IE42220B1

IE42220B1 - Carboxycyproheptadines,their preparation and use

Info

Publication number: IE42220B1
Application number: IE2406/75A
Authority: IE
Original assignee: Merck & Co Inc
Priority date: 1974-11-11
Filing date: 1975-11-05
Publication date: 1980-07-02
Also published as: ES442375A1; NL7512384A; LU73771A1; NL173398B; IL48365A; FI752920A; FI59583C; CH621114A5; PH13443A; AU8605775A; NO144422B; JPS6011029B2; FR2290203B1; DE2550395B2; CA1082177A; AT352126B; NO753562L; FI59583B; JPS5170769A; IE42220L

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

This invention provides 10,11 - dihydro - 3 - carboxycyproheptadine (l - methyl - 4 - (3 - carboxy - 10,11 - dihydro - 5H dibenzo [a,d] cyclohepten - 5 - ylidene)piperidine), which is useful as an appetite stimulant and as an antihistaminic agent.

The present invention also provides the N - oxide of the said compound and pharmaceutically acceptable salts of the said compound and its N - oxide. The free acid form of the 10,11 - dihydro - carboxycyproheptadine of the present invention has the following structural formula (i) it has unexpectedly been discovered .that ’ the 10,11 - dihydro 3 -carboxycyproheptadines of the present invention are appetite stimulants and antihistaminics substantially devoid of other pharmacological effects such as anticholinergic activity, which latter activity is so characteristic of compounds structurally related to cyproheptadine, including dihydro derivatives thereof.

In accordance with the present invention 10,11 - dihydro 3 - carboxycyproheptadine of the present invention is conveniently prepared from 3 - bromo - 10,11 - dihydro - 5H - dibenzo [a,d] cyclohepten - 5 - one (see, for example, U.S. Patent Specifications Nos. 3,306,934 and 3,014,911) by reaction with a 1 - methyl - 4 2 pi.peridylmagnesium halide in a suitable solvent such as tetrahydrofuran at 0°C to room temperature to provide 1 - methyl - 4 (3 - bromo - 10,11 - dihydro - 5 - hydroxy - 5H - dibenzo - |a,d] cyclohepfen - 5 - yl) - piperidine, which is dehydrated on treatment 5 wi th a suitable dehydrating agent such as a mineral or carboxylic acid or a carboxylic acid chloride or anhydride, either alone or in a solvent such as chloroform or glacial acetic acid to provide 1 - methyl - 4 - (3 - bromo - 10,11 - dihydro - 511 - dibenzo [a,djcyclohepten - 5 - ylidene)piperidine, which on conversion to the 10 3 - cyano species by treatment with cuprous cyanide in a solvent such as dimethylformamide or hexamethylene phosphoramide at 5O-2OO°C for 2-12 hours, followed by hydrolysis with a strong mineral acid at reflux temperature for 1-24 hours yields the desired 1 - methyl 4-(3- carboxy - 10,11 - dihydro - 5H - dibenzo [a,d]cyclohepten 15 5 - ylidene)piperidi.ne, viz. 10,11 - dihydro - 3 - carboxycyproheptadine, of the present invention. Alternatively, the Grignard reaction may follow the reaction with cuprous cyanide on the ketone; thus the next following treatment with mineral acid not only dehydrates but also converts the 3 - cyano substituent into the 20 desired 3 - carboxyl function.

The resulting 10,11 - dihydro - 3 - carboxycyproheptadine may then be oxidized to the desired N - oxide of the present invention. Preferably, however, (lie oxidation is conducted upon a suitable alkyl ester ol' the in I eruled i at e free acid which is prepared by 25 conventional techniques. For example, the ethyl ester may conveniently be prepared by reacting the free acid in ethanol in the presence of BFj (CII^CH,, ^0. Hydrogen peroxide is a suitable oxidizing agent, and the reaction may be conducted in any suitably inert protic solvent such as aqueous methanol or aqueous ethanol at 3° a tempera (.lire ol' from 0° to reflux for I'rom | In 72 hour,··.. foul pound - 3 43380 I may also conveniently be prepared by reduction of 3 - carboxy2 cyproheptadine. Compound X, with hydrogen at 1.5-7 kg/CTCi and room temperature in the presence of a noble metal catalyst such as palladium especially 5% palladium on carbon in a dilute mineral acid solvent such as 0.1 N hydrochloric acid.

