (5H-Dibeneo ^ a, d7cyclohepten-10-yloxy) N, H-dimethylpropylamine or an acid addition salt thereof romps here, 6ο Method according to claim 1 or 2, characterized in that that one has 2- (5H-MbenÄ / a, d / cyclohepten ~ 10-yloxy) N, N-dimethylethylamine or an acid addition salt thereof manufactures. 7. »Process according to claims 1 ~ 3 t characterized that 3-15H-Diben "o ^ a, d7oyclohepten-10-yloxy) tropaa , or makes an acid addition as the same » 909830/1485 bad original 8. Process according to claims 1-7 »characterized in that a ketone of the formula 3 (see the formula sheet) is reacted with a compound of the formula R * X in which X is a halogen atom or a sulfonate group of the formula -OSO ₂ -Rc represents _t in which Rk denotes an alkyl or aryl group, while ^, R ₂ and R, have the same meaning as in claim 1. 9β Method according to claim 8, daduroh · characterized in that the reaction is carried out in the presence of a basic condensing agent. 10. The method according to claim 8 or 9, characterized in that that the reaction is carried out in the presence of an inert organic solvent ..