FI59583B - PROCEDURE FOR THERAPEUTIC PREPARATION OF THERAPEUTIC ACID 1-METHYL-4- (3-CARBOXY-10,11-DIHYDRO-5H-DIBENZO (A, D) CYCLOHEPTEN-5-YLIDEN) PIPERIDIN OCH DESS N-OXID - Google Patents

Abstract

10,11-Dihydro-3-carboxycyproheptadine and its esters, amides and N-oxide are disclosed to have pharmaceutical utility as appetite stimulants and as antihistaminic agents. Also disclosed are processes for the preparation of such compounds; pharmaceutical compositions comprising such, compounds; and methods of treatment comprising administering such compounds and compositions.

Description

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28.03.75 USA 522676, 563285 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, Hew Jersey, USA (72) David Carroll Remy, North Wales, Pennsylvania, USA ( US) (7 ^) Oy Kolster Ab (5U) Method for the use of therapeutically useful 1-methyl-U- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine and its N oxide - For the preparation of therapeutically active compounds of 1-methyl-U- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d7'-cyclohepten-5-ylidene) piperidine and N-oxide This The invention relates to process 10,11-dihydro-3-carbocycloheptadine Z1-methyl-U- (3-carboxy-10,11-dihydro-5H-dibenzo [a, <47-cyclohepten-5-ylidene) piperidine], its N oxide and pharmaceutically acceptable salts. The compound in question is an appetite stimulant and an antihistamine. The free acid form of 10,11-dihydro-3-carboxycyproheptadine prepared according to the invention has the following structural formula (I): U.S. Pat. No. 3,09583 . However, neither carboxy derivative nor appetite stimulant compounds are described in this publication.

U.S. Patent 3,547,980 discloses carbonyl derivatives of cyclobenzaprine having sedative, antidepressant and antihistamine properties. However, these compounds are completely different in structure from the present compound.

GB 1,046,404 deals with cyproheptadine and 10,11-dihydrocyproheptadine but does not describe carboxy derivatives.

DE 2 102 196 discloses 3-carboxy-cyproheptadine Only as starting material without mention of other uses. The publication does not describe a 10,11-dihydro derivative.

FR 3558M, which corresponds in part to GB patent 1,046,404, relates to a very broad group of compounds, including the compound disclosed in the present application. However, the examples in the publication do not describe this. preparation of the compound and not the compound has not been characterized by physicochemical constants.

Surprisingly, it has been found that the 10,11-dihydro-3-carboxycyproheptadines prepared by the methods of the invention have an appetite stimulating and antihistaminic effect while lacking other pharmacological effects, such as anticholinergic activity, which is characteristic of structurally related compounds. including its dihydro-derivatives. Thus, the present invention relates to a process for the preparation of 10,11-dihydro-3-carboxycyproheptadine, its N-oxide derivative and its pharmaceutically acceptable salts having an appetite stimulating and antihistamine effect.

The 10,11-dihydro-3-carboxycyproheptadines of formula I can be conveniently prepared from 3-bromo-10,11-dihydro-5H-dibenzo [a, d7-cyclohepten-5-one. (see, e.g., U.S. Patent Nos. 3,306,934 and 3,014,911) by reacting it with 1-methyl-4-piperidylmagnesium halide in a suitable solvent such as tetrahydrofuran and the like at a temperature ranging from 0 ° C to room temperature of 3,59583. To obtain -4- (3-bromo-10,11-dihydro-5-hydroxy-5H-dibenzo [b, d7-cyclohepten-5-yl) piperidine, which is dehydrated by treatment with a suitable dehydrating agent such as a mineral acid, a carboxylic acid , chloride or anhydride and the like alone or in a solvent such as chloroform or glacial acetic acid to give 1-methyl-4- (3-bromo-10,11-dihydro-5H-dibenzo [b, c] cyclohepten-5-ylidene) piperidine, which converted to the 3-cyano derivative by treatment with cuprocyanide in a solvent such as dimethylformamide or hexamethylene phosphoramide at 50-200 ° C for 2-12 hours and then hydrolysis with strong mineral acid at reflux for 1-24 hours to give the desired 1-m ethyl 4- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine- (10,11-dihydro-3-carboxycyproheptadine). Alternatively, the Grignard reaction may be performed after the reaction of cuprocyanide and ketone; thus, subsequent treatment with a mineral acid not only dehydrates but also converts the 3-cyano substituent to the desired 3-carboxyl group.