A further procedure for the preparation of Compound I comprises forming a Grignard reagent from magnesium and 3 - bromo - 10,11 dihydrocyproheptadine prefeably in a solvent commonly used for Grignard reactions, such as diethyl ether or tetrahydrofuran, at -5 to 20°C., followed by treatment with dry carbon dioxide gas at the same temperatures until reaction is complete.

Another process for the preparation of a compound I comprises the alcoholysis of either Compound V or Compound VII with sulfuric acid in a C^_j alkdnol, especially methanol, and de-esterifying Lg the resulting ester with acid or alkali by standard procedures.

The following diagrams illustrate these processes. - 4 42220 SCHEME I Br N I CH, I CH, —Br X CH, XI - 5 42220 SCHEME II - 6 42220 Suitable pharmaceutical salts, of the 10,11 - dihydro - 3 carboxycyproheptadine and N - oxide of the present invention may be prepared by conventional means. Salts of the nitrogen atom of (lie piperidyl residue include the hydrochloride, .sulfate, phosphate, citrate, tartrate and succinate and salts of the carboxy Junction derived from alkali metals and alkaline earth metals such as sodium and potassium are preferred. These salts are generally equivalent in potency to the free acid form taking into consideration the stoichiometric quantities involved. in the method of treatment and pharmaceutical composition of the present invention it is noted that the precise unit dosage form and dosage level depend upon the case history of the individual being treated and consequently left to the discretion of the therapist. In general, however, the compounds of the present invention produce (he desired'effect of appetite stimulati on when given al. from ().()1 to 1().() mg. per kg. body weight, per day. Tile preferred form of delivery of the instant compounds for appetite stimulation of domestic animals is by solution in drinking water or preformulated feedstuffs. For human and animal administration, any of the usual pharmaceutical oral forms may be employed such as tablets, elixirs and aqueous suspensions comprising from 0.01 to 10.0 mg. of the compounds of this invention per kg. body weight given dally. Thus, for example, tablets given 2-4 times per day comprising from 0.5 to 50 mg. of the compounds of this invention are .suitable for human treatment. Sterile solutions ( representatively given for human treatment) for injection comprising from 0.1 to 10.0 mg. of the compounds of this invention given two to four times daily are also suitable means of delivery. When an antihistaminic effect is indicated, the above recil.ed dosage forms and levels are also appropriate. - 7 _ The following examples representatively illustrate but do not 1ϊm-ί t the product, compositional or method of treatment aspect of the present invention.

EXAMPLE 1 Preparation of 1 - methyl - 4 - (3 - carboxy-10,11 - dihydro 5H - dibenzo [a,d]cyclohepten - 5 - ylidene)piperidine Step A: - Methyl - 4 - (3 - bromo - 10,11 - dihydro - 5H - dibenzo [a,d]cyclohepten - 5 -ylidene)piperidine To an ice-cooled solution of 15.0 gm. (0.0523 mole) of 3 bromo - 10,11 - dihydro -5H - dibenzo [a,d]oyclohepten - 5 - one in 150 ml. of dry tetrahydrofuran is added dropwise over 0.5 hr., 100 ml of 0.53M 1 - methyl - 4 - piperidyl - magnesium chloride in tetrahydrofuran. The solution is stirred for one hour, and then the tetrahydrofuran is removed on a rotary evaporator. The red oily residue that remains is dissolved in benzene and water is added dropwise until a clear benzene supernatant and a gelatinuous aqueous phase is obtained. The benzene is decanted and the gelatinuous 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 residue that remains is triturated with acetonitrile.

The crystalline product is removed by filtration, washed with additional acetonitrile, collected and dried at 60°C. The product, 1 25 methyl -4-(3- bromo - 10,11 - dihydro - 5 - hydroxy -5H dibenzo[a,d] - cyclohepten - 5 - yl)piperidine, 9.66 gm. (65$) melts at 2O3-2O7°C.

A mixture of 9.66 gm of 1 - methyl - 4 - (3 - bromo - 10,11 dihydro - 5 - hydroxy -5H - dibenzo [a,d]cyclohepten - 5 - yl) 3θ piperidine and 130 ml. of 6N hydrochloric acid is stirred and refluxed for 0,5 hr. The bulk of the hydrochloric acid is removed - 8 42220 on a rotary evaporator and the residue is partioned between 5% aqueous sodium hydroxide and ether. The ethereal phase, is removed, washed with water, dried over magnesium sulfate, and filtered, and the ether is removed to give* 9.17 gm. of 1 - methyl - 4 (3 - bromo -10,11 - dihydro -5H - dibenzo [a,d]cyclohepten - 5 ylidene) - piperidine.

