TWI255269B - Hypersulfated disaccharides and methods of using the same for the treatment of inflammations - Google Patents

Abstract

Provided are compounds and compositions thereof that are useful for treating inflammation, particularly pulmonary inflammations including asthma and asthma-related pathologies such as allergy. Also provided are methods for using such compounds and compositions of the invention to treat patients suffering from, or predisposed to develop inflammation.

Description

1255269 A7 B7 V. INSTRUCTIONS () Field of the Invention: (Please read the notes on the back and then fill out this page) The present invention relates to a compound for treating or alleviating inflammatory conditions, a pharmaceutical composition and a method thereof, such as treatment of asthma. BACKGROUND OF THE INVENTION: An inflammatory response is a multifocal response produced by a host's damage to cells or vascular tissue. The inflammatory response is a side effect of the disease, and examples include leprosy, asthma, pneumonia, and even rheumatoid arthritis or tuberculosis. (Trowbridge and Emling, : A_R^view nf the Process.)

Quintessence Pub. Co. 1 997 ). Recently, non-specific anti-inflammatory treatments have blocked the inflammatory response directly at several reaction points in the reaction ladder. The specific reaction sites to be attacked include: a) regulating the complement system; b) inhibiting the release of soluble regulators from giant cells or other reactive cells; c) inhibiting the flow of immune response cells to the inflammatory reaction site; d) blocking the attachment of cells to the reaction The vessel wall; and e) preventing extravascular outflow of the immune response cells to the injured site. (See Trowbridge and Emling, previous note; Ryan and Majno, Am. J. Pathol. SA: 1 83-276, 1 9 9 7 ): and Liles and Van Voohis, J. Infect. Dis. 172:1574- 1 5 80 · 1 995 ) ° Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives printing asthma is a chronic disease of the lungs and small and small respiratory tract, 5% to 10% of people suffer from this disease (Plaut and Zimmerman, "Allergy and Mechanism of Hypersensitivity" in F_u !Ld-aULgilila 1_ irriTminologv. 3rd Ed., WE Paul (ed.), Raven Press, New York, NY 1993, pp. 1399-1425). Asthma is the most common slowness in children. Page 4 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1255269 V. Invention description () (Please read the note on the back and fill out this page) Sexual diseases are the most important reason for school children to take time off from school. It is estimated that adult asthma causes approximately 27 million visits per year; six million working days are lost; and 90.5 million working days are restricted. The incidence and mortality of global asthma is gradually increasing. A general review of asthma 'see Sheffer et al., The National Asthma Education Program: Expert panel report guidelines for the diagnosis and management of asthma, Med. Care li: MS 20, 993. In addition to humans, asthmatic reactions are also a growing problem for certain animals, such as the horse racing industry, which suffers from asthmatic reactions. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the consumer cooperatives. The most obvious feature of asthma is bronchospasm, or narrowing of the airways: the smooth muscles of the large and small respiratory tract of asthma patients contract, the mucus secretion increases, and the inflammatory response increases (Plaut and Zimmerman, ant.). Hogg pointed out that the inflammatory response during asthma is a typical response of tissues covered by mucosa, and is characterized by vasodilation, cytoplasmic exudation, and supplementation of inflammatory cells to inflamed sites such as neutrophils, mononuclear leukocytes, giants. Phagocytosis, lymphocytes, and eosinophils; and inflammatory regulators by resident tissue cells (eg, giant cells), or inflammatory cells (Hogg, "Pathology of Asthma," in Asthma as an Inflammatory Disease, O'Byrne (ed.), Marcel Dekker, Inc., New York, NY 1990, pp. 1-13).

Hagreave argues that there are many possible causes of asthma, such as allergic reactions, secondary reactions to infection, industrial or occupational exposure, inhalation of certain chemicals or agents, exercise, and vasculitis (Hagreavee/a/., J Allergy. Clinical Immunol. 11:1 0 1 3- 1 026, 1 986 ). In many pages 5 · This paper scale applies China National Standard (CNS) A4 specification (210x297 mm) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description () In the example, allergic asthma The episode consists of two stages, early and late 4-6 hours after bronchial stimulation (H arris ο η丨s Principles of IlLtergal.M.edjcine, 14th Ed., Fauci et al. (eds.), McGraw-Hill, NewYork, NY 1 998, pp. 141 9- 1426 ). Early symptoms can be self-healing, including a rapid inflammatory response that involves a response caused by the release of cellular regulators by giant cells. Late-stage reactions develop over several hours and can be characterized by histological methods, including early multi-type leukocytoplasmic influx and cellulose precipitation, and subsequent eosinophilic leukocyte infiltration. Many patients with allergic asthma are “double responders” and will have early (ie acute) and late reactions. In the dual responders, the respiratory impedance showed a two-fold increase in the 4-11 hours after the acute reaction (late phase response, LPR for short). Therefore, late-stage reactions and dual-responders are clinically important because late-stage reactions combined with inflammation of the respiratory tract can lead to prolonged airway hyperreactivity (AHR), asthma worsening, or hypersensitivity, increased symptoms, in general It also produces more severe clinical asthma symptoms that can last for days to months in some patients and require more aggressive treatment. Pharmacological studies in allergic animals have shown that bronchoconstriction, as well as patterns of inflammatory intracellular flow and regulatory release in dual responders, are quite similar to those of acute responders. Increased bronchial hypersensitivity (AHR) is characteristic of more severe asthma symptoms and is induced by both antigenic and non-antigenic stimuli. The late-response allergen-induced asthma and persistent hypersensitivity causes, and the inflamed lungs on page 6 of this paper scale apply to the Chinese National Standard (CNS) A4 specification (210X 297 mm) ......... ..•: meal........., ear:;.....line· (please read the notes on the back and fill out this page) 1255269 A7 B7 V. Inventions () (Please Read the notes on the back and fill out this page. Tissues are associated with white blood cells, especially eosinophils (Abraham W Am. Rev. Respir. Dis. L3 8:1 5 6 5- 1 57, 1 98 8 ). Eosinophilic leukocytes release several inflammatory sputum, including 1 5 _ Η E T E, C 4 type leukotrienes, PAF, cationic protein, eosinophilic leukocyte peroxidase. However, it is important to note that the respiratory tract is only a prototype of an organ or tissue infected with a late-stage response (LPR, s). Late bronchoconstriction and respiratory hypersensitivity (AHR) observed in patients with dual-response asthma are not limited to independent phenomena of asthma or pulmonary disease. In addition to the lungs, LPR's also appear in the skin, nose, eyes and body. According to a recent understanding of the LPR mechanism, clinical diseases known to be associated with allergic mechanisms (whether in the skin, lungs, nasal cavity, eye, or other organs) V contain tissue inflammatory processes followed by antibody-induced rapids An allergic or allergic reaction. This sequence of reactions is associated with giant cell regulators, which are produced by other resident cells in the target organ, or by giant cells added to the reaction site, or by basophilic leukocyte degranulation. The Ministry of Economic Affairs, the Intellectual Property Office, and the Consumer Cooperatives, which print traditional anti-asthmatic treatments, focus on completely avoiding allergens. However, such treatments are inherently difficult. In addition, treatment with pharmaceutical preparations can bring unfortunate side effects and sub-optimal The nature of pharmacokinetics. For example, the anti-asthmatic/3 2 adrenergic stimulant therapy is very useful for the treatment of bronchospasm, but it is not effective for inflammation of the respiratory tract or excessive bronchial bronchus. Therefore, Palmet et al. pointed out that the use of a long-acting no-adrenergic stimulant salmeterol (w/meiero/) can be used as the anti-asthmatic anti-page 7 paper standard for the Chinese National Standard (CNS) A4 specification (210X297). ''1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Inventions () Assisted by Inflammatory Therapy (Palmer ei a/·, New Engl. J. Med. 3 3 1:1 3 14 - 1 3 1 9, 1 994 ). However, Bhagat et al. alleged that frequent or prolonged use of adrenergic stimulants can cause poor control of asthma and increase the sensitivity of the respiratory tract to antigens, resulting from exercise, histamine, ethionylcholine, and other antigens. The protection of bronchoconstriction is therefore it ^ (Bhagat et al. Chest 10 8:123 5- 1 23 8 1995). i匕, long-term use alone / 3 2 adrenaline agents for the 2 adrenal receptors for down regulation (down regulation), suspected to worsen bronchial hypersensitivity " Another commonly used anti-asthmatic agent prescription theophylline (a kind Methylxanthines, characterized by a relatively high rate of absorption and clearance. Woolock et al. proposed the use of sebum steroids to treat advanced and respiratory hypersensitivity reactions. The report also pointed out that although it is safe for use in adult asthma patients, sebum steroids are highly toxic to children. Including adrenal suppression and reduction of bone density and growth (Woolock a/., Am. Respir. Crit. Care Med. UJj 148 1 - 1488, 1996). Volcheck argues that cromolyn is used to prevent early and late asthmatic inflammatory responses. However, if claranoic acid is to be effectively used to prevent the onset of asthmatic response, it is necessary to give cromolyn before the onset of asthma (Volcheck W a/ Postgrad Med· ΙΜΧ 3): 127-1 36, 1 998 ). Oxygen therapy is occasionally avoided or abandoned in allergic asthma treatments, especially in children, and these agents are not completely effective in controlling asthma because histamine is only one of many regulators. Applicable to China National Standard (CNS) A4 specification (210X297 mm) ...........: φ.......: order... line · (please read the back Note: Please fill out this page again) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Inventions () (Cuss, ''The Pharmacology of Aatiasthma Medications,'' in Asthma as an Inflammatory Disease· 〇, Byme, Ed. (Marcel Dekker, Inc., New York 1 990, pp. 1 99-250) and O'Byme, ''Airway Inflammation and Asthma," Asthma as an Inflammatory Disease, OByme (ed.), Marcel Dekker, Inc., New York, NY 1990, pp. 143- 1 57 ) °

