JPH023780B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to compounds having a lipid-regulating action and having a basic structure of the arylsulfonamide type, or physiologically acceptable salts of these compounds. The present invention also relates to a method for producing the above-mentioned compound and its salt. The compounds of the present invention have the general formula It is characterized by the following. In the formula, - R ₁ and R ₂ are the same or different,
Hydrogen atom, halogen atom, NO ₂ group, NH ₂ group,
_CF3 group, 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms
an alkyl group having 4, 1 to 6 carbon atoms;
preferably represents an alkoxy group having 1 to 4, -n+m+1 is 3 to 11, preferably 3,
equal to 5 or 10, − R ₅ and R ₆ are each independent, a hydrogen atom,
represents an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, or an alkoxy group having 7 to 9 carbon atoms, -R ₄ is a hydroxy group, or a group OR ₇ [wherein R ₇ is an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms], or

[Formula] Group [provided that R ₈ and R ₉ are the same or different and represent a hydrogen atom or an alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, or R ₈ and R ₉ together with the nitrogen atom to which they are bonded form a 5- or 6-membered nitrogen-containing heterocyclic group, particularly a piperidino group, a morpholino group, a pyrrolidino group, a pyrrole group or a pyrroline group. A preferred group of compounds of the present invention are compounds in the general formula () in which R ₆ represents a hydrogen atom. Such compounds have the general formula It is indicated by. where n+m+1 is from 3 to 11, preferably equal to 3, 5 or 10, - R ₅ is hydrogen, an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, or represents an aralkyl group having 7 to 9 carbon atoms, -R ₄ is a hydroxy group, OR ₇ [wherein R ₇ is a hydroxy group,
preferably an alkyl group having 1 to 4], or a group

[Formula] [However, R ₈ and R ₉ are the same or different from each other and represent a hydrogen atom, an alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, or R ₈ and R ₉ together with the nitrogen to which they are bonded form a 5- or 6-membered nitrogen-containing heterocyclic group, particularly a piperidino group, a morpholino group, a pyrrolidino group, a pyrrole group or a pyrroline group. Another preferred group of compounds of the invention are compounds in which R ₅ in formula () represents hydrogen. Such a compound has the following formula () It is indicated by. A more preferable compound among the above groups is the following formula () This is a compound represented by Preferred compounds of the present invention are R ₁ in formula ()
and R ₂ both represent hydrogen atoms or are different from hydrogen, halogen atom, NO ₂ group,
_NH2 groups, _CF3 groups, alkyl groups having 1 to 6, preferably 1 to 4 carbon atoms, and 1 to 6
, preferably 1 to 4 carbon atoms. Among the compounds represented by formulas () and () when both R ₁ and R ₂ are not hydrogen, preferred compounds are compounds in which R ₆ is hydrogen. Preferred compounds within this group are R ₁ and
Compounds of formula () when R ₂ is selected from NO ₂ , NH ₂ , OCH ₃ , CH ₃ , CF ₃ and halogen atoms, especially chlorine, and the benzene nucleus is replaced by three groups It is. Another preferable group of compounds in the above group is one in which R ₁ in formula () represents a hydrogen atom, and R ₂ represents a halogen atom, NO ₂ group, NH ₂ group, CF ₃ group, 1 to 6
, preferably 1 to 4 carbon atoms, and an alkoxy group having 1 to 6, preferably 1 to 4 carbon atoms. Such a compound has two substituents on its aromatic nucleus, and has the following formula () [In the formula, R ₂ , R ₄ and R ₆ follow the above definition]
Form a group indicated by . Preferred compounds in said group are of the formula [wherein n+m+1 is 3 to 11, preferably equal to 3, 5 or 10, and _R2 and _R4 are as defined above]. Preferred compounds in this group are those in which the benzene nucleus is substituted with CF ₃ and one group selected from NO ₂ , NH ₂ , OCH ₃ , CF ₃ , CH ₃ and halogens, especially chlorine. Another preferred group of compounds in the above group is compounds in which R ₁ and R ₂ in formula () both represent hydrogen atoms. Such compounds have monosubstituted aromatic nuclei, and have the following formula () Form a group indicated by . Preferred compounds according to the invention within this group are comprised of compounds in which R ₆ represents a hydrogen atom.
These compounds have the following formula () It is indicated by. Another preferred group of compounds of the invention are those having a CF ₃ substituent in the meta position of the benzene nucleus among the compounds of said group. Another preferred compound according to the invention is 1 in which the benzene nucleus is monosubstituted in the meta position by a _CF3 group.
It is a group of compounds. This group of compounds has the following formula () It is indicated by. In the formula (), R ₄ is a -hydroxy group, - group OR ₇ [However, R ₇ is an alkyl group having 1 to 6 carbon atoms, preferably a group C ₂ H ₅ ],

