EA012138B1 - Use of lipid conjugates in the treatment of diseases - Google Patents

Abstract

This invention provides for the use of a compound comprising a lipid or phospholipid moiety bond to a physiologically acceptable monomer, dimer, oligomer, or polymer, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof, for the preparation of a composition for treating a subject suffering from asthma, allergic rhinitis, or chronic obstructive pulmonary disease. This invention also provides for the use of a compound comprising a lipid or phospholipid moiety bond to a physiologically acceptable monomer, dimer, oligomer, or polymer, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof, for the preparation of a composition for preventing asthma, allergic rhinitis, or chronic obstructive pulmonary disease in a subject.

Description

The present invention provides the use of a compound containing a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer and / or its pharmaceutically acceptable salt or pharmaceutical product thereof, for the preparation of a composition for treating a patient suffering from asthma, allergic rhinitis or chronic obstructive disease lungs. This invention also provides the use of a compound containing a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer and / or its pharmaceutically acceptable salt or its pharmaceutical product for the preparation of a composition for the prevention of asthma, allergic rhinitis or chronic obstructive pulmonary disease in the patient.

State of the art

Lipid conjugates having a pharmacological activity of inhibiting the phospholipase A2 enzyme (PbA2, EC3.1.1.4) are known in the prior art. Phospholipase A2 catalyzes the decomposition of phospholipids according to §η-2 position with the formation of fatty acid and lysophospholipid. The activity of this enzyme correlates with various cellular functions, in particular with the production of lipid mediators, such as eicosanoids (prostaglandins, thromboxanes and leukotrienes), platelet activation factor and lysophospholipids. Since their discovery, lipid conjugates have undergone intensive laboratory research in order to achieve wider application in protecting cells and organisms from damaging agents and pathogenic processes.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the treatment of asthma.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the prevention of asthma.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000,

- 1 012138 to obtain a composition for the treatment of allergic rhinitis.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the prevention of allergic rhinitis.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the treatment of chronic obstructive pulmonary disease.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the prevention of chronic obstructive pulmonary disease.

In one embodiment, X in the general formula (A) is a polysaccharide. In one embodiment, the polysaccharide is carboxymethyl cellulose, while in another embodiment, the polysaccharide is glycosaminoglycan. In one embodiment, the glycosaminoglycan is hyaluronic acid, while in another embodiment, the glycosaminoglycan is heparin. In one embodiment, b in general formula (A) is phosphatidylethanolamine, which in one embodiment is dipalmitoylphosphatidylethanolamine.

Brief Description of the Drawings

FIG. 1.1: Inhibition of endothelin-1 (ET) -induced spasm of rat tracheal rings with lipid conjugates. A: Spasm of the rat trachea with Endstellin-1. B: Effect of NURE on ET-induced rat tracheal spasm.

FIG. 1.2: Effect of NURE and hyaluronic acid (HA) on ET-1-induced rat tracheal spasm.

FIG. 1.3: Effect of NURE and hyaluronic acid (HA) on Acetylcholine (AcSy) -induced spasm of isolated rat tracheal rings.

- 2 012138

FIG. 1.4: Effect of NURE, administered subcutaneously, on an early asthmatic reaction (EAB) caused by albumin inhalation.

FIG. 1.5: Effect of NURE on & PbL2 expression in the lungs of rats with OAA-induced asthma.

FIG. 1.6: Effect of NURE on the level of cysteinylleukotrienes (LTC ₄ , LTE ₄ and LET ₄ ) in ALV suffering from OAA-induced asthma in rats.

FIG. 1.7: Effect of NURE inhalation on the early and late asthmatic reactions (EAB and LAB, respectively) in OAA-sensitized, asthmatic rats.

FIG. 1.8: Effect of NURE inhalation on cysteinylleukotrienes (BTC ₄ , BTO _4, and BET ₄ ) in YOU OAA sensitized, asthmatic rats.

FIG. 1.9: Effect of NURE inhalation on N0 production by macrophages collected from BAA OVA sensitized, asthmatic rats.

FIG. 1.10: Effect of NURE inhalation on structural changes in the airways (airway remodeling) of OAA-sensitized, asthmatic rats.

