FI81570C - Process for the Preparation of Pharmaceutically Usable Phenyl (3-Hexamethyleneiminopropyl) Ketone - Google Patents

Description

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The present invention relates to a process for the preparation of phenyl- (3-hexamethyleniminopropyl) ketone. The present invention relates to a process for the preparation of phenyl- (3-hexamethyleniminopropyl) ketone as industrial products, the invention relates in particular to a process for the preparation of phenyl- (3-hexamethyleneiminopropyl) ketone and its addition salts. These new compounds can be used in therapy, especially as cardiovascular agents due to their useful vasodilating properties.

It is known that many (phenyl) - (aminoalkyl) ketone derivatives have already been described in which the phenyl ring is substituted by alkoxy and / or hydroxy groups, see in particular FR-A-1 492 256, FR-A-5636M, FR-A -2,404,003, FR-A-2,534,916, GB-A-1,078,975, GB-A-1,115,992, US-A-3,895,030 and A. BOUCHERLE et al., Chimie Thdrapeutique 2 (n: o 4) / 256-259, (1968), in which said derivatives have been described as anti-inflammatory agents, analgesics, antipyretics, anticonvulsants, sedatives, vasodilators and / or agents affecting the heartbeat (bradycardia). agents.

In particular, it is known from FR-A-2 404 003 that there is no structure-activity relationship in the phenyl (aminoalkyl) ketone group, but that the pharmacological effects change or disappear due to the nature of the substituents on the phenyl ring, the nature of the amino group and finally the CO group and the amino group. depending on the nature of the carbon groups.

It has now been found that the compounds of this invention, which are structurally different from those previously disclosed or proposed, are of particular interest as pharmaceuticals due to their superior vasodilatory properties and lower toxicity compared to their closest known analogs.

The results of the comparative tests shown in Table I below show that when comparing (a) to (2,4,6-trimethoxyphenyl) - (3-pyrrolidinopropyl) ketone hydrochloride (code No. LL 1656) disclosed in U.S. Pat. 3,895,030, sold under the trade name "Fonzylane" (international unregistered name: "buflome-dil hydrochloride"), which is a vasodilator reference substance, and (b) (2,4,6-trimethoxyphenyl) - (3-hexamethyleneiminopropyl) -li) -ketone hydrochloride (code no .: CRL 41 080) disclosed in FR-A 2 534 916 contains phenyl-3-hexamethyleneiminopropyl) ketone hydrochloride according to the present invention (code No: CRL 41 339) is much more active as a vasodilator when administered intraduodenally (duodenum) and is less toxic.

The novel phenylaminoalkyl ketone derivatives of this invention are characterized by, (a) a phenyl (3-hexamethyleneiminopropyl) ketone of formula (I): CO 2 (CH 2) 3 -N 2 - (1) or ( b) its addition salts.

The term "addition salt" as used herein means in particular acid addition salts which are prepared by reacting a free base of formula (I) with an inorganic or organic compound.

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3 81570 ten acids, and secondly it means ammonium salts.

Hydrogen chloride, hydrogen bromide, vinegar, ant, propion, oxalate, fumaric, maleic, amber, benzoic, cinnamon, almond, lemon, apple, wine, asparagine, glutamic, methanesulfonic and p-toluenesulfonic acids may be mentioned in particular as acids which can be used in the salt formation of the base of formula (I). CH3I and CH3Cl can be mentioned in particular from the compounds which enable the preparation of ammonium salts. In general, acid addition salts are more preferred than ammonium salts.

The base of formula (I) may be prepared by a method known per se, using conventional reaction mechanisms. The process recommended herein is that 4-hexamethyleneiminobutyronitrile is reacted with phenylmagnesium bromide for at least 1 hour at a temperature between 0-25 ° C in a suitable anhydrous solvent, preferably using more than 1 mole (preferably 2 moles) of C6H5MgBr per 1 mole of 4-hexamethyleneiminobutyronitrile. Suitable solvents for this include ethers such as dimethyl ether, diethyl ether, tetrahydrofuran and mixtures thereof.

Phenyl (3-hexamethyleneiminopropyl) ketone and its addition salts are useful agents in the treatment of diseases of the cardiovascular system; they act as peripheral vasodilators and agents for slow heartbeat.

The therapeutic composition according to the invention is one which, in addition to a physiologically acceptable excipient, contains as active ingredient at least one compound which is phenyl (3-hexamethyleneiminopropyl) ketone, a non-toxic addition salt thereof or a mixture thereof.

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It is natural that in this type of composition the active ingredient is used in a pharmaceutically effective amount.

According to the present invention, it is further recommended to use an agent which is phenyl (3-hexamethyleneiminopropyl) ketone or a non-toxic addition salt thereof for the manufacture of a vasodilator / for therapeutic use in patients suffering from and in need of lower limb circulatory disorders.

Other advantages and features of the invention will become more apparent from the following description of the preparation and the results of the pharmacological tests: however, these as such are not intended to limit the invention but only to illustrate it.

