KR101022335B1 - 4-2-dimethylamino-1-1-hydroxycyclohexylethylphenoxy derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and composition for the the prevention and treatment of central nervous system disease containing the same as an active ingredient - Google Patents

Abstract

The present invention provides a (4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a central nervous system containing the same as an active ingredient. The present invention relates to a composition for preventing and treating diseases, wherein the novel 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy derivative or a pharmaceutically acceptable salt thereof according to the present invention is a sugar. It exhibits equivalent activity to the biological and pharmaceutical activities of venlafaxine and its salts known in the art, and in particular, has better solubility in water than conventional venlafaxine derivatives: depression (including major depressive disorders, bipolar disorders and cases of depression), fibromyalgia , Anxiety, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder (premenstrual syndrome), attention deficit disorder, obsessive-compulsive personality disorder (including hair growth), social anxiety disorder, Eye disorders, autism, schizophrenia, obesity, anorexia nervosa, anorexia nervosa, Gilles de la Tourette Syndrome, vasomotor redness, cocaine and alcoholism, sexual dysfunction (including premature ejaculation), borderline personality disorder, chronic fatigue Prevention of central nervous system diseases including syndromes, urinary incontinence, pain (including neuropathic pains such as migraine, chronic low back pain, ring pain, central pain, diabetic neuropathy and postherpetic neuropathy), and Raynaud's syndrome And useful for treatment.

Central nervous system, Serotonin, Venlafaxine, ODV, O-desmethylvenlafaxine

Description

Novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative or pharmaceutically acceptable salt thereof, preparation method thereof, and prevention of central nervous system disease containing the same as an active ingredient and Therapeutic composition {4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivatives or pharmaceutically acceptable salts according to the formula and composition for the the prevention and treatment of central nervous system disease containing the same as an active ingredient}

The present invention provides a novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a backbone containing the same as an active ingredient. It relates to a composition for preventing and treating neurological diseases.

The conduction of excitement through nerves and the action of major organs are due to neurotransmitters. These neurotransmitters include cholinergic neurons that secrete acetylcholine by stimulation in the central and peripheral nervous systems, and adrenergic neurons that secrete noradrenaline. In addition, there are many neurotransmitters that are important in the central nervous system, including dopamine and serotonin. Adult GABA (γ-aminobutyl acid) is an example. Among them, the serotonin nervous system is closely related to mental illnesses such as worry, anxiety and depression. It is known that the distribution of the receptor is significantly reduced in patients with schizophrenia and dementia. The serotonin system in the brain is an important neurotransmitter that controls behaviors and physical functions, including anxiety and emotional anxiety, and is known to regulate various physiological and mental states.

In the central nervous system, serotonin (5-HT) is associated with the etiology of many diseases, particularly depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder. It is known to be an important cause of psychosis, such as migraine and panic disorder. Recent advances in pharmacy, molecular biology, and genetics of the serotonin nervous system have enabled the development of more advanced drug therapies for the treatment of certain central nervous system diseases. In fact, the general treatment for these diseases is currently believed to work by modulating the physiological activity of serotonergic substances.

O-desmethylvenlafaxine (ODV), a major metabolite of venlafaxine, blocks resorption of serotonin and norepinephrine [Klamerus, KJ et al., "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite ", J. Clin. Pharmacol. 32: 716-724 (1992). Thus, the ODV is used for the treatment of central nervous system diseases, especially depression, generalized anxiety disorders (see US 5,916,923; US 6,444,708; US 6,274,171; US 6,403,120; US 6,419,958; US 6,310,101). Venlafaxine hydrochloride tablets are sold under the trade name EFFEXOR.

The ODV has the chemical name 1- [2- (dimethylamino) -1- (4-phenol) ethyl] -cyclohexanol and is exemplified as fumarate salt in US Pat. No. 4,535,186. However, the fumarate salt of ODV has inadequate physicochemical and permeable properties. ODV is also illustrated as the free base in WO 00/32555.

The prior art associated with the ODV is as follows.

Succinate forms of ODV are disclosed in US Pat. No. 6,673,838. The succinate monohydrate form of ODV is known to be incorporated into sustained release hydrogel tablets to reduce side effects such as nausea, vomiting, diarrhea, and abdominal pain.

