HK1118275A - 7-(2-(4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyrid-1-yl)ethyl) isoquinoline besylate salt, preparation and therapeutic use thereof - Google Patents

Description

7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate, its preparation and therapeutic use

[0001] The present invention relates to novel salts of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline, the preparation thereof and therapeutic use thereof.

[0002] Document WO 2001/029026 describes 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline of the following formula (I).

Among other derivatives of tetrahydro-pyridine, this compound is described as a modulator of TNF-alpha activity (tumor necrosis factor in English)

[0003] The document WO 2001/029026 describes 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline as the free base or in the form of different salts, e.g. dihydrochloride, fumarate.

[0004] It has now been found that the monobenzenesulfonate salt-forming form of this same compound (also known as the benzenesulfonate salt) has advantageous properties which make it particularly suitable for use as an active ingredient in pharmaceutical products.

[0005] Accordingly, an object of the present invention is 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate, its preparation and therapeutic use.

The salt of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline besylate is defined in the following formula (II):

[0006] surprisingly, it has in fact been demonstrated that the besylate form of the compound of formula (I) has stability properties, especially with respect to humidity, also improved compared to the dihydrochloride or fumarate salt of this same compound.

[0007] It has also been shown that the hygroscopicity properties of the benzenesulfonate form of the compound of formula (I) are also improved compared to the dihydrogensulfate, diphenylsulfonate or dihydrochloride salt of this same compound.

[0008] According to the invention, the compounds of formula (I) can be prepared according to the process described in application WO 2001/029026. Hereinafter, when the preparation of these starting materials and reactants is not described, they are commercially available or described in the literature, or can be prepared according to the methods described therein or known to those skilled in the art.

[0009] The advantages associated with the besylate forms of the compound of formula (I) compared to the free base form or other salt forms (e.g. dihydrochloride and fumarate) can be derived from the physico-chemical analysis described below.

Example 1: preparation of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate

3.86g of benzenesulfonic acid were dissolved in 50mL of ethanol at 70 ℃ with stirring. 11g of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline in 60mL of ethanol is added to the ethanol solution of benzenesulfonic acid with stirring. The solution was then cooled from 70 ℃ to 20 ℃ with a thermal gradient of-20 ℃ per hour.

The recovered precipitate was then filtered, washed twice with 22mL portions of ethanol, and dried under vacuum at 50 ℃.

The title product was obtained in 99% purity as a white powder.

Yield: 87.3 percent

PF＝189.5℃

¹H NMR (303kHz, methanol-d)₄) δ (ppm): 2.93 (complex, 2H), 3.35-3.42 (complex, 2H), 3.59-3.64 (complex, 2H), 3.66 (wide t, J-5.13, 2H), 4.08 (wide s, 2H), 6.24(ddd, J-6.89, 3.46, 1.62, 1H), 7.34 (complex, 2H), 7.37 (complex, 1H), 7.57(t, J-7.70, 1H), 7.62(d, J-7.72, 1H), 7.72(d, J-7.91, 1H), 7.73(s, 1H), 7.79(dd, — 1.72, 1H), 7.81(dd, 2H), 7.82(d, J-5.57, 1H), 7.94(d, 1H), 8.94 (d, 8H), 8.05 (d, 8, 1H), 8.05, 1H), 8.5H, 1H, 5H, 1H, 8H, 1H, 5H, 1H, 7.9.

Comparison of the physico-chemical properties obtained with different salts.

Example 2: thermal stability

[0011] The chemical stability of the compounds of formula (I) in the form of dihydrochloride, dihydrogensulfate, fumarate, dibenzenesulfonate and monobenzenesulfonate salts was investigated.

Each of the five salts was subjected to heat, humidity and light under the following conditions:

-at a temperature of 80 ℃ for 14 days,

14 days at a temperature of 80 ℃ and a relative Humidity (HR) of 80%,

at 400W. h. m^-2Is exposed to light.

