JPS6033828B2 - 10,11-dihydro-3-carboxyproheptadine and its N-oxide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 10,11-dihydro-3-carboxyproheptadine (1-methyl-4-(3-carboxy-10,
11-dihydro-9-dibenzo[a,d]-cyclohepten-5-ylidene)piveridine) and the compound as an appetite stimulant and an antihistamine.

Also contemplated within the present invention are these salts,
esters, N-oxide derivatives and non-toxic, pharmaceutically effective compounds thereof. 10, 11 of the present invention
The free acid form of -hydro-3-carboxycycloheptadine has the following structural formula '1'. Unexpectedly, the 10,11-cyhydro-3-carboxycycloheptadine of the present invention was found to be an appetite stimulant and an antihistamine, substantially devoid of other pharmacological effects such as anticholinergic activity. did. This latter activity is a property of compounds structurally related to cyproheptadine and its dihydro derivatives. Therefore, the object of the present invention is to provide 10,11-cyhydro-3-carboxycycloheptadine and its salts, ester and N-oxide derivatives and non-toxic and pharmaceutically effective compounds thereof as appetite stimulants and antihistamines. This is the trowel provided. The 10,11-cyhydro-3-carboxycycloheptadine of the present invention converts 1-methyl-4-piveridylmagnesium halide into 3-fromo10,1
1-dihydro-9-day-dibenzo[a,d]cyclohepten-5-one is reacted with 1-methyl-4-(3-fromo-10,11-dihydro-5-hydroxy-9-day-dibenzo[a,d]cyclohepten-5-one in a suitable solvent such as tetrahydrofuran at 0°C to room temperature. - [a, d]cyclohepten-5-yl)piveridine is prepared and treated with a suitable dehydrating agent such as carboxylic acid, acid chloride, acid anhydride, alone or in a solvent such as chloroform or glacial acetic acid. 1-methyl-4-(3-furomo-1
0,11-dihydro-dibenzo[a,d]-cyclohepten-5-ylidene)piveridine is prepared and mixed with cuprous cyanide at 50-200 qo in a solvent such as dimethylformamide or hexamethylene phosphoramide.
It is reacted for 1 hour to convert into 3-cyano form, and then hydrolyzed with hydrochloric acid at far current temperature for 1 to 2 hours to obtain the desired 1-methyl-4-(3-cyano-10,11-) of the present invention. dihydro-hu-dibenzo, [a,d]cyclohepten-5
-ylidene)piveridine(10,11-dihydro-3-
(e.g., U.S. Pat. No. 33,069).
See No. 34 and No. 3014911. ). Alternatively, reaction of the ketone with cuprous cyanide followed by Grignard (
GrigMrd) reaction, and then reacted with a mineral acid to carry out a dehydration reaction and at the same time convert the 3-cyano group into a 3-carpoxyl form. The generated 10,11-sihydro3
-Carboxycycloheptadine can then be oxidized to the N-oxide of the present invention.

However, the oxidation is preferably carried out with the appropriate lower alkyl ester of the intermediate free acid prepared in a conventional manner. For example, the free acid in ethanol, BF3(C ratio CH2)20
Ethyl ester can be easily packaged by reacting in the presence of . Hydrogen peroxide is a suitable oxidizing agent and is reacted in any suitable inert protic solvent, such as aqueous methanol, aqueous ethanol, from 0 DEG C. to reflux for 1 to 7 hours. Compound (1) can also be prepared by preparing 3-carboxycycloheptadine, compound (x) in a dilute mineral acid solvent such as 0.1N hydrochloric acid with 1.5% palladium at room temperature in the presence of a noble metal catalyst such as 5% palladium on carbon. It can be conveniently produced by reduction with hydrogen gas at ~7k9/ml. Furthermore, as another method for producing compound (1), magnesium and 3-bromo-10,11-dihydrocyproheptadine are mixed in a Grignard reagent at -5 to 20°C in a solvent commonly used for Grignard reactions, such as ether or tetrahydrofuran. is prepared and then reacted with dry carbon dioxide gas at the same temperature until the reaction is completed.

Other methods for producing compound (1) or its ester include:
Compound (V) or (skin) is subjected to alcoholosis with sulfuric acid in a lower alkanol, particularly methanol.

