WO2010127600A1 - 6-deoxidized sulfone cyclodextrin derivatives and preparation method thereof - Google Patents

Abstract

6-deoxidized sulfone cyclodextrin derivatives with structure of formula (I) are provided by the present invention, which are prepared by the steps of oxidation 1 by using 6-deoxidized thioether amino acid cyclodextrin derivative or 6-deoxidized thioether cyclodextrin derivative as raw material to obtain 6-deoxidized sulfoxide cyclodextrin derivative, further oxidizing the resultant to obtain 6-deoxidized sulfonyl cyclodextrin derivative. In which, the 6-deoxidized thioether amino acid cyclodextrin derivative is prepared by following procedure: using acetic acid containing R₃ substituent group to obtain dihalide through halogenation, condensing with amino acid to obtain amide, adding sulfur reagent to obtain sulfur-containing compound, removing the protecting group to obtain sulfhydryl compound, and then condensing with halogenated cyclodextrin to obtain the product. The compound provided by the present invention can be used to antagonize muscle relaxation effect induced by muscle relaxant drugs in patients or animals, has reversal and antagonistic effect to muscle relaxation induced by muscle relaxant drugs, and can be used to prepare drugs which have antagonistic effect to muscle relaxation.

Description

 Description

6-deoxysulfone cyclodextrin derivative and preparation method thereof

Technical field

 The invention belongs to the field of chemical pharmacy, and relates to a 6-deoxysulfone-based cyclodextrin derivative and a preparation method thereof, mainly relating to a 6-deoxysulfoxide-based cyclodextrin derivative and a 6-deoxysulfone-based cyclodextrin derivative and preparation thereof Methods, and uses in the preparation of muscle relaxant drugs.

Background technique

 In 1980, Fujita. K. first reported the synthesis of monosubstituted 2-hydroxyethylthiocyclodextrin in Tetr.Lett. In 1993, Ling.C. and Darry.R. reported the synthesis of fully substituted 2-hydroxyethyl. Thiocyclodextrin, its structural formula is:

 In 1986, Tubashi, I. reported the synthesis of o-carboxyphenylthiocyclodextrin on LA.CS; in 1995, Guillo, F. reported the synthesis of carboxymethylthiocyclodextrin; in 1996, Baer, HH and Santoyo- Gonzalez, F. prepared 2,3-dihydroxypropylthiocyclodextrin. Its structural formula is:

B = HOOCCH ₂ ; PhCOOH; HOCH ₂ (HO) CHCH ₂ ;

 Patent CN1402737 reports the preparation of a similar compound having the chemical structure of formula (IV):

 IV

Wherein m is 0 to 7, n is 1 to 8 and m+n=7 or 8; Instruction manual

R is (-Ce)alkylene, optionally substituted by 1 to 3 OH groups or (CH ₂ ) r-phenylene-(CH ₂ ) _t -;

 r and t are each independently 0 to 4;

X^COOH, CONHR ₆ , NHCOR ₇ , S0 ₂ OH, PO (OH) ₂ , O (CH ₂ -CH ₂ -0) uH, OH or tetrazol-5-yl;

R ₆ is hydrogen, (Q 3 ) alkyl;

R ₇ is a carboxyphenyl group;

 u is 1 to 3.

 Sugammadex is a 6-mercaptocyclodextrin derivative in CN1402737, marketed in July 2007 by Schering-Plough's sugammadex (Bridion) for reversing the conventional neuromuscular blocking drug rocuronium or vecuronium , can immediately reverse the role of rocuronium used in adults, routinely reverse the use of rocuronium in children and adolescents (2 to 17 years old).

 Muscle relaxant relaxes skeletal muscle, also known as muscle relaxant, and is an important adjunct to general anesthesia to facilitate endotracheal intubation during general anesthesia induction and to maintain good muscle relaxation during surgery. The use of muscle relaxants can avoid the adverse effects of deep general anesthesia on the human body. The muscle relaxant is also suitable for the critical patient to eliminate the confrontation between the patient's spontaneous breathing and mechanical ventilation during mechanical ventilation, as well as to treat spastic diseases.

 The use of muscle relaxants requires attention to airway management, assisted breathing or controlled breathing depending on the degree of muscle relaxation, and to ensure effective and adequate ventilation per minute.

 The anesthesiology profession is recognized as a high-risk major. According to statistics from the World Health Organization (WHO), the average mortality rate in recent years in developed countries is 1:100,000~1:300,000, and in developing countries is 1:5000~: 10,000, which is even higher in some backward countries. A national major anaesthetic investigation of anesthesia by the French Ministry of Health (incorporating 198,103 anesthesia cases) found that postoperative respiratory depression (61% of deaths) was the leading cause of anesthesia-related deaths in this survey, but not everyone. Guess the intubation is difficult. It can be seen that the residual of postoperative neuromuscular blockade is a risk factor that should be highly valued.

 It is very difficult to judge whether the neuromuscular function returns to normal after the application of the muscle relaxant. Residual muscle relaxants can inhibit the response of the respiratory center to hypoxic ventilation; damage the inspiratory flow rate, cause upper airway obstruction and dysphagia; prolong hospital stay, increase postoperative complication rate and mortality; cause laryngeal muscle function Obstacle, the incidence of aspiration increased. Therefore, safe, effective, and antagonistic effects of residual muscle relaxants are important for clinical anesthesia.

The existing muscle relaxant anti-cholinesterase can temporarily inhibit the acetylcholinesterase which decomposes acetylcholine, increase the concentration of acetylcholine in the neuromuscular junction, and promote the return of neuromuscular excitation to normal. Anticholinergic esterases have neostigmine, phenol chloroammonium and pyridinium, which have a peak effect time of 7 to llmin, l~ Instruction manual

2min and 15~20min. Pyridinium has the slowest onset of action and therefore does not meet clinical requirements. At the same time, the complications or adverse reactions of anticholinergic drugs are also serious.

 Potassium channel blockers act in front of the neuromuscular junction, blocking potassium ions from flowing out of the nerve endings, prolonging the depolarization of the nerves and increasing the time and release of acetylcholine. However, these drugs are not specific and can act on all nerve endings, thus causing a variety of serious adverse reactions, which limits their clinical use.

 Sugammadex is capable of sequestering muscle-like muscles to detach from acetylcholine receptors and rapidly reverses neuromuscular blockade. It has properties not found in other muscle relaxant antagonists: it can be quickly applied to muscle relaxants in a short period of time. Antagonism is also applicable to small surgery with short time, and it can be used as a rescue medication for cases that are both incapable and incapable of ventilation. Since its action does not involve muscarinic receptors, it does not need to be combined with anticholinergic agents. It can also antagonize the effect of deep muscle relaxation, shorten the recovery time of muscle tension, and there is no poisoning of the arrow after antagonism. Sugammadex has significant advantages over existing muscle relaxant antagonists.

technical problem

 One of the objects of the present invention is to provide a 6-deoxysulfone-based cyclodextrin derivative, and another object of the present invention is to provide a process for producing a 6-deoxysulfone-based cyclodextrin derivative (I).

Technical solution

 It is an object of the present invention to provide a 6-deoxysulfone-based cyclodextrin derivative having the structure of the formula (I):

 Formula ( I )

Where m is one of 0, 1, 2, 3, 4, 5, 6, 7, 8;

 n is one of 1, 1, 2, 3, 4, 5, 6, 7, 8, 9;

 m+n is one of 6, 7, 8 or 9;

 q is one of 1 or 2;

R is (C _r C ₆ )alkylene, optionally substituted by 1 to 3 OH groups or (CH ₂ ) r-phenylene-(CH ₂ ) _t -, where r is 0, 1, 2, 3 Or one of 4, t is one of 0, 1, 2, 3 or 4; Instruction manual

X is COOH, CONHR^ NHCOR ₂ , S0 ₂ OH, PO (OH) ₂ , O (CH ₂ -CH ₂ -0) u

One of -H, OH or tetrazol-5-yl, which is hydrogen, (d- ₃ )fluorenyl or one of (d- ₃ )alkyl containing C00H, is a carboxyphenyl group, u is 1, One of 2 or 3.

