MXPA01001125A - Novel phenylethylamine derivatives, a method for the production thereof and their use as medicaments - Google Patents

Abstract

The invention relates to novel phenylethylamine derivatives, to a method for the production thereof and to their use as medicaments. The inventive phenylethylamines correspond to general formula (1).

Description

New derivéidos of phenylethylamine, procedure for its preparation and its use as a medicine DESCRIPTION OF THE INVENTION The present invention relates to novel phenylethylamine derivatives, to a process for their preparation, as well as to their use as a medicine. The phenylethylamine derivatives according to the invention correspond to general formula 1 (D in which R1 and R2, independently of one another, can mean hydrogen or fluorine, in the form of the free bases or the corresponding salts by addition of acids with pharmacologically harmless acids. Preferred are the following two compounds: Ref: 126338 Y As it was found, the compounds of the formula I according to the invention are distinguished by their multiple possibilities of application in the therapeutic sector, as well as by their efficacy by oral route. We must highlight the possibilities of application in which the antagonist properties of the LTB4 receptor play a role. In this case, mention should be made especially of: arthritis, asthma, chronic obstructive pulmonary diseases, for example chronic bronchitis, antitrypsin cti insufficiency, psoriasis, ulcerative colitis, inflammatory bowel diseases, gastropathy or enteropathy induced by non-steroidal antiphlogistic agents, cystic fibrosis, disease of Alzheimer, shock, .Lesions / ischaemia due to reperfusion, atherosclerosis, multiple sclerosis. With the new compounds, diseases or conditions in which it is important may also be treated. passage of blood cells to tissue (eg, metastases) through the vascular endothelium, or diseases and conditions in which the combination of LTB4 or another molecule (eg 12-HETE) with the LTB4 receptor influences proliferation of the cells (for example chronic myelocytic leukemia). The new compounds can also be administered in cortination with other active ingredients, for example those which find application for the same indications, or for example with antiallergic agents, secretolytic agents, β2-adrenergic agents, steroids administered inhalatively and orally, antihistatics, antagonists. of PAF, NSAID, as well as glucocorticoids. The administration can be carried out topically, orally, transdermally, nasally, parenterally or inhalatively. For the pharmacological and biochemical examination of the efficacy ratios, the tests are described, for example, in WO 93/16036, pages 15 to 17 ("Máuseohrtest" - test of the ear of mice), whose content is made here reference. The compounds according to the invention prove to be LTB4 antagonists of particularly high potency, both in vitro and in vivo. The two substances according to the invention show a binding to the highly related LTB4 receptor. In addition, in the above-mentioned "mouse ear" test, after oral administration, they show ED 50 values of 0.02 and, respectively, 0.03 mg / kg. The therapeutic or prophylactic c.osis depends - apart from the power of action of the individual compounds and the patient's body weight - on the condition and severity of the pathological state. In the case of oral administration, the dose is between 1 and 500 mg, preferably between 20 and 250 mg. In the case of administration by inhalation route, the patient is administered between approximately 0.5 and 25, preferably between 2 and 20 mg of active principle. The solutions for inhalation generally contain between about 0.5 and 5% of active principle. The new compounds can be administered in the customary preparative, for example as tablets, dragees, capsules, wafers, powders, granules, solutions, emulsions, syrups, aerosols for inhalations, ointments, suppositories. The following examples show some possibilities for the formulation of the administration forms: Formulation examples 1. Tablets a) Prepared according to the Pluronic fusion drawing process b) Improved wettability formulation 2. Suppositories Composition: Active ingredient according to the invention 100 parts by weight Lactose, powdered 45 parts by weight Cocoa butter 1555 parts by weight The components are processed in the usual manner to obtain suppositories weighing 1.7 g. 3. Powders for inhalation Micronized powder of active principle (compound of Formula I, granulometry, approximately 0.5 to 7 μm) are packaged in hard gelatin capsules in an amount of 5 mg, optionally with the addition of micronized lactose. The powder is inbaled from the usual apparatus for inhalation, for example according to German publication publication No. 33 45 722, to which reference is made. The new compounds can be prepared according to methods known per the known state of the art. For this, advantageously, the following three processes are especially suitable: 1. Reaction of the protected phenol of the general formula 2 (2. 