CZ24894A3 - Quaternary ammonium derivatives (-) and (+)-10- (azabicyclo/2.2.2/-oct-3-yl-methyl)-10h-phenothiazine, process of their preparation and pharmaceutical preparations in which they are comprised - Google Patents

Abstract

The description refers to dextrorotatory (+) and levorotatory (-) enantiomorphs of quaternary ammonium derivatives of 10-(1-azabicyclo[2.2.2.]oct-3-yl-methyl)-10 H-phenothiazine as per general formula (I), where R = C1-4 alkyl, cyclopropyl, X = halogen, dimethyl sulphate, p-toluenesulphonic acid as well as to the preparation of same and to the pharmaceutical compositions containing them.

Description

Quaternary ammonium derivatives of (-) and (+) - 10- (1-azabicyclo [2.2.2] oct-3-yl-methyl) -ΙΟΗ-phenothiazine, method of manufacture and pharmaceutical compositions containing them

Technical field

The present invention relates to dextrorotatory (+) and levorotatory (-) enantiomorphic quaternary ammonium derivatives of 10- (1-azabicyclo [2.2.2] oct-3-ylmethyl) 10H-phenothiazine, a process for the preparation of these compounds and pharmaceutical compositions thereof. they contain and can be used to treat diseases of allergic origin and other diseases in which bronchospasm occurs.

BACKGROUND OF THE INVENTION

From the literature, a derivative of phenothiazine, 10- (1-azabicyclo [2.2.2] oct-3-ylmethyl) -1CH-phenothiazine of the formula A (A'i, which has been described, for example, in French patent 2,034,605, together with their antihistamine properties.

European Patent Specification No. 159,059 (Guidotti S.o.A. Laboratories) discloses quaternary derivatives of the compound of formula A in the form of racemic modifications having significant activity against bronchial spasms.

SUMMARY OF THE INVENTION

It has now been unexpectedly found that quaternary mequitazine derivatives, namely enantiomeric quaternary derivatives of the general formula I

where

R is C 1 -C 4 alkyl or cyclopropyl;

X is a halogen atom, a dimethylsulfate group, or a p-toluenesulfonic acid residue, have different properties, so that each is particularly suitable for use for different therapeutic purposes.

The basis for the formation of said derivatives is the asymmetric carbon atom at the 3-position in the 1-azabicyclo [2.2.2] octane portion of the molecule. Every racemic quart! the derivative thus consists of two enantiomorphs (+) and (-) in a ratio of 50:50.

The term C 1 -C 4 alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isooutyl and tert-butyl.

The halogen atom may be iodine, bromine or chlorine.

In particular, it has been found that both enantiomorphs of formula I are equally effective against acetylcholine, but the dextrorotatory enantiomorph (+) is substantially more potent against histamine than the corresponding levorotatory enantiomorph. In addition, the dextrorotatory derivative is less toxic than the levorotatory derivative.

The dextrorotatory enantiomorphic compound is therefore a substance particularly suitable for use in the treatment of bronchoconstrictive and allergic diseases, particularly bronchial asthma and rhinitis, and other diseases in which histamine is involved, one of the major mediators of bronchoconstriction in asthma and abnormal nasal mucosal responses in the case of allergic rhinitis as well as diseases in which acetylcholine is involved, which controls muscle tension in the respiratory system and secretion of the nasal mucosa. It is known that there are a number of mediators involved in bronchoconstriction in asthma and rhinitis, the extent of which depends on the type and stage of the disease, as well as on the individual patient. The fact that the aforementioned dextrorotatory enantiomorphic compound has both types of effect at an acceptable concentration makes it particularly interesting for use in the treatment of said diseases.

The enantiomorphic compounds of the present invention can be obtained by separating racemic maquitazine of formula A, which is a mixture of both, into the left-handed and left-handed enantiomorphic derivatives by conventional chromatographic separation using a chiral phase. Particularly suitable is the use of cellulose-based preoarative chromatography columns, with a 94: 6 / hexane / ethanol / 93: 2 / hexane / methanol / 93: 0/3 mixture of hexane / methanol as eluent. The enantiomorphic compound thus obtained is then quaternized by treatment with the reagents (hereinafter referred to as the Example) without, however, being limited to its use.