Step B: - Methyl-4 -(3- cyano - 10,11 - dihydro -5H - dibenzo [a,d] cyclohcpten - 5 - ylidene) - piperidine A mixture of 9.17 gm (0.0249 mol) of 1 - methyl - 4 - (3 bromo - 10,11 - dihydro -5H - dibenzo [a,d] cyclohepten - 5 ylidene)piperidine, 4.58 gm. (Ο.Ο498 mol) of cuprous cyanide, and 30 ml. of dry dimethylformamide is stirred and heated under reflux for 6.5 hr. To the cooled solution (25°C.)is added 54 ml. of water, 27 ml. of a saturated aqueous solution of sodium cyanide, and 75 ml. uf benzene. The mixture is stirred until a two-phase system is «total tied. The benzene phase is removed and (.lie 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 and three 100-ml. portions of water, and dried over magnesium sulphate. After filtering, evaporation of the benzene gives 7.4H gm. of a crystalline residue. This material is dissolved in the minimum volume of chloroform and passed over an alumina column (15'' x 1'') packed in chloroform. The column is eluted with chloroform. Evaporation of the chloroform gives a crystalline product that is recrystallized from isopropyl alcohol to give pure 1 - methyl - 4 - (3 - cyano - 10,11 - dihydro - 5H dibenzo [a,d]cyclohepten - 5 - ylidene)piperidine, m.p. 152-154°C. Analysis Calc, for ^22^22^21 Calc.: C, «4.04; H, 7.05; N,x.9l. c, 83.87; II, 7.41,- N,5.73. - 9 Found: 42380 Step C: - Methyl -4-(3- carboxy -10,11 - dihydro -5Hdibenzo[a,d]cyclohepten - 5 - ylidene) - piperidine hydrochloride.

A mixture of 1.0 gm (0.00318 mol) of 1 - methyl -4-(3cyano - 10,11 - dihydro - 5H - dibenzo [a,d]cyclohepten - 5 - ylidene) piperidine and 20 ml. of 6N hydrochloric acid is stirred and. refluxed for l8 hours. After cooling,the mixture is filtered, and the collected solid is washed with 6N hydrochloric acid and then with ethanol. The dried material weighs 1.03 gm. (87%). Recrystallization from absolute ethanol gives pure 1 - methyl -4-(3carboxy - 10,11 - dihydro -5H - dibenzo[a,d]cyclohepten - 5 ylidene) piperidine hydrochloride, m.p. 3O4~3O7°C.

Analysis Calc, for: ^22^23^θ2* HC1: Calc.: 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 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 4-13 gm (0.0177 mol) of 3 - cyano - 10,11 dihydro -5H - dibenzo [a,d]cyclohepten - 5 - on® (prepared from the 3 - bromo ketone by reaction with CuCN according to the procedure of Example 1, Step B, when the appropriate substitution of reactants is made) in 40 ml. of tetrahydrofuran is treated with 42 ml. of O.43M 1 - methyl - 4 - piperidyl - magnesium chloride. The solution is stirred for one hour, and then the tetrahydrofuran is removed, on a rotary evaporator. The red-oily residue that remains is dissolved in benzene, and water is added dropwise until a clear benzene supernatant and a gelatinuous aqueous phase is obtained. The benzene is decanted and the gelatinuous aqueous phase is extracted with two 100-ml. portions of hot benzene. The combined benzene phases are washed with - 10 42220 six 200-ml. portions of water and then the benzene phase is evaporated on a rotary evaporator. The residue that remains is triturated with acetonitrile. The crystalline product is removed by filtration, washed with additional acetonitrile, collected and dried at 60°C. to give 2.SS g (49%) of crystalline VII ^Scheme II above) which is mixed with 60 ml. of 6N hydrochloric acid and refluxed for 24 hours to give 2.So gm. of I (Scheme ii). A mixture of 2.SO gm.of i acid 2 ml. of boron tr i.fluoricle etheratc- in 200 in I.. of absolute ethanol i.s refluxed for 8 hours. The solution is evaporated to dryness and the residue is partitioned between ether and aqueous sodium carbonate solution. The ethereal phase is removed, dried over a magnesium sulfate and filtered, and l.he ether is removed by evaporation. There is obtained 2.7 gm. of the ethyl ester VIII (Scheme II), which is dissolved in 100 ml. of methanol, 10 ml. of water, and 10 ml. of 30% hydrogen peroxide. After stirring for 4S hours at room temperature, a small scoop of 5% Pt./C is added and the mixture is stirred for an additional 2 hours to decompose the excess of hydrogen peroxide. The mixture is filtered and the solvent is evaporated to give chromatographically pure· ethyl ester -N - oxide IX (Scheme II). One gram 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 the· steam bath for 2 hours. The methanol is removed, 10 ml. of water is added to the residue, and glacial acetic acid is added dropwise to the stirred mixture until no further precipitate forms. The white solid t hat forms is removed by filtrat ion and is washed thoroughly with water. The product is collected and dried to give I - N oxide (XI) sesquihydrate; m.p. 208-209° (dec., foams); tic homognneous.