The resulting 10,11-dihydro-3-carboxycyproheptadine can then be oxidized to the desired N-oxide. However, the oxidation is preferably carried out on a suitable lower alkyl ester of the intermediate-free acid, which is prepared in a manner known per se. For example, the ethyl ester can be prepared by reacting the free acid in ethanol in the presence of BF 2 CH 2 Cl 2. Hydrogen peroxide is a suitable oxidizing agent and the reaction can be carried out in any suitable inert solvent such as aqueous methanol, aqueous ethanol and the like at 0 ° C to reflux for 1 to 72 hours. Compound I can also be conveniently prepared by reducing 3-carboxycyproheptadine, Compound X, with hydrogen at a pressure of 1-5.7 kg / cm 3 and at room temperature in the presence of a noble metal catalyst such as palladium, especially 5% palladium on carbon, in a dilute mineral acid such as 0.5N hydrochloric acid.

In another method for preparing Compound I, a Grignard reagent is formed from magnesium and 3-bromo-10,11-dihydrocyproheptadine in a solvent commonly used for the Grignard reaction, such as ether, tetrahydrofuran, or the like at about -5 to + 20 ° C, and then treated with dry carbon dioxide gas at the same temperature until the reaction is complete.

h 59583

Yet another process for the preparation of compound I or an ester thereof comprises the alcoholization of either compound V or VII with sulfuric acid in a lower alkanol, especially methanol. The ester obtained can be de-esterified with an acid or an alkali in a known manner. The following reaction schemes illustrate these processes.

5,59583

Scheme I

MgBr ^ Φ _ C)

O II

- Dr 1. Mg 2 · CO2

. 0 O

T L

CH3 III ύΗ3 IV

/) ^ CUCN y 'OHhydrolysis k - - v

CH 3 CK, T

J v 31

Oxidation β-N-oxide Js% Pd / C

CCO'COOH

o CH 2 HCl

X

6 59583

Figure II

MgCl OCO - ”* OGCH ö o II o VI Hb Ψ j £ \ / \ # \ '! IC1 rn

JiLeoonN

/ N (f) »OH

N) / -HCl 1 Ψ h2so4 1 CH, CH, 3

J l \ De-esterification VII

Esterification _____ \ / yS / Vv ^ <- -V Jl Ajcocr ^ (I ^ R e lower alkyl / C X vi11 ^ 3

V

"Ester hydrolysis θςχ>« «* ος» - o ^ Λ », Λ IX IN-oxide 4 7 59583 The appropriate pharmaceutical salts and N-oxide of 10,11-dihydro-3-carboxycyproheptadine can be prepared in a manner known per se. most preferred and comprising (related to the nitrogen atom of the piperidyl moiety): hydrochloride, sulfate, phosphate, citrate, tartrate, succinate, and the like, with respect to salts based on the carboxy group, salts derived from alkali and alkaline earth metals such as sodium and potassium are preferred. the salts are generally equivalent in effect to the free acid in view of their stoichiometric amounts.

In the following Tables I and II, the pharmacological properties of the 3-carboxy-10,11-dihydrocyproheptadine hydrochloride prepared according to the invention are compared with those of known compounds of close structure.

Table I

__mg / kg_ 3-carboxy-10,11-dicyproheptadine hydrocyproheptadine i-hydrochloride

Appetite activity (threshold dose) 0.0312 0.0312

Peripheral anticholinergic activity (ED ^> -80 6

Anticholinergic activity in the central nervous system (ED50)> 80 1.9

Table II

8 59583 _Antihistamine activity in guinea pigs____

Dose Number of animals EDcn mg / kg. used 50

Compound 5 after histamine induction of death free base dyspnea convulsive death against mg / kg ι.ρ.

controls 0/12 0/12 0/12 3-carboxy- 0.025 0/12 0/12 0/12 0.12 cyproheptadine- 0.05 0/12 0/12 0/12 hydrochloride 0.075 0/12 0/12 2 / 12 0.1 0 0/1 2 0/1 2 7/1 2 0.1 5 0/1 2 1/1 2 7/1 2 0.20 0/12 2/12 10/12 3-carboxy 0.025 0/12 0/12 2/12 0.06 10,11-dihydro-0.05 0/12 1/12 3/12 cyproheptadine- 0.75 0/12 2/12 9/12 hydrochloride 0.10 0 / 12 3/12 11/12 0.15 1/12 6/12 11/12 0.20 7/12 10/12 12/12

It can be seen from Table I that the compound according to the invention and the known cyproheptadine are equally active as appetite stimulants. However, the compound according to the invention has a much weaker anticholinergic effect. Table II, on the other hand, shows that the new 3-carboxy-10,11-dihydro-cyproheptadine hydrochloride is twice as active as the corresponding dehydro compound.