Table I below shows the results of the measurements carried out by high performance liquid chromatography (HLPC).

TABLE I

Condition/salt	Dihydrochloride salt	Dihydrogen sulfate salt	Fumarate salt	Diphenyl sulfonates	Benzenesulfonic acid salt
						Initial purity	97.0％	93.3％	97.9％	97.5％	98.2％
At 80 deg.C for 14 days	95.6％	91.9％	96.7％	97.5％	97.9％
						At 80 ℃ and 80% HR for 14 days	92.9％	88.5％	32.4％	96.2％	96.5％

It is thus clear that the compound of formula (I) in the form of its besylate salt shows the highest thermochemical stability.

Benzenesulfonates the compounds of formula (I) are also the least degrading salts when tested in temperature and humidity.

Example 3: water content

[0012] The water content of the five salts was investigated using thermogravimetric Analysis (ATG).

The ATG test was performed using a TA8000 instrument equipped with a TGA850 assembly. Temperature correction is usually done using indium melting.

The experimental parameters used were as follows:

initial temperature: 25 deg.C

Heating speed: 10 ℃/min

Final temperature: the dihydrochloride is 250 ℃, the fumarate is 300 ℃, the dihydrogensulfate is 200 ℃ or 250 ℃, and the diphenylsulfonate and benzenesulfonate are 250 ℃ or 300 ℃.

Purging of the system was performed using nitrogen at a flow rate of 70 mL/min.

The crucible used was a 70 μ l quartz crucible.

These results are listed in table II below.

TABLE II

Salt (salt)	Mass loss (% weight/weight)	Nature of the solvent
			Dihydrochloride salt	11.0	Water (W)
Dihydrogen sulfate salt	2.06	Solvent + water
			Fumarate salt	0.45	Solvent + water
Diphenyl sulfonates	0.72	Water (W)
			Benzenesulfonic acid salt	0.11	Water (W)

[0013] The ATG curve for the dihydrochloride salt shows that each anhydrous salt of the salt contains three water molecules, which can be considered to exist as the trihydrate. Water loss occurs at relatively low temperatures, which accounts for the weakly binding nature of this hydrate. Such a form is clearly disadvantageous in that its stoichiometric amount may vary with environmental conditions. Such results may indicate that the active ingredient may exist in different hydrate forms.

The fumarate salt showed no significant mass loss on the ATG in the range of 25 ℃ to 110 ℃, due to residual solvent and weakly bound water. Similarly, the mass loss of the dihydrogen sulfate and diphenylsulfonate salts on the ATG is due to residual solvent with weakly bound water followed by product decomposition at high temperature.

The dihydrogen and diphenyl sulfonates showed significant water pickup during the adsorption cycle at 30-80% relative humidity, which pharmaceutical compositions generally sought to avoid. The hysteresis observed on desorption indicates that the physical form of the product under investigation has changed, which is generally undesirable for active substances.

[0014] DVS tests were performed using the DVS-1 system. 20-32mg of product was used for each analysis, the temperature being maintained at 25 ℃. + -. 0.2 ℃. Nitrogen was used as a carrier gas at a flow rate of 100mL/min in the sample chamber. When 0.0002% equilibrium (dm/dt) was reached within 5min, the relative humidity was changed to 30% in increments according to a cycle from 30% to 95% and then to 0%.

The adsorption isotherm of the fumarate salt indicates that this salt is less hygroscopic. The adsorption isotherm of the dihydrochloride salt showed that 1.9 wt% water was obtained during the adsorption cycle at 30-80% relative humidity. However, this apparent adsorption is still acceptable because one observes a low hysteresis effect over the entire processing range of 20% to 95% HR.

Conversely, the benzenesulfonate salt was not hydrated, indicating excellent performance when the water adsorption isotherm was measured. This salt showed the worst hygroscopic of all of these tested salts. No hysteresis effect is recorded when measuring adsorbed and desorbed DVS, which may become significant for drug development.