 The 6-deoxysulfone-based cyclodextrin derivative (I) is a 6-deoxysulfoxide-based cyclodextrin derivative having a structure of the formula (Π) when q is 1.

 Type (Π)

 The 6-deoxysulfone-based cyclodextrin derivative (I), when q is 2, is a 6-deoxysulfone-based cyclodextrin derivative having a structure of the formula (ΠΙ):

 Formula (III)

 Another object of the present invention is to provide a process for the preparation of a 6-deoxysulfone-based cyclodextrin derivative (I): a 6-deoxythioether amino acid cyclodextrin derivative (V) or a 6-mercapto cyclohexane disclosed in CN1402737 The refined derivative (IV) is a raw material, and the 6-deoxysulfoxide-based cyclodextrin derivative (II) is obtained by the oxidation reaction 1, and the compound (II) is further subjected to an oxidation reaction 2 to obtain a 6-deoxysulfone-based cyclodextrin derivative. (ΠΙ).

Reaction formula: Instruction manual

 π

 l oxidation reaction 2

Wherein m, n, m+n, R, X, as described in the compound (I),

R ₃ is one of H, C 3⁄4, CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , (CH ₂ ) ₃ CH ₃ , C (CH ₃ ) ₃ or C ₆ H ₅ ;

1 ₄ is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₃ (CH ₃ ) CH, CH ₂ CH (CH ₃ ) ₂ , CH ₂ C ₆ One of H ₅ , CH ₃ SCH ₂ CH ₂ or H ₂ NC (O) CH ₂ .

The oxidizing agents used in the above oxidation reaction 1 and oxidation reaction 2 steps are peroxyacid salts and organic peroxides such as peroxosulfuric acid, H ₂ O ₂ , KC10 ₄ , H ₂ S0 ₄ , KMn 0 ₄ , Na ₂ 0 ₂ or K. _{One of the 2} 0 ₂ .

Another object of the present invention is to provide a structure of a 6-deoxythioether amino acid cyclodextrin derivative (V) and a preparation method thereof as follows: Instruction manual

Wherein: M, n, m+n are as described for compound (I);

R ₃ and R _{4 are} as defined for the compounds (π ) and (m);

R ₅ is phenyl or pyridyl;

 A is one of OH, C1 or Br.

 6-deoxysulfide amino acid cyclodextrin derivative (V) is prepared by using a substituted acetic acid (a) as a starting material and a halogenating reagent to obtain a double halide (b) by condensation reaction with an amino acid. Corresponding amide (c), then adding a sulfur reagent to introduce a sulfur-containing group to obtain a corresponding sulfur-containing compound (d), removing the protecting group to obtain a mercapto compound (e), and condensing with a halogenated cyclodextrin in the presence of a base A series of 6-deoxythioether amino acid cyclodextrin derivatives (V) and salts thereof.

The related hydrocarbons or aromatic hydrocarbons having a substituent of hydrogen and a short carbon chain, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or phenyl; The halogenating reagent is chlorine, bromine, thionyl chloride, phosphorus tribromide or phosphorus trichloride; the amino acids used are natural amino acids such as: gan, propyl, fluorene, bright, bright, asparagine, styrene Or methionine or the like; the sulfur reagent involved in the introduction of the sulfur-containing group is: thionicotinic acid, sodium disulfide, thioacetic acid, sodium thiosulfate or thiobenzoic acid, preferably thionicotinic acid; The removal of the protecting group means alkali hydrolysis, and the base used is an inorganic base such as ammonia water, sodium hydroxide or potassium, or an aqueous solution of sodium or potassium carbonate; in the condensation reaction with a halogenated cyclodextrin in the presence of a base, The description base refers to sodium or potassium hydride, sodium or potassium amide, sodium or potassium alkoxide; halogenated cyclodextrin refers to: 6, 7, 8 or 9-membered cyclodextrin substituted with chlorine, bromine or iodine; The obtained 6-deoxythioether amino acid cyclodextrin derivative and a salt thereof mean a potassium salt, a sodium salt or a lithium salt, preferably a sodium salt.

 A further object of the present invention is to provide the use of compounds II, III and V for the preparation of muscle antagonistic drugs. It has been confirmed by pharmacological experiments that the compounds II, III and V provided by the present invention can be used to reverse the neuromuscular relaxation induced by muscle relaxants in patients or animals, and have reversal and antagonism on muscle relaxation induced by muscle relaxants.

 The compound of any of the compounds II, III, and V provided by the present invention is mixed with a pharmaceutically acceptable adjuvant to obtain a pharmaceutical composition, which may be in the form of a tablet, a capsule or an injection.

 Beneficial effect

 The 6-deoxysulfoxide-based cyclodextrin derivative (11), the 6-deoxysulfonyl cyclodextrin derivative (m) and the 6-deoxythioether amino acid cyclodextrin derivative (V) provided by the present invention can be rapidly, Safe and effective antagonism of steroidal non-depolarizing muscle relaxants, combined with neuromuscular blockers, prevents them from acting at the neuromuscular junction, thereby reversing the effect of muscle relaxants, no significant adverse reactions, and the status of clinical anesthesia May be greatly changed. The anesthesiologist will increase the amount of muscle relaxant at the end of the surgery or complete the neuromuscular block when suturing the skin, and there will be no further concern, as long as the drug prepared by the compound of the present invention is administered, the patient's neuromuscular The conduction function can be quickly restored; for patients with burns, hyperkalemia or plasma pseudocholinesterase abnormalities, when succinylcholine is not available, rocuronium and the compounds prepared by the compounds of the invention are preferred. In addition, if the patient is found to have difficulty intubation after anesthesia induction or emergency intubation with non-depolarizing muscle relaxants, and the case of "unable to intubation, inability to ventilate" occurs, the compound of the present invention can be applied rapidly. Stop the muscle relaxant and quickly return to normal autonomous ventilation to ensure the patient's life safety.

The 6-deoxythioether amino acid cyclodextrin derivative (V) of the present invention is significantly different from the 6-fluorenylcyclodextrin derivative (IV) in CN1402737. When X in the compound (IV) is CONHRi, 1 is hydrogen, (d- ₃ )alkyl; and in the 6-deoxythioether amino acid cyclodextrin derivative (V) of the present invention, when X is CONHRi, 01 (:0011. The 6-deoxythioether amino acid cyclodextrin derivative (V) of the present invention is characterized in that the cyclodextrin is substituted at the 6-position with an amino acid, and the compound (IV) is substituted with a cyclodextrin. Is a non-amino acid. The compound 6-deoxysulfone sulfone cyclodextrin derivative (I) and 6-deoxythioether amino acid cyclodextrin derivative (V) of the present invention have stable and good water solubility and can be used for inversion. A drug candidate for drug-induced neuromuscular anesthesia. At the same time, it is rich in amino acids and has high safety, which is conducive to improving drug safety.

 Embodiments of the invention

The invention is further illustrated by the following examples, but is not intended to be used in any way. Explain the limitations of the book.