Analysis calcd. for C_ H NO .11/2 II 0; ZZ Z.5 J Z Calc. C, 70.19; H, 6.96; N, 3.72 Found: C, !7O.3O; H, 6.77; N, 3.51.

EXAMPLE 3 Pharmaceutical Compositions A typical tablet containing 1 mg. 1 - methyl - 4 - (3 carboxy - 10,11 - dihydro - 5H - dibenzo [a,djcyclohepten - 5 ylidene)-piperidine per tablet is prepared by mixing together with the active ingredient calcium phosphate, lactose and starch in the amounts shown in the tables below. After these ingredients have been thoroughly mixed, the appropriate amount of magnesium stearate is added and the dry mixture blended for an additional three minutes. This mixture is then compressed into tablets weighing approximately 124 mg. each. Similarly prepared are tablets containing 1 - methyl -4-(3- carboxy - 10,11 - dihydro 5H — dibenzo[a,djcyclohepten - 5 - ylidene)piperidine hydrochloride or 1 - methyl - 1 - oxo - 4 - (3 - carboxy - 10,11 - dihydro » 5Hdibenzo [a,djcyclohepten - 5 - ylidene)piperidine.

Tablet Formula Ingredient Mg. per tablet 1 - Methyl - 4 - (3 - carboxy 10,11 - dihydro - 5H - dibenzo [a,dj - cyclohepten - 5 - ylidene) piperidine 1 mg. Calcium phosphate 52 mg. Lactose 60 mg. Starch 10 mg. Magnesium stearate 1 mg.

Claims

1. 10,11 - Dihydro - 3 - carboxycyproheptadine.

2. 10,11 - Dihydro - 3 - carboxycyproheptadine N - oxide.

3. A pharmaceutically acceptable salt of a compound as claimed in

Claim 1.

4. A pharmaceutically acceptable salt of a compound as claimed in

2. Claim 2.

5. A method of preparing the compound claimed in Claim 1, that comprises hydrolysing 10,11 - dihydro - 3 - cyanocyproheptadine.

6. A method as claimed in Claim 5, including the step of preparing the 10,11 — dihydro — 3 - cyanocyproheptadine by treating' 10,11 — dihydro - 3 - bromocyproheptadine with cuprous cyanide in a solvent at 5O-2OO°C for 2 to 12 hours.

7. A method of preparing the compound claimed in Claim 1, that comprises treating 10,11 - dihydro - 3 - bromocyproheptadine with magnesium to form a Grignard reagent, followed by treatment with carbon dioxide.

3. A method as claimed in Claim 6 or 7, including the step of preparing the 10,11 - dihydro - 3 - bromocyproheptadine by reacting 3 - bromo - 10,11 - dihydro - 5H - dibenzo [a,d]eye! ohept.cn - 5 one with a I ~ methyl - 4 - piperidyl magnesium lialide in a suitable solvent al a temperature in tilt! range ,! (' room temperature t.o produce 1 - methyl - 4 - (3 - bromo - 10,11 - dihydro - 5 hydroxy - 5H - dibenzo [a,djcyclohepten - 5 - yl) - piperidine and dehydrating the latter.