[Formula] [However, R ₈ and R ₉ are the same or different from each other, hydrogen atoms, 1 to 6
, preferably 1 to 4 carbon atoms, or R ₈ and R ₉ together with nitrogen represent a 5- or 6-membered nitrogen-containing heterocyclic group, in particular a piperidino group, a morpholino group, or a pyrrolidino group. , forming a pyrrole group or a pyrroline group], - n+m+1 is 3 to 11, preferably 3,
Equal to 5 or 10. More preferred compounds of the invention within this group are those in which R ₆ is a hydrogen atom. Such a compound has the following formula () It is indicated by. In preferred compounds according to the invention, the value of n is advantageously 3, 5 or 10. In other preferred compounds of the invention, R ₄ advantageously represents a hydroxy group or an OC ₂ H ₅ group. The invention further relates to optical isomers of the compounds of formula () and physiologically acceptable salts of these isomers. A particularly preferred compound according to the invention is represented by the formula below. Synthesis of the compound according to the present invention The synthesis of the compound according to the present invention will be explained below. Process A: Eq. [In the formula, - R ₄ represents a group OR ₇ (R ₇ is an alkyl group having 1 to 6 carbon atoms), and - R ₁ , R ₂ , R ₅ and R ₆ follow the above definition] First manufacturing method of compound (process A)
So, halides, especially the formula A suitable acid chloride of the formula Amino ester of the formula or The hydrochloride of the amino ester represented by the following formula: React according to. In the above formula, R ₁ , R ₂ , n, m, R ₅ , R ₆ and R ₇
have the above meanings. When carrying out the process it is advantageous to follow the following procedure. After vigorous stirring of the amino ester or its hydrochloride (2×10 ⁻² mol) in anhydrous benzene (50 cm ³ ) at a temperature of 0 to 5° C., triethylamine (or other organic base of the tertiary amine type) was added to 15 Add ~20 cm ³ and after 5-10 minutes, add acid chloride (2 x 10 ^-2 mol),
If it is a solid, add it little by little, if it is a liquid, add it drop by drop. Add triethylamine in excess. This is because it is possible to neutralize the amino acid hydrochloride to the corresponding base form if necessary, and in each case also to the hydrochloric acid resulting from the condensation reaction of the acid chloride with the amino ester. This is because it can neutralize the The reaction medium is gradually brought to room temperature and after 12 hours the triethylamine hydrochloride crystals formed are filtered and washed with benzene. The organic phase is concentrated and then taken up in ethyl acetate (200 cm ³ ). The solution obtained is washed successively with dilute hydrochloric acid solution and dilute sodium bicarbonate solution and then dried and the solvent is evaporated. The residue thus obtained is, if necessary, subjected to chromatographic operations. The acid chlorides are commercially available, but if not available, they can be synthesized by conventional methods. Process A: Eq. Second manufacturing method (process A) of the compound represented by
is an acid halide, especially suitable formula Starting material is acid chloride, which is given by the formula The amino acid represented by and the following formula The resulting acid is then further reacted according to the formula
A suitable alcohol represented by R ₇ OH and the following formula This is a method of esterification by reacting according to the following. In the above formula, R ₁ , R ₂ , n, m, R ₅ , R ₆ and R ₇
follows the above definition. The second manufacturing method is carried out in the following steps. First, an acid is prepared by the following method. Amino acids (40mM) were added to anhydrous pyridine or anhydrous, 2,6
- Anhydrous organic base such as dimethylpyridine (15 cm ³ )
suspend or dissolve in Acid chloride (10mM) is then added in small portions or dropwise. The reaction mixture is stirred vigorously during the addition and maintained at a temperature below 20°C. This is then heated at 40° C. for 1 hour and stirred at room temperature for 12 hours. Pyridine is removed by concentrating under reduced pressure. A cold solution of dilute acid, such as dilute hydrochloric acid, is added to bring the pH below 3. If the product precipitates, it is filtered, washed with water and then dissolved in lower alcohol (ethanol or methanol). If necessary, decolorize with activated carbon and finally perform chromatography. If the product does not precipitate, it is extracted from the medium using ethyl acetate (or any other organic solvent with the same polarity). The extracted phase is dried over sodium sulfate, decolorized if necessary with activated carbon, concentrated under reduced pressure, and then subjected to chromatography. A variation of this method is to pour an ethereal solution of acid chloride onto an amino acid dissolved in caustic soda water (MAC CHESMY, SWAM,