Example 1 Synthesis of α-chloroacetylglycine

 Add 90 g (1.2 mol) of glycine acid to a 2000 mL four-reaction bottle, add about 400 mL of water to stir and dissolve, and gradually add 64 g (0.6 mol) of anhydrous sodium carbonate. After the addition and dissolution, the mixture was cooled with an ice salt bath, and about 135.5 g (1.2 mol) of α-chloroacetyl chloride was added dropwise with vigorous stirring, and the sodium carbonate solution was added dropwise to keep the reaction solution weakly alkaline. After stirring for 4 h, hydrochloric acid was acidified to pH = l. The mixture was extracted twice with ethyl acetate, and the combined extracts were combined and dried over anhydrous sodium sulfate and filtered and filtered, and the filtrate was evaporated under reduced pressure to leave crystals, which was stood overnight, filtered and dried to give 123.6 g of colorless crystals. 68%. Example 2 Synthesis of α-chlorophenylacetylglycine

 90 g (1.2 mol) of glycine was added to a 2000 mL four-neck reaction flask, and about 400 mL of water was added thereto to stir and dissolve, and 64 g (0.6 mol) of anhydrous sodium carbonate was gradually added thereto. After the addition and dissolution, the mixture was cooled with an ice salt bath, and about 226.85 g (1.2 mol) of α-chlorophenylacetyl chloride was added dropwise with vigorous stirring, and the sodium carbonate solution was added dropwise to keep the reaction solution weakly alkaline. Stirring was continued for 4 h and the hydrochloric acid was acidified to pH = l. The mixture was extracted twice with ethyl acetate. The combined extracts were combined and dried over anhydrous sodium sulfate and filtered and evaporated. The filtrate was evaporated to dryness and crystallised to stand overnight, filtered and dried to give colorless needle crystals 180.3. %. Example 3 Preparation of potassium salt solution of thionicotinic acid

(42 g, 0.75 mol) of sodium hydrosulfide, 150 ml of water, stirred and dissolved. Nicotinyl chloride (49.54 g, 0.35 mol) was added dropwise under ice cooling, and the temperature was controlled to not exceed 15 °C. After the addition is complete, continue to stir for 1 hour. The specification was then cooled to o °c, neutralized with hydrochloric acid, filtered to obtain a solid thionicotinic acid, and then slowly dissolved in potassium carbonate water, and filtered to obtain 60.6 g of a yellow aqueous solution of potassium thionicotinate, yield 97.7%. Example 4 Synthesis of α-nicotinylacetylglycine

〇

Η _? Ν,

 ΟΗ

 7.5g (O.lmol) glycine was dissolved in 60ml dilute sodium hydroxide solution, the ice salt was cooled to below 0 °C, while 11.3g (0.1mol) α-chloroacetyl chloride and 50ml dilute hydroxide were added dropwise with vigorous stirring. The sodium solution was kept alkaline, and stirring was continued for 1 hour after the addition. Then, 17.73 g (0.1 mol) of potassium thionicotinic acid potassium salt solution was added, and the mixture was allowed to stand overnight. Hydrochloric acid was acidified to pH3, solid was precipitated, filtered, washed with water and dried to give a white solid 20.3 g, yield 80%. Example 5 Synthesis of α-nicotinoylpropionylglycine

 7.5 g (O.lmol) glycine was dissolved in 60 ml of dilute sodium hydroxide solution, the ice salt was cooled to below 0 ° C, and 12.7 g (0.1 mol) of α-chloropropionyl chloride and 50 ml of dilute hydroxide were added dropwise while stirring vigorously. The sodium solution was kept alkaline, and stirring was continued for 1 hour after the addition. Then, 17.73 g (0.1 mol) of a potassium salt aqueous solution of thionicotinic acid was added and allowed to stand at room temperature overnight. Hydrochloric acid was acidified to pH 3, and a solid was precipitated, which was filtered, washed with water and dried to give a white solid (22.3 g, yield: 83.5%). EXAMPLES ό (Synthesis of X-nicotinoylphenylacetylglycine)

7.5 g (O.lmol) glycine was dissolved in 60 ml of dilute sodium hydroxide solution, the ice salt was cooled to below 0 ° C, and 22.76 g (0.1 mol) of α-chlorophenylacetyl chloride and 50 ml of dilute hydrogen were added dropwise while stirring vigorously. The sodium oxide solution was kept alkaline, and stirring was continued for 1 hour after the addition. Then add 17.73g (O.lmol) of thionicotinic acid The potassium salt solution of the book is placed at room temperature overnight. Hydrochloric acid was acidified to pH 3, and a solid was precipitated, which was filtered, washed with water and dried to give a white solid (27 g, yield: 81.8%). Synthesis of benzoquinone ugly glycine

7.5 g (O.lmol) glycine was dissolved in 60 ml of dilute sodium hydroxide solution, the ice salt was cooled to below 0 ° C, and 11.3 g (0.1 mol) of a-chloroacetyl chloride and 50 ml of dilute hydroxide were added dropwise while stirring vigorously. The sodium solution was kept alkaline, and stirring was continued for 1 hour after the addition. Then, 17.63 g (0.1 mol) of a potassium salt solution of thiobenzoic acid was added and allowed to stand at room temperature overnight. Hydrochloric acid was acidified to pH 3, and a solid was precipitated, which was filtered, washed with water and dried to give a white solid (21.38 g, yield: 84.4%). Synthesis of benzoyl phenyl phenylglycine

7.5g (O.lmol) glycine was dissolved in 60ml of dilute sodium hydroxide solution, the ice salt was cooled to below 0 °C, and 18.9g (0.1mol) of α-chlorophenylacetyl chloride and 50ml of dilute hydrogen were added dropwise while stirring vigorously. The sodium oxide solution was kept alkaline, and stirring was continued for 1 hour after the addition. Then, 17.63 g (0.1 mol) of a potassium salt solution of thiobenzoic acid was added and allowed to stand at room temperature overnight. Hydrochloric acid was acidified to pH 3 to precipitate a solid, which was filtered, washed with water and dried to give a white solid. Example 9 Synthesis of 2-mercaptoacetyl-glycine

Add 500 g of sodium sulfide (NaS'9H20) to a 500 mL beaker, add about 150 mL of water to stir and dissolve. Continue to add 17.6 g (0.55 mol) of sublimed sulfur, heat and stir to dissolve, and react to obtain brown red sodium disulfide. Solution, spare. 83.35 g (0.55 mol) of α-chloroacetylglycine was added to a 2000 mL four-necked flask, and 500 mL of water was added thereto, and 28.5 g (0.27 mol) of anhydrous sodium carbonate was gradually added thereto with stirring, and stirred to dissolve. Then add the obtained The sodium disulfide solution is described, and the reaction temperature is controlled to not exceed 35 ° C, and the reaction is stirred for 10 h to form α-dithiobisacetylglycine. The acid was acidified to pH = 1 with cooling in an ice water bath to decompose excess sulfide. The solution after completion of the reaction was filtered, and the filtrate was placed in a 2000 mL four-necked flask. 82 g (1.25 mol) of zinc powder was added in portions in an ice water bath and stirred. After the addition, the reaction was continued at room temperature for 2 to 3 hours, and left overnight. (The storage container is filled as much as possible or protected with nitrogen to increase the yield, the same below). After filtration, the filtrate was extracted with ethyl acetate for 3 to 4 times and dried over anhydrous sodium sulfate overnight. Filtration, the filtrate was concentrated to a slight amount of crystal precipitation, placed at a low temperature, filtered, and dried in vacuo to give crude 2-mercaptoacetyl-glycine. Example 10 Synthesis of 2-Mercaptobenzoyl-glycine