FIG. 1.11: Effect of NURE on remodeling of the respiratory tract of a rat suffering from asthma; histological morphometry.

FIG. 1.12: Effect of NURE inhalation on T # a production by macrophages collected from BAB OVA sensitized, asthmatic rats.

FIG. 1.13: Mitigation of OAA-induced bronchospasm by Nure inhalation prior to stimulation.

FIG. 1.14: Mitigation of OAA-induced bronchospasm by Nure inhalation after stimulation.

FIG. 2.1: CMPE protects the BCM cells from membrane destruction caused by the combined action of hydrogen peroxide (produced by glucose oxidase = CO) and exogenous phospholipase A2 (RL ₂ ).

FIG. 2.2: CMPE protects the BCM cells from degradation of glycosaminoglycans by hydrogen peroxide (produced by CO).

FIG. 2.3: NURPE protects LE from copper-induced oxidation.

FIG. 3.1: Effect of various lipid conjugates on LB8-induced 1L-8 production.

FIG. 3.2: Effect of NURE on HPP-induced chemokine production.

FIG. 3.3: Effect of NURE on LTA-induced L-8 production.

FIG. 3.4: Effect of NURE on LB8-Induced Expression of 1CAM-1 and E-Selectin.

FIG. 3.5: Effect of NURE on L8-Induced Activation of S-kB in LUMEC.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides lipid conjugates that exhibit a wide range of combinations of cytoprotective pharmacological activity. These compounds can alleviate airway obstruction in asthma, protect mucous tissue in gastrointestinal diseases, suppress immune responses, facilitate skin hypersensitivity reactions, inhibit cell proliferation associated with vascular damage and immune response, and inhibit cell migration associated with vascular disease and central vascular disease. nervous system, weaken oxidative damage to tissue proteins and cell membranes, prevent the spread of viruses, reduce farms potential activity that destroys tissue, and reduce intracellular levels of chemokines and cytokines. Thus, these compounds are useful in the treatment of a variety of disease states including asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease, obstructive respiratory disease, colitis, Crohn’s disease, central nervous system stroke, multiple sclerosis, contact dermatitis, psoriasis, and cardiovascular diseases, invasive medical procedures, aggressive cell proliferative disorders, antioxidant therapy, hemolytic syndromes, sepsis, acute respiratory distress Indra syndromes response to tissue transplants, autoimmune diseases, viral infections and conjunctivitis giperchuvstzitelny.

In one embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

B — Ζ — Υ - Χ

- -Ιη (A) where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and

- 3 012138 η is a number from 1 to 1000, to obtain a composition for the treatment of asthma.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

b — Ζ — Υ - Χ —’p (A) where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the prevention of asthma.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the treatment of allergic rhinitis.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the prevention of allergic rhinitis.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the treatment of chronic obstructive pulmonary disease.

- 4 012138

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the prevention of chronic obstructive pulmonary disease.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for treating a patient suffering from obstructive respiratory disease.

In yet another embodiment, the invention provides the use of a compound represented by the structure of general formula (A):

Where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η is a number from 1 to 1000, to obtain a composition for the prevention of obstructive respiratory disease.

In one embodiment, obstructive respiratory disease is asthma. In yet another embodiment, obstructive respiratory disease is rhinitis. In yet another embodiment, obstructive respiratory disease is allergic rhinitis. In yet another embodiment, the obstructive respiratory disease is a chronic obstructive pulmonary disease. In another embodiment, obstructive respiratory disease is sinusitis.

In one embodiment, X in the general formula (A) is a polysaccharide. In one embodiment, the polysaccharide is carboxymethyl cellulose, while in another embodiment, the polysaccharide is glycosaminoglycan. In one embodiment, the glycosaminoglycan is hyaluronic acid, while in another embodiment, the glycosaminoglycan is heparin. In one embodiment, b in general formula (A) is phosphatidylethanolamine, which in one embodiment is dipalmitoylphosphatidylethanolamine.

In one embodiment, treatment or prophylaxis refers to delaying the onset of symptoms, reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing episodes of disease-related symptoms, reducing

- 5 012138 latent symptoms, mitigation of symptoms, reduction of secondary injuries, reduction of secondary infections, prolonging the life of patients, preventing relapse of the disease, reducing the number or frequency of relapses, increasing the intervals between relapses, increasing the duration of progression, accelerating remission, inducing remission, increasing remission, accelerating recovery or increased effectiveness or decreased resistance to alternative treatment.