9. A method of preparing the compound claimed in Claim 1, that comprises reducing the compound of formula:

c 4

10. A method as claimed in Claim 9j in which the reduction is carried out with hydrogen at room temperature over a noble metal catalyst.

5

11. A method of preparing the compound claimed in Claim 1, that comprises deesterifying a compound of formula:

where R is

1-5

COOR

12. A method as claimed in Claim 11, including the step of preparing the starting material by reacting 10,11 - dihydro - 3 cyanocyproheptadine or 1 - methyl - 4 - (3 - cyano - 10,11 - dihydro 5 - hydroxy - 5H - dibenzo [a,d]cyclohepten - 5 - yl)piperidine with sulfuric acid in the C^_^ alkanol.

13. A method as claimed in Claim 12, including the step of preparing the 10,11 - dihydro - 3 - cyanocyproheptadine by reacting

3 - bromo - 10,11 - dihydro - 5H - dibenzo [a,d]cyclohepten - 5 one with a 1 - methyl - 4 - piperidyl magnesium halide in a suitable solvent at a temperature in the range 0°C to room temperature to produce 1 - methyl - 4 - (3 - bromo - 10,11 - dihydro - 5 - hydroxy 5H - dibenzo [a,d]cyclohepten - 5 - yl)piperidine and dehydrating the latter to produce 10,11 - dihydro - 3 - bromocyproheptadine, followed by treating that compound with cuprous cyanide in a solvent at 50-200°C for 2 to 12 hours.

14» A method as claimed in Claim 12, including the step of pre—

14 422 3 0 paring f,ho 1 - methyl - 4 - (3 - cyano - 10,11 - dihydro - 5 hydroxy - ill - dibenzo [a,djcyclohepten - 5 - yl) - piperdlne by reacting 3 - bromo - 10,11 - dihydro - 5H - dibenzo [a,djcyclohepten - 5 - one with a 1 - methyl - 4 - piperidyl magnesium o

halide in a suitable solvent at a temperature in the range 0 C to room temperature to produce 1 - methyl — 4 — (3 — bromo - 10,11 — dihydro - 7 - hydroxy -

15. A method of preparing the compound claimed in Claim 2, that comprises oxidizing the compound claimed in Claim 1.

16. A method of preparing- the compound claimed in Claim 2, that comprises esterifying the compound claimed in Claim 1, oxidizing the resulting ester to produce an ester of the compound claimed in Claim 2 and then deest.er i fying this compound.

17- A method as claimed in Claim 16, in which I lie esterification is carried out by reacting tlie .starting compound with ethanol in the presence of BF 3 (C 2 H,.) 2 0 to farm the ethyl ester and the oxidation is carried out with hydrogen peroxide.

l3. A method as claimed in Claim 15, 16 or 17, including the step of preparing the starting material by a method as claimed in any one of Claims 5 to 14.

19. A method of producing a compound as claimed in Claim 2 substantially as hereinbefore described in Example 2.

20. A method of producing the compound claimed in Claim 3, substantially as hereinbefore described in Example 1.

21. The compound claimed in Claim 1, when prepared by a method as claimed in any one of Claims 5 to 14.

22. The compound claimed in Claim 2, when prepared by a method a.s claimed in any one of Claims 15 to 19.

23. A compound as claimed in Claim 3, when prepared by a method as claimed in Claim 20 or an obvious chemical equivalent of such a method.

15 422.20

24. A pharmaceutical composition comprising a compound as claimed in Claim 1 or 3 and a pharmaceutical carrier.

25. A pharmaceutical composition comprising a compound as claimed in Claim 2 or 4 and a pharmaceutical carrier.

5 26. A pharmaceutical composition comprising a compound as claimed in any one of Claims 21 to 23 and a pharmaceutical carrier.

27. A composition as claimed in any one of Claims 24 to 26 in the form of a tablet, elixir or aqueous suspension.

28. A composition as claimed in any one of Claims 24 to 26 in

10 the form of a sterile injectable solution.

29. A composition as claimed in any one of Claims 24 to 26 in the form of a preformulated animal feedstuff.

30. A composition as claimed in any one of Claims 24 to 26 in water-dispersible form.

15 31. A composition as claimed in any one of Claims 24 to 26 substantially as hereinbefore described in Example 3.

32. A method of treatment comprising administering in unitary dosage form to a non-human animal a compound as claimed in any one of Claims 1 to 4 and 21 to 23.