Pansh et al., WO 88/05301, disclose that naturally occurring various sulfated polysaccharides are believed to have anti-inflammatory properties. These include hyaluronic acid, chondroitin sulfate, brown sulphate and carrageenan lamba, which act as inhibitors or block endogenous glycosidase (edoglycosylase) activity (eg heparin) Enzyme). Heparin or heparin derivatives such as heparin oxidized or reduced by periodic acid also produce similar activities. Biologically active regulatory substances such as histamine, heparin, TNF-a, LTB4, proteases, and many cytokines released from reactive cells (eg, giant cells) have been used to study anti-inflammatory agents or targets. Potential (Goodman & Gilman's " The Pharmacological Basi ς nf Therapeutics", Hardman, et aL, eds., McGraw-Hill, 10th ed. pp. 734 (2001); Buetler & Cerami, Ann. Rev. Immunol. Z : 625-55; (1989)) A basic theory advocated by many people indicates that inflammatory responses can be fine-tuned, inhibited, or even prevented by up- or down-regulating an intermediate compound in the reaction ladder. Cohen shoots (W092/19249; U.S. Patent No. 5,474,987; US Pat. No: 5,686,43 1; US Pat. No; page 9 3 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm). .............meal.........Book: L...Line· (Please read the notes on the back and fill out this page) 1255269 A7 B7 V. DESCRIPTION OF THE INVENTION () (Please read the note on the back and fill out this page) 5,908,837) Prove that low molecular weight heparin (molecular weight between 3kDa and 6 kDa) reduces the secretion of TNF-α. However, Cohen A did not propose or suggest modification of low molecular weight heparin.

Cohen's subsequent research (see W094/1 1006; U.S. Patent No. 5,861,382; and U.S. Patent No. 6,020,323) confirms that the original hypothesis can down-regulate specific parts of TNF-alpha secretion, so in some cases 'It is effective as an anti-inflammatory compound. The main compound proposed by C 〇he η is Ν-sulfated 4-deoxy-4-ene-iduronic acid glucosamine or Ν-acetylated 4-deoxy-cardio-iduronic acid glucose Four variants of amines. It is worth noting that there are seven variants that have been replaced by additional sulfation. After testing, six of them have a neutral ability to inhibit TNF-α activity, whereas one variant is effective in enhancing TNF-α activity. The relationship between the degree of sulfation of heparin and the inflammatory response of the Ministry of Economic Affairs' Intellectual Property Office staff consumption cooperative has not been clarified. Overall, the previous research direction was the persulfation from the reaction site. Kennedy (U.S. Patent No. 5,990,097) discloses that a selective 2-oxo[3-oxy-desulfated heparin is effective as an inhibitor of airway smooth muscle hyperplasia, which is usually associated with an inflammatory response in the lungs. In addition, Kilfeather argues (Brit·J. Pharmacol, ilA: 1442-1446, 995) that heparin or low molecular weight heparin inhibits in vitro serum-induced bovine tracheal smooth muscle when sulfate roots are not modified or removed. Cell proliferation. The difference between Kennedy and Kilfeather's dispute is not just about sulfation, but Kilfeather uses a low molecular weight heparin fragment (molecular weight > 3 kDa), while Kennedy does. Although the previous study used heparin (eg, Kennedy) or low score on page 10, this paper scale applies the Chinese National Standard (CNS) A4 specification (210X297 public) A7 B7 1255269 V. Inventive Note () Heparin (Cohen), Ahmed (U.S. Patent No. 5,6 9 〇, 9 } nickname and U.S. Patent No. 5,9,80,865) uses ultra low molecular weight heparin having a molecular weight of less than 3 kDa and a heparin having a molecular weight greater than 3 kD a used by Cohen. The clips are different. In addition, Cohen administered low molecular weight heparin in a non-oral, oral or topical manner; Ahmed revealed that ultra low molecular weight heparin can also be administered via inhalation, intraocular, intranasal or bronchial routes. The topic of persulfation is only mentioned by Cohen in the study of sulfuric acid substitution of disaccharides and is limited to N-sulfated 4-deoxy-4-indole-idurose glucosamine or N-acetamidine. The three reaction sites of 4-deoxy-4-ene iduronic acid gluconate have limited research results, and only four active deformables are obtained. Therefore, the trend in this field of research is to emphasize desulfation and to stay away from persulfation studies. Therefore, the use of music therapy for the treatment of gas is faced with many shortcomings. In general, traditional agents have a short duration of action and may be partially or completely ineffective when applied after antigenic challenge. What's more, some agents have serious side effects, such as /3 2 adrenergic stimulants and sebum steroids, the safety of these drugs is relatively narrow, and patients receiving these drugs must be carefully monitored. (WO 94/06783, WO 99/06025, U.S. Patent No. 5,690,901, and U.S. Patent No. 5,980,865). Therefore, it is necessary to identify and develop improved compositions and methods to treat or alleviate the symptoms of inflammatory reactions in allergic reactions such as allergic reactions, asthma, and asthma related conditions. These methods and compositions should pay particular attention to the shortcomings of conventional methods of treatment. Page 11 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)...............................:... ..线· (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing 1255269 A7 B7 V. INSTRUCTIONS () SUMMARY OF THE INVENTION AND SUMMARY: The present invention provides various compounds and pharmaceutical compositions. And methods for treating or reducing the symptoms of inflammation in mammals. More specifically, the present invention relates to the treatment of pulmonary inflammatory responses, including asthma or asthma related diseases such as allergic reactions or inflammatory diseases. The present invention overcomes the shortcomings of conventional anti-asthmatic treatments. Thus, the compounds, pharmaceutical compositions and methods of the present invention are capable of preventing, reversing, and/or alleviating the symptoms of asthma and asthma-related diseases, particularly late-stage reactions resulting from antigen challenge in asthmatic patients. In one aspect, the invention proposes a novel disaccharide compound having the general structure of Formula I:

...................訏:"......Line· (Please read the notes on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Office staff Printed by the consumer cooperative, Ri, R2, R3, R4, R5 and R6 are sulfate, phosphate or hydrogen. In certain embodiments of the invention, (a) Ri, R2, R3 'R4, R5, and R6 may each be a sulfate or a phosphate; or (b) at least R1, R2, R3, R4, R5, and R6 The five lines are respectively sulfate or ^ _ 社 rb / J / four; or (c), R2, R3, R4, R5 and R6 whose main / > R 5 are respectively sulfate or phosphate; or (d) Ri, R2, R3, 4 D and R6, at least three of which are respectively sulfate or phosphate; and bis, Ri, R2, R3, R4, R5 and R6, at least two of which are respectively 12 pages

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description () root or phosphate. For all of the above specific examples (a) to (e), special attention should be paid to (i) if both R3 and R4 are sulfates, at least one of Ri, R2, R5 and R6 is sulfate or phosphate; Ii) if R3, R4 and R5 are both sulfates, at least one of Ri, R2 and R6 is sulfate or phosphate; (iii) if both Ri and R4 are sulfate and not sulfate, then R2 At least one of Rs and R6 is sulfate or phosphate. Another aspect of the invention is that, in certain embodiments, a disaccharide is present in a population of compounds having formulas II through VIII:

Page 13 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) .......................Set-.... .. line (please read the note on the back and fill out this page) 1255269 A7 B7 V. Invention Description ()

In other specific embodiments of this application of the invention, the disaccharide is present in the compound of formula IX to XV:

.............meal.........訏—.·]............ (Please read the notes on the back and fill out this page) Economy Ministry of Intellectual Property Bureau employee consumption cooperative printing

Page 14 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 Ministry of Economic Affairs Zhihui Property Bureau staff consumption and consumption ί 社 Printing V. Inventions (

In a specific embodiment of one aspect of the invention, the invention comprises a compound of formula XVI: 0^4 Η wherein Ri, R3, R4, R5 and R6 are each a sulfate or a phosphate. In one embodiment of this application of the invention, the structure of the disaccharide is of formula VIII:

Where 'Ri, R3, R4, R5 and R6 are the sulphate. Page 15 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)..............Feng. ........,玎...-......MW (please read the notes on the back and fill out this page)

1255269 A7 B7 V. INSTRUCTION DESCRIPTION () In another aspect, the invention features a pharmaceutical composition for treating or alleviating the symptoms of an inflammatory response in a mammalian lung. The composition comprises at least a pharmaceutically effective amount of a compound of formula I:

...........: Food: (Please read the notes on the back and fill out this page.) The Ministry of Economic Affairs, Intellectual Property Officer X, Consumer Cooperatives, printed R!, R2, R3, R4, R5 and R6 is sulfate, citrate or hydrogen. In certain embodiments of the invention, (a) R1 'R2, Rs, R4, R5, and r6 are respectively sulfate or phosphate; or (b) at least five of R1, R2, R3, R4, R5, and R6 The roots are respectively sulfate or phosphate, or (c) Rl, R2, R3, fU, R5 and R6, at least four of which are respectively sulfate or phosphate; or (d) Rl, R2, R3, R4, R5 and R6 at least three of which are respectively sulfate or phosphate, or (e) R1, R2, R3, R4, R5 and R6, at least two of which are respectively sulfate or acid chloride. For all of the above specific examples (a) to (e), special attention should be paid to (i) if both R3 and ^^ are sulfates ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (ϋ) If R and Han 4 are both sulfate and R3 is non-sulfate, then at least one of R2 and R6 is sulfate or phosphate; (iii) if only R4 and R5 are sulfuric acid Root, then the chemical composition is enriched in the compound. Page 16 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 DON) § 1255269 A7 B7 V. Description of the Invention (In some embodiments of another aspect of the invention, in a pharmaceutical composition A disaccharide is present in a population of compounds having formulas II through VIII:

m

..............Feng.........ΤΓ-...-......Line· (Please read the notes on the back and fill out this page) Property Officer X Consumer Co., Ltd. Printed

Page 17 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description () Other aspects of the invention under this aspect In an embodiment, the disaccharide in the pharmaceutical composition is present in the compound of formula IX-XV:

Page 18 (Please read the notes on the back and fill out this page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1255269 A7 B7