3) with an ethylamine derivative of the general formula 3, in which Pd can mean a protective group suitable for the protection of the phenols, but also hydrogen, PG can represent a protective group suitable for the protection of amines, being able to mean n or 1, and m can mean one of the integers 1 or 2; And it can mean fluorine, chlorine, bromine or iodine or an alkyl-Ci-Cj radical or an aryl sulfonate radical. The compounds are reacted with basic adjuvants, such as, for example, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, alkali metal alkoxylates, in inert solvents under the chosen reaction conditions, such as formamides - preferably dimethylformamide ( DMF) -, alkyl-C? ~ C4-nitriles g preferably acetonitrile, C 1 -C 4 -alkyl esters of carboxylated acids - preferably acetic acid ethyl ester or formic acid ethyl ester -, aromatic or aliphatic hydrocarbons - preferably toluene -, or branched C 1 -C 4 -alcohols or not branched In the next reaction step, the protective groups are separated, in particular with inorganic or organic acids, in suitable solvents or by hydrogenolysis or, respectively, with other processes known from the state of the art, which are commonly used. for the separation of specific protective groups. 2. Reaction of two compounds of general formulas 4 and 5: in which PGi can mean hydrogen or a suitable protecting group for the protection of phenols; PG can represent a protective group suitable for the protection of amines, which can mean n or 1, and m can mean one of the integers 1 or 2; And it can mean fluorine, chlorine, bromine or iodine or a C 1 -C 4 alkyl radical or an aryl sulfonate radical, and R 1, as well as R 2 have the meaning mentioned at the beginning. The compounds are reacted with basic adjuvants, such as, for example, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, alkali metal alkoxylates in solvents - inert under the chosen reaction conditions - such as formamides - preferably dimethylformamide (DMF) - C 1 -C 4 -nitriles, preferably acetonitrile -, C 1 -C 4 -alkyl esters of carboxylic acids - preferably acetic acid ethyl ester or formic acid ethyl ester -, aromatic or aliphatic hydrocarbons - preferably toluene -, or in branched or unbranched C-C4 alcohols. In the next reaction step, the protective groups are removed, in particular with inorganic or organic acids, in suitable solvents or by hydrogenolysis or, respectively, with other processes known from the state of the art, which are used usually for the separation of specific protective groups. 3. Nitrostyrene reduction (6) (6) The compounds according to the invention can be prepared by reduction of the nitrostyrene (6) by heterogeneous or homogeneous hydrogenation with the aid of suitable catalysts, with the aid of complex hydrides or with boranes in suitable solvents. Thus, the reduction can be effected, for example, in a solvent from the group of methanol, ethanol or in a higher alcohol, DMF or water in the presence of a catalyst from the Raney nickel group, Pd / C, platinum or with reagents for hydrides - especially complex hydrides of the group NaBH4, Ca (BH4) 2, LiAlH4 or other aluminum hydrides or boron - at temperatures in a range of 0 to 100 ° C and under a hydrogen pressure of at least 760 Torr (1,013 bar ), to give the corresponding amine of the general formula 1. The protective groups mentioned above in the description of the preparation process, as well as the process conditions, which must be maintained for the protection of the phenolic hydroxyl groups and, respectively, the secondary or primary amines, as well as their subsequent separation, are sufficiently known from the current state of the art [TW Greene, P.G. Wuts, Protective Groups in Organic Synthesis. 2nd edition, J. Wiley / VCH, New York 1991]. Likewise, from the current state of the art, the conditions for the reduction of the nitro compounds and the reduction agents required for this are sufficiently known [J. March: Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 4th edition, Wiley, New York 1992 and bibliographical citation]. Other executions of the process, of different types, are apparent from the present description for the person skilled in the art. However, it is expressly emphasized that these examples and the description that corresponds to them should be considered only for the purpose of clarification and should not be considered as a limitation of the invention.