In one embodiment, the symptoms are primary, while in another embodiment, the symptoms are secondary. In one embodiment, primary means a symptom resulting from infection by a pathogen, while in another embodiment, secondary means a symptom that is derived or dependent on the primary case.

In one embodiment, the invention provides a method of treating a patient suffering from obstructive respiratory disease, comprising the step of administering to the patient a compound comprising a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer and / or its pharmaceutically acceptable salt or its pharmaceutical product, in an amount effective for treating a patient suffering from obstructive respiratory disease. In yet another embodiment, the invention provides a method of treating a patient suffering from obstructive respiratory disease, comprising the step of administering to the patient any one of the compounds of the invention in an amount effective to treat a patient suffering from obstructive respiratory disease. In another embodiment, the obstructive respiratory disease is asthma.

In one embodiment, the physiologically acceptable monomer is any one of salicylate, salicylic acid, aspirin, monosaccharide, lactobionic acid, maltose, amino acid, glycine, carboxylic acid, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate; or where the physiologically acceptable dimer or oligomer is a dipeptide, disaccharide, trisaccharide, oligopeptide or diyl trisaccharide monomer unit of heparin, heparan sulfate, keratin, keratan sulfate, chondroitin, chondroitin sulfate, dermatin, dermatan sulfate or dermatan sulfate; or wherein the physiologically acceptable polymer is a glycosaminoglycan polizhelin (gematstsel), alginate, hydroxyethyl starch (getastartch), polyethylene glycol, polycarboxylated polyethylene glycol, chondroitin sulfate, keratin, keratin sulfate, heparan sulfate, dermatin, dermatan sulfate, carboxymethylcellulose, heparin, dextran, or hyaluronic acid. In yet another embodiment, the physiologically acceptable polymer is chondroitin sulfate. In yet another embodiment, the chondroitin sulfate is chondroitin-6-sulfate, chondroitin-4 sulfate, or a derivative thereof. In yet another embodiment, the physiologically acceptable polymer is hyaluronic acid.

In one embodiment, the lipid or phospholipid moiety is phosphatidic acid, acylglycerol, monoacylglycerol, diacylglycerol, triacylglycerol, sphingosine, sphingomyelin, chondroitin-phosphate-ylate-ylate-sulfide, yl-phosphate, yl-sulfide, yl-phosphate, yl-phosphate, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-phosphate, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-phosphate, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-phosphate, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfide, yl-sulfate, yl-phosphonylate-ylate-sulfide-ylate-phosphate groups their ether or alkylphospholipid derivatives, and a physiologically acceptable monomeric or polymeric moiety is any of aspirin, lactobionic acid, altozy, glutaric acid, polyethylene glycol, carboxymethylcellulose, heparin, dextran, gematselya, getastarcha or hyaluronic acid. In yet another embodiment, the phosphalipid moiety is phosphatidylethanolamine.

In one embodiment, the obstructive respiratory disease is a violation of the patency of the lumen of the bronchi into the lungs, manifested by respiratory failure, increased respiratory rate (tachypical), or radiological signs of airway obstruction. Obstructive respiratory disease includes asthma, acute pulmonary infections, acute respiratory distress syndrome, chronic obstructive pulmonary disease, rhinitis and allergic rhinitis. In one embodiment, the pathophysiological characteristic features of airflow obstruction correspond to smooth muscle spasm and accumulation of infiltrates in and around the membranes of the airways.

In one embodiment, asthma is a painful process where the bronchi can be narrowed, which is manifested by difficulty breathing. In one embodiment, the symptoms include wheezing, shortness of breath (particularly exhalation), bloating, or a combination thereof. In one embodiment, factors that can exacerbate asthma include rapid changes in temperature or humidity, allergens, upper respiratory tract infections, exercise, stress, smoking (cigarettes), or a combination thereof.

In one embodiment, rhinitis includes inflammation of the nasal mucosa. In one embodiment, allergic rhinitis is an inflammatory response in the nasal

- 6 012138 outlets for an allergic stimulus. In one embodiment, symptoms include nasal congestion, sneezing, nasorrhea, itchy nose, or a combination thereof.