V. INSTRUCTIONS (B) In this embodiment, in one embodiment of the invention, the disaccharide in the pharmaceutical composition comprises a compound of formula XVI:

Wherein Ri, R3, R4, R5 and R6 are respectively sulfate or phosphate. In a specific embodiment of the invention, the disaccharide in the pharmaceutical composition comprises a compound of formula VIII: (Please read the notes on the back and fill out this page)

0R4 印 Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, where Ri, R3, R4, R5 and R6 are sulfate. In another application, the invention particularly provides a method for treating or reducing the symptoms of an inflammatory response in a mammal, the method comprising at least one pharmaceutical composition in accordance with the practice of the invention. In some embodiments of the present invention, the pharmaceutical composition is effective for treating lung inflammation. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). 1255269 A7 Five Ministry of Economic Affairs Intellectual Property Bureau Employee consumption cooperative printing - ____ Β 7____ invention description () f Please read the notes on the back and then 'write this page' should be. Methods useful for treating pulmonary inflammatory responses include, in various ways well known in the art, such as a pump, a squeeze-actuated nebulizer, a metered dose inhaler, or a spray, etc. The composition is delivered into the bronchi. Brief Description of Type I: Figure 1 is a line graph comparing the percentage change of sheep's response to antigen at different time points after the antigen (time = 〇) was applied to the sheep (ie, S R l ). The punctual dots represent only the antigen, the solid squares represent the antigen plus 〇·25 mg/kg a.2.+ C.2. The disaccharide is administered intravenously; and the open triangle represents the antigen plus 0.25. The 811-25-1 persulfated disaccharide in mg/kg is intravenously injected with an unrestricted composition of the present invention. The data showed that six sheep (sample number η == 6 ) were exposed to the antigen and were not treated with any drug; pretreatment was performed with Α·2. + c.2·disaccharide after several days. Or by adding 81 1-25-1 persulfate disaccharide to the antigen, the antigen-induced mean standard deviation % (mean soil SE%) of the SRL is changed. Figure 2 is a bar graph 'not showing a number of representative compounds in the invention (B = compound 730-57; C = compound 730-96; D = compound 811-25) compared to a = A. 2.+ C.2. The positive effect of sulphated disaccharide in early response. Compounds A to D have the same carbon atom backbone structure, but the number of sulfated groups is different (the degree of sulfation of these compounds is A < B < C < D ). Page 20, the paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 public) A7 B7 1255269 V. Description of the invention (Fig. 3 - histogram) shows several representative compounds in the present invention ( B = compound 73 〇-57; c = compound m-96; D = compound (please read the back of the note first and then fill out this page) 811-25) compared to A = A.2. + c.2. The sulphated disaccharide in the late reaction of the positive work κ conjugates VIII to D have the same carbon atom backbone structure 'but the number of sulfation groups is different (the degree of sulfation of these compounds is a < b < c < d) The Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed, Figure 4 is a line chart, and a histogram showing the first time in a multi-dose study with several representative compounds of the invention. Experimental results. This experiment is intended to establish the optimal dose range for allergic reactions in allergic sheep. Figure 4A: The data shows that five sheep (n=5 samples) were exposed to the antigen without any When the drug is treated; compared to the antigen plus 81b 25-1 persulfated disaccharide (total agent) i mg), the SR1-induced antigen-induced mean ± standard deviation % is changed as a histogram showing the results of pre-treatment of AHR in allergic sheep. Five sheep (sample 5) were exposed to the antigen and were not treated with any drug; compared to several days later, the antigen plus spray 811_25_丨 persulfate disaccharide was pretreated (total dose)丨亳)), the average of the respiratory units and the standard deviation pD4〇〇 (mean soil SE PD400) at 24 hours after the basic criteria and antigen challenge. Figure 5 is a line chart and a The histogram 'shows the second of the multiple dose studies of several compounds of the invention. Page 21 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 , invention description () (please read the precautions on the back and then fill out this page) The results of the experiment. This experiment is to establish an optimal dose range for allergic reactions in allergic sheep. Figure 5A: Data display , five sheep (sample number = 5 ) Exposure to antigen and without any drug treatment; pretreatment with total 2.5.2. + C. 2 . disaccharide (total dose 2.5 mg) or antigen plus The upper 8 1 1-2 5 -1 persulfated disaccharide (total dose 2.5 mg), the refractive error-induced mean standard deviation % of the SRL was changed. The standard deviation is shown in Fig. 5 B The figure is a bar graph showing the results of pre-treatment of AHR in allergic sheep. The information shown is that five sheep (sample number η = 5) were exposed to the antigen without any drug treatment; Pretreatment with A.2.+ C.2. disaccharide (total dose 2.5 mg) or peroxidation of 8 1 1 -2 5 -1 persulfate disaccharide compared to several days later ( The total dose is 2.5 mg), and the mean standard deviation of the respiratory units is PD400 (mean soil SE PD400) at 24 hours after the basic standard and antigen challenge. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed L5 Figure 6 is a line graph and a bar graph showing the results of the third experiment in a multi-dose study with several representative compounds of the present invention. This experiment is intended to establish an optimal dose range for allergic reactions in allergic sheep. Figure 6A: Data show that five sheep (n=5) were exposed to the antigen and were not treated with any drug; compared to several days later, A. 2 . + C.2. Pretreatment (total dose 5 mg), or with antigen plus 8 1 1 -2 5 -1 persulfated disaccharide (total dose 5 mg), page 22 This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210X297 mm) 1255269 A7 B7 V. Inventive Note () (Please read the precautions on the back and fill out this page) The % of the standard deviation of the antigen-induced mean of the sRL is changed. The standard deviation is shown in the figure. Figure 6B is a bar graph showing the results of pretreatment of AHR in allergic sheep. The information shown is that five sheep (sample number η = 5) were exposed to the antigen and were not treated with any drug; compared to several days later with Α.2. + C.2. Treatment (total dose 5 mg), or with antigen plus 81 1-25-1 persulfated disaccharide (total dose 5 mg), 24 hours after the basic standard and antigen challenge, breath units The average value of the soil standard deviation PD400 (mean soil SE PD400) 0 The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints Figure 7 is a line graph and a bar graph showing several representative compounds of the present invention The second experimental result in the multiple dose study experiment was performed. This experiment is intended to establish an optimal dose range for allergic reactions in allergic sheep. Figure 7A: Data show that five sheep (sample number η = 5) were exposed to the antigen and were not treated with any drug; compared with a few days later with A. 2 . + C.2. Pretreatment (total dose 10 mg), or antigen plus 8 1 1 -2 5 -1 persulfated disaccharide (total dose 10 mg), the antigen-induced mean standard deviation of the SRL Changed. The standard deviation is shown in the figure. Figure 7B is a bar graph showing the results of pretreatment of AHR in allergic sheep. The information shown is that five sheep (sample number η = 5) were exposed to the antigen and were not treated with any drug; compared to a few days later with A.2. + C.2. Disposal treatment (total dosage 10 m page 23) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 V. Invention description ((Please read the back note first and then fill in this page) g) 'Or by the addition of 8 1 1 - 2 5 -1 persulfated disaccharide (total dose of 10 mg), on average, and 24 hours after antigen challenge, the average of its breath units The standard deviation of the soil value is PD4〇〇 (mean soil SE PD400). Detailed Description of the Traveling Example: The present invention provides various novel compounds, pharmaceutical compositions and methods for treating or reducing the symptoms of inflammation in mammals. More specifically, The present invention relates to the treatment of pulmonary inflammatory response, including asthma or asthma related diseases such as allergic reactions or inflammatory diseases, and the present invention overcomes the disadvantages of conventional anti-asthmatic therapies. Accordingly, the present invention provides various pharmaceutical compositions capable of treating or alleviating Asthma or asthma related symptoms of dairy animals. The present invention also provides methods for utilizing these compounds or compositions as a treatment for asthma or asthma related diseases. The methods and compositions of the present invention can be used as useful therapeutic tools. Preventing, reversing, and/or alleviating the symptoms of asthma and asthma-related diseases, especially those in which asthmatic patients are challenged by antigens. The present invention also provides various methods and compositions that can be manipulated or fine-tuned to accommodate In the case of treatment, there are fewer side effects at the same time. The Ministry of Economic Affairs, Intellectual Property Office, and the consumption of the company, the meaning of the technical and scientific terminology used here, unless specifically explained, common with the skilled artisans The understanding is the same, which is also the subject of this patent. The references herein are known to a variety of methodologies or materials well known to those skilled in the art. The authoritative references to the general theory of pharmacology include The Pharmacol by Goodman and Gilman It is called Ba-sLs_of Therapeutics, 10th Ed., McGraw Hill Companies Page 24 Zhang scale applicable Chinese National Standard (CNS) A4 size (210χ 297 mm) A7 B7 five Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives printed 1,255,269 invention is described in ()

Inc., New York (2001). Red, any suitable materials and/or methods known to those skilled in the art can be used in the practice of the present invention. Exemplary materials and methods have been described in the present invention. Various materials, reagents, and the like, which are mentioned below and in the examples which follow, are obtained from commercial piping unless otherwise specified. The understanding of the skilled artisan is to be construed as being incorporated by reference in the specification of the disclosure of the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of Any conflicts between any of the references cited herein, as well as the particular arguments therein, differ from each other in the form of the latter to address it. Similarly, any conflicts between the definitions of words and sentences known to those skilled in the art, and the different words and sentence definitions will be presented separately in the form of the latter to solve them. One application of the present invention provides novel disaccharide compounds having the structure of Formula I:

Wherein Ri, R2, R3, R4, R5 and R6 are a sulfate, a phosphate or a hydrogen. In certain embodiments of the invention, (a) h, r2, R3, R4, R5, and R6 are respectively sulfate or phosphate; or (b) Ri, R2, R3, R4, R5, and R6, at least The five series are different from J for sulfate or phosphoric. Page 25 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and fill out this page) 麝定 - 1255269 A7 B7 V. INSTRUCTIONS () Roots; or ((:) 111, 112, 113, 4, 1^5, and 1^6, at least four of which are sulfate or phosphate, respectively; or (d) Ri, R2 And at least three of R3, R4, R5 and R6 are respectively sulfate or phosphate; or (e) Ri, R2, R3, R4, R5 and R6, at least two of which are respectively sulfate or phosphate. All of the above specific examples (a) to (e) require special attention (i) if both R3 and R4 are sulfates, at least one of R!, R2, R5 and R6 is sulfate or phosphate; Ii) if R3, FU and R5 are both sulfates, at least one of shells 4 Ri, R2 and R6 is sulfate or phosphate; (iii) if both Ri and R4 are sulfuric acid And R; not sulfate, at least one of R2, R5 and R6 is sulfate or phosphate. In certain embodiments of another application of the invention, the disaccharide is present in a compound of formula II to VIII In the group: (Please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives [

Page 26 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 V. Invention description ()

In other embodiments of the invention in this aspect, the disaccharide is present in the group of compounds of formula IX-XV:

(Please read the notes on the back and fill out this page)

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

Page 27 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 V. Invention description ()

In this application, in one embodiment of the invention, the disaccharide system is comprised of a compound of formula XVI:

(Please read the notes on the back and fill out this page.) Printed by the Intellectual Property Office of the Ministry of Economic Affairs. The Ri, R3, R4, R5 and R6 systems are respectively sulfate or phosphate. In the same application, in one embodiment of the invention, the disaccharide system is comprised of a compound of formula VIII:

Page 28 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1255269

Invention description

Wherein R3, R4, r5 and R6 are sulfate groups. A person skilled in the art will find that the compounds of the present invention form or form salts, for example, the test, which is a sub-alkaline metal or an alkaline earth metal such as sodium, potassium, magnesium or barium; Or Ming, n # u and organic test (such as: amine or moth) or the side of the invention: go, Γ: class is sodium salt and unloading salt. Make it possible to experience this two for any mammal Animal, an invention (advantage of method. Therefore, root: animal) comprises human and non-human mammals, in particular; in addition, the invention particularly provides a pharmaceutical composition for treating or reducing the lungs of a mammal A symptom of an inflammatory response, the composition comprising at least one pharmaceutically effective amount of a compound of the formula:

Among them, Ri, R2, R3, R4, r5 and r6 are sulfate, phosphate or hydrogen. In certain embodiments of the invention, (a) Ri, R2, R3, R4, R5, and R6 are respectively sulfate or phosphate; or (b) Ri, R2, R3, R4, R5, and R6. At least five lines are respectively sulfate or phosphate; or (c) Ri, R2, R3, R4, R5 and R6, at least four of which are on page 29 - 'This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210X 297 mm) .............•装.........·订...Repair (please read the notes on the back and fill out this page) Economy Ministry of Intellectual Property Bureau employee consumption cooperative printing 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description () respectively sulfate or phosphate; or (d) Ri, R2, R3, R4, R5 and At least three of R6 are respectively sulfate or phosphate; or (e) Ri, R2, R3, R4, R5 and R6, at least two of which are respectively sulfate or phosphate. For all of the above specific examples (a) to (e), special attention should be paid to (i) if both R3 and R4 are sulfates, at least one of the shells U Ri, R2, R5 and R6 is sulfate or phosphate; (ii) if both Ri and R4 are sulfates and R3 is non-sulfate, at least one of R2, R5 and R6 is sulfate or phosphate; (iii) if only R3, R4 and R5 are sulfates, This chemical composition is then enriched in the compound. In this application, in certain embodiments of the invention, the disaccharide system of the pharmaceutical composition is present in a population of compounds having formulas II through VIII:

Page 30 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) ...........•装.........V·..... .. (Please read the notes on the back and fill out this page) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed V. Inventions ()

In other embodiments of the invention in this aspect, the disaccharide in the pharmaceutical composition is present in the compound of formula IX-XV:

Page 31 This paper scale applies to China National Standard (CNS) A4 specification (210X297 public Chu) .......................... ...纛(Please read the note on the back and then fill out this page) 1255269 A7 B7 V. INSTRUCTION DESCRIPTION () In this application, in one embodiment of the invention, the pharmaceutical composition is included in formula XVI. In the compound group:

(Please read the precautions on the back and fill out this page.) Where R1, R3, R4, R5 and R6 are U or sulfate or phosphate. In a specific embodiment of the invention, the pharmaceutical composition comprises a compound of formula VIII:

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative, where Ri, R3, R4, F〇- and R6 are sulfate. As described above, those skilled in the art will recognize that the compounds of the present invention may be miscible with metals or form salts with metals, such as alkali or alkaline earth metals such as sodium, potassium, #5, strontium or barium; Chain, zinc, copper, knot, strontium, silver, pot or sputum; or organic test (eg amino acid). The currently preferred salts are sodium salts and salt. Page 32 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 V. Description of the invention (After careful classification, the type of inflammatory response includes respiratory diseases such as allergic rhinitis. For seasonal or perennial sneezing, nasal spray, nasal congestion, recurrent conjunctivitis and pharyngitis. Other types include fish rhinitis, characterized by nasal mucosal edema, runny nose and nasal congestion. Most cases are Caused by common viruses. Pulmonary diseases such as endogenous or exogenous stagnation of f-type asthma, any inflammatory lung disease, severe chronic bronchitis, secondary inflammatory reaction caused by L-blister bronchitis, Chronic obstructive pulmonary disease, pulmonary fibrosis, Goodpasture's syndr〇me, and any pulmonary symptoms associated with white blood cells, including, but not limited to, spontaneous pulmonary fibers Degenerative and any other autoimmune lung disease. Also included are abnormalities in the ears, nasal opening, and throat, such as acute otitis externa, rickets, and external ear. Mold disease. The present invention includes respiratory diseases such as traumatic and infectious tympanitis, acute ear pharyngeal otolaryngitis, acute serous otitis media, and fish and chronic sinusitis. The term "inflammation of the lungs" includes any Inflammatory lung disease, severe chronic bronchitis, secondary pulmonary inflammatory response due to chronic bronchitis, chronic obstructive pulmonary disease, pulmonary fibrosis, Gud Pasteur syndrome, and any lung associated with white blood cells Symptoms, including but not limited to spontaneous pulmonary fibrosis and any other autoimmune lung disease. The term "asthmatic" as used herein refers to a condition caused by an allergen, the symptoms of which include persistent or intermittent Difficulty breathing and accompanied by asthma, the patient feels chest contraction' and produces symptoms of cough and gasping. The so-called "asthma-related disease" refers to the nature of the symptoms mainly inflammatory reaction and accompanying the bronchus. Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and then fill out this page) ▼ Install · Book · Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Workers, Consumer Co., Ltd. Printed A7 B7