The exact unit dosage form and dosage concentration of the compositions containing a compound of formula I will depend on the particular patient being treated. In general, however, a compound of formula I will be administered to provide an appetite stimulating effect of about 0.01 to 10.0 mg / kg / body weight per day. When administering a compound of formula I to domestic animals to stimulate appetite, it is preferred to dissolve it in drinking water or preformed nutrients. For administration to humans and animals, it is administered in conventional oral pharmaceutical forms, such as tablets, syrups, and aqueous suspensions, containing from about 0.01 to about 10 mg of 9,59583 of a compound of formula I per kg of body weight per day. Thus, for example, tablets may be administered 2 to 4 times daily with about 0.5 to 50 mg of a compound of formula I. Sterile solutions (for human administration) for injection comprise about 0.1-10.0 mg of a compound of formula I for administration 2-4 times a day. The dosage forms and concentrations described above are also appropriate to provide an antihistamine effect.

The following examples illustrate the present invention.

Example 1 1-Methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [d, d] cyclohepten-5-ylidene) piperidine

Step A: 1-Methyl-4- (3-bromo-10,11-dihydro-5H-dibenzoic acid)

Ca. (d7-cyclohepten-5-ylidene) piperidine In an ice-cooled solution of 15.0 g (0.0523 moles) of 3-bromo-1,01-dihydro-5H-dibenzo, 47-cyclohepten-5-one in 150 ml: In dry tetrahydrofuran, 100 ml of 0.53M 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran are added dropwise over 0.5 hours. The solution is stirred for 1 hour and then the tetrahydrofuran is removed on a rotary evaporator. The remaining red oily residue is dissolved in benzene and water is added dropwise until a clear benzene solution and a gel-like aqueous phase are obtained. The benzene is decanted off and the gel-like aqueous phase is extracted with two 100 ml portions of hot benzene. The combined benzene phases are washed with six 200 ml portions of water and then the benzene phase is evaporated on a rotary evaporator. The remaining residue is mixed with acetonitrile. The crystalline product is removed by filtration, washed with acetonitrile, collected and dried at 60 ° C. Product 1-Methyl-4- (3-bromo-10,11-dihydro-5-hydroxy-5H-dibenzo [a, d] cyclohepten-5-yl) piperidine, 9.66 g (65%) melt 203-207 ° C.

A mixture of 9.66 g of the product obtained above and 130 ml of 6N hydrochloric acid is stirred at reflux for 0.5 hour. Most of the hydrochloric acid is removed on a rotary evaporator and the residue is partitioned between 5% sodium hydroxide and ether. The ether phase is removed, washed with water, dried over magnesium sulfate, filtered and the ether is removed to give 9.17 g of 1-methyl-4- (3-bromo-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) -piperidine.

10 59583

Step B: 1-Methyl-4- (3-cyano-10,11-dihydro-5H-dibenzo [a, d7-cyclohepten-5-ylidene) -piperidine

A mixture of 9.17 g (0.0249 moles) of 1-methyl-4- (3-bromo-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine, 4.58 g (0, 0498 moles) of cuprocyanide and 30 ml of dry dimethylformamide, stirred and refluxed for 6.5 hours. To the cooled solution (25 ° C) are added 54 ml of water, 27 ml of aqueous sodium cyanide solution and 75 ml of benzene. The mixture is stirred until a 2-phase system is obtained. The benzene phase is removed and the aqueous phase is extracted with two 75 ml portions of benzene. The combined benzene phases are washed with 100 ml of aqueous 0.1M sodium cyanide, three times with 100 ml portions of water and dried over magnesium sulphate. After filtration and evaporation of the benzene, 7.40 g of crystalline residue are obtained. This material is dissolved in the smallest possible volume of chloroform and passed through an alumina column (15 "x 1") in chloroform. The column is eluted with chloroform. Evaporation of chloroform gives a crystalline product which is recrystallized from isopropyl alcohol to give pure 1-methyl-4- (3-cyano-10,11-dihydro-5H-dibenzo-Ca, d7-cyclohepten-5-ylidene) piperidine. , mp 152-154 ° C.

Analysis for the compound: ^ 22 ^ 221 ^

Calculated: C, 84.04; H, 7.05; N, 8.91.

Found: C, 83.87; H, 7.41; N, 8.73.