JACS, 59 , 1116). Esterification is carried out as follows. The ^above acid (2 x 10 ^-2
mole). Then add perchloric acid (1.5 cm ³ ). The resulting mixture is heated to 50° C. until the starting material disappears and the ester forms. Process A: Eq. Third manufacturing method (process A) of the compound shown by
Now, the formula Starting material is an appropriate acid represented by the formula A suitable amino ester shown by and the following reaction formula React according to. In the above formula, R ₁ , R ₂ , n, m, R ₅ , R ₆
and R ₇ follow the above definitions. This process is carried out in the following steps. A solution of the acid (10 ⁻² mol) dissolved in a minimum of dimethylformamide (DMF) or hexamethylphosphorylamide (HMPA) is cooled to −15° C. with magnetic stirring. Next, 1 on the alkyl part
N-alkylamines having ~4 carbon atoms and in which the amine moiety is derived from a tertiary amine, such as N-methylmorpholine (1.1 cm ³ =10 ^-2 mol) and alkyl chloroformates (with 1 to 4 carbon atoms in the alkyl moiety). carbon atoms), for example isobutyl chloroformate (1.3 cm ³ ), are sequentially added to the solution. After 5 minutes, a minimum amount of the amino ester in DMF (10 ^-2 mol) is poured into this medium. For amino ester hydrochloride, N-methylmorpholine (1.1 cm ³ = 10 ^-2 mol)
It is best to neutralize it with After 4 hours, the reaction mixture was reduced to 0.
Pour into a dilute solution of sodium bicarbonate or potassium bicarbonate at °C. If the product precipitates, the crystals are washed with water, dissolved in ethyl acetate, and the organic phase is washed with a dilute acid such as hydrochloric acid to bring the pH below 3. After drying the solution over sodium sulfate, the solvent is evaporated and the residue is chromatographed. Process B: Eq. [In the formula, R ₄ represents a hydroxy group] A first method for producing a compound represented by (Process B)
Now, the above formula Second manufacturing method (process A) of the compound represented by
As in the case of the expression A suitable acid chloride of the formula An appropriate amino acid shown in and the following reaction formula React according to. The following examples generally illustrate the preparation of compounds according to the process described above. Example 4 Preparation of 4-(3-trifluoromethylbenzenesulfonylamino)butyric acid Omega-aminobutyric acid (5 x 10 ^-2 moles = 5.15 g) was added to pyridine (100 cm ³ ) maintained at about 20°C in a water bath with magnetic stirring, and to this was added trifluoromethylbenzenesulfonyl chloride (2 x 10 ^-2 moles =
4.89g) was added little by little. The reaction mixture was then heated to 40°C for 1 hour.
The solvent was evaporated and the resulting residue was washed with 3% hydrochloric acid (200 cm ³ ) and extracted with ethyl acetate (first
(extracted using 400 cm ³ and then twice using 100 cm ³ each). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The product was dissolved in methanol, decolorized with activated charcoal, concentrated and chromatographed on silica H using toluene/ethyl acetate/acetic acid (80:20:2) as eluent. The fraction containing 4-(3-trifluoromethylbenzenesulfonylamino)butyric acid was concentrated, and this compound was recrystallized from a water/ethanol mixture (41% yield). Example 4 Preparation of 4-(3-trifluoromethylbenzenesulfonylamino)-butyric acid ω-Aminobutyric acid (5 x 10 ^-2 mol = 5.15 g) was added to pyridine (100 cm ³ ) and maintained at about 20°C in a water bath with magnetic stirring, and trifluoromethylbenzenesulfonyl chloride (2 x 10 ^-2 Mol = 4.89
g) was added dropwise. The reaction mixture was then heated to 40°C for 1 hour.
The solvent was evaporated, the residue was collected in 100 cm ³ of water, and 2N hydrochloric acid was added to the resulting solution to a pH value of 2.3. The precipitate was centrifuged, dried and recrystallized in benzene (42% yield). The compounds produced by this process are shown in Table and Table ', respectively.