If necessary, the resulting ester can be deesterified with acid or alkali using basic methods. The following figure illustrates the method. Figure 1: Suitable pharmaceutical salts of 10,11-cyhydro-3-carboxycycloheptadine and N-oxide of the present invention;
Ester and amide foams are made in conventional manner.

The salt form is the best and contains the following (
related to the nitrogen atom of the piveridyl residue): hydrochloride,
For example, salts based on carboxy groups are preferably salts made from alkali and alkali metals such as sodium and potassium. These salts are equivalent in potency to the free acid, taking into account the stoichiometric amounts used. In therapeutic methods and pharmaceutical compositions employing the compounds of this invention, the precise unit dosage form and amount administered will depend on the medical history of the individual being treated.

Therefore, it is left to the discretion of the doctor. But in general,
The compound of the invention may be administered at 0.0 per kilogram of body weight per day.
A good appetite-stimulating effect can be obtained when 1 to 10.0 milligrams is given. Suitable forms of administration of the compounds for increasing the appetite of livestock are in the form of solutions in drinking water or in the form of preformulated feed.

For human and veterinary administration, a number of oral dosage forms such as tablets, elixirs, aqueous suspensions containing from 0.01 to 10.0 milligrams per kilogram of body weight per day of the compound of the invention may be used. I can do it. For example, 2 to 50 mg per day containing 0.5 to 50 milligrams of a compound of the invention.
Tablets administered in 4 doses are good for human treatment. 2-4 times a day
Contains 0.1 to 10.0 milligrams of a compound of the invention administered in single doses.

Sterile solution for injection (typically given for human treatment)
are also suitable means of administration. If an antihistamine effect is required, the dosage forms and dosages mentioned above are adapted. The following examples are exemplary and are not intended to limit the products and compositions of the present invention.

Example 11-methyl-4-(3-carboxy-10,
Production process A of 11-dihydro-QH-dibenzo[a,d]cyclohepten-5-ylidene)piveridine: 1-Methyl-4-(3-bromo-10,11-dihydro 9H-dibenzo[a,d]cyclohepten-5-ylidene)-piveridine 150 ml of dry tetrahydride.

15.0 grams (0.0523 mol) of 3-bromo-10,11-dihydro-SH-dibenzo [a.
d] To an ice-cold solution of cyclohepten-5-one, 100 ml of a 0.53 M solution of 1-methyl-4-piveridylmagnesium chloride in tetrahydrofuran is added dropwise over 30 minutes. The solution is allowed to stand for 1 hour and then the tetrahydrofuran is removed on a rotary evaporator. Dissolve the remaining red oily residue in benzene and add water dropwise until a clear benzene top and a gelatinous aqueous phase are obtained. The benzene is decanted off and the gelatinous aqueous phase is extracted twice with 200 ml of hot benzene. The combined benzene phase is washed 6 times with 200 ml of water and then the benzene phase is removed on a rotary evaporator. The remaining residue is ground with acetonitrile, and the crystalline product is heated, washed with acetonitrile, and dried at 60°C. Product 1-Methyl-4-(3-fromo-10,11-dihydro-5-hydroxy-9-dibenzo-[a,d]cyclohebuten-5-yl)piveridine 9.66 grams (65 cents), mp 203-207q0.9 .66 grams of 1-methyl-4-(3-bromo-10,11-dihydro-5-hydroxy-QH-dibenzo[a,d]cyclohepten-5-yl)piveridine and 130 milliliters of 6
Add a mixture of normal hydrochloric acid to 0. Reflux immediately.

Most of the hydrochloric acid is removed on a rotary evaporator and the residue is partitioned between 5 percent sodium hydroxide and ether. The ether phase is taken, washed with water and dried over magnesium sulfate. When this is treated in a furnace and the ether is removed, 9.1
7 grams of 1-methyl-41 (3-fromo10,11
-dihydroQH-dibenzo[a,d]cyclohepten-5-ylidene)piveridiso. Step B: 9.17 grams (0.0249 mol) of 1-methyl-4-(3-thia/-10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)piveridine
1-methyl-4-(3-bromo-10,11-dihydroporridge-dibenzo[a,d]cyclohepten-5-ylidene)piveridine, 4. Spot Gram (0.0498 mol)
6. Candle a mixture of cuprous cyanide and 30 ml of dry dimethylformamide; Heat and reflux between insect cages.