 Sodium sulfide (NaS'9H20) 132g (0.55mol) was added to a 500 mL beaker, and about 150 mL of water was added to stir and dissolve. Further, 17.6 g (0.55 mol) of sublimed sulfur was added, and the mixture was heated and stirred to dissolve, and the reaction was carried out to obtain a brown-red sodium disulfide solution. ,spare. To a 2000 mL four-necked flask, 125.2 g (0.55 mol) of α-chlorobenzoylglycine was added, and 500 mL of water was added thereto, and 28.5 g (0.27 mol) of anhydrous sodium carbonate was gradually added thereto with stirring, followed by stirring to dissolve. Then, the obtained sodium disulfide solution was added dropwise while controlling the reaction temperature to not exceed 35 ° C, and the reaction was stirred for 10 hours to form α-dithiobisbenzoylglycine. After cooling in an ice water bath, sulfuric acid was added to ρ Η = 1, and the excess sulfide was decomposed. The solution after completion of the reaction was filtered, and the filtrate was placed in a 2000 mL four-necked flask. 82 g (1.25 mol) of zinc powder was added in portions in an ice water bath and stirred. After the addition, the reaction was continued at room temperature for 2 to 3 hours, and left overnight. (The storage container is filled as much as possible or protected with nitrogen to increase the yield, the same below). After filtration, the filtrate was extracted with ethyl acetate for 3 to 4 times and dried over anhydrous sodium sulfate overnight. Filtration and concentration of the filtrate until a small amount of crystals were precipitated, placed at a low temperature, filtered, and dried in vacuo to give a crude product of 2-carbylbenzoyl-glycine.

Example 11 Synthesis of 2-mercaptoacetyl-glycine

30 g (0.12 mol) of a-nicotinoyl acetylglycine was suspended in 100 ml of water, neutralized with sodium hydrogencarbonate, and then added with concentrated aqueous ammonia (30 ml), left at room temperature overnight, and then filtered to remove the precipitated benzamide. Description Book ammonia, acidified with hydrochloric acid. The aqueous solution was extracted with ethyl acetate, concentrated, and the solid was separated, filtered, and dried to give white crystals (14.6 g). Example 12 Synthesis of 2-mercaptobenzoyl-glycine

30 _g (0.11 mol) a-nicotinoyl benzoylglycine was suspended in 100 ml of water, neutralized with sodium hydrogencarbonate, and then added with concentrated aqueous ammonia (30 ml), left at room temperature overnight, and then filtered to remove the precipitated benzamide. Ammonia, acidified with hydrochloric acid. The aqueous solution was extracted with ethyl acetate, concentrated, and then evaporated, and filtered, and dried to give white crystals of 16.88 _g . Example 13 Synthesis of 2-mercaptoacetyl-glycine

 30 g (0.11 mol) of 2-mercaptobenzoyl-glycine was suspended in 100 ml of water, neutralized with sodium hydrogencarbonate, and then added with concentrated aqueous ammonia (30 ml), left at room temperature overnight, and then filtered to remove the precipitated benzamide. Acidified with hydrochloric acid. The aqueous solution was extracted with ethyl acetate, concentrated, and then evaporated, and then evaporated to give white crystals. Example 14 Synthesis of 2-mercaptobenzoyl-glycine

30g (0.11mol) of a-benzoyl benzoyl glycine was suspended in 100ml of water, neutralized with sodium bicarbonate and added The book was filled with 30 ml of concentrated ammonia water, left at room temperature overnight, and then filtered to remove the precipitated benzamide. The filtrate was dehydrated under reduced pressure and acidified with hydrochloric acid. The aqueous solution was extracted with ethyl acetate, concentrated, and then evaporated, and filtered and evaporated to give white crystals. Example 15

 Refining of N-(2-mercaptoacetyl)-glycine: It is dissolved at a temperature of 50 to 5 times ethyl acetate at 50 Torr, and can be decolorized by adding 0.01% of activated carbon, left overnight, filtered under reduced pressure, and dried under vacuum to obtain a purified product. The melting point is measured, and if necessary, it is recrystallized 1 to 2 times to obtain a finished product of about 60 g, a yield of about 65%, m.p. 96 to 98 ° C (literature yield 29%, m.p. 96-97.5 C).

 Triphenylphosphine (30.1 g, 15 eq.) was dissolved in dry dimethylformamide (160 mL). iodine (30.5 g, 15.6 eq.) was added over 10 min. Υ·cyclodextrin (10 g, 7. 7 mmol), the mixture was heated at 70 ° C for 24 hours. The mixture was cooled, and sodium methoxide (3.1 g of sodium in 50 ml of methanol) was added to the mixture. 300 ml of methanol, evaporated to dryness, 500 ml of water was added to the residue, and the solid was collected by filtration; the filtrate was concentrated under reduced pressure, and precipitated with ethanol, and dried under vacuum at 70 ° C to obtain a yellow solid 6-total deoxy-6-all Iodo-gamma-cyclodextrin (16.2 g) was used without further purification.

The hydrazine-(2-mercaptoacetyl)-glycine (1.22 ml, 14. 0 mmol) was dissolved in dry dimethylformamide (45 ml) at room temperature. 1,23 g, 30. 8 mmol, 60%). Stirring the mixture for 30 minutes. To this mixture, 6-to-deoxy-6-periodide in 45 ml of dry dimethylformamide was added dropwise. Γ-cyclodextrin (3.12 g, 1. 40 mmol) solution. After the addition, the reaction mixture was heated to 70 Torr and held for 12 hours. After cooling, water (10 ml) was added to this mixture and the volume was concentrated to 40 ml in vacuo, and ethanol (150 ml) was added thereto to cause precipitation. The solid precipitate was collected by filtration and dialyzed for 36 hours. The volume was concentrated to 20 ml in vacuo, ethanol was added thereto, and the precipitate was collected by suction and dried to give a white solid, yield 47%. Example 16 Instruction manual

 Refining of N-(2-mercaptopropionyl)-glycine: It is dissolved at a temperature of 5 to 6 times of ethyl acetate at 50 Torr, and can be decolorized by adding 0.01% of activated carbon, left overnight, filtered under reduced pressure, and dried under vacuum to obtain a purified product. The melting point is measured, and if necessary, it is recrystallized 1 to 2 times to obtain a finished product of about 60 g, a yield of about 65 %, m. p. 96 to 98.

 Triphenylphosphine (30.1 g, 15 eq.) was stirred and dissolved in dry dimethylformamide (160 liters). Iodine (30.5 g, 15.6 eq.) was added over 10 minutes with heat evolution. Dry Υ·cyclodextrin (10 g, 7.7 mmol) was added, and the mixture was heated at 70 ° C for 24 hours. The mixture was cooled, and sodium methoxide (3.1 g of sodium in 50 ml of methanol) was added to the mixture. Pour methanol into 800 ml, evaporate to dryness, add 500 ml of water to the residue, collect solids by filtration, concentrate the filtrate under reduced pressure, add ethanol to precipitate, and dry at 70 ° C to obtain a yellow solid 6 - fully deoxygenated -6-all iodo-γ-cyclodextrin (16.2 g).

The hydrazine-(2-mercaptopropionyl)-glycine (1. 22 ml, 14. 0 mmol) was dissolved in dry dimethylformamide (45 ml) at room temperature, and the solution was added to hydrogenation in three portions. Sodium (1,23 g, 30. 8 mmol, 60%), the mixture was stirred for further 30 minutes, and 6-to-oxygenated 6-all-iodine in 45 ml of dry dimethylformamide was added dropwise to the mixture. A solution of γ-cyclodextrin (3.12 g, 1.40 mmol) was added, and after the addition, the reaction mixture was heated to 70 ° C for 12 hours. After cooling, water (10 ml) was added to this mixture and the volume was concentrated to 40 ml in vacuo, and ethanol (150 ml) was added thereto to cause precipitation. The solid precipitate was collected by filtration and dialyzed for 36 hours. The volume was concentrated to 20 ml in vacuo, and ethanol was added thereto, and the precipitate was collected by suction and dried to give a white solid, CD-13, weighing 1.3 g, yield 43%. Ή NMR spectrum of CD-13 in heavy water (D ₂ 0): 51.46 (CH ₃ , d, 3H), 2.55 (CH ₂ , m, 2H), 3.02 (CH, m, H), 3.65 (CH, m, H), 3.72 (2CH, s, 2H), 4.12 (CH ₂ , s, 2H), 4.16 (CH, m, H), 5.01 (CH, s, H) ppm. Example 17 Instruction manual

 Refining of N-(2-mercaptobenzoyl)-glycine: Dissolve in 5~6 times of ethyl acetate at 50 °C, add 0.01% activated carbon to decolorize, place overnight, filter under reduced pressure, vacuum dry to obtain fine product. The melting point is measured and, if necessary, recrystallized 1 to 2 times to obtain a finished product of about 60 g, a yield of about 65 %, m. p. 96 to 98 ° C (literature yield 29%, m.p. 96 to 9715 ° C).