【table】

Table: As a variant of the process described in the examples, the acid chloride can be removed in an organic solvent which is inert towards it and immiscible with water, such as chloroform, dioxane, benzene, toluene, preferably Another method is to pour the solution obtained by dissolving in ether into an amino acid in an aqueous solution such as an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution (MAC
(See CHESMY, SWAM, JACS, 59 , 1116). The following example illustrates this method. Example Production of compound n゜1038 1.545g of 4-aminobutyric acid in ^30cm3 of N soda
(0.015 mol), 3.7 g in 30 ^cm3 of ethyl ether
(0.015 mol) of 3-trifluoromethylbenzenesulfonyl chloride was added dropwise with vigorous stirring. After stirring for 4 hours, the organic phase was removed and the pH of the aqueous phase was brought to 3 with 2N hydrochloric acid. The formed precipitate was drained, washed with water until the Cl ^- ions disappeared, and then dried. The compounds produced according to this process are listed in Table and Table ', respectively.

【table】

[Table] Process B: Formula In a second process (process B) for the preparation of compounds according to the invention of the formula: - in a first step, the formula According to either of the two processes A or A described above for synthesizing the compound shown in
produce an ester of the desired acid; - in a second step, convert the resulting ester to the following reaction equation: Hydrolyze to the corresponding acid according to To perform the second step of this process, follow these steps: 1N to 5N alkali metal base or alkaline earth metal base in an alcoholic medium, preferably such that the corresponding alcohol has 1 to 4 carbon atoms.
1N to 5N ethanol soda, more specifically
Add 10 ⁻² moles of ester to 2N ethanol soda (50 cm ³ ) and stir magnetically at room temperature for 12 hours. 2N~
The reaction medium is neutralized in a cold bath using an acid such as 10N concentrated hydrochloric acid, and when the pH is below 3, it is extracted with a water-immiscible organic solvent such as ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The following examples illustrate the preparation of compounds of the invention generally according to the methods previously described. Example Production of compound N゜1129 Ester A was suspended in a mixture of 2N soda and ethanol. After standing overnight at room temperature with magnetic stirring, the reaction medium was evaporated to dryness in vacuo and the residue was again dried at 200 °C.
cm ³ of water and 2N hydrochloric acid was added to adjust the pH to 3. The precipitate was drained, washed with water until Cl ^- ions disappeared, and then dried in vacuum. Yield is 80%
It was hot. Example 6 Preparation of (3-trifluoromethylbenzenesulfonylamino)hexanoic acid Ester A (2 x 10 ^-2 moles = 7.35 g) was suspended in a mixture of 2N sodium hydroxide (20 cm ³ ) and ethanol (10 cm ³ ). After standing overnight at room temperature with magnetic stirring, the reaction medium was evaporated to dryness in vacuo. The residue was collected in 30 cm ³ of water and 2N hydrochloric acid was added to bring the pH to 8. The precipitate was dried, washed with water until the Cl ^- ions disappeared, and then dried in vacuo (80% yield). The compounds produced by this method are shown in Table and Table ', respectively.

