DE2550395C3 - 10ll-dihydro-S-carboxycyproheptadine - Google Patents

Description

(d) a compound of the general formula VIII

COOH

(D

COOR

(VIII)

its N-oxide and the pharmaceutically acceptable salts, characterized in that in in a manner known per se

(a) 1-Mcthyi-4- (3-cyano-10,11-dihydro-SH-dibenzo [a, d] cycloheptene - 5 - ylidene) - piperidine

CN

CH,

hydrolyzed and optionally the free one Acid oxidized to N-oxide:

(b) l-MelhyI-4- (3-carboxy-5-dibenzofa, d] cyeloheptatrienylidcn (-piperidine

COOH

reduced and, if desired, oxidized the reduction product to the N-oxide;

(el! -Methyl-4- (3-bromo-1 (), II-dihydro-5H-dibcnzo [a, d] cycloheptin - 5 - ylidene) - piperidine

Br

CH,

with magnesium to form a Grignard compound u η sumisctzt, closing this a η wherein R is a lower alkyl group, or the N-oxide derivative thereof is saponified.

3. Medicaments containing an effective amount of the compounds according to claim 1.

The invention relates to 10.1 l-dihydro-3-carboxycyproheptadine [I - methyl - 4 - (3 - carboxy - 10.11 - di-

i> hydro - 5 H - dibenzo [a, d] cycloheptcn - 5 - ylidene) - piperidine], which stimulates the appetite and is effective as an anlihistaminic agent. Included in the invention are also the N-oxide as well as the pharmaceutically acceptable salts, low molecular weight esters and the

• »o amides of these compounds. The invention relates to furthermore a process for the preparation of these compounds and it also relates to pharmaceutical compositions, which contain these compounds. 10.1 l-dihydro-3-carboxycyproheptadine equivalent

4j of the invention has the following structural formula I:

COOH

Surprisingly, it has been found that the compounds according to the invention are used as appetite stimulants and antihistamines are effective without affecting the other pharmacological effects such as one aiiticholinergic activity, which is characteristic of compounds that are structurally related with cyprohcptadine, including the dihydroderivytcn thereof.

10.1 l-dihydro-3-earboxyeyprohcptadine becomes easy made from 3-bromo-IO, l l-dihydro-SH-tliben-

zo [a, d] cycJohepten-5-one (see U.S. Patents 33 06 934 and 30 14 911) by reaction with 1-methyl-4-piperidyl magnesium halide in a suitable solvent such as tetrahydrofuran at OC to room temperature with formation of l-methyl-4- (3-bromo-10,11 - dihydro - 5 - hydroxy - 5 H - dibenzo [a, d] cycloheplen-5-yl) piperidine, which is then dehydrated by treating with a suitable dehydrating agent, such as a mineral acid, carboxylic acid, chloride or anhydride either alone or in ι ο a solvent such as chloroform or glacial acetic acid to form I-methyl-4- (3-bromo-10,11-dihydro - 5 H - dibenzo [a, d] cyclohepten - 5 - ylidene) - piperidine, which is then converted into the 3-cyan derivative is made by treating with copper (I) cyanide in a solvent such as dimethylformamide or hexamethylene phosphoramide, at 50 to 200 ° C for 2 to 12 hours, followed by hydrolysis with a strong mineral acid at reflux temperature, which takes 1 to 24 hours the desired 1-methyl-4- (3-carboxy-10,11-dihydro - 5 H - dibenzo [a, d] cyclohepten - 5 - ylidene) - piperidine (10,11 - dihydro - 3 - carboxycyproheptadine) obtained according to the invention. Alternatively, the reaction can be followed by the Grignard reaction connect with copper (I) cyanide with the ketone, with the then following treatment with mineral acid not only does dehydration take place, but also the conversion of the 3-cyano group into the desired 3-carboxyl function.

The 10.1 l-dihydro-3-carboxycyproheptadine thus obtained can then be oxidized to the desired N-oxide according to the invention. Preferably, however, the oxidation is carried out on a suitable lower alkyl ester of the π- free acid formed as an intermediate product, which can be prepared in a conventional manner. For example, you can easily produce the ethyl ester by reacting the free acid in ethanol in the presence of

BF ₃ (CH ₃ CH ₂ J ₂ O.