WO 02/064543 A2 discloses a formulation showing the use of hydroxypropyl methylcellulose (HPMC) as a hydrogel matrix.

US 4,535,186 discloses (R / S) -1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol and its metabolite 1- [2- (dimethylamino) -1- (4-hydroxyphenyl) ethyl] cyclohexanol and 1- [1- (4-methoxyphenyl) -2- (methylamino) ethyl] cyclohexanol are disclosed.

US 5,530,013 discloses the use of venlafaxine in inducing cognitive enhancement.

US 5,506,270 discloses the use of venlafaxine in a method of treating hypothalamic amenorrhea in women who are not depressed.

US 5,788,986 and US 5,554,383 disclose the use of serotonin reuptake inhibitors in changing the habit of dogs.

US 6,348,494 discloses O-α-acyloxyalkylethers of ethers of ODV, in particular 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol, methods for their preparation and pharmaceutical compositions thereof and Disclosed is the use.

Accordingly, the present inventors are studying to synthesize ODV derivatives having high solubility in water while maintaining the activity of ODV. 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol The thiophene and furanyl derivatives were synthesized, and the compounds were found to have high solubility in water and exhibited equivalent or more activities compared to those of conventional ODV.

It is an object of the present invention to provide novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivatives.

Another object of the present invention is to provide a method for preparing the 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative.

Another object of the present invention to provide a composition for preventing and treating central nervous system diseases containing the 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative as an active ingredient. There is.

In order to achieve the above object, the present invention provides a novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative or a pharmaceutically acceptable salt thereof.

In addition, the present invention is prepared by reacting a compound of formula 2 with a thiophenation reagent or a puroylation reagent in the presence of a reaction solvent and an amine, to form 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy Provided is a method for preparing a 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative for preparing a C derivative.

Furthermore, the present invention provides a method for preventing central nervous system diseases containing the 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and A therapeutic composition is provided.

The novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivatives or pharmaceutically acceptable salts thereof according to the present invention are useful in the biology of venlafaxine and salts thereof known in the art and Since it shows the same activity as the pharmaceutical activity, and especially solubility in water compared to the conventional venlafaxine derivatives. Depression (including major depressive disorders, bipolar disorder and case depression), fibromyalgia, anxiety, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder (premenstrual syndrome), attention deficit disorder, obsessive-compulsive personality disorder (hair growth Social anxiety disorder, panic anxiety disorder, autism, schizophrenia, obesity, anorexia nervosa, anorexia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine and alcoholism, sexual dysfunction (including premature ejaculation) ), Borderline personality disorder, chronic fatigue syndrome, urinary incontinence, pain (including neuropathic pain such as migraine, chronic low back pain, ring pain, central pain, diabetic neuropathy and postherpetic neuropathy), Raynaud's syndrome It can be used to treat or alleviate central nervous system diseases, including the like. In addition, it can be usefully used in the induction of cognitive enhancement and prescription for smoking cessation or other tobacco use.

The present invention provides a novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative represented by Formula 1 below, a pharmaceutically acceptable salt thereof, or an isomer thereof.

(In the formula 1,

또는

이고,R ¹ and R ² are independently or independently H,

or

ego,

Where X is S, O or N,

R ³ is H, a methyl group or an ethyl group,

* Denotes stereocenter, coordination means R, S or racemate)

More specifically illustrating the novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative represented by Formula 1 is as follows:

(1) 4- [2-dimethylamino-1- (1-thiophencarbonyloxycyclohexyl) ethyl] phenyl thiophene-2-carboxylate;

(2) thiophenyl 1- [2-dimethylamino-1- (4-hydroxyphenyl) ethyl] cyclohexane;

(3) 4- [2-dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenyl thiophene-2-carboxylate;

(4) 4- [1- (1-furancarbonyloxycyclohexyl) -2-dimethylaminoethyl] phenylfuranate;

(5) furanyl 1- [2-dimethylamino-1- (4-hydroxyphenyl) ethyl] cyclohexane; And

(6) 4- [2-dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenyl furanate.

The derivative of Formula 1 is a pharmaceutically active derivative of 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol, a venlafaxine metabolite.

The present invention includes not only the derivative of Formula 1 or a pharmaceutically acceptable salt thereof, but also possible isomers, solvates, and hydrates that can be prepared therefrom.