 Triphenylphosphine (30.1 g, 15 eq.) was stirred and dissolved in dry dimethylformamide (160 ml). Iodine (30.5 g, 15.6 eq.) was added over 10 min. Dry Υ·cyclodextrin (10 g, 7.7 mmol), and the mixture was heated at 70 ° C for 24 hours. The mixture was cooled, and sodium methoxide (3.1 g of sodium in 50 ml of methanol) was added to the mixture. The mixture was poured into methanol (800 ml), evaporated to dryness, and then, 500 ml of water was added to the residue, and the solid was collected by filtration, and the filtrate was concentrated under reduced pressure. The precipitate was precipitated from ethanol and dried at 70 ° C to give a yellow solid 6-deoxy-6 - All iodo-gamma-cyclodextrin (16.2 g), which was used without further purification.

Ν-(2-Mercaptobenzoyl)-glycine (1.22 ml, 14. 0 mmol) was dissolved in dry dimethylformamide (45 mL) at room temperature. Sodium hydride (1,23 g, 30. 8 mmol, 60%). Stirring the mixture for 30 minutes. To this mixture was added dropwise ₆ _deoxy_ ₆ _ all in 45 ml of dry dimethylformamide iodo a _{γ-cyclodextrin (3.12} g, L ₄₀ mmol). after the addition, the reaction mixture was heated to 70 ° C and held for 12 hours. After cooling, water (10 ml) was added to this mixture and the volume was concentrated to 40 ml in vacuo, and ethanol (150 ml) was added thereto to cause precipitation. The solid precipitate was collected by filtration and dialyzed for 36 hours. The volume was concentrated to 20 ml in vacuo, ethanol was added thereto, and the precipitate was collected by suction and dried to give a white solid, yield 50%. Ή NMR spectrum of the compound in heavy water (D ₂ 0): S2.69, 2.44 (CH ₂ , m, 2H), 3.02 (CH, m, H), 3.73 (2CH, s, 2H). 4.14 ( CH ₂ , s, 2H), 4.76 (CH, d, H), 5.03 (CH, s, H), 7.06 (CH, d, H), 7.25 (CH, m, H), 7.34 (CH, t, H) ppm. Example 18

Preparation of 6-all deoxy-6-per(2-carboxyethyl) sulfoxide-γ-cyclodextrin, 6-all deoxy-6-per(2-carboxyethyl)sulfone-γ-cyclodextrin Description

 CD-I CD-2 CD-3

6-Deoxyoxy-6-per(2-carboxyethyl) sulfide was suspended in 100 ml of acetic acid in cyclodextrin 108.9 g (50 mmol), and 8.5 g (75 mmol) of 30% H _{2 2 2} aqueous solution was added dropwise with stirring. After reacting for 6 hours, an alcohol was added to the reaction liquid to precipitate a solid, and methanol was recrystallized to obtain 6-perdeoxy-6-per(2-carboxyethyl) sulfoxide-γ-cyclodextrin (CD-2). Excess H ₂ O _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-2 in heavy water (D ₂ 0): δ2.57 (CH ₂ , t, 2H), 2.73 (CH ₂ , q, 2H), 2.81 (CH ₂ , t, 2H), 3.02 (CH, m, H), 3.71 (2CH, s, 2H), 3.90 (CH, m, H), 5.02 (CH, m, H) ppm.

6-perdeoxy-6-per(2-carboxyethyl) sulfide-γ-cyclodextrin 108.9 g (50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of a 30% H ₂ O ₂ aqueous solution was added dropwise with stirring. , maintaining the reaction at 40-60 ° C for 5 hours, adding alcohol to the reaction liquid to precipitate a solid, and recrystallizing methanol to obtain 6-perdeoxy-6-per(2-carboxyethyl)sulfone-γ-cyclodextrin (CD- 3). Excess 3⁄40 _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-3 in heavy water (D ₂ 0): δ2.73 (CH ₂ , t, 2H), 3.01 (CH, m, H), 3.53 (CH ₂ , q, 2H), 3.66 ( CH ₂ , d, 2H), 3.76 (2CH, d, 2H), 3.92 (CH, m, H), 5.0 (CH, m, H) ppm. Example 19

 6-total deoxy-6-all (2-carboxyethyl) sulfoxide-a-cyclodextrin, 6-deoxy-oxy-6-per(2-carboxyethyl) sulfone-a-cyclodextrin preparation

 CD-4 CD-5 CD-6

6-Deoxy-6-per(2-carboxyethyl) sulfide-α-cyclodextrin (81.7 g, 50 mmol) was suspended in 100 ml of acetic acid, and 8.5 g (75 mmol) of 30% H ₂ O ₂ was added dropwise with stirring. The aqueous solution was reacted at room temperature for 6 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to give 6-deoxyoxy-6-per(2-carboxyethyl) sulfoxide-a-cyclodextrin (CD-5). Excess 0 _{2 in the} filtrate was removed by the addition of sodium thiosulfate. CD-5 in heavy water (D ₂ 0) Ή NMR spectrum of the specification: δ2.54 (CH ₂ , t, 2H), 2.71 (CH ₂ , q, 2H), 2.84 (CH ₂ , t, 2H), 3.05 (CH, m, H), 3.77 ( 2CH, s, 2H), 3.9 5 (CH, m, H), 5.08 (CH, m, H) ppm.

6-Deoxyoxy-6-per(2-carboxyethyl) sulfide-α-cyclodextrin (81.7 g, 50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of 30% H ₂ O ₂ was added dropwise with stirring. The aqueous solution was kept at 40-60 ° C for 5 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to obtain 6-perdeoxy-6-per(2-carboxyethyl)sulfone-α-cyclodextrin (CD). -6). Excess H ₂ O _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-6 in heavy water (D ₂ 0): S2.79 (CH ₂ , t, 2H), 3.00 (CH, m, H), 3.52 (CH ₂ , q, 2H), 3.69 ( CH ₂ , d, 2H), 3.75 (2CH, d, 2H), 3.92 (CH, m, H), 5.06 (CH, m, H) ppm. Example 20

 6-total deoxy-6-all (2-carboxyethyl) sulfoxide - P-cyclodextrin, 6-all deoxy-6-all (2-carboxyethyl) sulfone -P-cyclodextrin preparation

 CD-7 CD-8 CD-9

6-Deoxyoxy-6-per(2-carboxyethyl) sulfide-β-cyclodextrin (95.3 g, 50 mmol) was suspended in 100 ml of acetic acid, and 8.5 g (75 mmol) of 30% H ₂ 0 ₂ was added dropwise with stirring. The aqueous solution was reacted at room temperature for 6 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to give 6-deoxy-oxy-6-per(2-carboxyethyl) sulfoxide-β-cyclodextrin CD-8. Excess filtrate Η ₂ 0 ₂ was removed by addition of sodium thiosulfate. Ή NMR spectrum of CD-8 in heavy water (D ₂ 0): 52.59 (CH ₂ , t, 2H), 2.71 (CH ₂ , q, 2H), 2.83 (CH ₂ , t, 2H), 3.08 (CH , m, H), 3.75 (2CH, s, 2H), 3.9 4 (CH, m, H), 5.04 (CH, m, H) ppm.