Hydrogen peroxide is a suitable oxidizing agent and the reaction can be carried out in any suitable inert protic solvent such as aqueous methanol or aqueous ethanol at temperatures in the range from 0 ⁰ C to the reflux temperature for a period of 1 to 72 hours. The compound I can also be prepared simply by reducing 3-carboxycyproheptadine, the compound X, with hydrogen at a pressure of 1.5 to 7 kg / cm ² and at room temperature in the presence of a noble metal catalyst such as palladium, and in particular a 5% Palladium-on-carbon catalyst in the presence of a dilute mineral acid solvent such as 0.1 n-hydrochloric acid.

Another method of making compound I is to form the Grignard compound from magnesium and 3-bromo-10, l 1-dihydrocyproheptadine in a solvent such as is commonly used for Grignard reactions, such as an ether or tetrahydrofuran about -5 to 20 "C, followed by treatment with dry carbon dioxide gas at the same temperature until the implementation is complete.

Another procedure for the preparation of the compound I or its low molecular weight ester exists in the alcoholysis of either compound V or VlI with sulfuric acid in a low molecular weight Alkanol, especially methanol. If desired, the ester thus obtained can by customary processes saponified with an acid or with alkali. The following equation describes the specified Procedures.

Scheme I.

(III)

hydrolysis

^ _x Ji-COOH • HCI

CH ₃

(V)

oxidation

CH ₃

(I)

5% Pd / C H,

1 —N-oxide I!

> COOH

HCI

CH.,

(X)

Scheme II

CuCN

-COOH

HCI

HCI

CH,

(I)

Saponification

Esterification

• N ' CU,

(VlIIl

oxidation

O (VI) MuCl

-NN-- 'i
CH,

^; \
j CN

HO,

CH.,

(VII)

R = lower alkyl

ROH H, S O,

Saponification

J-COOH

O <N

(IX)

CH,

1 - N-oxide

Suitable pharmacological salts, low molecular weight Ester and the amide of 10.1 l-dihydro-3-carboxycyprohcptadine and the N-oxide according to the invention can be prepared by conventional methods. The acid addition salts are particularly preferred and include: hydrochlorides, sulfates, phosphates, citrates, Tartrates and succinates. As far as salts regarding The carboxy function come into consideration are salts of alkali and alkaline earth metals, such as sodium and potassium are preferred. These salts are generally as effective as the free acid, if one the stoichiometric amounts used in each case are taken into account.

The quantities required for a therapy and also the quantities used for the manufacture of drugs required depend on the type of case to be treated. In general, the connections effect according to the compound the desired effect of appetite stimulation when used in amounts of / 0.01 to about 10.0 mg per kg of body weight per day are taken. The preferred application form of the compounds according to the invention as an activity stimulator for pets exists in the form of solutions in drinking water or in prepared feed. Any of the customary pharmacological administration forms can be used for the treatment of humans and animals to be used for oral ingestion, i.e. tablets. Elixirs or aqueous Suspensions containing 0.01 to 10.0 mg of the compounds according to the invention per kg of body weight per day provide. For example, tablets can be produced for the treatment of people, which are taken two to four times a day and which are about 0.5 to about 50 mg according to the invention Connections included. Sterile solutions typically used in human treatment for injection contain about 0.1 to about 10 mg of the compounds according to the invention and can be administered two to four times a day. The antihistamine effect also comes in the aforementioned dosage amounts expressed.