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 7-G 1255269 V. Invention description () _ engine. Therefore, the characteristics of both asthmatic and asthma-related conditions include spontaneous bronchial stenosis caused by treatment in a short period of time, or because of varying degrees of synovial contraction (痉挛), mucosal edema, and bronchi and bronchioles. Mucus. In general, these symptoms are caused by the release of sputum and the release of vasoactive substances (such as histamine bites such as globular or prostaglandins). Typical examples of "asthmatic related conditions" include, but are not limited to, non-asthmatic conditions characterized by hypersensitivity of the respiratory tract (eg, chronic bronchitis, emphysema, and fibrotic sac). Furthermore, given that we have discovered The effect of sulfating disaccharide, the present invention <effectively treating the following symptoms: (1) late reaction and inflammatory reaction in a site other than the lung, such as (a) allergic rhinitis, (b) allergic dermatitis, c) allergic conjunctivitis; (2) diseases other than the lungs in which the inflammatory response plays a major role, including (i) inflammatory bowel disease, (ii) rheumatoid arthritis and other collagen vascular diseases, (iii) vascular balls Nephritis, (iv) inflammatory skin disease, and (v) sarcoma. The term "treating or alleviating symptoms" as used herein refers to a situation in which the symptoms of the patient are reduced, prevented and/or reversed after administration of the compound of the present invention. Therefore, a compound of the present invention which can treat or alleviate the symptoms of asthma or asthma-related diseases can reduce, prevent and/or reverse the early asthmatic reaction caused by antigenic challenge in a dual-reactive individual; in addition, it can also be applied to Reduce, prevent, and/or reverse the late-onset asthmatic response of dual-reactive individuals with antigenic challenge; π $ ap and more useful for reducing, preventing, and/or reversing dual-reactive individuals And the production of the early and late 34th page of the paper scale Le (four) Vision (CNS) A4 specifications (2 Κ) χ ^ χ χ χ χ χ χ χ χ χ χ χ χ χ χ .,玎.........Φ (Please read the back: /i and then fill out this page) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing · V. Invention description (period asthmatic response The skilled artisan, a small farmer, knows the method described herein and knows that the compound of the present invention is applied to the positive effect of 髀皙3 'σ 贝 勿 勿 者 者 者 或 或 或 或 或 或 罄 罄 罄 罄 罄 罄 罄 罄 罄 罄 罄The spleen and phlegm doctor will understand the compounds, compositions and methods described herein. At the same time as the sputum is used, it is necessary to have a clinical evaluation by an experienced doctor (physician or veterinarian) # to determine the next steps. Therefore, the first division will be evaluated according to standard methods. Any improvement in the treatment of pulmonary inflammatory response. This assessment facilitates the decision of the subsequent steps and, if applicable, provides a reference for increasing or decreasing the dosage of the pharmaceutical composition administered in accordance with the present invention. "Antigens" and "allergens" are molecules that induce allergic reactions and/or asthmatic symptoms in asthmatic patients, such as dust 'pollen.' Therefore, individuals with asthma are affected by allergens or antigens. 』' means that the individual is exposed to a sufficient amount of allergens or antigens that induce an asthmatic response. Especially in animal studies, it has been found that the compounds and compositions obtained according to the present invention have therapeutic effects (a) can be used for the prevention of antigens. Acute bronchial sphincter response (ABR) and excessive bronchial sensitivity, also known as airway hypersensitivity (AHR); and (b) mammalian The subsequent AHR produced by the original challenge is improved after treatment. The production of the compound of the present invention is obtained by the following examples/and the following methods of heparin. Although the following procedure is the use of porcine heparin, any mammalian Heparin can be used in the manufacture of the compounds of the invention. Here, although the sulfated disaccharides used in the methods and compositions of the present invention are typically derived from naturally occurring heparin, the present invention also encompasses from hepatitis B sulfate. The paper size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm). ......, please read the following notes on the back of the page. 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Office staff The consumer cooperative prints five, invention instructions (), sulfated dermatan, chondroitin sulfate, polysulfate pentose acid and / or other glycosaminoglycans and mucopolysaccharides from sources such as mucopolysaccharides. In addition, the compounds of the present invention can be artificially synthesized in accordance with standard organic chemical techniques. In the present invention, a pharmaceutical composition "containing a large amount" of a particular compound represents an amount of the compound higher than the amount formulated. For example, if a compound is known to have a specific compound of less than 10% and the compound is increased to more than 10% in a composition, the composition "contains a large amount" of the compound. The compounds of the present invention are formulated in a "pharmaceutically acceptable carrier" in any of the well-known pharmaceutically acceptable vehicles, including diluents and excipients (see Remington's Pharmaceutical) Sciences. 18th Ed., Gennaro, Mack Publishing Co., Easton, PA 1990; and Remington: The Science and Practice of Pharmacy. Lippincott, Williams & Wilkins, 1 995). Although the type of pharmaceutically acceptable carrier/vehicle used in the preparation of the pharmaceutical composition of the present invention varies depending on the mammal receiving the composition, in general, "pharmaceutically acceptable vehicle" It is physiologically inactive and not toxic. The formulation of the composition of the present invention may contain more than one compound of the present invention (for example, a disaccharide with five sulfates, and a disaccharide with six sulfates), and any other pharmacological agents. Learn to be active ingredients (such as heparin). The compounds of the present invention can be used in a pharmaceutically acceptable vehicle by means of a formulation known to those skilled in the art. Composition of the present invention on page 36 1 2 paper scales applicable to China National Standard (CNS) A4 specifications (21〇χ 297 public Chu) .............·装... .....Set:-...... (Please read the notes on the back and fill out this page) Five Ministry of Economic Affairs Intellectual Property Bureau X Consumer Cooperative Printed Ϊ-7 Ϊ255269 Λ7 _____B7, invention description () ° The second route is applied, however, the preferred mode of administration is the inhalation route. The present invention is suitable for the following modes of administration: oral, inhalation, rectal, sputum # (including intravitreal or intracardiac), nasal, local (including cavities and sublingual), vaginal, or parenteral ( These include subcutaneous injections, muscle/young injections, intravenous injections, intradermal injections, and intratracheal injections. In addition, according to the general method of A, , , , _ /, the domain, a polymer can be added to facilitate the continuous release. In the case of inhalation administration, a composition of the present invention is combined with a pharmaceutically acceptable vehicle, such as physiological saline or may be, as is known to those skilled in the art. Inhalation method is passed. Such inhalation methods and equipment include, but are not limited to, metered dose inhalers plus spray propellants such as CFC or HFA or other physiologically and environmentally acceptable propellants. Other included equipment are breath-controlled inhalers, multi-dose dry powder inhalers, and aerosol inhalers. In a specific embodiment, the composition of any of the compositions of the present invention, which is inhaled, is affected by a pump or a compression-activated inhalation of sodium. In certain embodiments of the invention, inhaled administration and efficacy may be affected by methods such as metered dose inhalers (MDI) or sprays. In the present invention, for the sake of convenience, the preparation of the composition is in unit dose form 2, and can be prepared by the aforementioned conventional pharmaceutical techniques. These techniques include the step of combining a pharmaceutically acceptable carrier with a compound of the invention, such as diluents and shapings. In general, the preparation of the formulation will be active ingredients and liquid vehicles, or precision. Divided solid media, or both. The paper size of this page applies to the Chinese National Standard (CNS) A4 specification (21〇χ297 public) (Please read the note on the back and fill out this page again) 1255269

V. Description of the invention (

Both have the right to make W Yu, evenly combined, and then, if necessary, add Zheng. .earth

' J , ; and the preparations for the ingestion, including the preparations of the inhaled equipment known as those skilled in the art. These preparations may include vehicles such as powders and powders. The inhalable composition used in the present invention may comprise at least a liquid or powdery composition with a living substance, which is suitable for use in a spleen or a bronchial route; or A fixed dose of aerosol composition is administered via an aerosol device. In the present invention, a suitable liquid composition contains at least an active ingredient placed on a "liquid inhalation carrier", such as isotonic saline or bacteriostatic water, and other skilled persons. Known vectors. These solutions may be administered by "pump" or "compression-actuated inhalation spray" or by any other conventional means that may cause or assist the patient's lungs to inhale the necessary dosage composition. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives (please read the notes on the back and fill out this page). For example, in all applications of the present invention, a suitable powdered composition containing a compound includes a pharmaceutically acceptable powder preparation method. , the product is formed with the lactose or other inert powder suitable for intrabronchial application. The powdered composition can be applied via sub-packaging, including but not limited to a sprayer or a capsule that can be broken. The patient may place the capsule in a device that will puncture the capsule and blow the powder to form a stable and breathable state. It is prepared from a composition containing the compound of the present invention, and may be Aerosol preparations used in the manner described, typically including propellants, surfactants, and co-solvents, or filled with conventional containment aerosols with metering valves. Page 38 4 This paper scale applies to China National Standard (CNS) A4 specifications. (210X 297 mm) 1255269 A7 B7 V. Description of the invention (device. (Please read the notes on the back and fill out this page). Suitable for oral administration. The composition comprises at least a compound for treating an inflammatory reaction in the lungs in various applications of the invention, and these pharmaceutical compositions may be presented in separate units, such as capsule film tablets, tablets, pills, or lozenges, each unit Each of which has a known amount of the powdered or granulated active ingredient; or is placed in an aqueous or non-aqueous liquid, in a solution or suspension; or in a liquid emulsion in which the oil is dissolved in water or in an oil-soluble emulsion, And presented in the form of a large pill, etc. In addition, the application of the compositions of the present invention may be affected by aqueous solutions, suspensions, or hopping agents (e 1 i X ir ), powders, ingots, miniaturized particles, and infiltration. The effect of a pressurized drug delivery system. The manufacture of a bond is compressed or shaped with one or more accessory ingredients. The compressed tablet is prepared by compression in a suitable machine, the active ingredient being in powder form in the machine or Free-flowing granules, optionally with binders, lubricants, inert diluents, preservatives, surfactants, or dispersing agents. Shaped tablets are in a suitable machine. After molding, the powdered compound is mixed and moistened with an inert liquid diluent. The tablet may be coated or cut and may be formulated to slow or control the release of the active ingredient. Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Printing In the present invention, a composition preparation suitable for topical application in the mouth comprises a mouth-containing bond (containing at least an ingredient placed in a wall-flavoring agent, the flavoring agent is usually a sugar and a gum arabic or a tragacanth); Containing at least an active ingredient in an inert agent such as gelatin and glycerin, or sucrose and gum arabic; and a mouthwash (containing at least the ingredients to be applied in a suitable liquid vehicle). Applicable to China National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 V. Inventive Note () (Please read the back note first and then fill out this page) In the present invention, a composition preparation suitable for topical application to the skin, Including ointments, creams, gels, lotions, and pastes, which comprise at least a pharmaceutically acceptable carrier ingredient. A topical drug delivery system utilizes a skin patch containing the ingredients to be administered. In the present invention, a formulation preparation suitable for rectal administration may be in the form of a suppository containing a suitable base comprising at least, for example, cocoa butter. In the present invention, a composition preparation suitable for nasal administration and a vehicle thereof is solid, and contains a coarse powder of a particle size, for example, in the range of 20 to 500 μm, in the form of application and olfactory agent. The application is the same, that is, the container containing the powder is lifted to the vicinity of the nose, and then passed through the nasal cavity via rapid inhalation. Formulations suitable for administration, if the vehicle is a liquid, for example, by nasal spray, aerosol, or nasal spray, containing an aqueous or oily solution of the compositions of the present invention. Formulations suitable for vaginal administration may be presented in the form of vaginal suppositories, suppositories, thrombus, creams, gels, pastes, blister packs, or spray formulations in accordance with the practice of the present invention, in addition to The compounds of the invention are also those pharmaceutically acceptable vehicles which are also suitable vehicles known in the art. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed In accordance with the use of the present invention, compositions suitable for parenteral administration comprise aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, stabilizers, buffers, bacteriostats, And solutes which are equivalent to the osmotic pressure of the blood of the recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents as well as thickening agents. The preparation can be placed in a single-dose or multiple-dose container, for example, a seal note. Page 40 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1255269 V. Invention description () (Please Read the precautions on the back and fill out this page. Bottles and vials; and store in a freeze-dried (lyophilized) state. In this case, just add sterile liquid vehicle, such as water for injection before use. Injectable solutions and suspensions can be prepared immediately from the aforementioned sterile powders, granules, and lozenges. In another application, the invention particularly provides a method of treating or reducing the symptoms of an inflammatory response in a mammal, the method comprising at least administering a sufficient amount of the pharmaceutical composition of the invention. In certain embodiments of the invention, the pharmaceutical composition is effective in treating an inflammatory response in the lung. A method useful for treating an inflammatory response in the lung comprises administering the composition into the bronchi in a variety of ways well known in the art, such as Baopu, a compression-actuated inhaler, a metered dose inhaler, or by means of an aerosol spray. . The composition used in this application of the present invention is the same as the two other applications of the foregoing invention. This application of the invention specifically proposes a method for treating or ameliorating the symptoms of an inflammatory response in the lungs of a mammal, the method comprising at least administering a pharmaceutically effective amount of a pharmaceutical composition comprising at least a compound of formula I:

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative, where Ri, R2, R3, R4, R5 and R6 are sulfate, phosphate or hydrogen. In some specific embodiments of the present invention, (a) Ri, R2, R3, R4, page 41, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1255269 V. Invention Description () R5 and R6 may be sulfate or sulphate, respectively; or (b) R1, R2, R3, R4, R5 and 尺6, at least five of which are respectively sulfate or phosphate; or (C) Rl, anaesthesia 2 At least four of R3, Ruler 4, R5 and R6 are respectively sulfate or phosphate; or (d) Ri, R2, R3, R4, R5 and R6, at least three of which are respectively sulfate or phosphate; (e) At least two of R1, r2, R3, R4, R5 and R6 are respectively sulfate or phosphate. Special attention should be paid to all of the above specific examples (a) to (e) (i) if both R3 and R4 are sulfates, at least one of Ri, R2, r5 and R6 is sulfate or phosphate; Ii) If R3, R4 and R5 are all sulfates, at least one of Ri, R2 and R6 is sulfate or phosphate; if (Hi) is sulfated with R4 and r3 is not sulfate, then R2 At least one of R5 and R6 is sulfate or phosphate. In another embodiment, the present invention is directed to a method for treating or ameliorating a symptom of a pulmonary inflammatory response in a mammal, the method comprising administering at least a pharmaceutically effective amount of a pharmaceutical composition, The pharmaceutical composition comprises at least a group of compounds of the formulae II to VIII....................0^....,玎.........泰' (Please read the notes on the back and fill out this page.) Printed by the Consumer Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs.

This paper scale applies to China National Standard (CNS) A4 specification (210Χ 297 mm) 1255269 A7 B7 V. Invention description ()

(Please read the note on the back and then fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print 7'; In other specific embodiments of this application of the present invention, the present invention relates to a mammal that can treat or alleviate mammals. A method for the symptom of an inflammatory reaction in the lung, the method comprising at least administering a pharmaceutically effective amount of a pharmaceutical composition comprising at least a compound of the formula IX to XV: page 43 of the paper scale applicable to the Chinese national standard ( CNS) A4 specification (210X 297 mm) 1255269 A7 B7 V. Invention description ()

............•装.........,.........(Please read the notes on the back and fill out this page) Bureau employee consumption cooperative printing

Page 44 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1255269 A7 B7 V. Inventive Note () In one embodiment of the present invention, the pharmaceutical composition is at least disaccharide Compounds containing formula XVI:

(Please read the notes on the back and fill out this page.) Among them, Ri, R3, R4, R5 and R6 are respectively sulfate or phosphate. In one embodiment of this application of the invention, the pharmaceutical composition comprises a disaccharide compound of formula VIII:

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, where Ri, R3, R4, R5 and R6 are sulfate. It will be apparent to those skilled in the art that the compounds of the present invention may be mismatched with metals or form salts with metals, such as, for example, metal or soil of the soil test, such as sodium, potassium, mother, error or pin; or inscriptions, words, Copper, cone, Chin, Syrian, sputum or iron; or organic test (eg amino acid). The currently preferred salts are sodium salts and the 45th page is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). 1255269 A7 B7 Five invention instructions (potassium salt when applicable (eg for asthma treatment) The compounds of the present invention can be administered prior to, simultaneously with, or in the exposure of the mammal to the antigen. It will be appreciated by those skilled in the art that the particular sequence in which the compound of the invention is administered to the antigen will be selected. The specific compounds are different. In addition, when the antigen is exposed, the timing of the composition of the present invention will vary depending on the condition of the case and different mammals. The experienced physician will carefully observe the patient and change The timing or sequence of the composition is applied to achieve an optimal application effect. To be, the compositions of the present invention have therapeutic effects, and clinical changes include alleviating the typical symptoms or symptoms of asthma and related conditions (eg, difficulty breathing, gas mouth) , sputum, bronchial hypersensitivity); and improved lung function tests. This is a part of the patient's symptoms and the view of the physician The amount of the dose depends on the condition to be treated, the particular compound of the invention to be administered, and other clinical factors, such as age, body weight, condition of the mammal, and route of administration. For example, when the present invention, the compound contains at least For five or six sulfation groups, only a lower, compound dose is required, and the symptoms caused by antigen challenge are positive. In other words, when the compound of the present invention has only three or four sulfation Cough (please read the note on the back and then fill out this page) When the Ministry of Economic Affairs' Intellectual Property Bureau employees consume cooperatives to print the base circle, 'the higher dose is needed, and the symptoms caused by the antigen challenge can achieve the same positive effect as the former. (i.e., the same degree of reduction in early and/or late response to antigenic challenge). It is understood that mammals administered with the compounds of the present invention do not need to suffer from asthma or asthma related diseases. , page 45 of the present invention, the paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X297 public interest) Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperative Printed 1255269 Α7 V. Inventive Note (The substance can be pre-administered to individuals who are susceptible to asthma and/or asthma-related diseases before any symptom symptoms occur. For example, if you notice a body during the pollen season, asthma The symptoms are prone to deterioration, the compound of the invention may be administered to each of its sputum (e.g., via oral administration), and/or it may be pre-administered to a pollen-rich area (e.g., a chemical garden) w. Similarly, if a body is A member of the present invention may be pre-administered with a compound of the present invention to prevent the onset of asthma, without experiencing a gas attack. The term "pharmaceutical effective amount" (therapeutic dose) is used herein. By the treatment, the dosage of the treatment is expected to achieve the desired therapeutic result. In addition, one skilled in the art will recognize that the compound of the present invention is combined with another anti-asthmatic compound (e.g., a sebum steroid hormone) upon administration and/or administration. It may be possible to reduce or increase the therapeutically effective dose of the compound of the invention. Thus, the present invention k modifies the manner of administration/treatment of a particular mammal in a particular emergency. As shown in the following examples, an effective dose can be easily determined, for example, starting from a lower dose by experience and gradually increasing 'simultaneously assessing its positive efficacy (eg, early and/or late response after antigen exposure) Reduction). In a further application of the present invention, a mammal (ie, a double responder) suffering from a late response to an antigen, and then exposing the patient to an antigenic challenge is administered orally or parenterally (eg, IV or iM). The active composition containing the compound is applied in a manner. Those skilled in the art will recognize that the number of times a compound of the invention is administered will vary from patient to patient, and that the number of times will be based on the particular medical need of the patient at any particular time. Without limiting the number of daily intakes of the present invention, page 47 is suitable for the paper scale........................., 7:...... (please Read the back of the note first and then fill out this page) 1255269 A 7 B7 V. Invention Description (Previously, in general, the number of times you want to take daily is two to four times. The following examples can further describe the invention. The specific embodiments, and the nature of the invention are not limited thereto, and those skilled in the art can use the routine experiment to find or identify various equivalents of the specific materials and procedures referred to herein. These equivalents are all within the scope of the invention and are In the scope of the following patent applications (please read the notes on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Officer X Consumers Club Printed on page 48. This paper scale applies to China National Standard (CNS) A4 specification (210Χ 297 PCT) 1255269 V. INSTRUCTIONS (Examples) Example 1: Heparinization and cleavage reaction sulphate sulphate selection. ΡαΡ刀< Preparation, sulphated disaccharide can be used in the control sample, And as the system The starting material of the persulfate compound (see Examples 2 and 3, such as _, λ, ^ Γ). The operation H 4 used & describes the partial degradation of sodium heparin, One of a variety of formulas. At room temperature, 25 grams of commercially available (porcine) heparinized sodium (from SPL, ... (4), for example, muscle) is added to a " 3 A liter of water In a large beaker, stir it into a slurry, at this time

Add 2 liters of water and follow the walls of the women's r*, X%, and stir until the complete heparinized sodium is completely dissolved. Then, the pH of the heparin solution was adjusted to 5 98. To this solution, 17.25 g of sodium nitrite (〇·25 mmol,; τ·β — γ, acs grade) was added to complete the heparin nitrite cleavage reaction under control. At about 2 3, about 35. 1 ml of 37% sodium chloride was slowly added and stirring was continued for ten minutes to bring the pH to 3.00. The released nitrogen dioxide produces bubbles and turns the solution yellow-green. Between 0 and 1 20 minutes, the record of pH and temperature changes is as follows: ..........·装.........Book (please read the notes on the back and fill in the form) Page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed on page 49 This paper scale applies China National Standard (CNS) A4 specification (210X297 mm) 1255269 Λ7 ____ Β7 V. Invention description () Time (minutes) PH temperature ( °c ) 0 ---.. -1 3.00 23.0 15 2.92 23.0 30 2.55 23.0 45 2.35 23.0 60 2.27 —-- 22.5 75 --- 2.21 22.0 90 2.19 21.5 105 2.17 21.0 120 2.1β 20.0 After the solution Slowly add about 22:5 ml of 50% sodium hydroxide to bring the p Η value to 6.7 5 ' to stop the reaction. Example 2: Ultrafiltration of Pyrolyzed Heparin Preparation Ministry of Commerce Intellectual Property Office Staff Consumer Cooperative Printed Collection Typical disaccharide exudates (<3000 Da) and concentrate (> 3 000 Da) of the present invention are available in a variety of ways. Method, one of the following codes of practice will be described. Other methods known to those skilled in the art may be used instead. The lysed heparin solution obtained in Example 1 was diluted with deionized water (dIH20) (Millipore (Bedford, MA)) to a total volume of 8 liters, and filtered, Pellicon 2, 3k, PLBC-C, with an area of 0.5 cm ^ 2 ( Cable: Cat # P2 PLBCC 05). (Molecular weight cutoff 3 kDa) to collect and extract heparin oligosaccharides up to 3 kDa (3000 Dow) (ie, infiltration on page 50 〃 paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) 1255269 A7 B7 V. INSTRUCTIONS () The liquid is composed of oligosaccharides below 300 〇Dorden). Time temperature inlet outlet SETT Flow volume DF (°〇pressure pressure (ml/min) 2:58 26 60 52 46 862 0 0 3:22 pm 32 60 52 46 960 36 liters 4.75 pm 4:02 33 60 52 46 975 65 liters of 8.12 The concentrate (ie, nitrous acid-treated heparin greater than 3 kDa) was subjected to a second cleavage reaction with a 20 M nitrite solution to further induce degradation of heparin. The same type of filter (ie, molecular weight cut off) 3 kD a ) After ultrafiltration of the second treated oligosaccharide preparation, the resulting extract (molecular weight less than 3 kD a ) is added to the first excess exudate and then reverse osmosis It was concentrated to a final total volume of 2.5 liters, which was then cooled and dried. Example 3: Reduction of oligosaccharide preparation with sodium borohydride The lyophilized oligosaccharide preparation (50 g) was ice bathed Dissolved in 1 liter of purified water cooled to 2 -1 01: Add sodium bicarbonate (21 g) to the cooled oligosaccharide solution, and stir the preparation until completely dissolved. 0.5 M sodium borohydride solution 0.01 M oxyhydrogen in 400 ml The sodium solution was slowly added to the cooled oligosaccharide/sodium bicarbonate solution over a period of 60 minutes. The sodium borohydride solution was added to reduce the aldehyde-containing emulsion mixture. It is an alcohol-containing oligomer mixture. In the 2 -1 〇 page 51, the paper size applies to the Chinese National Standard (CNS) A4 specification (210Χ 297 mm) (please read the back note before writing this page) ▼ Binding. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1255269 A7 B7 V. Invention description ()