The enantiomorphic compounds of the invention are particularly suitable for the manufacture of pharmaceutical preparations for topical use mainly by inhalation or directly on the nasal mucosa and also for oral administration. The type of pharmaceutical composition suitable for administration of the active ingredient according to the invention will be further exemplified in Example 3.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (-) - 1-methyl-3- (10H-phenothiazin-10-ylmethyl) -1-azoniabicyclo [2.2.2] octanodide] (I), R = CH 2, X = I / g, 0 1 mole of the (-) enantiomorphine mequitazine derivative obtained by preparative chromatographic separation on a column packed with a chiral phase from a racemic mixture is suspended in 200 ml of acetonitrile. The suspension is stirred for 10 minutes until homogenization is achieved. Methyl iodide (50 ml, 0.2 mol) was added and the solution heated to 50 ° C for 16 hours. The reaction mixture was then allowed to cool first to 20 ° C and then to 0 to 4 ° C and maintained at this temperature for 43 hours. The crystalline solid is filtered off under vacuum, washed with ethyl ether on the filter and then dried under vacuum at 50 ° C to constant weight.

In this way, 42 g of the desired product are obtained in a yield of S0% as a cream-colored crystalline solid having the following physicochemical properties:

(o)

HPLC Nucleosil C ^ g, column 150 x 4.6 eluent: MeOH / CHgCN / NH4 PC4 0.425% = 43/25/32 flow rate: 0.5 ml / min, lambda = 254 nm injection amount: 4 gamma in methanol: main peak retention time: 6.4 min melting point: 142-144 ° C / alpha / ³⁰ : -21.3 ° (1% CH, OH)

H, 5.59; I, 27.35; N, 6.03; S, 6.89 Found: C, 54.06; H, 5.60; I, 27.20; N, 5.94. 6.80%.

• β-ΝΜΚ (CDCl 3): 7.21 - 6.84 (2m, 8H, 1 ', 2', 3 ', 4,' 6 ', 7', 8 ', 97), 4.27- 3.93 (m, 2H, (9)), 9.93-3.46 (m, 6H, (2, 6, 7)), 3.21 (s, 3H, (10)), 2.71 (m, 1H, (3)), 2.30 (d, 1H, (4)), 1.99-1.77 (2m, 4H, (5,8)), ¹³ C-NMR (CDCl 3): 144.62 (C-9 ' a, C-10 ' a), 127.77 (C-1 ', C.4 ', C-6 ', C-9 '), 126.97 (C-4 ') α, C-5'a), 123.26 (C-2 ', C 3'),

116.25 (C-3 ', C-7 '), 60.49 (C-9), 57.38 (C-6), 57.21 (C-7),

52.54 (C-3), 43.30 (C-2), 32.05 (C-10), 24.87 (C-8), 20.90 (C-4), 19.57 (C) -5).

The optical purity of the product was determined using the free base by HPLC on a chiral phase column. column: CHIRACSL OD ^(R) eluent: hexane / ethyl alcohol = 94/6 flow rate: 0.5 ml / min, lambda = 254 nm injection amount: 4 gamma in hexane / ethanol major peak 93% at retention time 15.03 min.

Example 2 (+) - 1-methyl-3- (1H-phenothiazin-10-ylmethyl) -1-azodiabicyclo [2.2.2] octanodide] (I), R = CHg, X = I / g, 0, 03 mol of (+) - enantiomorphic mequitazine, obtained by separation of the racemic mixture by preparative chiral phase column chromatography, is suspended in 160 ml of acetonitrile. The suspension is stirred for 10 minutes until homogenization. Methyl iodide (40 mL, 0.64 mol) was added and the resulting solution was heated to 50 ° C for 16 hours. The reaction mixture was allowed to cool to 20 ° C and then to 0 to 4 ° C for 48 hours. The resulting solid crystals are suction filtered, washed on the filter with ethyl ether and then dried under vacuum at 50 ° C to constant weight.

like who

In a yield of 94%, 35 g of the desired product are obtained as a white solid crystalline solid having the following physicochemical properties.

The ΊH-NI-1R and the values are identical to those of Example 1.

HPLC: data as in Example 1.

Chiral phase HPLC: major peak (97%) at retention time 16.73 minutes.

M.p .: 142-145 ° C.

/ alpha / g ⁰ + 21 ° (1% _CH3 OH)

5.59, I 27.35, N 6.03, S 6.89% 5.62, I 27.18, N 5.96, S 6.82%.

Analysis for ^C 25 ^H 2i ^IK 2 ³ Calculated: C 54.31, H Found C 54.00, H

Example 3

In vitro tests

In a small cylinder fitted with a metering valve, a pharmaceutical composition having the following composition was loaded:

active ingredient / (+) or (-) - compound

1) 100 ALIGN! mg Sorbitan trioleate (Arlacel 85 ^R ) 20 May mg Freon 11 ^R 3380 mg Freon 12-114 ^R (65: 35) 10500 mg

The roller allows the measurement of a single dose containing 50 to 200 micrograms of active ingredient.