To this cooled solution (25°C) are added 1 ml of water, 27 ml of a saturated aqueous solution of sodium cyanide, and 75 ml of benzene. Stir the mixture until it becomes a two-phase system. The benzene phase is taken and the aqueous phase is extracted twice with 75 ml of benzene. The combined benzene phases are washed with 100 ml of 0.1 molar aqueous sodium cyanide solution, three times with 100 ml each of water and dried over magnesium sulfate. After filtration, penzene was distilled off to give 7.40 grams of crystalline residue. This material is dissolved in a very small amount of chloroform and passed through an alumina column (15" x 1") packed in chloroform. The column is eluted with chloroform. The chloroform is removed to obtain a crystalline product. This was recrystallized from inpropyl alcohol to obtain pure 1-methyl-4-(3-cyano-10).
, 11-dihydro9-dibenzo[a,d]cyclohepten-5-ylidene) piberidine. Melting point 15
2-154pm ○. Elemental analysis: Calculated value as C22 22N2: C84.04, day 7.05 N8.91 Actual value:
C83.87, Day 7.41, N8.73 Step C: 1-methyl-4-(3-carboxy-10,11-dihydro-
9 days-Dibenzo[a,d]cyclohepten-5-ylidene)pibe IJ 1.0 g (0.00318 mol) of 1-methyl-4-(3-cyano-10,11-dihydro-dibenzo[a, d] A mixture of cyclohepten-5-ylidene) piperidine and 20 ml of 6N hydrochloric acid is heated and refluxed for one morning.

After cooling, the mixture is placed in a furnace. The collected solids are washed with 6N hydrochloric acid and then with ethanol. Dry weight 1.
03 grams (87 percent). Recrystallize from absolute ethanol to obtain pure 1-methyl-4-(3-carboxy-10,
11-dihydro 9-day-dibenzo[a,d]cyclohepten-5-ylidene)piveridine hydrochloride, melting point 304~
3070. Elemental analysis: Calculated value as C22 23N02HCI: C71.43, day 6.54, N3.79, CI
9.59 Actual value: C71.01, day 6.87, N3.7
3CI9.44 Example 21-methyl-1-oxo 4
Preparation of 1-(3-carboxy-10,11-dihydro-9H-dibenzo[a,d]cyclohepten-5-ylidene)piveridine 4.13 grams (0.0177 mol) of 3-cyano 1 in 40 ml of tetrahydrofuran
0,11-dihydro 9H-dibenzo[a,d]cyclohepten-5-one (Example 1: Prepared by reacting 3-furomoketone with CuCN by appropriately changing the reactants according to the method of Step B.

) is reacted with 42 ml of 0.43 mol 1-methyl-piveridylmagnesium chloride.
The solution is evaporated for 1 hour and then the tetrahydrofuran is removed on a rotary evaporator. Dissolve the remaining red oily residue in benzene and add water until a clear besozene liquid and a gelatinous aqueous phase are obtained. The penzene is decanted off and the gelatinous aqueous phase is extracted with two 100 ml portions of hot benzene. The combined benzene phase is washed six times with 200 ml each. benzene phase. Tarry
Distill with an evaporator. Triturate the retentate with acetonitrile. The crystalline product was filtered, further washed with acetonitrile, and dried at 60 qo.2. Spotted gram (
49%) of the crystallization dish (Figure 0, top figure). This was mixed with 60 ml of 6N hydrochloric acid and refluxed for 2 hours to give 2.80 grams of 1 (Figure 1, top). 2.
A mixture of 8 grams of 1 and 2 milliliters of phorontrifluoride-ether in 200 milliliters of absolute ethanol is refluxed for 8 hours.

The solution was drained, and the residue was partitioned between ether and an aqueous sodium carbonate solution. The ether phase is taken, dried over magnesium sulfate, filtered, and the ether is distilled off. 2.7 grams of ethyl ester W (Figure b, top) are obtained.

Dissolve this in 100 ml of methanol, 10 ml of water, and 10 ml of 30% hydrogen peroxide. After 48 hours at room temperature, add 1 teaspoon of 5% Pt/0. The mixture is allowed to stand for an additional 2 hours to decompose excess hydrogen peroxide. Filter the mixture;
The solvent is removed to give chromatographically pure ethyl ester-N-oxide (Figure 2, top). 1 gram of ethyl ester N-oxide (K) is dissolved in 10 ml of methanol containing 2 ml of 2N potassium hydroxide.

