SU1768030A3 - 5-arginylaminonaphthalene-1-sulfamides dihydrochlorides as semiproducts for synthesis of 5-arginylaminonaphthalene-1-sulfamides - Google Patents

Abstract

The essence of the invention: the product is di-hydrochlorides of 5-arginyl aminonaphthalene-1-sulfamides in the form of SOoUC. Ri R, where Ri is H; Ra - СНз, CaHs, СзН, from iso-СзН, СзНд, iso-С4-Нэ, tert-С Нд, СБС,) -ССН2; or Ri R2 is CH3, C2Hs; iMMNRiRz- -NfCK2} -20-CH2CH2; -yfCH2facH2 G-cTsTG) -3cng Reagent 1: N-tert-butyloxycarbonylarginine hydrochloride. Reagent 2: 5-aminonaphthalen-1-cyclohexyl sulfamide. Reaction conditions: DM FA, toluene, pyridine, di-tert-butylylcarbonate, CP-COOH 8 table. WITH

Description

This invention relates to the field of bioorganic chemistry of 5-amino-naphthalenesulfonamide derivatives, specifically to the novel dihydrochlorides 5-arginylminonaphthalene-1-sulfamides of general formula I

2HCVArgNH4p /

GL1

(

 i

where Ri H; R2 CH3, CaHs, SzNu, iso-Sz-H,

/ -h

C4HD, iso-C -Se, CsHn,

; or RI

 Ra - CH3, C2H5; or NRiR2,

V

/, S N. / t, i

as intermediates for the production of 5-arginyl aminonaphthalen-1-sulfamide (ANSA), which are used as substrates for the ANCA analysis of aminopeptidases (analysis of the enzymatic activity of aminopeptidases using substrate mixtures containing aminonaphthalene sulfamide detection groups).

5-Arginylaminononaphthalen-1-sulfamide bromohydrates are known as intermediates for the preparation of 1-substituted arginyl aminonaphthalene-sulfates: pentamethyleneamine, butplamine, 3-hydroxy-M.M-pentamethyleneamine derivatives. The indicated bromohydrates are obtained by condensation of bromohydrates of N-substituted arginine with 5-aminonaphthalene-1-sulfamides using the carbodiimide method followed by

S

§

with about

 with

acid. The conversion of the obtained bromo hydrates to the desired products is carried out by treatment No. 2, with a pH of 7.8.

The disadvantage of the bromhydrates used is instability, which makes them inconvenient for long-term storage and further production of 5-arginylamine-naphthalene-1-sulfonamides. HBr released during storage reduces sulfamide bond, and the resulting free Br oxidizes labile groups of chromogenic substrates.

The target product is obtained with an insufficiently high yield (40%).

The purpose of the invention is the discovery in the range of arginylnaphthalenesulfonamides of new compounds more stable during storage, the use of which as intermediates makes it possible to obtain 5-aminonaphthalen-1-sulfonamides with a higher yield.

The goal is achieved by the synthesis of dihydrochloride 5-arginyl aminonaphthalene-1-sulfamides I, which are stable during storage, soluble in water, and the pH values of the solutions are close to neutral (at a concentration of 1 103 M compounds I in water pH 6.3-6.5) . They can be sustained for a long time even after cleavage of the hydrochlorides as free bases. The stability of substances I is characterized by the constant physicochemical characteristics of Rf,

, PMR, m.p., elemental analysis (see tab.1). The dihydrochlorides I are obtained by acylation of free 5-amino naphthalene-1-sulfamide with the peptide, i-peratome, i-peratome, i-1 -t-butyloxycarbonylarginine, in the presence of an excess of di-tert-butylpyrocarbonate, and without isolating the N-tert-butyloxycarbonylargylaminoaphthalene-1-1-N-tert-butyloxycarbonylarginylminonaphthalene-1-yloxycarbonylcarboxylate, and without isolating the N-tert-butyloxycarbonylargylamino-naphthalene-1-1-N-tert-butyloxycarbonylarginimine naphthalene-1-hydroxychloride, i.e. the reaction mixture with trifluoroacetic acid in methylene chloride; after treatment with NaHCOs and saturation with dry HC, dihydrochlorides of 5-arginylamino-naphthalene-1-sulfamides are obtained. Their use as intermediates for the production of arginyl ANSA allows to obtain the desired products in 54–84% yields (see Table 2) versus 35–40% using known intermediates.