The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, thiophene derivatives, monohydrogen thiophene derivatives, dihydrogen thiophene derivatives, metathiophene derivatives, Pyrothiophene derivatives chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxal Latex, malonate, succinate, suverate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, di Nitro benzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, Chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene -1-sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.

Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

The present invention also provides a process for the preparation of the novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative.

The novel 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenoxy derivative according to the present invention is represented by Scheme 1 below, in the presence of a reaction solvent and an amine, The compound may be prepared by reacting with a compound of Formula 3 or Formula 4.

(In Reaction Scheme 1, *, R ¹ , R ² , R ³ and X are the same as defined in Formula 1)

In this case, the starting material 1- [2- (diamino) -1- (4-hydroxyphenyl) ethyl] cyclohexanol racemic compound of Formula 2 was prepared by the method disclosed in Example 26 of US Patent No. 4,535,186. Can be. The enantiomers can be separated from one another by standard resolution techniques known in the art, alternatively the enantiomers of venlafaxi using boron tribromide or ethanethiol anions. It can be obtained by O-demethylation of.

In the production method according to the present invention, the reaction solvent may be an inert solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, but is not limited thereto.

In the production method according to the present invention, the amine may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine, cyclohexylamine, diisopropylamine and the like, but is not limited thereto. .

In the production method according to the invention, the reaction may be carried out at room temperature or near 0 ℃, preferably -5 ~ 5 ℃.

Furthermore, the present invention provides a composition for preventing and treating central nervous system diseases containing the derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The composition containing the derivative of Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient exhibits the same activity as the biological and pharmaceutical activities of venlafaxine and salts thereof known in the art, and particularly to conventional venlafaxine derivatives. Because of its good solubility in water. Depression (including major depressive disorders, bipolar disorder and case depression), fibromyalgia, anxiety, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder (premenstrual syndrome), attention deficit disorder, obsessive-compulsive personality disorder (hair growth Social anxiety disorder, panic anxiety disorder, autism, schizophrenia, obesity, anorexia nervosa, anorexia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine and alcoholism, sexual dysfunction (including premature ejaculation) ), Borderline personality disorder, chronic fatigue syndrome, urinary incontinence, pain (including neuropathic pain such as migraine, chronic low back pain, ring pain, central pain, diabetic neuropathy and postherpetic neuropathy), Raynaud's syndrome It can be used to treat or alleviate central nervous system diseases, including the like. In addition, it can be usefully used in the induction of cognitive enhancement and prescription for smoking cessation or other tobacco use.

The composition containing a derivative of Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be used in the form of a general pharmaceutical preparation.

That is, the derivative of formula 1 according to the present invention can be administered in various formulations, oral and parenteral, in actual clinical administration. In addition, when formulated, in addition to the active ingredient, it may be prepared by including one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, as necessary. Other conventional additives such as buffers and bacteriostatic agents can be added.

Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, and the like, which may comprise at least one excipient in the compound, for example starch, calcium carbonate, sucrose (Sucrose) or lactose (Lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.

In addition, liquid preparations for oral administration include suspending agents, liquid solutions, emulsions, and syrups, and various excipients, for example, wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. This may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Furthermore, the pharmaceutical compositions of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection. To formulate into parenteral formulations, the compounds are mixed in water with stabilizers or buffers to prepare solutions or suspensions, which are formulated in unit dosage forms of ampoules or vials.

The compound according to the invention is preferably included in 0.1 to 50% by weight relative to the total weight of the composition. However, the composition as described above is not necessarily limited thereto, and may vary according to the condition of the patient, the type of disease, and the degree of progression.

Preferred dosages of the compounds according to the invention depend on the condition and body weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer from 0.01 mg / kg to 10 g / kg, preferably from 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

Example 1 Synthesis of 4- [2-dimethylamino-1- (1-thiophencarbonyloxycyclohexyl) ethyl] phenyl thiophene-2-carboxylate hydrochloride

4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol (2.63 g, 0.01 mol) was added to tetrahydrofuran (150 mL), dissolved at 45 ° C, and cooled to room temperature. . After triethylamine (6.12 mL, 0.044 mol) was added and stirred for 20 minutes, 2-thiophenecarbonyl chloride (2.35 mL, 0.022 mol) was added dropwise and stirred at room temperature for 2 hours. After the reaction was completed, it was filtered. Then, tetrahydrofuran (20 mL) was added thereto, washed, and the solvent was evaporated. Ethyl acetate and deionized water (200 mL) were then added. The mixture was stirred at room temperature for 10 minutes and then separated to remove the water layer. After washing with 1N HCl (200 mL), dried over magnesium sulfate (10 g), filtered and the solvent was evaporated. 100 mL of ethyl acetate was added thereto, stirred for 1 hour, filtered, and washed with ethyl acetate to obtain the target compound (3.9 g, 75%).