Tests for efficacy

The enanthicorphic compounds of Examples 1 and 2 were compared to verify their pharmacological and toxicological properties (particularly with respect to antagonism of acetylcholine and histamine on isolated guinea pig trachea) to inhibition of guinea pig acetylcholine and histamine induced bronchoconstriction (Xonzett-Roessler method) ) and acute toxicity in mice.

The results showed that both enantiomorphic compounds are competitive acetylcholine and histamine antagonists in guinea pig trachea. Both substances are equally effective in the case of acetylcholine (? A ₂ is 7/96 for levorotatory and 7/31 for dextrorotatory derivative) / but the dextrorotatory compound (+) is significantly more potent (pA ₂ 9/05) than the levorotatory compound. -) (pA ₂ 7/09) in the case of histamine. The results (obtained in vitro were confirmed by in vivo tests), which showed that both compounds are capable of inhibiting the bronchial constriction induced by acetylcholine with the same potency, but when this condition was induced by histamine, the dextrorotatory compound (+) is far from more potent than the levorotatory compound (-), ED-θ is 63 for the dextrorotatory and 239 nmol / kg for the levorotatory compound.

Toxicological tests

In acute toxicity tests following intravenous administration of both substances in mice, it has been shown that LD ^ g and 95% confidence limits for the dextrorotatory substance are 3.65 (3.45 - 3.36) mg / kg, so this substance is substantially less Toxic than the levorotatory derivative whose LD 50 is (2.63 (2.61 -2.74) mg / kg).

The results of the efficacy tests are summarized in Table 1 below.

Table 1

In vitro tests

Antagonisation of acatylcholine and histamine on isolated guinea pig

9A2 acatyloholin pA hist histamine levorotatory (-) example 1 7.95 7.09 levorotatory (+) example 2 7.81 8.05

In vivo tests

Inhibition of bronchospasm induced in guinea pigs by acetylcholinam or histamine and acatyloholin histamine

ED _5Q (nmol / kg) left-handed (-) 65 239 Example 1 Right-handed (+) Example 2

Acute toxicity to mice

LD-θ / mg / kg and maze confidence at 95%) levorotatory compound (-) Example 1 2.53 (2.51-2.74) dextrorotatory compound (+) Example 2 3.55 (3.45-3, 35).

Represented by:

Claims (11)

PATENT CLAIMS 1. Quaternary ammonium darivatives of (-) - 10- (1-azabicyclo [2.2.2] oct-3-yl-methyl) -phenothiazine of the general formula I wherein: R is alkyl of 1 to 4 carbon atoms or cyclooropropyl; X represents a halogen atom / dimethyl sulfate group or a p-toluenesulfonic acid residue. 2. Quaternary ammonium derivatives of (+) - 10- (1-azabicyclo [2.2.2] oct-3-ylmethyl) -ΙΟΗ-phenothiazine of the general formula I X wherein R and X are as defined in claim 1. Quaternary ammonium derivatives according to claims 1 and 2, wherein R represents methyl and X represents iodine. Quaternary ammonium derivatives of the formula I according to claims 1 and 2, wherein R represents methyl and X represents chlorine. Quaternary ammonium derivatives of the formula I according to claims 1 and 2, wherein R represents methyl and X represents bromine. Quaternary ammonium derivatives of the formula I according to claims 1 and 2, wherein R represents methyl and X represents a dimathylsulfate group. Quaternary ammonium derivatives of the formula I according to claims 1 and 2, in which R represents methyl and X represents a p-toluenesulphonic acid residue. A process for the preparation of quaternary anonium derivatives of (-) and (+) -10- (1-azabicyclo [2.2.2] oct-3-yl-4-yl) -10H-phenothbiazine of the formula I wherein R and X are as defined above, characterized in that the racemic mixture of mequitazine of formula A (A) is separated into the corresponding dextrorotatory and levorotatory enantiomorph by chromatographic separation using a chiral phase and the enantiomorph derivatives thus obtained are quaternized using appropriate reagents. Pharmaceutical composition for the treatment of bronchial asthma and rhinitis, characterized in that it comprises, as its active ingredient, a dextrorotatory (+) - enantiomorphic compound of the formula I according to claims 2 to 7. Pharmaceutical composition for the treatment of bronchial asthma, characterized in that it comprises, as its active ingredient, a levorotatory (-) - enantiomorphic compound of the formula I according to claims 1 and 3 to 7. A process for the manufacture of a pharmaceutical composition according to claims 9 and 10, characterized in that a pharmaceutically effective amount of (+) or (-) - 10- (1-azabicyclo [2.2.2] oct-3-ylmethyl) quaternary ammonium derivative 1-OH-fanothiazine of formula I wherein R and X are as defined in claim 1, mixed with suitable carriers for the manufacture of a pharmaceutical composition suitable for topical use or for oral administration.