Synthesis example (7) (8) 3.8 g of the THP-protected ether 7, 2.7 g of the BOC-protected amine 8 and 1.5 g of potassium carbonate (K2C03) are boiled under reflux in 100 ml of acetonitrile for a period of 5 hours. h. Then, the reaction medium / solvent is distilled off. The residue is partitioned between water and acetic acid ethyl ester. The organic phase is separated and dried over sodium sulfate (Na 2 SO 4). After the drying agent is filtered off, the solution is concentrated by evaporation and the residue is purified chromatographically with toluene / acetone 95: 5 on silica gel. Yield 2.3 g. The product is dissolved in 20 ml of acetic acid ethyl ester and 10 ml of a 3 M solution of HCl in acetic acid ethyl ester and stirred for 12 h at room temperature. The precipitated crystals dissolve in little methanol, and the product is precipitated with ether. After filtering with suction and drying, 1 g of compound (1), R = F, is obtained. with melting point 173 ° C. The compound (1), R = H. is prepared analogously. Melting point: 182 - 185 ° C. To the disclosure of the German patent application No. 198 34 713.8, whose priority claims the present application, reference is made in all its content to the present.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (10)

1. f.
2. Claims
3. Having described the invention as above, it is claimed co: r? property contained in the following claims: 1 Phenylethylamine derivatives corresponding to the general formula 1 (1) characterized in that: R and R ", independently of each other, can mean hydrogen or fluorine, in the form of the free bases or the corresponding salts by the addition of acids with pharmacologically harmless acids 2. Derivative of phenylethylamine in accordance with Claim 1, characterized by the formula in the form of the free bases or the corresponding salts by the addition of acids with pharmacologically harmless acids. 3. Derivative of phenylethylamine according to claim 1, characterized by the formula in the form of the free bases or the corresponding salts by addition of acids with pharmacologically harmless acids. 4. Process for the preparation of compounds of the general formula 1, characterized by a compound of the. formula (2) (2) (3) it is reacted with an ethylamine derivative of the general formula 3, in which PGi can mean a protective group suitable for the protection of phenols, or hydrogen; PG can represent a protective group suitable for the protection of amines, which can mean n or 1, and m can mean one of the integers 1 or 2; And it can mean fluorine, chlorine, bromine or iodine or an alkyl-Ci-C4 radical or an aryl sulfonate radical, and R1, as well as R2 have the meaning mentioned at the beginning, in the presence of an auxiliary base from the group of alkali or alkaline earth hydroxides , alkali metal or alkaline earth metal carbonates, alkali metal alkoxylates, in inert solvents under the chosen reaction conditions, such as formamides - preferably dimethylformamide (DMF) -, C 1 -C 4 alkyl nitriles, preferably acetonitrile -, alkyl esters -C? -C of carboxylic acids - preferably acetic acid ethyl ester or formic acid ethyl ester -, aromatic or aliphatic hydrocarbons - preferably toluene -, or branched or unbranched C-C4 alcohols, in the next step of The protective groups are separated by other processes known from the prior art and the product of the reaction is isolated. 5. Process for the preparation of compounds of the general formula 1, characterized in that a compound of the general formula 4 is reacted with a compound of the formula
4. PGi can mean hydrogen or a suitable protective group for the protection of phenols; PG can represent a protective group suitable for the protection of amines, which can mean n zero or 1, and can mean m one of the integers 1 or 2;
5. And it can mean fluorine, chlorine, bromine or iodine or a C 1 -C 4 alkyl radical or an aryl sulfonate radical, and R 1, as well as R 2 have the meaning mentioned at the beginning, in the presence of an auxiliary base of the group of alkali hydroxides or alkaline earth metals, alkaline or alkaline earth metal carbonates, alkali metal alkoxylates, in solvents; inert under the chosen reaction conditions, such as formamides - preferably dimethylformamide (DMF) -, alkyl-C? -C -nitriles, preferably acetonitrile-, C-C4-alkyl esters of carboxylic acids - preferably ethyl acetate or ethyl ester of formic acid -, aromatic or aliphatic hydrocarbons - preferably toluene -, or branched or unbranched C alco-C alco alcohols, and in the next reaction step the protective groups are removed - preferably with inorganic or organic acids in suitable solvents or by hydrogenolysis by methods known per se.
6. 6. Process for the preparation of compounds of the general formula 1, characterized by a nitrostyrene of the general formula 6 (6) is reduced in a solvent from the methanol, ethanol or higher alcohol group, DMF or water in the presence of a catalyst from the Raney nickel group, Pd / C, platinum or with reagents; for hydrides - especially complex hydrides of .. NaBH group, Ca (BH4) 2, LiAlH4 or other aluminum or boron hydrides at temperatures in a range of 0 to 100 ° C and under a hydrogen pressure above 760 Torr (1,013 bar ), to give the corresponding amine of the general formula 1.
7. 7. Pharmaceutical preparation characterized in that it contains a compound of the general formula 1 according to any of claims 1, 2 or 3, and its salts by adding acids together with adjuvants and usual support substances.
8. 8. Use of the compounds according to any of claims 1, 2 or 3 as a medicine.
9. 9. Use of the compounds according to the claim or as a medicament with an LTB4 antagonist effect.
10. 10. Use of the compounds of the general formula I, their stereoisomers as well as their salts by the addition of acids for the preparation of a medicament for the therapeutic treatment of arthritis, asthma, chronic obstructive pulmonary disease, such as chronic bronchitis, psoriasis , ulcerative colitis, ga tropathies or enteropathies induced by non-steroidal antiphlogistic agents, cystic fibrosis, Alzheimer's disease, shock, reperfusion injury / ischemia, atherosclerosis, multiple sclerosis. its preparation and its use as a medicine SUMMARY OF THE INVENTION The present invention relates to novel phenylethylamine derivatives, to a process for their preparation, as well as to their use as medicaments. The phenylethylamine derivatives according to the invention correspond to the general formula