Arginyl-ANSA I dihydrochlorides are also prepared by acylation of 5-amino naphthalen-1-sulfamides of the free base with -nitro-M-tert-butyloxycarbonylarginine in the presence of di-tert-butylpyrocarbonate, removal of the protective groups is carried out by hydrogenation in hydrogen chloride solution methanol in the presence of a Pd / C catalyst to obtain

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Eat 2HCI salts of arginyl-ANSA I. The use of dihydrochlorides to obtain the target products provides 64.8-79.4% yields against 35-40% of the prototype. In addition, the resulting intermediates in the form of 2HCI arginyl-ANSA salts (unlike the free bases of arginyl-ANSA, which are strong bases, have a pKa of the guanidine group of arginine 12.5, which leads to their gradual decomposition). for its stability, and if necessary, can be decomposed into free bases with high yields of 91-96%

Example 1. 5-Arginine-laminonaphthalen-1-cyclohexyl sulfamide dihydrochloride. 3.3 g of M-tert-bugyloxycarbonylarginine hydrochloride (monohydrate) are dissolved in 10 ml of dry dimethylformamide, and 30 ml of dry toluene are added. The solution is evaporated under reduced pressure to 10 ml, cooled to 10 ° C, 0.8 ml of dry pyridine and 2.7 ml of di-t-butyl pyrocarbonate are added. Stir for 1 h, add 3.3 g of 5-aminonaphthalen-1-cyclohexylsulfate and 40 g portions over 40 minutes. The mixture is stirred for 3 hours at 20 ° C, after which 1.3 ml of di-tert-butyl pyrocarbonate is added and stirred for another 16 hours. The reaction mixture is poured into 100 ml of dry ether, stirred for 10 minutes. the ether is decanted, the oily residue is poured over 50 ml of a mixture of trifluoroacetic acid - methylene chloride (1: 1), the reaction mixture is stirred for 1 hour at 20 ° C, concentrated to 10 ml and poured 100 ml of dry ether. The resulting product is filtered, dried in a vacuum desiccator, dissolved in 20 ml of water, filtered, unreacted aminonaphthalene sulfamide. The aqueous solution is extracted with 80 ml of n-butanol, the organic layer is separated, washed with 5% aqueous NaHCOs to pH 7-8 (aqueous layer), then with water (twice 10 ml), concentrated to 15 ml and saturated with dry HCl. The solvent is evaporated under reduced pressure, the oily residue is triturated with ether, the crystalline precipitate formed is filtered off and dried. 4.40 g (82%) of chromatographically and analytically pure product are obtained, mp. 168-171 ° C, Rf 0.42 (silufol, butanol-CH3COOH-water 4: 1: 2), “L ° + 17.7 (CI, SNZON). PMR (DMSO): 1.23 (CH2); 3.20 (CH).

Found,%: C 49.28; H 6.71; N 15.89; S 5.30; From 13.02.

C22H34NeS03Cl2

Calculated,%: C 49.53; H 6.42; N 15.75; S 6.01; CI 13.29

Other examples of the synthesis of the compounds of example 1 are collected in table 2, mp, Rf, elemental analysis and PMR data for the compounds are given in table 1.