B e i s ρ i e I 1

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

Level a

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

To an ice-cold solution of 15.0g (0.0523 mol) of 3 - bromine -10.11 - dihydro - 5 H - dibenzo [a, d] cyclohptcn-5-one in 150 ml of dry tetrahydrofuran are added dropwise over a period of 0.5 hours K) O ml of 0.53 ml of 1-methyl-4-piperidyl magnesium chloride given in tetrahydrofuran. The solution will be

Stirred 2 »I hour and then tetrahydrofuran is means a rotary evaporator removed. The red, oily residue is dissolved in benzene and added dropwise water is added until a clear, benzene layer and a gelatinous aqueous phase are obtained

2j becomes. The benzene is decanted and the gelatinous, aqueous phase is hot with two 100 ml portions Benzene extracted. The combined benzene phases are washed with six 200 ml portions of water and then the benzene phase is on a rotary evaporator

it> evaporated. The residue is treated with acetonitrile. The crystalline product obtained is recovered by filtration, washed with additional acetonitrile, collected and then dried at 60.degree. The product obtained is l-methyl-4-O-bromo-lO.I I-dihydro-5-hydroxy-5 H-dibenzo [a, d] cyclohepten-5-yl) piperidine in an amount of 9.66 u (65%), which melts at 203-207 C.

A mixture of 9.66 g of l-methyl-4- (3-bromo-10.11 - dihydro - 5 - hydroxy - 5 H - dibenzo [a, d] cyclo-

4 (i hcpten-5-yl) piperidine and 130 ml of 6N hydrochloric acid is stirred and refluxed for 0.5 hours. The main amount of hydrochloric acid is removed on a rotary evaporator and the residue is taken up in 5% sodium hydroxide solution and ether. The ether phase is removed, washed with water, dried over magnesium sulfate, filtered and the ether removed, leaving 9.17 g 1 - methyl - 4 - (3 - bromo - 10.11 - dihydro - 5 H - dibenzo [a, d] cyclohepten-5-ylidene (-piperidine receives.

Level B.

1 -Melhyl-4- (3-cyano-10,11-dihydro-5 H -dibenzo [a.d] -cyclohepten-5-ylidene) piperidine

A mixture of 9.17 grams (0.0249 moles) of 1-methyl-4- (3-bromo-10.11 -dihydro-5 H -dibenzo [a, d] cyclohepten-5-ylidene) piperidine, 4.58 g (0.0498 mol) copper (I) cyanide and 30 ml of dry dimethylformamide is stirred and heated under reflux for 6.5 hours.

54 ml of water, 27 ml of a saturated aqueous solution of Sodium cyanide and 75 ml of benzene were added. The mixture is stirred until it becomes a two-phase system receives. The benzene phase is removed and the aqueous phase is extracted with two 75 ml portions of benzene. The combined benzene phases are mixed with 100 ml of aqueous 0.1 M sodium cyanide and then with three 100 ml portions Water and washed over magnesium

sulfate dried. After filtering and evaporation of the benzene, 7.40 g of a crystalline one are obtained Residue. This material comes in one smaller. Volume of chloroform; i dissolves and about a Alumina column (38 cm 2.5 cm) given. the Column is eluted with chloroform. When the chloroform is evaporated, a crystalline product is obtained, that when recrystallizing from isopropyl alcohol pure l-methyl-4- (3-cvano-l (). l l-dihydro-5H-dibenzo [a.d] cyclohepten-5-ylidene ! -piperidine. Melting point 152 to 154 ° C.

Analysis calculated for CVH ₂₂ N ₂ :

Calculated ... C 84.04. H 7.05, N 8.91%;
found ... C 83.87, H 7.41. N 8.73%.

Level C

l-methyl-4- (3-carboxy-IO, l 1-dihydro-

5H-dibenzo [a, d] cyclohepten-5-ylidene) -

piperidine hydrochloride

A mixture of 1.0 g (0.00318 mol) I-methyl-4 - (3 - cyano - 10.11 - dihydro - 5 H - dibenzo [a, d] cyclohepten-5-ylidene) piperidine and 20 ml of 6N hydrochloric acid is stirred for 18 hours and under Heated to reflux. After cooling, the mixture is filtered and the collected residues become with on-hydrochloric acid and then with Washed ethanol. The dried material weighs 1.03 g (87%). When recrystallizing from absolute Ethanol gives pure l-methyl-4- (3-carboxy-10.11 - dihydro-5H - dibenzo [a, d] cyclohepten - 5 - ylidene) piperidine hydrochloride, that melts at 304-307 "C.