[0015] From these analytical results, it follows that the besylate salt of the compound of formula (I) has properties of hygroscopicity and stability which are superior to those of the other tested salts, both under dry heat and under moist heat, and which make it particularly suitable for the manufacture of pharmaceutical products.

The physicochemical properties of the compound of formula (I) in the form of a benzenesulphonate also allow preservation under the usual conditions compatible with the light, temperature and humidity present, without the need to take very mandatory precautions.

[0016] The 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate salt has the property of modulating TNF- α. Thus, it can be used for the preparation of a medicament, in particular for the treatment of diseases associated with immune or inflammatory disorders.

[0017] Such diseases include atherosclerosis, autoimmune diseases, diseases that cause demyelination of neurons (e.g., multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases, pulmonary idiopathic fibrosis, cystic fibrosis, glomerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorption, osteoporosis, Paget's disease, multiple myeloma, retinitis pigmentosa, toxic shock, sepsis, endotoxic shock, graft-versus-host reaction, graft rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, disseminated lupus erythematosus, hemodynamic shock, ischemic pathology (myocardial infarction, stroke, myocardial ischemia, coronary vasospasm, angina pectoris, cardiac insufficiency, heart attack), post-reperfusion ischemia attack, malaria, mycobacterial infection, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpes virus), opportunistic infections associated with aids, tuberculosis, psoriasis, atopic and contact skin diseases, diabetes, cachexia, cancer, radiation-related damage.

[0018] Thus, according to a further aspect, the present invention is directed to a pharmaceutical product comprising 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate salt.

These drugs are in therapy, in particular in the treatment and prevention of clinical symptoms associated with the degeneration or inflammation of the immune system or in which inflammation and immune complications may be involved.

[0019] Thus another object of the invention is the use of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate for the preparation of a medicament for the treatment of a disease associated with an immune or inflammatory disorder.

[0020] According to other aspects, the present invention relates to pharmaceutical compositions containing as active ingredient 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate salt. These pharmaceutical compositions contain an effective dose of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline besylate salt, and at least one pharmaceutically acceptable excipient. The excipients may be selected from conventional excipients known to those skilled in the art depending on the pharmaceutical dosage form and the desired mode of administration.

[0021] These pharmaceutical compositions can be in any form suitable for oral, parenteral or intravenous administration, such as tablets, dragees, capsules, troches, oral or injection suspensions or solutions and the like, in combination with suitable excipients. The dosage of all these dosage forms is advantageously such as to allow the administration of 1 to 1000mg per patient in one or more doses per day. There may be special cases where either high or low dosages are appropriate; such dosages are not outside the scope of the present invention.

According to the conventional practice, the appropriate dose for each patient is determined by the physician according to the mode of administration, the weight and the response of the patient. By way of example, a unit dosage form for tablet administration may contain the following composition:

-7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-

Tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate 50.0mg

-croscarmellose sodium: 6.0mg

-corn starch: 15.0mg

-hydroxypropyl methylcellulose 2.25mg

-magnesium stearate: 3.0mg

[0022] According to another aspect of the invention, the invention also relates to a method of treatment of a clinical condition associated with inflammation or with a deterioration of the immune system, or where inflammation and immune complications may be involved, which comprises administering to a patient an effective amount of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline besylate salt.

Claims (6)

1. 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline besylate salt.
2. A process for the preparation of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate, characterized in that a solution of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline in ethanol is reacted with a solution of benzenesulfonic acid in ethanol.
3. 3. Pharmaceutical product, characterized in that it contains 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate salt.
4. 4. Pharmaceutical composition, characterized in that it comprises as active ingredient 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline benzenesulfonate salt and at least one pharmaceutically acceptable excipient.
5. Use of 7- (2- (4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydro-pyridin-1-yl) ethyl) isoquinoline besylate salt in the manufacture of a medicament for the treatment of a disease associated with an immune or inflammatory disorder.
6. 6. Use according to claim 5, for the preparation of a medicament for the treatment of rheumatoid arthritis.