6-Deoxy-6-per(2-carboxyethyl) sulfide-β-cyclodextrin (95.3 g, 50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of 30% H ₂ O ₂ was added dropwise with stirring. The aqueous solution was kept at 40-60 ° C for 5 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to obtain 6-perdeoxy-6-per(2-carboxyethyl)sulfone-β-cyclodextrin CD-. 9. Excess H ₂ O _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-9 in heavy water (D ₂ 0): δ2.81 (CH ₂ , t, 2H), 3.07 (CH, m, H), 3.51 (CH ₂ , q, 2H), 3.69 ( CH ₂ , d, 2H), 3.79 (2CH, d, 2H), 3.93 (CH, m, H), 5.05 (CH, m, H) ppm.

Example 21

Preparation of 6-perdeoxy-6-per(2-carboxyethyl) sulfoxide-δ-cyclodextrin, 6-perdeoxy-6-per(2-carboxyethyl)sulfone-δ-cyclodextrin Description

 CD-10 CD-11 CD- 12

6-Deoxyoxy-6-per(2-carboxyethyl) sulfide-δ-cyclodextrin CD-10 (122.5 g, 50 mmol) was suspended in 100 ml of acetic acid, and 8.5 g (75 mmol) of 30% H was added dropwise with stirring. _{2 2 2} aqueous solution, reacting at room temperature for 6 hours, adding alcohol to the reaction liquid to precipitate a solid, and recrystallizing methanol to obtain 6-perdeoxy-6-per(2-carboxyethyl) sulfoxide-δ-cyclodextrin CD-11 . Excess 3⁄40 _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή Nuclear magnetic resonance spectrum of CD-11 in heavy water (D ₂ 0): S2.59 (CH ₂ , t, 2H), 2.77 (CH ₂ , q, 2H), 2.86 (CH ₂ , t, 2H), 3.03 (CH, m, H), 3.76 (2CH, s, 2H), 3.92 (CH, m, H), 5.06 (CH, m, H) ppm.

6-Deoxyoxy-6-per(2-carboxyethyl) sulfide-δ-cyclodextrin CD-10 (122.5 g, 50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of 30% H was added dropwise with stirring. ₂ O ₂ aqueous solution, keeping the reaction at 40-60 ° C for 5 hours, adding alcohol to the reaction liquid to precipitate a solid, and recrystallizing methanol to obtain the product 6-fully deoxy-6-per(2-carboxyethyl) sulfoxide-δ- Cyclodextrin CD-12. Excess 3⁄40 _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-12 in heavy water (D ₂ 0): S2.80 (CH ₂ , t, 2H), 3.08 (CH, m, H), 3.54 (CH ₂ , q, 2H), 3.70 ( CH ₂ , d, 2H), 3.73 (2CH, d, 2H), 3.9 (CH, m, H), 5.01 (CH, m, H) ppm. Example 22

 6-total deoxy-6-all (2-propionylglycine) sulfoxide-γ-cyclodextrin, 6-perdeoxy-6-per(2-propionylglycine)sulfone-γ-cyclodextrin preparation

 CD-13 CD- 14 CD-15

6-Deoxyoxy-6-per(2-propionylglycine) sulfide-γ-cyclodextrin CD-13 (122.9 g, 50 mm _O l) was suspended in 100 ml of acetic acid, and 8.5 g (75 mmol) was added dropwise with stirring. The aqueous solution of % H ₂ O _{2 was} reacted at room temperature for 6 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to obtain 6-perdeoxy-6-per(2-propionylglycine) sulfoxide-γ-cyclodextrin CD. -14. Excess H ₂ O _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Nuclear magnetic resonance spectrum of CD-14 in heavy water (D ₂ 0): 51.56 (CH ₃ , d, 3H), 2.75 (CH ₂ , m, 2H), 3.01 (CH, m, H), 3.69 (CH, m, H), 3.76 (2CH, s, 2H), 3.92 (CH, m, H), 4.18 (CH ₂ , s, 2H), Instruction manual

5.07 (CH, s, H) ppm.

6-Deoxyoxy-6-per(2-propionylglycine) thioether-γ-cyclodextrin CD-13 (122.9 g, 50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of 30% 3⁄4 O was added dropwise with stirring. ₂ aqueous solution, maintaining 40-6 CTC reaction for 5 hours, adding alcohol to the reaction liquid to precipitate a solid, and recrystallizing methanol to obtain 6-perdeoxy-6-per(2-propionylglycine) sulfone-γ-cyclodextrin CD-15 . Excess H ₂ O _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-15 in heavy water (D ₂ 0): S1.59 (CH ₃ , d, 3H), 3.02 (CH, m, H), 3.53 (CH ₂ , m, 2H) > 3.78 ( 2CH, s, 2H), 3.93 (CH, m, H), 4.13 (CH, s, H), 4.19 (CH ₂ , t, 2H), 5.05 (CH, s, H) ppm. Example 23

 Preparation of 6-total deoxy-6-all (2-propionylglycine) sulfide-α-cyclodextrin

3-Mercaptopropionic acid (1. 22 ml, 14. 0 mmol) was dissolved in dry dimethylformamide (45 ml) at room temperature. To this solution was added sodium hydride (1,23 g) in three portions. 30. 8 mmol, 60%). Stirring the mixture for 30 minutes. To this mixture, 2.7 g of 6-perdeoxy-6-periodo-α was added dropwise in 45 ml of dry dimethylformamide. - cyclodextrin solution. After the addition, the reaction mixture was heated to 70" C for 12 hours. After cooling, water (10 liters) was added to the mixture and the volume was concentrated to 40 ml in vacuo, to which ethanol was added ( 150 ml) resulted in a precipitate. The solid precipitate was collected by filtration and dialyzed for 36 hours. The volume was concentrated to 20 mL in vacuo, and then ethanol was added, and the precipitate was collected by suction and dried to give the title compound (CD-16). 1 g. Ή NMR spectrum of CD-16 in heavy water (D ₂ 0): 51.55 (CH ₃ , d, 3H), 2.59 (CH ₂ , m, 2H), 3.01 (CH, m, H), 3.68 (CH, m, H), 3.71 (2CH, s, 2H), 4.11 (CH ₂ , s, 2H), 4.20 (CH, m, H), 5.05 (CH, s, H) ppm.

 Preparation of 6-total deoxy-6-all (2-propionylglycine) sulfoxide-a-cyclodextrin, 6-all deoxy-6-all (2-propionylglycine) sulfone-a-cyclodextrin

CD- 16 CD- 17 CD- 18 Instruction manual

6-Deoxyoxy-6-per(2-propionylglycine) thioether-a-cyclodextrin CD-16 (92.2 g, 50 mmol) was suspended in 100 ml of acetic acid, and 8.5 g (75 mmol) of 30% H was added dropwise with stirring. _The aqueous solution of ₂ 0 _{2 was} reacted at room temperature for 6 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to give the product CD-17. Excess 3⁄40 _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Nuclear magnetic resonance spectrum of CD-17 in heavy water (D ₂ 0): 51.57 (CH ₃ , d, 3H), 2.65 (CH ₂ , m, 2H), 3.02 (CH, m, H), 3.69 (CH, m, H), 3.77 (2CH, s, 2H), 3.93 (CH, m, H), 4.14 (CH ₂ , s, 2H), 5.01 (CH, s, H) ppm.