In one embodiment, chronic obstructive pulmonary disease is a progressive pathological process, mostly resulting from smoking. In one embodiment, chronic obstructive pulmonary disease includes difficulty breathing, wheezing, coughing, which may be a chronic cough, or a combination thereof. In one embodiment, chronic obstructive pulmonary disease can lead to complications, which in one embodiment may include bronchitis, pneumonia, lung cancer, or a combination thereof.

Colitis is a chronic disease of the gastrointestinal tract, manifested by discomfort in the abdomen, diarrhea and radiological and histological diagnostics, characteristic signs of mucosal damage include epithelial erosion. Crohn's disease is a similar disorder that typically affects the small intestine, but which may involve other areas of the gastrointestinal tract.

Multiple sclerosis is a white matter disease, manifested by motor weakness or sensory disturbances, or both, usually diagnosed by analysis of cerebrospinal fluid or magnetic resonance imaging. Visual disturbances, including blindness, are also characteristic. In the areas of painful activity, the blood-brain barrier is damaged.

A skin hypersensitivity reaction, otherwise known as contact dermatitis, is manifested by external signs of tissue irritation, such as local redness, swelling, and itching. In fact, some substances can cause this condition, and it is one of the most complaints diagnosed by dermatologists.

Psoriasis is also one of the most dermatological diseases found in 1-2 per thousand people. In most cases, the elbows, knees, gluteal folds and scalp are affected. In active psoriatic lesions (plaques), the frequency of cell divisions is enhanced. Prolonged use of local glucocorticoids is often accompanied by a loss of their effectiveness.

Cardiovascular diseases are manifested by narrowing of the gaps of blood vessels and, as a result, ischemic syndromes in the target organs supplied with them, such as the heart, kidneys and brain. Ischemia, or a decrease in blood delivery, is the result of a narrowing of blood vessels. Signs and symptoms of cardiovascular disease include, but are not limited to, angina pectoris, weakness, respiratory failure, transient ischemic attack, stroke (stroke), and renal failure. Diagnosis is based on clinical signs in combination with auxiliary diagnostic tests, such as blood tests, electrocardiogram, echocardiography and angiography. Atherosclerosis is a common element in cardiovascular diseases in which the narrowing of blood vessels is caused by scar-like plaques formed as a result of reactivity, migration and cell proliferation and as a result of local deposition of fat, cholesterol and lipoproteins. In particular, it is important in this regard, the accumulation of low density lipoproteins (BOB), which can be enhanced by oxidative damage. It is believed that plaques are a site for both acute and chronic stenotic lesions, where the risk of tissue ischemia increases.

Stenotic or narrowing damage to blood vessels appears not only with atherosclerosis, but also with other systemic cardiovascular disorders. Among them are arterial hypertension, vasculitis, including vasculitis associated with organ transplantation, and coagulation disorders. Many of these disorders, in particular hypertension, atherosclerosis, and vasculitis, appear together in some patients.

Reperfusion injury and / or damage due to ischemia / reperfusion refers to tissue damage and initiates necrosis due to the resumption of blood supply to pre-ischemic tissue. This phenomenon is recognized as an important component of ischemic and postischemic types of damage, in particular the brain and heart tissue. One pathophysiological mechanism that prevails in reperfusion is the damaging effect of reactive oxygen species, otherwise known as oxidative damage or free radical damage. Nitric oxide and its radicals are also involved in pathophysiology. The production of these harmful chemical species refers to the local accumulation, adhesion and movement of leukocytes to the site of damage.