Preparation of phenyl (3-hexamethyleneiminopropyl) ketone hydrochloride

Example 1; code number; CRL 41339).

Other designations; 1-benzoyl-3-hexamethyleneiminopropane hydrochloride or (4-hexamethyleneimino-1-butyryl) benzene hydrochloride).

88 ml of a 3M solution of phenylmagnesium bromide in diethyl ether at 0 [deg.] (0.2650 mol) are poured in a solution of 22 g (0.1325 mol) of 4-hexamethyleneiminobutyronitrile in 50 ml of diethyl ether within 1 hour. The reaction mixture is left overnight at room temperature (15-20 ° C), then poured into a mixture of ice water (220 mL) and HCl 12 N (110 mL). Stir for 1 hour, after which the precipitate formed is isolated by filtration and then suspended in water. The solution is made alkaline with NaOH and then extracted with diethyl ether to give 26 g of a bright yellow oil. This oil is treated with diethyl ether and HCl.

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5 81,570 to give a precipitate which is recovered. Recrystallization from anhydrous ethanol gives 25.8 g (yield: 69.2%) of CRL 41 339 as a white powder which is highly soluble in water (100 g / l). Mp (dec.) ~ 192 C.

The results of the experiments performed with CRL 41 339 are shown below.

I. Toxicity

When administered intraperitoneally to mice, the LD-0 (highest non-lethal dose) is greater than 64 mg / kg, the LD-30 (lethal dose to 30% of treated animals) is approximately 128 mg / kg, and the LD-100 (lowest lethal dose for all treated animals) is less than or equal to 256 mg / kg.

II. Cardiovascular examination

Cardiovascular studies have been performed in non-butute anesthetized dogs, CRL 41 339 is administered intraduodenally as a solution in physiological saline (double distilled water containing 9 g / l NaCl at pH 7.5 (maximum concentration of CRL 41 339 is 32.4 mg / mL).

Three dogs (mean weight; 14.3 kg) are anesthetized with nembutal, administered CRL 41 339 intraduodenally in successive doses of 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg. kg, 5 mg / kg and 10 mg / kg, after which two of these dogs receive an additional dose of CRL 41 339 (10 mg / kg) intravenously.

Arterial blood pressure, heart rate, blood flow through the femoral artery, blood flow through the vertebral artery, and rectal and skin temperatures are measured.

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It has been found that CRL 41 339, when administered id, greatly increases (from 2.5 mg / kg - i.e. a cumulative dose of 4.1 mg / kg) flow in the femoral artery, but does not alter arterial blood pressure or heart rate, and that it lowers respiratory rate.

An additional dose of CRL 41,339 of 10 mg / kg i.v. causes a reduction in blood pressure and a small heart rate.

The effects of isoprenaline, when tested at a cumulative dose of 19.1 mg / kg CRL 41 339 when administered intradermally, are slightly reduced in terms of heart rate and are unchanged compared to diastolic blood pressure: isoprenaline at 1 μg / kg diastolic blood pressure changes from 117 mmHg (i.e. about 1.5 x 104 Pa) to 37 mmHg (i.e. 4.9 x 103 Pa after dosing of CRL 41 339, whereas the change is from 144 mmHg (i.e. about 1.9 x 10 4 Pa) ) to about 36 mmHg (i.e., about 4.8 x 103Pa) in control animals (i.e., anesthetized dogs given isoprenaline alone) and the heart rate changes from 175 beats / minute to 238 beats / minute after administration of CRL 41,339. , while in control animals said heart rate increases from 188 beats / minute to 253 beats / minute.

It has also been observed that noradrenaline-induced hypertension is reduced by CRL 41 339 (at a cumulative dose of 19.1 mg / kg id): noradrenaline at 2 μg / kg increases systolic blood pressure from 160 mmHg (i.e. about 2.1 x 104 Pa) 253 mmHg (i.e. approximately 3.3 x 104 pairs) at a dose of CRL 41,339.

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1,81570 thereafter at a cumulative dose of 19.1 mg / kg id, whereas in control animals (anesthetized dogs given noradrenaline alone) the systolic blood pressure rises from 181 mmHg (i.e. about 2.4 x 10 * Pa) to 301 mmHg (i.e. about 4 x 104 Paziin).

III Comparative Experiments The compound CRL 41 339 of the present invention has been compared with analogous compounds (i.e., reference compound A-1, and compound A-3) and a homologous compound (compound A-2). The results shown in Table I below show the superiority (Ex I) of CRL 41,339 over previously known, structurally related products in terms of both toxicity and peripheral vasodilatory activity.

IV Clinical trials

In clinical trials, good results were obtained as a vasodilator in a premature human after administration of CR1 41,339, especially in the treatment of (i) arterial inflammations in the lower extremities and (ii) arterial or venous ulcers in the lower extremities.

Dosage recommendations for administration of tablets or gelatin capsules to humans are that each contains 100 mg of CRL 41 339, with a dosage amount of 2-3 tablets or gelatin capsules per day.