6-Deoxyoxy-6-per(2-propionylglycine) thioether-α-cyclodextrin CD-16 (92.2 g, 50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of 30% H was added dropwise with stirring. _The aqueous solution of ₂ O _{2 was} kept at 40-60 ° C for 5 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to give the product CD-18. Excess 3⁄40 _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-18 in heavy water (D ₂ 0): S1.58 (CH ₃ , d, 3H), 3.04 (CH, m, H), 3.57 (CH ₂ , m, 2H), 3.73 ( 2CH, s, 2H), 3.94 (CH, m, H), 4.11 (CH, s, H), 4.16 (CH ₂ , t, 2H), 5.07 (CH, s, H) ppm. Example 25

 6-total deoxy-6-all (2-propionylglycine) thioether-β-cyclodextrin preparation

The tiopronin (0.42 g, 2.6 mmol) was dissolved in 2 ml of dry DMF. After completely dissolved, NaH (O.llg, 2.75 mmol, 60%) was added portionwise to the solution under ice-cooling. To the mixture, 0.7 g (0.37 mmol) of 6-perdeoxy-6-periodo-β-cyclodextrin solution of 1.3 ml of dry DMF was added dropwise thereto for 30 minutes, and the reaction mixture was heated to 20 ° C for reaction. After 12 hours, the plate was completely followed by the reaction. A small amount of water was added, the pH was adjusted to about 6, a small amount of ethanol was added, a large amount of diethyl ether was added, and a white precipitate was precipitated. The mixture was washed with ethyl acetate, centrifuged, and dried in vacuo to give a soft solid. . Ή NMR spectrum of CD-19 in heavy water (D ₂ 0): 61.51 (CH ₃ , d, 3H), 2.57 (CH ₂ , m, 2H), 3.00 (CH, m, H), 3.61 (CH, m, H), 3.75 (2CH, s, 2H), 4.16 (CH ₂ , s, 2H), 4.21 (CH, m, H), 5.08 (CH, s, H) ppm. Example 26

Preparation of 6-perdeoxy-6-per(2-propionylglycine) sulfoxide-P-cyclodextrin, 6-perdeoxy-6-per(2-propionylglycine)sulfone-P-cyclodextrin

 CD-19 CD-20 CD-21

6-Deoxy-oxy-6-per(2-propionylglycine) thioether-β-cyclodextrin (107.57 g, 50 mmol) was suspended in 100 ml of acetic acid, and 8.5 g (75 mmol) of 30% H 2 O 2 aqueous solution was added dropwise with stirring. After reacting for 6 hours, an alcohol was added to the reaction liquid to precipitate a solid, and methanol was recrystallized to obtain 6-perdeoxy-6-per(2-propionylglycine) sulfoxide-β-cyclodextrin CD-20. Excess H202 in the filtrate was removed by the addition of sodium thiosulfate. Nuclear magnetic resonance spectrum of CD-20 in heavy water (D ₂ 0): 51.54 (CH ₃ , d, 3H), 2.73 (CH ₂ , m, 2H), 3.01 (CH, m, H), 3.63 (CH, m, H), 3.73 (2CH, s, 2H), 3.95 (CH, m, H), 4.14 (CH ₂ , s, 2H), 5.07 (CH, s, H) ppm.

6-Deoxyoxy-6-per(2-propionylglycine) thioether-β-cyclodextrin (107.57 g, 50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of a 30% 3⁄4 O ₂ aqueous solution was added dropwise with stirring. The reaction was maintained at 40-60 ° C for 5 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to obtain 6-perdeoxy-6-per(2-propionylglycine) sulfoxide-β-cyclodextrin CD-21. . Excess H ₂ O _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-21 in heavy water (D ₂ 0): 51.59 (CH ₃ , d, 3H), 3.07 (CH, m, H), 3.52 (CH ₂ , m, 2H), 3.76 (2CH, s, 2H), 3.91 (CH, m, H), 4.11 (CH, s, H), 4.14 (CH ₂ , t, 2H), 5.00 (CH, s, H) ppm. Example 27

 Preparation of 6-total deoxy-6-all (2-propionylglycine) sulfide-δ-cyclodextrin

The tiopronin (0.42 g, 2.6 mmol) was dissolved in 2 ml of dry DMF. After completely dissolved, NaH (O.llg, 2.75 mmol, 60%) was added portionwise to the solution under ice-cooling. After 30 minutes, 1.3 ml of dry DMF lg (0.4 mmol) of 6-perdeoxy-6-periodo-δ-cyclodextrin solution was added dropwise to the mixture, and the reaction mixture was heated to 20 ° C for reaction 12 Hour, the plate was followed to complete the reaction, a small amount of water was added, the pH was adjusted to be equal to 6, a small amount of ethanol was added, a large amount of diethyl ether was added, and a white precipitate was precipitated, washed with ethyl acetate, centrifuged, and dried in vacuo to give a solid (yield) of </ RTI><RTIgt; Ή NMR spectrum of CD-22 in heavy water (D ₂ 0): 51.52 (CH ₃ , d, 3H), 2.53 (CH ₂ , m, 2H), 3.03 (CH, m, H), 3.69 (CH, m, H), 3.78 (2CH, s, 2H), 4.14 (CH ₂ , s, 2H), 4.23 (CH, m, H), 5.09 (CH, s, H) ppm. Description of the Invention Example 28

 6-total deoxy-6-all (2-propionyl 3⁄43⁄4 glycine) sulfoxide-δ-cyclodextrin, δ-perdeoxy-6-all (2-propionylglycine) sulfone-indole-cyclodextrin preparation

 CD-22 CD-23 CD-24

6-Deoxyoxy-6-per(2-propionylglycine) thioether-δ-cyclodextrin (138.3 g, 50 mmol) was suspended in 100 ml of acetic acid, and 8.5 g (75 mmol) of 30% H ₂ 0 ₂ was added dropwise with stirring. The aqueous solution was reacted at room temperature for 6 hours, and an alcohol was added to the reaction mixture to precipitate a solid, which was recrystallized from methanol to give 6-dedeoxy-6-per(2-propionylglycine) sulfoxide-δ-cyclodextrin (CD-23). Excess H ₂ O _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή Nuclear magnetic resonance spectrum of CD-23 in heavy water (D ₂ 0): 51.58 (CH ₃ , d, 3H), 2.70 (CH ₂ , m, 2H), 3.02 (CH, m, H), 3.69 (CH, m, H), 3.71 (2CH, s, 2H), 3.94 (CH, m, H), 4.14 (CH ₂ , s, 2H), 5.09 (CH, s, H) ppm.

6-Deoxyoxy-6-per(2-propionylglycine) thioether-δ-cyclodextrin (138.3 g, 50 mmol) was suspended in 100 ml of acetic acid, and 28.3 g (250 mmol) of 30% H ₂ O ₂ was added dropwise with stirring. The aqueous solution was kept at 40-60 ° C for 5 hours, and an alcohol was added to the reaction liquid to precipitate a solid, which was recrystallized from methanol to obtain δ-perdeoxy-6-per(2-propionylglycine)sulfone-β-cyclodextrin (CD). -twenty four). Excess 3⁄40 _{2 in the} filtrate was removed by the addition of sodium thiosulfate. Ή NMR spectrum of CD-24 in heavy water (D ₂ 0): 51.51 (CH ₃ , d, 3H), 3.03 (CH, m, H), 3.55 (CH ₂ , m, 2H), 3.79 (2CH, s, 2H), 3.93 (CH, m, H), 4.11 (CH, s, H), 4.14 (CH ₂ , t, 2H), 5.06 (CH, s, H) ppm. Example 29

Healthy adult rabbits, injected into the ear vein, given rocuronium 100u _g / k _g , 3ml kg, observe, when the ears are drooping, record the dose and muscle start time. After muscle relaxation, rapid ear vein injection of 3mg/kg of CD-2, CD-3, CD-8, CD-9, CD-13, CD-14, CD-15, CD-19 to CD-24, 10 The second administration is completed. Record the rabbit ear erection time. The results are shown in Table 1: Instruction manual

 No. Compound code Luo]^Bromoammonium Anti-allergic When the ears are erected, the action returns to normal.