Example 2. 5- (M-Nitro-g tert-butyloxycarbonyl) arginyl aminonaphthalene-1-pentamethylene sulfamide. 3.2 g (Mch-nitro-1G- -tert-butyloxycarbonyl) arginine, 0.8 ml of dry pyridine and 2.4 ml of di-tert-butylpyrocarbonate are stirred in 10 ml of dry dioxane at 20 ° C for 1 , 5 hours. In the resulting solution, 2.9 g of 5-aminonaphthalen-1-pentamethylenesulfimide are added in small portions over 50 minutes. The reaction mixture was stirred for 4 hours, another 1.6 ml of di-tert-butyl pyrocarbonate was added and stirred for 17 hours. The dioxane was then evaporated under reduced pressure, the oily residue was dissolved in acetone and passed through an alumina chromatography column. , elute with ethyl acetate-methanol (1: 1). The fraction containing the desired product is boiled for 0.5 h with activated carbon, filtered, the filtrate is evaporated. The oily residue is triturated with dry diethyl ether, the resulting precipitate is filtered off and air dried. 3.73 g (63%) are obtained by chromatography and analytically pure product, m.p. 117-121 ° C, Rf 0.70 on Silufol plates

(ethyl acetate-methanol 19: 1) a) 0 -5.8 (CI, acetone).

Found,%: C 52.77; H 6.51; N 16.71; S 4.83.

C26H37N7SO

Calculated,%: C, 52.78; H 6.30; N 16.58; S 5.42.

Similarly, other N-protected 5-arginylamino-naphthalene-1-sulfamides were obtained. Their outputs are given in table 3, physico-chemical properties in table 4.

Example 3. 5-arginine-laminonaphthalen-1-pentamethylenesulfamide ida hydrochloride. 5.92 g of 5- (HN-nitro G-tert-butyloxycarbonyl) arginylminonaphthalene-1-pentamethylene sulfamide was dissolved in 150 ml of dry methanol, 10 ml of 4.4 n was added. HCl in methanol and 2 g of catalyst (10% Pd / C). Stir in a stream of hydrogen for 25 h at 20 ° C, add another 2.5 g of catalyst and 4.5 ml of HCl in methanol, stir in a stream of hydrogen for another 23 h. After that, the reaction mixture is filtered, the filtrate is evaporated, the oily residue is triturated with dry diethyl ether, filtered and washed with ether. Obtained 4.73 g (91%) of the desired product, so pl. 141-145 ° C

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Rf 0.40 (same system), 6.3 (CI; SNZON). PMR (DMCO): 1.38 CH2, 3.06 (CH2). Found,%: C 48.76; H 6.45; N 15.94; S 5.64; CI 13.24.

C2lH32N6S03Cl2

Calculated,%: C 48.55; H 6.21; N 16.18; 56.17; CI 13.65.

Other examples of the synthesis of compounds according to this method are collected in table 5. The yields of the target products arginyl-ANSA, calculated on the synthesis of LH-nitro-M ° Cret-butyloxycarbonyl-arginine, are given in Table 6.

Description of the final products.

Example 4. 5-Arginyl-aminonaphthalene-1-pentamethylene sulfamide. 5.2 g (0.01 mol) of 5-arginyl aminonaphthalene-1-pentamethylene sulfamide dihydrochloride are dissolved in 50 ml of water, 200 ml of n-butanol are added to the solution in a separating funnel and (in 20 ml portions, shaken after each portion ) 5% aqueous NaHCOs to pH 7 (aqueous layer). The organic layer is washed with water twice in 20 ml and evaporated to 10-15 ml. The residue is triturated with 150 ml of dry ether, filtered off, washed with ether, dried. Obtain 4.15 g (93%) of the target product, so pl. 138-143 ° C, Rf 0.40 (the same

system), sgY + 6.9 (CI; SNZON).

Found,%: C 56.24; H 6.77; N 18.85; S 6.54.

C2iH3oNeS03

Calculated,%: With 56.48; H 6.77; N 18.82; 57.18.

Other examples of the preparation of arginyl-ANSA according to example 4 are collected in Table 7.