Step C: 1-Methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [e, d] cyclohepten-5-ylidene) piperidine hydrochloride

A mixture of 1.0 g (0.00318 moles) of 1-methyl-4- (3-cyano-10.11-dihydro-5H-dibenzo, d7-cyclohepten-5-ylidene) piperidine and 20 ml of 6N hydrochloric acid is stirred at reflux for 18 hours. . After cooling, the mixture is filtered and the recovered material is washed with 6N hydrochloric acid and then ethanol. The dried substance weighs 1.03 g (87%). Recrystallization from absolute ethanol gives pure 1-methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [a, c (cyclohepten-5-ylidene)) piperidine hydrochloride, mp 304-307 ° C. for: HCl;

Calculated: C, 71.43; H, 6.54; N, 3.79; Cl, 9.59. Found: C, 71.01; H, 6.87; N, 3.73; Cl, 9.44.

11 59583

Example 2 Preparation of 1-methyl-1-oxo-4- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine

A solution of * +, 13 g (0.0177 moles) of 3-cyano-1, 0.11-dihydro-5H-benzo, d7-cyclohepten-5-one (prepared from 3-bromoketone by reacting it with CuCN in step 1 of Example 1) B) with 40 ml of tetrahydrofuran, treated with 42 ml of 0.43 M 1-methyl-4-piperidylmagnesium chloride, The solution is stirred for 1 hour and then the tetrahydrofuran is removed on a rotary evaporator. The remaining red oily residue is dissolved in benzene and water is added dropwise until a clear benzene solution and a gel-like aqueous phase are obtained. The benzene is decanted off and the gel-like aqueous phase is extracted with two 100 ml portions of hot benzene. The combined benzene phases are washed with six 200 ml portions of water and then the benzene phase is evaporated on a rotary evaporator. The remaining residue is mixed with acetonitrile. The crystalline product is removed by filtration, washed with acetonitrile, collected and dried at 60 ° C to give 2.88 g (49%) of crystals VII (Reaction Scheme II above), which is mixed with 60 ml of 6N hydrochloric acid and heated to reflux. 24 hours to give 2.80 g of compound I (Reaction Scheme II). A mixture of 2.80 g of compound I and 2 ml of boron trifluoride etherate in 200 ml of absolute ethanol is heated under reflux for 8 hours. The solution is evaporated to dryness and the residue is partitioned between ether and aqueous sodium carbonate solution. The ether phase is removed, dried over magnesium sulphate, filtered and the ether is removed by evaporation. 2.7 g of ethyl ester VIII (reaction scheme II) are obtained, which is dissolved in 100 ml of methanol, 10 ml of water and 10 ml of 30% hydrogen peroxide. After stirring for 48 hours at room temperature, a little 5% Pt / C is added and the mixture is stirred for a further 2 hours to decompose the excess hydrogen peroxide. The mixture is filtered and the solvent is evaporated to give chromatographically pure ethyl ester N-oxide IX (Reaction Scheme II). 1 g of ethyl ester N-oxide IX is dissolved in 10 ml of methanol containing 2 ml of 2N potassium hydroxide. The solution is heated on a steam bath for 2 hours. The methanol is removed, 10 ml of water are added to the residue and, while stirring, glacial acetic acid is added dropwise to i2 59583 until no more precipitate forms. The white substance formed is removed by filtration and washed well with water. The product is recovered and dried to give 1-N-oxide sesquihydrate; mp. 208-209 ° C (decomposes, foams); road homogeneous.

Analysis for the compound: ^ 22 ^ 23 ^ 3 '^ 1/2 HgÖ

Calculated: C, 70.19; H, 6.96; N, 3.72.

Found: C, 70.30; H, 6.77; N, 3.51.

Example 3 1-Methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine hydrochloride

A solution of 0.43 g (0.00162 mol) of 1-methyl-4- (3-carboxy-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine hydrochloride 2 in 5 ml of 0.1 N hydrochloric acid hydrogenated for 12 hours using 50 mg of 5% palladium / carbon with an initial hydrogen pressure of 2.72 atm. Water (15 mL) is added and the mixture is filtered to remove the catalyst. The filtrate is concentrated to dryness in vacuo and the residue is recrystallized from 10 ml of absolute ethanol. The product is collected and dried at 100 ° C under vacuum to give 0.16 g of 1-methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine hydrochloride, m.p. 307-310 ° C.