 LI LI quantity (μβ) 量 quantity (mg) time

 1 saline 300 6 3 minutes 40 seconds 4 minutes 52 seconds

 2 CD- 2 300 6 1 minute 15 seconds 1 minute 24 seconds

 3 CD-3 300 6 0 minutes 54 seconds 1 minute 12 seconds

 4 CD-8 300 6 0 minutes 30 seconds 0 minutes 45 seconds

 5 CD-9 300 6 0 minutes 37 seconds 0 minutes 56 seconds

 6 CD- 13 300 6 0 minutes 15 seconds 0 minutes 16 seconds

 7 CD-14 300 6 0 minutes 16 seconds 0 minutes 16 seconds

 8 CD- 15 300 6 0 minutes 15 seconds 0 minutes 17 seconds

 9 CD- 19 300 6 0 minutes 12 seconds 0 minutes 12 seconds

 10 CD-20 300 6 0 minutes 13 seconds 0 minutes 14 seconds

 11 CD- 21 300 6 0 minutes 12 seconds 0 minutes 12 seconds

 12 CD-22 300 6 0 minutes 35 seconds 0 minutes 37 seconds

 13 CD-23 300 6 0 minutes 40 seconds 0 minutes 44 seconds

 14 CD-24 300 6 0 minutes 36 seconds 0 minutes 37 seconds Example 30

 6-Deoxythioether amino acid cyclodextrin derivative (V) The preparation process of the lyophilizate of the pharmaceutical composition is achieved by the following steps:

 (1) taking the amino acid cyclodextrin derivative refined product under aseptic conditions, placing it in a container, adding 30-70 times by weight of water for injection to dissolve, adding a medicinal base to adjust the pH value to 6-8;

 (2) Adding medicinal excipients, autoclaving and sterilizing according to the requirements of the injection, filtering by microporous membrane, the filtrate is divided into 0.4-0.8ml each, and the quick freezing method is used to reduce 10-15 °C per minute. Until the solution is cooled to -30 to -50 ° C, maintained for 2-3 hours, and then warmed to -20 to -35 ° C, sublimation drying, the product is taken out, sealing is obtained as a colorless loose block Things.

 The pharmaceutically acceptable base described in the step 1 is sodium carbonate, sodium hydrogencarbonate or potassium carbonate.

Claims

Claim

A 6-deoxysulfone-based cyclodextrin derivative characterized by having a knot of the formula (I)

 (I)

 Where m is one of 0, 1, 2, 3, 4, 5, 6, 7 or 8;

 n is one of 1, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

 m+n is one of 6, 7, 8 or 9;

 q is one of 1 or 2;

R is an alkylene group of C _r C ₆ , optionally substituted by 1 to 3 0H groups or (CH ₂ ) r -phenylene-(CH ₂ ) _t -, where r is 0, 1, 2, 3 or One of 4, t is one of 0, 1, 2, 3 or 4;

X is one of C00H, CONHR NHC0R ₂ , S0 ₂ 0H, PO (OH) ₂ , 0 (CH ₂ -CH ₂ -0) u -H, 0H or tetrazol-5-, which is hydrogen, (d_ ₃₎ a hospital or an alkyl group containing a C00H (D_ _3), is a carboxyphenyl group, u is 1, 2 or 3 a.

 The 6-deoxysulfone-based cyclodextrin derivative according to claim 1, wherein the 6-deoxysulfone-based cyclodextrin derivative (I) when q is 1, is 6 a deoxysulfoxide-based dextrin derivative having the structure of formula (II):

The 6-deoxysulfone-based cyclodextrin derivative (I) is a 6-deoxysulfone-based dextrin derivative having a structure of the formula (ΠΙ) when q is 2. Claim

 The method for preparing a 6-deoxysulfone-based cyclodextrin derivative according to claim 1 or 2, which is characterized by the following steps: using a 6-deoxythioether amino acid cyclodextrin derivative (V) Or using 6-deoxythioether cyclodextrin derivative (IV) as a raw material, by oxidation reaction 1, to obtain a 6-deoxysulfoxide-based cyclodextrin derivative (Π), the compound (Π) is obtained by oxidation reaction 2 to obtain 6- Deoxysulfone-based cyclodextrin derivative (III),

 Reaction formula:

 Oxidation reaction 2

 III

n, m+n, R, X, as claimed in claim 1, Claim

R ₃ is one of H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , (CH ₂ ) ₃ CH ₃ , C (CH ₃ ) ₃ or C ₆ H ₅ ;

1 ₄ is H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₃ (CH ₃ ) CH, CH ₂ CH (CH ₃ ) ₂ , CH ₂ C ₆ One of H ₅ , CH ₃ SCH ₂ CH ₂ or H ₂ NC (0) CH ₂ ;

The oxidation reaction and the oxidation reaction using an oxidizing agent 2 is an organic peroxide or a peroxy acid salt, selected acid _{peroxide, H 2 0 2, KC10 4} , H 2 S0 4, KMn0 4, Na 2 0 2 or K _{One of the 2} 0 ₂ .

The preparation method according to claim 3, wherein the 6-deoxythioether amino acid cyclodextrin derivative (V) is produced by the following steps: starting from acetic acid (a) having a R ₃ substituent; The starting material and the halogenating reagent are halogenated to obtain a dihalide (b), which is condensed with an amino acid to obtain an amide (c), and then a sulfur reagent is added to obtain a sulfur-containing compound (d), and the protecting group is removed to obtain a mercapto compound (e). Condensation with a halogenated cyclodextrin in the presence of a base to give a 6-deoxythioether amino acid cyclodextrin derivative (V) or

,

 Reaction formula:

M, n, m+n as claimed in claim 1,

R ₃ and R _{4 are} as claimed in claim 3, Claim

R ₅ is phenyl or pyridyl;

 A is one of OH, C1 or Br.

 The substituted acetic acid (a) is hydrogen and a short carbon chain alkane or an aromatic hydrocarbon, and one of methyl, ethyl, propyl, isopropyl, butyl, t-butyl or phenyl is used; The halogenating reagent is one of chlorine gas, bromine, thionyl chloride, phosphorus tribromide or phosphorus trichloride; the amino acid used is a natural amino acid; the sulfur reagent is selected from thionicotinic acid, disulfide. One of sodium, thioacetic acid, sodium thiosulfate or thiobenzoic acid; the removal of the protecting group means alkali hydrolysis, the base used is an inorganic base, sodium hydroxide or potassium, sodium or potassium carbonate Aqueous solution; the base in the condensation reaction with the halogenated cyclodextrin is sodium or potassium hydride, sodium or potassium amide, sodium or potassium alkoxide; the halogenated cyclodide used is selected by chlorine, bromine or iodine. a 7, 7, or 9-membered ring cyclodextrin; the obtained amino acid cyclodextrin derivative and a salt thereof are a potassium salt, a sodium salt or a lithium salt.

 The preparation method according to claim 4, wherein the natural amino acid is one selected from the group consisting of glycine, cyan, guanidine, bright, isoluminescence, asparagine, phenylpropanoid or methionine.

 The use of a 6-deoxysulfone-based cyclodextrin derivative according to claim 1 or 2 for the preparation of a muscle antagonistic drug.

 The preparation method according to claim 4, wherein the compound V is used for the preparation of a muscle relaxant drug.