Heat this solution on a water bath for 2 hours. Remove the methanol and add 10 ml of water to the residue. Add glacial acetic acid dropwise under the sandpaper until no precipitate forms. The resulting white solid is removed by filtration and thoroughly washed with water. The product is taken and dried to give 11N-oxide sesqui/hydroleha. Melting point 208-209°C (decomposition, foaming), oc homogeneous. Elemental analysis: C22nd 23N03, 11/2nd day 20 Calculated value: C70.19 day 6.96N3.72 Actual value: C70.30, day 6.77, N3.51 Example 3 Pharmaceutical composition in 1 sen 1 milligram of 1-methyl-4-(3-hydroxy-10,11-dihydro-QH-dibenzo[a,d
A typical tablet containing cyclohepten-5-ylidene)piveridine is prepared by combining the active ingredients, calcium bricate, lactose, and starch in the amounts shown in the table below.

After thoroughly mixing these ingredients, add the corresponding amount of magnesium stearate and mix the dry mixture for another 3
Mix for a minute. This mixture is then compressed into tablets each weighing about 124 milligrams. 1-Methyl-4-(3-carboxy-10,11-dihydro 9-dibenzo[a,
d] cyclohepten-5-ylidene)piveridine hydrochloride, or 1-methyl-1-oxo-4-(3-carboxy-10,11-dihydro-9H-dibenzo[a,d]
Tablets containing cyclohepten-5-ylidene)piveridine are similarly prepared.

Tablet Composition Ingredients Milligrams per tablet 1-Methyl-4-(3-hydroxy-10,11-dihydro-OH-dibenzo[a,d]cyclohepten-5-ylidene) Piveridine 1 mg Calcium phosphate 52 mg Milk
sugar 60 mg starch
10 mg Magnesium stearate 1 mg Technical aspects of the present invention and related inventions are as follows.

1.Hydrolysis of a compound of formula a, followed by oxidation to the N-oxide if necessary; Reaction with magnesium to form a Grignard reagent, followed by reaction with carbon dioxide and, if necessary, subsequent oxidation to the N-oxide; or deesterification of compounds of formula {d} or deesterification of N-oxide derivatives. reaction (in the formula, R is lower alkyl);

A process for preparing compounds of the formula and N-oxide derivatives or pharmaceutically effective salts thereof.

2 10,11-dihydro-3-, which is characterized by reacting 3-bromo-10,11-dihydrocyproheptadine with cuprous cyanide and hydrolyzing the resulting 3-cyano-10,11-dihydrocyproheptadine. Process for Preparing Carboxybroheptadine and Non-Tablet Pharmaceutically Active Salts.

3-10,11-dihydro-3- characterized by hydrolysis of 3-cyano-10,11-dihydrocyproheptadine
Process for producing carboxycyp-hebutadine.

4 10, characterized by reacting 10,11-dihydro-3-carboxysibroheptadine with an oxidizing agent;
11-dihydro 3-carboxycyproheptadine-N
- Process for the preparation of oxides and non-synthetic pharmaceutically active salts and esters thereof.

5. A pharmaceutical composition characterized by a therapeutically effective amount of 10,11-dihydro-3-carboxycyproheptadine or its N-oxide or a pharmaceutically effective salt thereof and a pharmaceutical carrier.

6. A drug characterized in that it contains therapeutically beneficial amounts of 10,11-dihydro-3-carboxycyproheptadine and its non-toxic, pharmaceutically effective salts, esters and pharmaceutical carriers in unit dosage form. Composition.

7 10,11-dihydro-3-carboxysibroheptadine-N-oxide and non-toxic pharmaceutically effective salts, esters and drug carriers thereof containing a therapeutically effective amount in unit dosage form. A pharmaceutical composition characterized by:

8. A method of treatment characterized in that a therapeutically effective amount of 10,11-dihydro-3-carboxyp-hebutadine and its non-toxic, pharmaceutically effective salt, ester, is administered in unit dosage form.

9. A method of treatment characterized by the administration in unit dosage form of a therapeutically effective amount of 10,11-dihydro-3-carboxycyproheptadine-N-oxide and its non-toxic, pharmaceutically effective salts, esters. .

10. The invention in several forms as described above.

Claims (1)

[Claims] 1. A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼, its N-oxide or its salt, and its ester.