¹ H-NMR (400 MHz, DMSO): δ 1.1 to 1.6 (m, 9H), 2.2 (s, 1H), 2.59 to 2.64 (d, 6H), 3.60 to 3.63 (d, 1H), 3.94 to 4.00 ( t, 1H), 4.22 to 4.24 (d, 1H), 7.20 to 7.23 (t, 1H), 7.27 to 7.32 (q, 2H), 7.51 to 7.53 (d, 1H), 7.79 to 7.80 (q, 1H), 7.94-7.95 (q, 1H), 8.00-8.01 (q, 1H), 8.10-8.11 (q, 1H), 10.25 (s, 1H).

< Example  2> Thiophenyl  1- [2-dimethylamino-1- (4- Hydroxyphenyl )ethyl] Cyclohexane  synthesis

4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol (1.316 g, 0.005 mol) was added to tetrahydrofuran (75 mL) and dissolved at 45 ° C., followed by 0 ± 2 ° C. Cooled in. After triethylamine (1.53 mL, 0.011 mol) was added and stirred for 20 minutes, 2-thiophencarbonyl chloride (0.58 mL, 0.0055 mol) was added dropwise and stirred at room temperature for 2 hours. After the reaction was completed, it was filtered. Then, tetrahydrofuran (20 mL) was added thereto, washed, and the solvent was evaporated. Ethyl acetate and deionized water (200 mL) were then added. The mixture was stirred at room temperature for 10 minutes and then separated to remove the water layer. Then 1N HCl (200 mL) was added, stirred for 10 minutes, and then separated to remove the ethyl acetate layer. After ethyl acetate (50 mL) was added to adjust the pH to 8-8.5 and then separated to remove the water layer. Then dried over magnesium sulfate (10 g), filtered and the solvent was evaporated. Acetone (10 mL) was added, stirred for 30 minutes at 10 ± 2 ° C, filtered and washed with acetone to obtain the target compound (0.35 g, 18.8%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.6 to 1.3 (m, 9H), 1.75 (s, 6H), 1.77 to 1.81 (d, 1H), 2.21 to 2.27 (m, 2H), 2.59 to 2.61 (t, 1H), 3.59 to 3.63 (q, 1H), 6.31 to 6.33 (d, 2H), 6.68 to 6.70 (d, 2H), 6.73 to 6.76 (m, 1H), 7.20 to 7.22 (q, 1H) , 7.36-7.37 (m, 1 H).

Example 3 Synthesis of 4- [2-dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenyl thiophene-2-carboxylate

After performing the same method as in Example 2, the final compound was filtered through a solvent evaporation and vacuum drying to give the target compound (0.30 g, 16.1%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.8 to 1.8 (m, 10H), 2.34 (s, 6H), 2.34 to 2.39 (dd, 1H), 3.03 to 3.06 (dd, 1H), 3.32 to 3.38 (t, 1H), 7.12-7.19 (m, 5H), 7.64-7.66 (d, 1H), 7.95-7.96 (d, 1H).

< Example  4> 4- [1- (1- Furancarbonyloxycyclohexyl )-2- Dimethylaminoethyl ] Of phenylfuranate  synthesis

4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol (2.63 g, 0.01 mol) was added to tetrahydrofuran (150 mL), dissolved at 45 ° C, and cooled to room temperature. . After triethylamine (5.56 mL, 0.040 mol) was added and stirred for 20 minutes, 2-furoyl chloride (2.35 mL, 0.025 mol) was added dropwise and stirred at room temperature for 2 hours. After the reaction was completed, it was filtered. Then, tetrahydrofuran (20 mL) was added thereto, washed, and the solvent was evaporated. Next, 100 mL of ethyl acetate and deionized water were added. The mixture was stirred at room temperature for 10 minutes and then separated to remove the water layer. After addition of 1N HCl (100 mL) was stirred for 10 minutes and separated to remove the ethyl acetate layer. Thereafter, 100 mL of ethyl acetate was added, and the pH was adjusted to 8 with saturated sodium hydrogen carbonate, followed by separation to remove the water layer. Then, dried over magnesium sulfate, filtered and the solvent was evaporated to obtain the target compound (3.1 g, 68.7%).