Invasive medical interventions, such as arterial or vein catheterization or open surgery, are often associated with tissue ischemia due to damage to blood vessels, as well as reperfusion injury, which can occur during invasive procedures. Thus, the preservation of the effectiveness of blood vessels and the prevention of reperfusion injury are an object of intensive research in medical science. Such procedures performed for diagnostic and therapeutic purposes and adjuvant drugs are generally described for the prevention of complications of damage to blood vessels and restenoses. The formation of such lesions involves many participants, including the coagulation of blood elements,

- 7 012138 blood cells, and structural elements and cells of the wall of a blood vessel. For example, arterial restenosis that occurs after successful balloon angioplasty is often caused by a narrowing of the internal diameter of the artery by proliferation (proliferation) of smooth muscle cells in the area of irritation due to balloon angioplasty. This new stenotic lesion may contain different types of cells, including white blood cells that accumulate at the site of damage due to migration processes and local proliferation. Two events (cell migration and proliferation) almost certainly determine the coordinated interaction of various cytokines, which are probably released earlier by accumulated macrophages at the site of the source of tissue damage. Thus, leukocytes contribute to stenotic damage resulting from migration processes, local proliferation, penetration through endothelial barriers, accumulation of cholesterol-rich lipoproteins, transformation into foam cells and secretion of cytokines. This cell proliferation and narrowing of the lumen of the blood vessel, however, limits or limits the coronary arteries or cerebral circulation. Postoperative restenoses may also appear, for example, in the peripheral vascular system.

In the context of the present invention, the term cardiovascular disease means narrowing of the lumen of blood vessels resulting from atherosclerosis, vasculitis, invasive interventions, in particular artery or vein catheterization, and the ischemic syndromes associated with them.

Transplantation of tissues, grafts and organs is often complicated by the appearance of a host-type transplant and a graft-versus-host syndrome, which can occur acutely or chronically in a transplant recipient. The graft source may be allogeneic (from a similar species) or xenogenic (from another species). Whether these complications are caused by hyperactivity of the immune system or another mechanism, vasculitis remains a common complication of tissue transplant procedures. Moreover, vascular lesions related to reperfusion injuries are considered a major factor in the postoperative failure of tissues and transplanted organs.

Autoimmune diseases are conditions in which a change in a patient’s clinical status refers to a perverted cellular and / or humoral immune response. In the majority, autoimmune diseases in the USA are represented by juvenile diabetes, Hashimoto and Grave thyroiditis, rheumatoid arthritis, Crohn’s disease and ulcerative colitis, chronic active hepatitis, vitaligo, glomerulonephritis, uveitis, multiple sclerosis, scleroderma, myreniopic dermatitis, hemi-myopic dermatitis, hemi-myopic dermatitis, hemi-myopic dermatitis, hemi-myopic leukemia, and hemi-myopic dermatitis systemic lupus erythematosus and pemphigus.

Hyperproliferative cellular disorders, such as cancer, in which cells occur primarily in organs in place or spread from other sources (metastasize), is one of the leading causes of death in the United States. Malignant neoplasms are often highly resistant to all forms of treatment, including powerful antiproliferative drugs and radiation. More and more, the medical community is becoming aware of the critical role that vascularization is associated with the primary and metastatic forms of the disease. Like other cell clusters, cancer cells are dependent on adequate blood supply and in fact, it is known that cancer cells stimulate the process of vascularization through the release of growth factors that affect endothelial cells and smooth muscle cells, forming new blood vessels, thereby ensuring cancer growth.

Metastasis, the spread of cancer cells to ectopic places, is often a vascular dependent process, as it often refers to hematogenous spread.

The physiological barrier, represented by the wall of the blood vessel, includes elements such as endothelial cells and the substance of the basement membrane, normally highly selective for the passage of cells. However, metastasized cells destroy this barrier using a number of mechanisms, some of which are presented in the scientific literature. For example, such abnormal cells produce hydrolytic enzymes that destroy the intercellular substance and the binding components of the vascular barrier, such as collagen, heparinase and hyaluronidase. Thus, a critical factor in the process of metastasis is the ability of cancer cells to penetrate or penetrate the wall of a blood vessel, thus invading new tissue after moving with circulating blood. Cancer cells release chemical mediators, known as cytokines and chemokines, which facilitate the process of metastasis, with the help of many aspects, including angiogenesis.