Under Qc, the reaction preparation was stirred for three hours, after which the concentration of P was reduced to 4.0 with concentrated hydrogen chloride to stop the reaction. Thereafter, the enthalpy of the solution was adjusted to 6.7 5 with sodium hydroxide, and finally the volume was concentrated to a minimum by reverse osmosis, and then the reduced oligosaccharide was cooled; the east drying method was stored. Thereafter, the reducing oligosaccharide preparation of less than 3 kDa was fractionated by Size Exclusion Chromatograph (SEC) using Bio-Rad Bio gel P6 resin (extracted with 〇2M ammonium hydrogencarbonate). After fractional distillation, the four sugars are collected according to the salt. The collected fractions were analyzed by carbazole assay, and the distribution of the collected fractions was obtained by plotting the absorbance of the fraction of 305 nm corresponding to the number of fractions. Similar fractions are gathered together on the profile and then lyophilized to give a separate fraction such as an ammonium salt and the ammonium bicarbonate is removed. The cation exchange was carried out with Amberlite IR120Plus ion exchange resin (Sigma-Aldrich) to convert the salt into a sodium salt form. Finally, the cold-dried fractions were subjected to cation exchange with Amberlite IR 12OPlus ion exchange resin (commercially available from Sigma-Aldrich) in accordance with the manufacturer's instructions to convert the ammonium salt to the sodium salt form. From a fraction, A. 2 . + C . 2 . .............·Installation: (Please read the notes on the back and fill out this page.) Booking · Ministry of Economic Affairs, Intellectual Property Office, employee consumption, bamboo, i print, page 52, paper scale Applicable to China National Standard (CNS) A4 Specification (210X 297 mm) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed V. Inventive Note () Analyze the disaccharide fraction by NMR to confirm the fraction, About 85% of the oligosaccharides have the following structure:

Among them, in the A.2.+ C.2. fraction, about 3-5% of the molecules are compounds having the following structure:

Example 4: Preparation of a typical persulfated disaccharide To illustrate a process which can be used to prepare a typical persulfated disaccharide of the present invention, two methods are described herein.

Method I A.2.+ C.2. fraction (2.5 g) in sodium disaccharide sodium salt is placed in 50 ml of water. According to the instructions of the manufacturer, this solution and Do we X 500WX200 acid resin can be used. Sigma-Aldrich Commercial) Anti-page 53 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) .............·装........ .订-:......Φ {Please read the notes on the back and fill out this page) 1255269 A7 — B7 99 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Instructions () (Please read the back of the note first) Matters fill out this page) should be turned into a protonated form. The acidic filtrate was further neutralized with tetrabutylammonium hydroxide, and the solution was freeze-dried to obtain a tetrabutylammonium ion as a fluffy solid. After that, anhydrous DMF was added to a mixture of di-tetrabutylammonium salt and trimethylammonium sulfite (5.22 g) under argon. The reaction mixture was heated at 50 ° C for 48 hours. The solution was then cooled to room temperature. After cooling, 100 ml of sodium acetate was added to a saturated solution of ethanol, and the mixture was stirred at room temperature for 20 minutes, diluted with 2.5 liters of water, and then passed through a membrane of 500 Dalton (i.e., 0.5 kDa). It. The concentrate (ie greater than 0.5 k D a) is cooled; the east is dry. After being dried in the east, the concentrate was redissolved in 0.2 M ammonium bicarbonate solution, and chromatographed with Bio-Rad Biogel P6 resin (Bio-Rad, Hercules, CA) according to the instructions of the manufacturer. M ammonium bicarbonate was washed to obtain a persulphated disaccharide salt (3.5 g). A portion of the ammonium salt (2.4 grams) was reacted with Amberlite IR 1 20 Plus ion exchange resin (commercially available from Sigma-Aldfich) according to the manufacturer's instructions and converted to a white solid sodium salt form (2.31 g). Method Π 0.5 g of the disaccharide sodium salt (a mixture obtained from the A.2. + C.2 fraction obtained in Example 3) and 3 g of trimethylammonium sulfite were placed under argon. It was heated at 60 ° C for 48 hours in 15 ml of DMF. The reaction mixture was cooled to room temperature, diluted with 20 mL of 10% aqueous sodium acetate and stirred at room temperature for 20 min. 100 ml of ethanol was added and the reaction mixture was concentrated under high vacuum to give a solid residue. Remaining page 54 This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1255269 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 ——--- V. Invention Description () Filter in 500 ml of water and filter with 500 Dalton membranes (three times with 5 ml of water). The concentrate containing the concentrate (i.e., distributed to greater than 5 Torrol) was lyophilized to give a yellowish white solid product. By the above method, a persulfated disaccharide can be obtained. One of the fractions was obtained, named 811-25-1, which was confirmed by NMR analysis to have the following structure (data not provided):

Example 5: Pulmonary evaluation of treated sheep To demonstrate the efficacy of a typical disaccharide of the present invention in the treatment/alleviation of allergic reactions, an acute bronchial sphincter response to an antigen of only 4 ^ c α ris suum ) was demonstrated with six heads. Sheep as a model for all research. In order to measure the respiratory airflow impedance of the lungs, the sheep were inserted into the tracheal cannula with the ankle ring and the respiratory airflow impedance was measured by the esophageal balloon catheter technique. The thoracic gas volume was measured by body plethysmography. These methods are accepted and well known in the literature. The data obtained are expressed as "specific RL (. abbreviated as, SRL), expressed as RL by thoracic gas volume (Vtg)). Before and after inhaling buffered saline, page 55::: This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public double) ............Installation.... .....订* .......Φ (please read the note on the back and then fill out this page) 1255269 A7 B7 V. Inventive Note () and the increase in the concentration of carbachol (carbachol) 0.25, 0.5, 1.0, (please read the precautions on the back and then fill out this page) 2 · 0 and 4.0 % wt / v ο 1 solution), the SRl of ten breaths after each application, to get accumulated Dose and response curve. Measurement of respiratory response, determination of carbon choline (in respiratory form) Medium) Increases the S RL to a pro vocation dose (PD 4 ο ο ) above 400% of the baseline. A respiratory unit is defined as a 1% carbon cholesteric solution. For studies of the respiratory tract, The baseline of respiratory response (PD400) was determined for each animal, and then the pd4G() of the test sheep's respiratory tract was challenged by the antigen challenge during the different days of the experiment, and immediately after the antigen challenge and each of the first 8 hours. The SRL was measured every hour. After 24 hours after the antigen challenge, the PD4〇 after antigen challenge was measured. The data obtained are as follows: (a) The mean value of SRL change is soil SE; (b) PD4〇o Percentage of baseline; and (c) acute bronchial sphincter response (ABR)% protection; and (d) respiratory hypersensitivity (AHR) % protection SRL (% change) = (post-excited SRL - baseline SRL) X10Q (a) Baseline SRl PD400 (Baseline%) = PD double X 100 after challenge (b) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Baseline SRl ABR% Protection = (Control Group ASRL% - Test Compound ASRL·%) X100 (c) Control group Z\SRl% Page 56 This paper scale applies to China National Standard (CNS) A4 Specification (210X 297 GM) 1255269 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Invention Description () AHR% 俣 = = (test compound PD4 〇〇 - control antigen PD change) X100 (d) Baseline PD·-control group antigen PD400 Example 6: Intravenous administration of persulfated disaccharide in dual-reactive allergic sheep To assess respiratory response, before and after inhalation of buffered saline, and in carbon bile In the case of a gradual increase in the concentration of carbachol (〇·25, 0·5, 1. 〇, 2.0, and 4.0% wt/vol solution), SR1 of ten breaths after each application to obtain cumulative dose and response Graph. The measurement of respiratory sputum response is a measure of the cumulative excitation dose (PD4〇o) of carboquine (in the respiratory unit) such that SRl to 400% is above baseline. A respiratory unit is defined as a 1% carbon choline solution. The entire procedure was repeated at least 14 days later, but each animal was given an intravenous injection of a test sulphated disaccharide or persulfate disaccharide one hour before antigen challenge (for control animals) No intravenous injection was given before antigen challenge. In a first experiment, the antigenic response of a asthmatic double-reacting sheep can be determined and pre-treated with a sulphated disaccharide A.2.+ C.2 fraction (ie, prior to antigen challenge) The effect of intravenous injection for one hour. The first group of six sheep were given antigen only at time = 〇, while the second group of 7T heads and sheep were given intravenously at time == _ 1 (ie, 1 hour before antigen challenge). · 2 5 mg / kg of A. 2 . + C . 2 . and applied antigen at time = 0. Sheep that were intravenously injected with 0.25 mg/kg of A.2.+ C.2. sulphated disaccharide fraction, in early response (3 days after antigen challenge), page 57, applicable to Chinese National Standard (CNS) A4 specifications (2丨0x297 public Chu) f Please read the notes on the back and then fill out this page} _装·订· % 1255269 A7 B7 V. Inventive Note () In time, it is affected by antigenic challenge A small decrease; however, A.2· + C. 2. Pretreatment seems to have no effect on late response (3-8 hours after antigen challenge) (data not provided). However, pretreatment with persulfated disaccharide has greatly improved the response of sheep to antigenic stimulation. At time = -1, a pre-treatment was performed to sm. 2 5 mg/kg of persulfate 811-25-1 disaccharide. Six sheep were injected intravenously before antigen challenge, compared to six The sheep in the control group received the antigen challenger only at time = 0, and the response was much lower. Compared to the control group, the reduction in antigen-induced response in animals treated with sulfated disaccharide was evident in both early and late reactions (data not shown). Fig. 1 shows a persulfate obtained in the manner described in Example 4, with A _2 · + C · 2. (i.e., obtained as described in Example 3) and 8 1 1 - 2 5 -1 (i.e., in the manner described in Example 4). The results of the pretreatment and the control animals, wherein the pretreatment with 8 1 1 - 2 5 -1 showed a double response to the reduction/treatment compared to the control animals administered only with the antigen. The striking effect of sheep's early and late response to antigenic challenge. It was also found that the higher doses of 8 1 1 -25-1 'have a positive effect on the early and late response to antigen challenge in reducing/treating double-reacting sheep compared to control animals administered only antigen. At time = -1, a pre-treatment was performed to treat the six sheep with an intravenous injection of 8 1 1 - 2 5 -1 disaccharide at a dose of 〇·25 mg/kg before antigen challenge. Sheep in the six-head control group received antigen challengers only at time = 0, and the response was much lower. The early and late-stage reactions caused by antigenic challenge in double-reacting sheep were also studied. A.2. + C.2. disaccharide or 81 1-25-1 persulfate disaccharide. National Standard (CNS) A4 Specification (2丨0X 297 mm) (Please read the note on the back and fill out this page) Order · Ministry of Economic Affairs Smart Bureau Member X Consumer Consuming Printing 1255269 A7 ___________B7______ V. Invention Description ( The treatment was performed in comparison with the control group to which only the antigen was administered. For early and late-stage reactions, at time = _ ,, pre-treatment, intravenous injection of t U t g / kg of persulfate disaccharide, compared to animals receiving only antigen (control animals) Or when receiving an antigenic challenge at time = 0 =, the response is much lower.静脉 25 mg / - kg of A.2. + C. 2 intravenously injected animals (data not provided), 811 25-1 has a remarkable positive effect on reducing the response caused by antigenic challenge. Therefore, the results described in the present example show that all of the animals pretreated with the pre-stone salt of the present invention were intravenously pretreated, and it was found that the antigen-inducing reaction was reduced in the early stage as well as in the control group. Late reactions are visible. (Please read the precautions on the back and fill out this page.) Set Example 7: Allergic reactions to double-reacting sheep with persulfated disaccharide Φ Application by the Ministry of Economic Affairs, Ministry of Finance, Fisheries and Production Co., Ltd.