Thus, the use of dihydrochlorides of 5-argichylaminonaphthalene-1-sulfamides as intermediates for the synthesis of 5-arginyl aminonaphthalene-1-sulfamides allows increasing the yield of the target substances up to 54-84% against 35-40% of the prototype, and the stability of the intermediates ensures accuracy ANSA analysis of amino peptidases. Table 8 presents the elemental analysis data for 5-arginilam nonafthalen-1-sulfamides.

Claims (1)

Invention Formula Dihydrochlorides of 5-arginyl aminonaphthalen-1-sulfamides of the general formula 55 2ns. AgdynR R, ( H, where Ri H; Ra СНз, C2Hs, СзНу, from-Сз-Ну,, from-С4-Сэ, t-С4Нд, CsHn, or Ri Ra СНз, CaHs; or NRiR2 5 -NvJG 4 ../ -; i quality of intermediate products for the preparation of 5-arginylamino-naphthalen-1-sulfamides. Physico-chemical characteristics and data of elemental analysis of dihydrochloride Jj-arginilaminonaphalene-h-sulfamides Silufol, (butanol-acetic acid-water 1: 1: 2) C1, ClljOH NDP-spectrum of arginyl aminonaphthalen-1-dimethylsulfonamide dihydrochloride 5: 2.65 (s, 6H, 2CHg) f 1, b (m, AN, 2CH2); 3.2 Mm, 2H, SNg); , 5 (m, 1H, CH); 5, LP-O 1 (1ZN, 6H - naphthalene, SH, 11H), 8 PMR spektrlh remaining dihydrochloride 5-arginilaminonaftalin-1-sulfamide signals protonoa arginine and naphthalene choltsa identical to the corresponding signals ariginilaminonaftali dihydrochloride 5-1-dimetilsulfechida. therefore, the table gives the signals of the protons R, R2. Table 1 Table 2 Preparation of dihydrochlorides of 5-arginyl aminonaphthalen-1-sulfamides in Example 1 and the yields of the final product of 5-arginylaminonaphthalene-1-sulfamides calculated on the basis of synthesis for the initial N-tert-butyloxycarbonylarginine 2HC1-ArgHM- @ RI (OVso2biC 2 od 2 N-tert-butyloxycarbonylarginine loading: 3.3. Condensing agent: di-tert.-butylpyrocarbonate pyridine (0.8 ml) Solvent: dimethylformamide (10 ml) Reaction time: 21 hours, temperature 20 ° С Aminonaphthalene-1-sulfamides. V v Arginyl aminonaphthalene-1-sulfamides, 2 Talitsa Getting 5- (and -nitro-H-tert-butyloxycaronyl) argintyla naphtslin-1-sulfamido in example 2 HN CNH (CH, VCHCOHN- (, 02NHN25 | H-SO, (CHjhCCONH g NR2 Download protected arginine: 3.2 g Condensing agent: di-tert-butylpyrocarbonate d ml) in pyridine (0.8 ml) Solvent: dioxane (Yu ml) Reaction time: 21 hours, temperature 20 ° С  Ethylece-a - methanol (19: 1), Silvol. C1, acetone. , oooeuev vouo33MeueH4ux progamm and zopropilamich not byde. p  5 a a-v: isesum zide. Table5 Obtaining dihydrochloride 5-arginylamine-1-sulfonamides according to example 3 Table The yield of the final product 5-arginyl aminonaphthalen-1-sulfamide, calculated on the synthesis of the starting N-nitro-N-tert-butylcarbonylarginine (3.2 g) one Table Preparation of 5-arginyl aminonaphthalene-1-sulfamide according to example 4 of ArgHNX (5) 4O S02NX / Starting compound: 5-aryginyl-aminonaphthalene-1 sulfonamide dihydrochloride Solvent: water (50 ml) Medium: n-butanol (200 ml) Neutralization was carried out with 5% aqueous NaHCOa before (aqueous layer) lfa X R Tablata Elemental analysis data for 5-arginylminonzphthalen-1-sulfamides ArgNH-Yu