Cellular release of cytokines and chemokines carries an important regulatory function in maintaining health; however, when a hyperactive response to stress or disease occurs, these compounds can be produced in excess and damage the tissue, thereby giving rise to a painful condition with subsequent deterioration. Cytokine hyperproduction is involved in a large number of diseases, such as sepsis, damage to the respiratory tract and lungs, kidney failure, transplant response, skin lesions, intestinal damage, cancer and metastasis

- 8 012138, central nervous system disorders, vaginal bacterial infections, etc. Two examples in which this occurs are systemic infections, in particular, with the growth of bacteria in the blood (septicemia) and in the pulmonary condition known as acute (or mature) respiratory distress syndrome (ΑΚΌ8). At ΑΚΌ8, the lungs fill with fluid, interfering with gas exchange and causing pulmonary failure. Despite the appearance of platelet aggregation, the main agents that cause a pathological response are monocytic phagocytes and leukocytes, which adhere to the endothelial lining and cause respiratory damage during oxidative damage and release chemokines such as Ogo α, ΕΝΑ-78, CX3X and MCP-1 addition to leukotrienes, thromboxanes and prostaglandins. Monocytic phagocytes, mainly macrophages in the alveoli and in the vascular bed, also release oxidants, mediators and a series of destructive enzymes that directly damage endothelial cells and cause leukocytes to release their lysosomal enzymes. Mortality exceeds 50%. The most common causes of ΑΚΌ8 are infection, aspiration, smoking, and inhalation of toxic substances, as well as systemic processes that began outside the lungs, including bacterial septicemia. Septic syndrome and shock are triggered by the interaction of a number of microbial products in the blood, in particular, gram-negative endotoxins, with the mediator system of the host. There are approximately more than 500,000 cases per year, in which the leading role is played by an increase in the prevalence of antibiotic-resistant organisms. A number of host mediators are involved in the pathogenesis of sepsis and septic shock (referred to generally as sepsis), including factors released from stimulated cells, in particular cytokines, tumor necrosis factor-α (ΤΝΡ), Wow α, ΕΝΑ-78, CX3X and MCP-1, ΝΡκΒ transcription factor, lysosomal enzymes and leukocyte oxidants and metabolic products of arachidonic acid, among others.

Erythrocyte lysis or hemolysis may be a hereditary or acquired disease that causes progressive anemia, iron deficiency, or jaundice. Among the acquired syndromes are membrane anomalies caused by the direct toxic effects of a snakebite or infectious agents, including viral, bacterial and parasitic origin, in particular malaria; exposure to oxidizing substances through ingestion and disease; or as a result of mechanical trauma, abnormal blood vessels. These latter conditions, known as microangiopathic hemolysis, are thought to be similar in mechanism to hemolysis due to the passage of blood through prosthetic implants, such as heart valve prostheses. Hereditary fragility of erythrocyte membranes often appears due to intracellular enzyme or structural defects, such as glucose-6-phosphatase deficiency, sickle cell anemia, and thalassemia. Erythrocyte lysis is one of the limiting factors for the storage time of blood products, in particular with photodynamic virocidal treatments with the formation of free radicals, such as γ-radiation.

Acquired immunodeficiency syndrome is considered a fast-growing global epidemic transmitted through blood products. The transmission and development of this disease is dependent on the infectious activity of the patient's immunodeficiency virus. Therapeutic measures are limited primarily to the administration of transcriptase inhibitors, high-cost drugs and poorly tolerated by patients.

Oxidative damage refers to the effect of peroxidation and the production of free radicals in body tissues. To some extent, the production of peroxides is a normal, physiological process, associated, for example, with the role of immune recognition. However, under stress and in a painful state or during the natural course of time, such as physiological aging, the accumulation of these unstable chemical groups in tissue structures, including membrane components and blood proteins, leads to irreversible damage. Substances with antioxidant effects can protect against oxidative damage. Such protection has been the subject of many scientific publications.

Diseases caused by intracellular bacterial parasites are one of the predominant forms of sexually transmitted diseases and often not respond to traditional antibiotic therapy. A vaginal infection of syATufa 5pcc1c5 is a prime example.

In one embodiment, the present invention provides methods of treating diseases based on the administration of lipids covalently linked through their polar head groups to physiologically acceptable chemical groups, which may have a high or low molecular weight.