¹ H NMR (400 MHz, DMSO) δ 1.1 to 1.7 (m, 8H), 2.12 (s, 6H), 2.20 to 2.23 (d, 1H), 2.63 to 2.66 (m, 3H), 2.96 to 3.02 (t, 1H), 4.09 to 4.14 (m, 1H), 6.47 to 6.49 (m, 1H), 6.56 to 6.58 (m, 1H), 7.07 to 7.08 (d, 1H), 7.14 to 7.16 (d, 2H), 7.30 to 7.33 (d, 2H), 7.33-7.34 (d, 1H), 7.56-7.57 (t, 1H), 7.65-7.66 (q, 1H).

< Example  5> Furanil  1- [2-dimethylamino-1- (4- Hydroxyphenyl )ethyl] Cyclohexane  synthesis

4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol (2.63 g, 0.01 mol) was added to tetrahydrofuran (150 mL) and dissolved at 45 ° C., followed by 0 ± 2 ° C. Cooled in. After triethylamine (2.78 mL, 0.02 mol) was added and stirred for 20 minutes, 2-furoyl chloride (1.08 mL, 0.011 mol) was added dropwise and stirred for 2 hours. After the reaction was complete, the solvent was evaporated. Next, 100 mL of ethyl acetate and deionized water were added. The mixture was stirred at room temperature for 10 minutes and then separated to remove the water layer. Then dried over magnesium sulfate (10 g), filtered and the solvent was evaporated. The target compound was obtained by column chromatography (methyl chloride: methanol = 4: 1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.8 to 1.8 (m, 8H), 2.00 to 2.03 (d, 1H), 2.28 (s, 6H), 2.60 to 2.63 (d, 1H), 2.66 to 2.68 ( d, 1H), 3.24 to 3.31 (t, 1H), 4.06 to 4.08 (d, 1H), 6.34 to 6.36 (d, 2H), 6.48 to 6.50 (q, 1H), 6.96 to 6.98 (d, 2H), 7.10-7.11 (d, 1 H), 7.57 (s, 1 H).

< Example  6> 4- [2-dimethylamino-1- (1- Hydroxycyclohexyl )ethyl] Phenyl Furanate  synthesis

The target compound was obtained by the same method as the method of Example 5.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.8 to 1.8 (m, 10H), 2.33 (s, 6H), 2.60 to 2.63 (d, 1H), 3.01 to 3.05 (dd, 1H), 3.31 to 3.37 ( t, 1H), 6.37-6.39 (d, 1H), 6.96-6.98 (d, 1H), 7.09-7.18 (m, 4H), 7.35-7.36 (d, 1H).

Experimental Example Solubility Measurement

In order to determine the solubility of the ODV thiophene derivative according to the present invention in water, the following solubility experiment was performed.

(1) Preparation of internal standard

First, 500 ml was prepared by diluting venlafaxine 100 mg in water as an internal standard (ISTD) to increase accuracy.

(2) Calibration curve setting

Thereafter, 50, 65 and 80 mg of the compound prepared in Example 1 were diluted in 100 ml of water to prepare ODV thiophenate solution at concentrations of 0.5, 0.65 and 0.8 mg / ml. The ODV thiophenate solution and the internal standard were analyzed by HPLC, and the calibration curve was set by measuring the peak area ratio of the ODV thiophenate and the internal standard according to the ODV thiophenate concentration. The calibration curve was set to the average value measured by repeating the HPLC analysis several times.