Analysis calculated for C ₂₂ H ₂₃ NO ₂ - 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%.

wash and then dried at 60 ° C., 2.88 g (49%) of the crystalline compound VIl (scheme II) obtained, which then with 60 ml of 611 hydrochloric acid is mixed and refluxed for 24 hours, with 2.80 g of the compound I (Scheme II). A mixture of 2.80 g of the compound I and 2 ml of boron trifluoride etherate in 200 ml of absolute ethanol are refluxed for 8 hours treated. The solution is evaporated to dryness and the residue is between ether and an aqueous sodium carbonate solution divided. The ether phase is removed and dried over magnesium sulfate and fillricrt and the ether is evaporated. 2.7 g of Älhyleslers VIII (Scheme II), the is dissolved in 100 ml of methanol with the addition of 10 ml of water and 10 ml of 30% hydrogen peroxide. After stirring for 48 hours at room temperature, a spatula tip of 5% Pt / C is added and the mixture is added the mixture is stirred for a further 2 hours in order to decompose the excess hydrogen peroxide. The mixture is filtered and the solvent is evaporated, whereby the chromatographically pure ethyl ester-N-oxide IX (Scheme 11) is obtained. 1 g of the ethyl ester N-oxide IX is dissolved in 10 ml of methanol, which Contains 2 ml of 2N potassium hydroxide, dissolved. 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, with stirring, glacial acetic acid becomes added dropwise until no further precipitate forms. The white solid that forms is removed by filtration and washed thoroughly with water. The product is collected, whereby one I-N-oxide sesquihvdral with a melting point of 208 to 209 ° C (decomposition, foaming). Thin layer chromatography shows that it is a homogeneous Product is.

Analysis calculated door C ₂₂ H ₂₃ NO., 1 1/2 H ₂ O:
Calculated ... C 70.19, H 6.96, N 3.72%;
found ... C 70.30, H 6.77, N 3.51%.

Example 2

Production of 1-methyl-l-oxo-4- (3-carboxy-

10.1 l-dihydro-5 H-dibenzo [a, d] cycloheptene

5-ylidene) piperidine

A solution of 4.13 g (0.0177MoI) 3-cyano-10.11 -dihydro-5H - dibenzo [a, d] cyclohepten - 5 - one (produced from 3-bromo ketone by reaction with CuCN according to the method described in Example 1, Step B using the appropriate reactants) in 40 ml of tetrahydrofuran is treated with 42 ml of 0.43 ml of 1-methyl-4-piperidylmagnesium chloride. The solution is stirred for 1 hour and then tetrahydrofuran is removed on a rotary evaporator. The red, oily residue is taken up in benzene and water is added dropwise until a clear, benzene supernatant solution and a gelatinous aqueous phase are obtained. The benzene is decanted and the gelatinous 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 evaporated on a rotary evaporator. The remaining residue is treated with acetonitrile treated. The crystalline product is collected by filtration, with additional acetonitrile report

The pharmacological effects of 10.1! -Dihydro - 3 - carboxy - cyproheptadine (compound according to the invention) and cy proheptadine (known comparative compound) are compared.

I. Appetite stimulating effect

Adult male cats, caged individually, are given water ad libitum and a preweighed amount of a cat feeder, the amount thereof, for a period of 3 hours each day is chosen so that there is always something left over. The feed intake on the day of drug tracking is compared with the corresponding value on the previous day. The compounds to be examined be taken 30 minutes before feeding in the form of a suspension in 1% methyl cellulose in water administered. The pure carrier is also administered in each case as a control. The compounds to be examined are administered in each dose to a group of 10 animals each.

The results are compiled in the table below.

Tabel

dose
(mg / kg, ρ. ο.)