In one embodiment, lipid compounds (lipid conjugates) of the present invention are described by the general formula:

- 9 012138 [phosphatidylethanolamine-Υ] η-Χ [phosphatidylserine-Υ] η-Χ [phosphatidylcholine-Υ] η-Χ [phosphatidylinositol-Υ] η-Χ [phosphatidylglycerol-Υ] η-Χ acid -Χ [lysophospholipid-Υ] η-Χ [diacyl-glycerol-Υ] η-Χ [monoacyl-glycerol-Υ] η-Χ [sphingomyelin-Υ] η-Χ [sphingosine-Υ] η-Χ [ceramide-Υ ] η-Χ where

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer; and η, the number of lipid molecules bound to X is a number from 1 to 1000.

In one embodiment, η is a number from 1 to 1000. In another embodiment, η is a number from 1 to 500. In another embodiment, η is a number from 1 to 100. In another embodiment, η is a number from 100 to 300. In another embodiment, η is a number from 300 to 500. In another embodiment, η is a number from 500 to 800.

In one embodiment, the lipid compounds of this invention, known herein as lipid conjugates (lipid conjugates), discovered to date, have numerous and potent pharmacological effects in addition to their ability to inhibit the extracellular form of the phospholipase A2 enzyme. A set of compounds containing phosphatidylethanolamine covalently linked to a physiologically acceptable monomer or polymer is referred to herein as PE conjugates. Related derivatives, among which phosphatidylserine, phosphatidylcholine, phosphatidylinositol, phosphatidic acid or phosphatidylglycerol are used as a lipid fragment instead of phosphatidyl ethanolamine, provide an equivalent therapeutic result based on the biological experiments described below for lipid conjugates and structural similarities. Other derivatives of lipid conjugates related to this invention are lipid conjugates in which at least one of the fatty acid groups of the lipid moieties at the C1 or C2 positions of the glycerol base is replaced by long chain alkyl groups linked by either an ether or alkyl bond rather than an ester bond .

As shown by the structural formula of the lipid conjugates presented here, these compounds may contain from one to one thousand lipid moieties linked to one physiologically acceptable polymer molecule.

The introduction of lipid conjugates into a variety of animal and cellular models of diseases causes significant and unexpected cytoprotective effects that are used in the treatment of diseases. They are able to stabilize cell membranes; inhibit cell proliferation; suppress the production of free radicals; suppress nitric oxide production; reduce cell migration through biological barriers; to influence the level of chemokines, including MCP-1, ΕΝΑ-78, Wow α and CX3X; manifestations of gene transcription and modification of the expression of MHC antigens; strengthen directly the cell membranes and change the water structure of the cell surface; inhibit the absorption of oxidized lipoproteins; prevent spasm of smooth muscles of the respiratory tract; inhibit the release of neurotransmitters; reduce the expression of tumor necrosis factor-α (ΤΝΡ-α); modify the expression of transcription factors, such as ΝΡκΒ; suppress extracellular destructive enzymes, including collagenase, heparinase, hyaluronidase in addition to PBA2; and suppress leukocyte viral infection. Thus, lipid conjugates provide long-lasting cytoprotective effects on an organism suffering from diseases, where one or more pathophysiological mechanisms of cell damage cause an oxidative shock, causing an increase in membrane fragility; hyperproliferation of cells, causing an increase in the formation of stenotic plaques in the vascular tissue, angiogenesis and the onset or malignancy of cancer, or psoriasis; altered cell migration, causing the growth of brain damage or metastasis of tumor cells; excessive production of chemokines and cytokines associated with central nervous system strokes (С№), sepsis, ΑΚΌ8 or immunological

- 10 012138 diseases; damage to the cell membrane causing an increase in ΟΝ8 strokes, SU8 disease or hemolysis; peroxidation of blood proteins and cell membranes, causing atherosclerosis or reperfusion injury; excessive production of nitric oxide, causing an increase in ΟΝ8 strokes, reperfusion injury and septic shock; interaction with major histotropic antigens (MHCs) is associated with autoimmune diseases and alloimmune syndromes, such as transplant rejection.

In one embodiment of the present invention, the beneficial pharmacological properties of lipids or lipid conjugates may be acceptable for clinical use and are described herein as methods of treating diseases. The biological basis of these methods can be easily demonstrated using standard cellular and animal disease models, as described below.