At this time, HPLC analysis conditions are as shown in Table 1.

column ODS, 5 μm, 4.6 × 250 mm Injection volume 20 μl Mobile phase (A) phosphate buffer solution / (B) acetonitrile (70: 30-30: 70 concentration gradient) Flow rate 1.5 ml / min detection 226 nm * Preparation of phosphate buffer: dissolve 8.89 g of Na ₂ HPO ₄ .2H ₂ O and 2.5 g of 1-octane sulfonic acid sodium salt in 1000 ml of water, and then add 10% H ₃ PO ₄ solution to pH 3.0. Manufactured by adjusting and filtering

(3) solubility measurement

After dissolving the excess (about 400 mg) of the ODV thiophenate compound prepared in Example in 2 ml of water, the undissolved compound was filtered to prepare a saturated solution. Water was added to 1 ml of the saturated solution and diluted to 20 ml. After the dilution process, the saturated solution was diluted so that the dilution factor was 800 times, and the solution and the internal standard were analyzed by HPLC to determine the peak area ratio of the ODV thiophenate and the internal standard. The solubility was measured by substituting the measured value into the calibration curve, calculating the concentration when the dilution factor was 800 times, and multiplying the dilution factor.

As a comparative example, a conventionally used ODV succinate compound was used. The solubility was measured by the same method except that the concentrations of 0.1, 0.15, and 0.2 mg / ml were set when the calibration curve was set. The results are shown in Table 2. .

division Solubility (mg / ml) Example 1 413.0 Comparative Example (ODV Succinate) 84.2

As shown in Table 2, the ODV thiophenate compound according to the present invention had a solubility in water of 413.0 mg / ml, which was about 4 times higher than the conventional ODV compound (84,2 mg / ml).

Thus, the 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy derivative (ODV thiophenate compound) according to the present invention exhibits excellent solubility in water, thereby making it a conventional ODV compound. It can be useful for the treatment of diseases in which ODV is used instead.

< Formulation example  1> Preparation of Pharmaceutical Formulations

<1-1> Powder  Produce

2 g of derivative of formula 1

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of Tablet

100 mg of derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

<1-3> Preparation of Capsule

100 mg of derivative of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> Preparation of Injection Solution

10 μg / ml derivative of Formula 1

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

The derivative of formula 1 was dissolved in an appropriate volume of sodium chloride BP for injection, and the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, and the volume was adjusted with sodium chloride BP for injection and thoroughly mixed. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

Claims (10)

4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. [Formula 1]

(In the formula 1, One of R ¹ and R ² is H, and the other is

Or Both R ¹ and R ²

ego, Where X is S or O, R ³ is H, * Denotes stereocenter, coordination means R, S or racemate) The method of claim 1, wherein the derivative (1) 4- [2-dimethylamino-1- (1-thiophencarbonyloxycyclohexyl) ethyl] phenyl thiophene-2-carboxylate; (2) thiophenyl 1- [2-dimethylamino-1- (4-hydroxyphenyl) ethyl] cyclohexane; (3) 4- [2-dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenyl thiophene-2-carboxylate; (4) 4- [1- (1-furancarbonyloxycyclohexyl) -2-dimethylaminoethyl] phenylfuranate; (5) furanyl 1- [2-dimethylamino-1- (4-hydroxyphenyl) ethyl] cyclohexane; And (6) 4- [2- (dimethylamino) -1- (1), characterized in that it is selected from the group consisting of 4- [2-dimethylamino-1- (1-hydroxycyclohexyl) ethyl] phenyl furanate. -Hydroxycyclohexyl) ethyl] phenoxy derivative or a pharmaceutically acceptable salt thereof. As represented by Scheme 1 below, the compound of formula 2 is reacted with the compound of formula 3 in the presence of a reaction solvent and an amine to give 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] A process for producing the 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy derivative according to claim 1 for preparing a phenoxy derivative. Scheme 1

(In Reaction Scheme 1, *, R ¹ , R ² , R ³ and X are the same as defined in Formula 1) 4. The 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy derivative according to claim 3, wherein the reaction solvent is acetonitrile, tetrahydrofuran or dimethylformamide. Manufacturing method. 4. The 4- [2- (dimethylamino) compound according to claim 3, wherein the amine is triethylamine (TEA), diethylamine (DEA), diisopropylethylamine, cyclohexylamine or diisopropylamine. ) -1- (1-hydroxycyclohexyl) ethyl] phenoxy derivative. 4. The preparation of 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy derivative according to claim 3, wherein the reaction is performed at room temperature or -5 to 5 ° C. Way. delete delete delete delete