Average feed intake

(Control / test)

M ethyl ce Il U loose
Methyl cellulose c
Melhvlccllulosc

181/195 210/198

195/184

Dose Average Fuller Intake

(mg / kg, p.o.) (control / test)

Cyproheptadine 10,11-dihydro-

0.0156

0.0312

0.0624

0.125

0.25

0.5

1.0

2.0

4.0

8.0

·) Significant increase in feed consumption )

* significant decrease in feed consumption j - * -> -

3-carboxy cyproheptadine 176/190 180/190 133/196 *) 126/152 *) 146/179 *) 174/204 *) 137/195 *) 175/198 179/220 *) 145/170 *) 146/256 *) 134/221 *) 154/243 *) 169/229 *) 136/175 140/212 *) 170/154 156/192 *) 182/67 + 184/252 *)

K)

15th

2 «

25th

30th

35

From the above values it follows that neither the vehicle alone nor a dose of 0.0156 mg / kg of either of the compounds under study causes an increase in feed consumption. Both test compounds make an appetite-stimulating one Effect at the next higher dose of 0.0312 mg / kg noticeable, suggesting that both compounds have a similar threshold dose. Above 1 mg / kg, the appetite-stimulating effect of cyproheptadine disappears while such an effect was not detectable with the compound of the invention up to a dose of 8 mg / kg is. Thus, both compounds have approximately the same threshold dose during the effective dose range of the compound of the invention is significantly larger compared to cyproheptadine.

Both compounds show a duration of action of more than 18 hours when administered at 0.5 mg / kg.

II. Antihistamine effect

55

Male and female guinea pigs of the Duncan-Hartley strain (200 to 300 g body weight) receive the test compounds orally 30 minutes before they are placed in single chambers and extracted from a histamine acrosol (0.5% base) for 3 minutes . The animals are then removed from the chamber and observed for symptoms of shortness of breath for 10 minutes. During this time, animals die without protective treatment. The ED ₅ ,, value is determined based on the proportion of animals saved from death. The EDsn value for the compound of the invention is 0.12 mg / kg and for cyprohepladine 0.29 mg / kg. The connection of the invention is therefore more effective by factor 2.3.

III. Anticholinergic effect
A. Central effect

Female CF, mice with a body weight of 18 to 25 g receive the compound of the invention, cyproheptadine or 1% methyl cellulose by the oral route 1 hour before an intravenous injection of 1.5 mg / kg oxotremorine. 5 minutes after the administration of oxotremorine, the behavior of the mice is examined on a wooden stick 2.5 cm in diameter rotating at 6 rpm. If a mouse can stay on the spinning rod for 15 seconds, it is considered to be protected against the tremor induced by oxotremorine. The En ₃₀ values are determined by regression analysis. These values are 1.9 mg / kg for cyproheptadine and> 80 mg / kg for the compound of the invention.

B. Peripheral Effect

The peripheral anticholinergic effect of the compounds to be investigated and of 1% methyl cellulose is determined on female CF, mice by measuring the pupil diameter 60 minutes after the compounds have been administered using an ocular micrometer. _{The dose (ED, 5} ) required to dilate the pupil to 1.5 micrometer units is determined by regression analysis. A value of 6 mg / kg results for cyproheptadine and a value of> 80 mg / kg for the compound of the invention.

From the above experiments it can be seen that the compound of the invention is approximately the same size Has an appetite-stimulating effect like cyproheptadine, but the dosage width of the compound the invention is much larger. The antihistamine activity of the compound of the invention is essential greater than that of the comparative compound, while anticholinergic effects in the compound of the In contrast to the comparative compound, the invention is practically completely absent.

IV. Toxicity

For the compound of the invention, the LD ₅₀ when administered intraperitoneally to mice is 191 mg / kg. The corresponding value for cyproheptadine is 55 mg / kg. For the compound of the invention, the corresponding dose when administered orally is 781 mg / kg.

Claims (2)

Patent claims: 1. 10.11 - dihydro - 3 - carboxycyproheptadine, its N-oxide and the low molecular weight esters, amides and pharmaceutically acceptable salts of these connections. 2. Process for the preparation of I-methyl-4- (3-carboxy-10,11 -dihydro-5H-dibenzo [a, d] -cyclohepten-5-ylidene) -piperidine of the formula 1 treated with carbon dioxide and, if desired, oxidized the free acid to the N-oxide or