The efficacy of administering the typical compounds and methods of the present invention by inhalation is determined in accordance with the procedures set forth in the foregoing examples. For respiratory studies, there is one exception, after measuring the baseline of respiratory response (PL(10)) for at least fourteen days, the procedure is repeated 30 minutes before the antigen challenge (time = 〇) (ie, time = _〇5), or immediately after the measurement of the antigen-stimulated SRL value, inhaled administration of each of the animals with a sulfated disaccharide or persulfated disaccharide. L In the first Shao study, the effect of suspending persulfated disaccharide in water and taking it by inhalation was analyzed. Figures 4 to 7 show several doses. Page 59 1255269 Five Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed Λ7 B7 Invention Description () The results of the analysis, in which the total dose of persulfated disaccharide is 1, 2 · 5, 5.0, and 丨〇. 〇, when the time before the antigen challenge (time = 〇) = -0.5, the 811-25-ι dissolved in water is administered by inhalation. From Figures 5 to 7, it can be found that in all animals, 2.5-1 〇 mg (total dose) 81 卜 25-1 pre-treatments were compared to control animals receiving antigen challenge only at time two 〇 'It can reduce its early and late reactions caused by antigenic challenge. Figures 4A through 7A further show the efficacy of different doses of 811-25-1 suspended in water' and inhalation of AHR. In summary, these data indicate that physicians can choose to use the persulfate disaccharide dose of the present invention depending on whether they wish to have a significant inhibition of early or late response. In the second part of the study, the persulfated disaccharide was dissolved in phosphate buffer (PBS) and administered by inhalation prior to antigen challenge. For double-reacting sheep, 0.25 mg/kg of 811-25-1 was suspended in PBS for inhalation administration. The pretreatment was lower than that of the control animals that received only antigen challenge. Reaction with late stage (data not provided). Example 8: Oral administration of hyperreactive allergic sheep with persulfated disaccharide This example is in accordance with the test animal and evaluation method set forth in Example 3, and for respiratory studies, with one exception, in measuring respiratory response After at least fourteen days of baseline (PD4〇Q), repeat the procedure, apply the pounds before the 4 antigen challenge (time = 〇) 90 minutes (ie, time = _ 1 5). China National Standard (CNS) A4 specification (210X297 public).............·Installation: (Please read the note on the back and fill out this page) % 1255269 A7 B7 V. Invention Description () Oral administration was carried out at 0. 5 mg/kg of persulfated disaccharide 81 b25__1 for each animal (for control animals, oral administration was not performed with sugar before antigen challenge). Animals receiving pretreatment of 81 1-25-1 orally administered at 0.5 mg/kg had a change in the SR1 ratio of early and late-stage reactions compared with the control animals. In the oral administration of 〇5 mg/kg 81 1-25-1 10 minutes before the antigen challenge, double-reacting sheep (in comparison with the control only animals with double antigen) were challenged by the early stage of antigen challenge. Late response was reduced (data not available). Example 9: Efficacy of persulfated disaccharide in early asthma in sheep. According to the procedure of the previous examples, administration by intravenous injection will have the same critical atom backbone structure (compounds A to D) but the number of phosphate groups is different. (The degree of phosphation between these compounds can be expressed as A &lt; B &lt; C &lt; D) for allergic sheep. The laboratory has shown in order to demonstrate the efficiency of the persulfated disaccharide of the present invention in inhibiting the inflammatory response (more precisely, for early asthma). Figure 2 is a bar graph showing the early response to treatment as compared to a disaccharide with a lower carbonaceous structure (compared to A2A2 + C.2.) but with a lower degree of sulfation ( b di compound 730-57 'C = compound 730-96; D = compound 811-25), the per-sulfation of the disaccharide has a positive effect. Further Example 9 ································································································ ---^ (Please read the notes on the back and fill out this page), one or two economic department Intellectual Property Bureau employees consumption cooperatives printed 1255269 A7 B7 V. Inventions () (Please read the notes on the back and fill in This page is a disaccharide with a carbon atom backbone structure (compounds A to D) but a different number of phosphate groups (the degree of phosphation between these compounds can be expressed as A&lt;B&lt;C&lt;D) for allergic sheep . The laboratory has shown in order to demonstrate the efficiency of the persulfated disaccharide of the present invention in inhibiting the inflammatory response (more precisely, for early asthma). Figure 3 is a bar graph showing the late response to treatment, compared to the backbone with the same carbon atom backbone (compared to A = A. 2. + C · 2 ·) but with a lower degree of sulfation Sugar (B = compound 730-57; C = compound 730-96; D = compound 811-25), the per-sulfation of the disaccharide has a positive effect. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; There are many ways in which the invention can be modified and modified. Thus, for example, a person skilled in the art can use the routine experiment to find or identify various equivalents of the specific materials and procedures referred to herein. These equivalents are all within the scope of the invention and are covered by the following patent applications. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff and Consumers Co., Ltd. Page 62 This paper scale applies the Chinese National Standard (CNS) A4 specification (210X 297 mm).

Claims (1)

1255269 A8 B8 C8 D8 VI. Scope of Application 1. A compound of the formula I, which comprises at least: Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative, where Ri, R2, R3, R4, R5 and R6 are sulfate, phosphate or hydrogen; and (a) where R1, R 2, R 3, R 4, R 5 And the R 6 system is respectively a rock salt or a phosphate; (b) wherein at least five of R!, R2, R3, R4, Rs and R6 are respectively sulfate or phosphate; or (.) 2, at least four of the rulers 3, 4, 1^5 and 1^6 are sulfate or phosphate; or (d) wherein at least three of Ri, R2, R3, FU, R5 and R6 are respectively sulfuric acid Root or phosphate; or (e) wherein at least two of Ri, R2, R3, R4, R5 and 6 are respectively sulfate or phosphate; and presuppose that if (i) R3 and R4 are sulfates, Then at least one of Ri, R2, R5 and R6 is sulfate or phosphate; or (ii) R3, R4 and R5 are both sulfate, shell I Ri, R2 and R6 page 63. ......·Installation: (Please read the notes on the back and fill out this page.) Order · Spring paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 1255269 A8 B8 C8 D8 々, Patent application scope At least one of them is sulfate or phosphate; or (iii) Ri and R4 are both sulfate' and R3 is not sulfate, then at least one of R2, R5 and R6 is sulfate or phosphate 0 (please read first) Precautions on the back side Fill in this page) One Pack · Set · Printed by the Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives "Page 64 This paper scale applies China National Standard (CNS) A4 specification (210X 297 mm)