Example 4 1-Methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine hydrochloride

A flame-dried and nitrogen-purged flask equipped with a stirrer, a condenser equipped with a CaCl 2 drying tube and a dropping funnel is charged with 0.68 g (0.028 moles) of magnesium turnings and 2 ml of tetrahydrofuran. The mixture is heated to reflux and 0.81 g of 1-methyl-4-chloropiperidine and iodine crystal are added. The Grignard reaction begins immediately. Solution containing 5.0 g (0.0136 mol) of 1-methyl-4- (3-bromo-10,11-dihydro-5H-dibenzo [a, d7-cyclohepten-5-ylidene) piperidine in 25 ml tetrahydrofuran, is added dropwise over one hour to a low reflux solution. When the addition is complete, the mixture is refluxed for 4 hours, cooled to room temperature, after which it is poured onto crushed dry ice, which is used in excess. The mixture is stirred and allowed to warm to room temperature. Ether (150 ml) and 6N hydrochloric acid (150 ml) are added and the mixture is stirred until a biphasic system is obtained. The aqueous acid phase is separated off 13,59583 and washed once more with ether. The aqueous acid phase is basified by adding a 40% solution of sodium hydroxide, after which the solution is filtered. The clear aqueous phase is extracted with 200 ml of ether and then acidified by adding 6N hydrochloric acid. The solution is concentrated on a rotary evaporator at 60-70 ° C to a volume of about 100 ml. During this concentration, 1-methyl-N- (3-carboxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine hydrochloride crystallizes from solution. The liquid is decanted from the solid and the crystalline residue is taken up in 50 ml of water. This water is decanted and the residue is triturated with 50 ml of absolute ethanol. The product is collected by filtration, washed with cold absolute ethanol and dried to give 1.30 g (26%) of 1-methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo, d / cycloheptene). 5-ylidene) piperidine hydrochloride, m.p. 304-307 ° C. The mixture of the previously prepared authentic substance and the substance obtained above has a melting point of 304-307 ° G. The homogeneity of the product was determined by fluorination on silica gel (TLC) using n-butanol, acetic acid, water (5,2,3) and the previously prepared authentic material and the same. a mixture of the product with TCL,

Example 5 1-Methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [d, d] cyclohepten-5-ylidene) piperidine hydrochloride

A solution of 1.27 g of 1-methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo [e, d] cyclohepten-5-ylidene) piperidine ethyl ester (m.p. 85-87 ° C) In 5 ml of ethanol with 1 ml of 2N potassium hydroxide, stir and heat on a steam bath for 2 hours. The ethanol is removed by evaporation under reduced pressure. The residue is dissolved in 5 ml of water and 6N hydrochloric acid is added until the mixture becomes acidic. The precipitate formed is collected by filtration, washed with cold water, absolute ethanol and dried in a vacuum oven at 60 ° C to give 0.80 g of 1-methyl-4- (3-carboxy-10,11-dihydro-5H-dibenzo), d7cyclohepten-5-ylidene) piperidine hydrochloride, m.p. 306-310 ° C, the homogeneity of which was determined by thin layer chromatography.

Claims (2)

1. Menetelmä terapeuttisesti käytettävän kaavan COOH ch3 mukaisen yhdisteen, sen N-oxidi-johdannaisen ja sen pharmaseuttisesti hyväksyttävien suolojen valmistamiseksi, tunnettu siitä, one (a) hydrolysoidaan yhdiste, young kaava on CN v chen (b) pelkistetään yhdiste, young kaava on COOH sNr ch3 minkä jälkeen haluttaessa hapetetaan N-oxidiksi; (c) käsitellään yhdistettä, young kaava on 59563 ch3 magnesiumilla Grignard reagent in muodostamiseksi ja sen jälkeen käsitellään hiilidioksidilla, minkä jälkeen haluttaessa hapetetaan N-oxidiksi; tai (d) de-esteröidään yhdiste, young kaava on COOR 7Γ viii ch3 tai sen N-oxidi-johvandainen, jossa kaavassa R on alempi alkyyli; minkä jälkeen haluttaessa saatu kaavan In the mukainen yhdiste tai sen N-oxydijohvandainen muutetaan sinänsä tunnetulla tavalla farmaseuttisesti hyväksyttäväksi suolaksi. 16 59583 A process for the preparation of a therapeutically useful compound of the formula "CH3 its N-oxide derivative and pharmaceutically acceptable salt: thereof, wherein the compound (a) hydrolyses a compound having the structure: v CH3 followed by, if desirable, oxidation to N-oxide; (b) reducing a compound of the formula COOH X ch 3 added by, if desired, oxidation to N-oxide; (c) treating a compound of the formula