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9 81 570 V Additional tests

The results of additional experiments with CRL 41 339 are shown below.

a) Mutagenic activity

CRL 41 339 has been found to have no mutagenic activity, especially against Salmonella typhimurium.

b) Effect on rabbit ear blood circulation

CRL 41 339 is administered in an aqueous solution of pH 6.5 (prepared just before use) to the stomachs of Half Top rabbit groups (3 males, average weight 3.5 kg; and 3 females, average weight 3.3 kg) at a dose of 2 ml / kg. The same animals are used as control animals for themselves, in which case they are given distilled water in the stomach in exactly the same volumes. The following parameters are measured: terminal small vein diameter, arterial pulse, ear skin temperature, heart rate, and rectal temperature.

It has been found that in awake Half Top rabbits, gastric administration of CRL 41 339 moderately dilates terminal small arteries for 0.5 h, greatly increases arterial pulse and arterial heart rate / heart rate ratio without altering heart rate, causes an important and sustained increase in ear skin temperature and does not diameter.

c) Effect on isolated canine veins

The perimeter of the external skin veins of the femoral arteries and legs of nembutal anesthetized dogs is cut and placed in 81 570 aerated (02: 96%; CO2: 4%, by volume) Krebs-Henseleit solution and kept at 37 ° C and stretched to 0.5 g. . These vessels are shrunk with either 10 μM noradrenaline in the presence of 10-6 M propanolol, or 50 mM potassium chloride (KCl) in the presence of 3 x 10-6 M phentolamine. CRL 41 339 is tested in cumulative doses.

CRL 41 339 has been shown to have no effect on femoral artery shrinkage induced by potassium chloride in the presence of phentolamine (n = 5) or external skin veins in the upper arm (n = 4), but it accelerates artery (n = 5) n = 4) end of shrinkage, the molar concentrations (CI-50) that reduce shrinkage by 50% are as follows:

- with artery CI-50 = (5.9 + 3.09) x 10 “6 M

- intravenously CI-50 = (1.3 + 0.68) x 10-4 M.

d) Effect on the hindquarters of rats perfundated

CRL 41 339 has an important vasodilatory effect in noradrenaline-contracted hindquarters of nembutally anesthetized rats.

The duration of said effect is increased by a dose of CRL 41,339. The important anti-noradrenaline activity of CRL 41 339 is believed to be related to the vasodilatory activity of said compound CRL 41 339.

e) Comparison of salts

Three dogs anesthetized with nembutal and weighing an average of 12.9 kg are used as control animals and are administered intravenously to the femoral artery phenyl (3-hexamethyleneiminopropyl) gel 11 81570 Toni hydrochloride, fumarate and citrate 1, code No. CR1 41 339, Ex 2, code No. CR1 41339A, and Ex 3, code No. CR1 41 339B) equimolar doses, respectively.

It was found that the amounts of compounds injected did not alter blood pressure or heart rate.

On the other hand, these three compounds have important arterial dilating activity as shown by the results shown in Table II below and can be seen from femoral artery flow (mean of 5 experiments per product and dose).

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Table II

i i i i i | Product Code No Dosage Passenger arterial flow | _ | _ | _ | _ (Ml / min) _ | j Ex 1 (a) | CRL 41 339 | 0 | 64 | j Ex 1 (a) j CRL 41 339 j 10 “7M j 83 | | Ex 1 (a) j CRL 41 339 j 10 “6M j 117 j | Ex 1 (a) CRL 41 339 | 10 "5M | 166 |

Il II I

I Ex 2 (b) CRL 41 339A 0 | 64 | j Ex 2 (b) I CRL 41 339A | 10 “7M | 76 j j Ex 2 (b) | CRL 41 339A j 10_6M j 117 j I Ex 2 (b) j CRL 41 339A j 10_5M j 168 j

II II I

I Ex 3 (c) | CRL 41 339B | 0 | 79 | | Ex 3 (c) j CRL 41 339B | 10 "7M j 90 j | Ex 3 (c) | CRL 41 339B j 10-6M | 127 | | Ex 3 (c) | CRL 41 339B | 10" 5M | 197 | I --------- ------------------------------------------------- 1 Notes (a) Phenyl (3-hexamethyleneiminopropyl) ketone hydrochloride is metered in at pH 6.

I I

| (b): phenyl- (3-hexamethyleneiminopropyl) ketone- | fumarate is administered i.a. at pH 4; |

I I

| (c): phenyl- (3-hexamethyleneiminopropyl) ketone- j citrate is administered i.a. at pH 4. |

I_I

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Claims (2)

A process for the preparation of pharmaceutically useful phenyl (3-hexamethylene-iminopropyl) ketone of the formula (I) (N-CO- (CH , characterized in that 4-hexamethylene imino-butyronitrile is reacted with phenylmagnesium bromide for at least one hour at a temperature between 0-25 ° C in a suitable anhydrous solvent, in a ratio of over one mole of phenylmagnesium bromide per one mole 4-hexamethyleneimino-butyronitrile. 2. Process according to claim 1, characterized in that phenyl (3-hexamethylene-iminopropyl) -ketone hydrochloride is prepared. Il