【table】

[Table] Other synthesis methods: The following formula From the compound of The method for preparing the compound will be explained. In the above formula, the radical R ₄ represents OH or an alkoxy group having 1 to 6 carbon atoms. This process involves converting an alkyl halide such as alkyl iodide R ₅ into It consists of reacting according to From a practical point of view the procedure is as follows. Sulfonylamino acids (1 mM) are dissolved by addition of excess strong aqueous base (caustic soda, caustic potash). The alkylating agents used are alkyl or aralkyl halides (the halides are chlorides, bromides or iodides) or alkyl sulfates (dimethyl sulfate,
diethyl sulfate). Add this alkylating agent drop by drop at low temperature,
If necessary, maintain the PH of the reaction mixture at a value above 10. The reaction medium is heated for 3 to 24 hours (this time is determined depending on the alkylating agent) at a temperature between 60 °C and 100 °C and, after cooling, an immiscible solvent (ether, ether,
Extract the aqueous phase with TMF, benzene, ethyl acetate), preferably ether. The aqueous phase is then brought to a pH≦3 by addition of an inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid), preferably hydrochloric acid. The precipitate is removed and recrystallized from a suitable organic or aqueous solvent. The following examples illustrate preparations according to this embodiment and generally follow the procedure described above. Example 4 Methylation of 4-(3-trifluoromethylbenzenesulfonylamino)butyric acid (compound n°1038) 4 g of methyl iodide were added dropwise to 3.1 g of 4-(3-trifluoromethylbenzenesulfonylamino)butyric acid (1×10 ⁻² mol) in 30 cm ³ of sodium hydroxide N with stirring. The reaction mixture was brought to 80° C. for 4 hours. After cooling the aqueous phase was extracted with ether. After removing the organic phase, the aqueous phase was brought to PH3 with 2N hydrochloric acid. The precipitate was centrifuged, washed with water and dried. The melting point of the obtained compound (compound n゜1174) is 115
The yield was 80%. Other processes: The compound of (In the above formula, R ₁ , R ₂ , R ₅ , R ₆ , R ₈ and R ₉ have the above-mentioned meanings.) This method uses the following formula reacting the acid with thionyl chloride according to
Then, the following reaction equation reacting a suitable amine with an acid chloride according to the method. From a practical point of view, the operation is as follows. The acid is dissolved in anhydrous benzene and excess thionyl chloride is added. After refluxing, the reaction mixture is evaporated to dryness and the residue is taken up again with a suitable amine. 40℃
After heating between and 60° C., the reaction mixture is taken up again with ethyl acetate. The organic phase was treated with 2N hydrochloric acid and then with water.
After subsequent washing with sodium carbonate solution and evaporation, a crystalline residue corresponding to the amide is obtained. The following examples illustrate preparations according to the invention and generally follow the procedure described above. Example Production of compound n゜1130 0.85 to 0.01 mol of acid A in 20 cm ³ of anhydrous benzene
ml (1.43 g or 0.012 mole) of distilled thionyl chloride was added. The reaction medium was brought to 60° C. for 5 hours. After evaporation to dryness in vacuo, the residue was taken up in 10 cm ³ of benzene and then 10 cm ³ of freshly distilled piperidine were added dropwise. Next, the reaction medium is
It was brought to 70° C. for 2 hours and then evaporated to dryness in vacuo.
The residue was dissolved in 150 cm ³ of ethyl acetate. The organic phase obtained was washed with water, then with N-hydrochloric acid, then with water and dried over sodium sulfate. The crystals obtained by evaporation were recrystallized from benzene (yield:
73%). Compounds of the invention were prepared according to the same procedure as in the Examples and are collected in the following table.

【table】

【table】

Claims (1)

[Claims] Linear formula [In the formula, R ₁ and R ₂ are the same or different, hydrogen atom, halogen atom, NO ₂ group, NH ₂
represents a group, CF ₃ group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, n+m+1 is 3 to 11, and R ₅ and R ₆ are the same R ₄ is a hydroxy group, the group OR ₇ (R ₇ is an alkyl group having 1 to 6 carbon atoms), or a group [formula] (wherein R ₈ and R ₉ are the same or different, hydrogen atoms, or 1 to 6, preferably 1 to 4 R ₈ and R ₉ together with nitrogen represent a 5- or 6-membered nitrogen-containing heterocyclic group, in particular piperidino, morpholino, pyrrolidino, pyrrole or pyrroline group)]. 2 R ₁ and R ₂ are the same or different, a hydrogen atom, a halogen atom, an NO ₂ group,
represents an NH ₂ group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, where n+m+1 is 3, 5 or 10, and R ₅ and R ₆ are each hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms, and R ₄ is a hydroxy group or a group OR ₇ (R ₇ is an alkyl group having 1 to 4 carbon atoms). The compound according to claim 1, characterized in that it represents an alkyl group). 3 R ₁ and R ₂ are the same or different, a halogen atom, NO ₂ group, NH ₂ group, CF ₃
2. A compound according to claim 1, characterized in that it represents a group, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms. 4. The compound according to claim 1, wherein either R ₅ or R ₆ is a hydrogen atom. 5. The compound according to claim 1, wherein R ₅ is a hydrogen atom. 6. The compound according to claim 5, wherein R ₁ and R ₆ are hydrogen atoms. 7. The compound according to claim 5, wherein R ₁ and R ₂ are hydrogen atoms. 8. The compound according to claim 5, wherein R ₁ , R ₂ and R ₆ are hydrogen atoms. 9 formula [In the formula, n+m+1 is an integer from 3 to 11,
2. A compound according to claim 1, wherein R ₄ is a hydroxy group or an alkoxy group having 1 to 6 carbon atoms. 10. A compound according to claim 9, characterized in that n+m+1 is 3, 5 or 10. 11 Claim 10, characterized in that n+m+1 is 3 and R ₄ is a hydroxy group.
Compounds described in Section. 12. The compound according to claim 1, which is represented by the following formula.