While the pharmacological activity of the lipid conjugates described here may be due to the nature of the lipid fragment, the numerous and diverse combinations of pharmacological characteristics observed for lipid conjugates show the ability of the structures of the compounds to essentially act as several different drugs in the same chemical group. Thus, for example, internal damage to the mucous membranes that occurs with colitis or Crohn's disease can be attenuated by any one or all of the pharmacological activities, such as immune suppression, anti-inflammatory effect, antioxidant effect, suppression of nitric oxide production or stabilization of membranes. Protection of blood vessels from intraluminal damage that can occur with atherosclerosis can be caused by the action of antiproliferative, antichemokine, antioxidant, or anti-migration effects. The treatment of asthma, allergic rhinitis, chronic obstructive pulmonary disease or obstructive respiratory disease may include any of the many effects of lipid conjugates, leading to inhibition of the production of nitric oxide, antichemokine, antiproliferative or membrane stabilizing effects.

Vascular tissue proliferation is an element of both atherogenesis of sclerotic plaques and a sign of primary or metastatic growth of cancerous lesions. Stabilization of biological membranes can prevent hemolysis, as well as damage to the intestinal mucosa. Decreased chemokine levels can weaken ΆΚΌ8, as well as inhibit atherogenesis. Antioxidant protective activity can protect against reperfusion injury and ischemia / reperfusion, as well as central nervous system stroke, atherosclerosis, and hemolysis. These and other advantages of the present invention will be apparent to those skilled in the art from the following description.

The use of one chemical object with strong antioxidant, membrane-stabilizing, antiproliferative, anti-chemokine, anti-immigration and anti-inflammatory activity leads to an increase in cytoprotection similar to that of several different substances, each of which has such activity. The use of a single agent having multiple actions, in comparison with a combination or many different agents leads to a single delivery of the active molecule, thereby simplifying drug metabolism, reducing toxicity and simplifying delivery. The compounds of the present invention also exhibit properties that are present only in the combined molecule, but not in the individual components.

In one embodiment, the compounds of the invention can be used for the acute treatment of transient conditions or can be administered chronically, especially in the case of progressive, recurrent or degenerative diseases. In one embodiment of the present invention, the concentrations of the compounds will depend on various factors, including the nature of the condition being treated, the condition of the patient, route of administration, and individual tolerance of the compositions.

In another embodiment of the invention, the invention provides low molecular weight lipid conjugates, previously not discovered and not known, having pharmacological activity, of the general formula:

- 11 012138 [phosphatidylethanolamine-Υ] η-Χ [phosphatidylserine-Υ] η-Χ [phosphatidylcholine-Υ] η-Χ [phosphatidylinositol-Υΐη-Χ [phosphatidylglycerol-Υ] η-Χ фосф ат η acid [lysophospholipid-Υ] η-Χ [diacylglycerol-Ύ] η-Χ [monoacylglycerol-Υ] η-Χ [sphingomyelin-Υ] η-Χ [sphingosine-Υ] η-Χ [ceramide-Υ] η-Χ

Υ either absent or a spacer group having a length in the range of 2-30 atoms; and

X is salicylate, salicylic acid, aspirin, monosaccharide, lactobionic acid, maltose, amino acid, glycine, carboxylic acid, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid, dide cholic acid, cholesteryl gemmisuccinate, dipeptide, disaccharide, trisaccharide, oligosaccharide, oligopeptide or di- or trisaccharide monomeric unit of heparin, heparan sulfate, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, dermatin, dermatan sulfate, dextran, or hyaluronic acid, glycosaminoglycan, polygelatin (hemestsel), alginate, hydroxyethyl starch (getastarch), polyethylene glycol polyethylene glycol polyethylene glycol chondroitin-4-sulfate, keratin, keratin sulfate, heparan sulfate, dermatin, dermatan sulfate, carboxymethyl cellulose, heparin, dextran or hyaluronic acid; and n, the number of lipid molecules corresponding to X is a number from 1 to 1000.

In one embodiment of the present invention, n is a number from 1 to 1000. In another embodiment, n is a number from 1 to 500. In yet another embodiment, n is a number from 1 to 100. In yet another embodiment, n is a number from 100 up to 300. In yet another embodiment, n is a number from 300 to 500. In yet another embodiment, n is a number from 500 to 800.

In yet another embodiment of the invention, these lipid conjugate derivatives have a wide spectrum of pharmaceutical activity and, as pharmaceuticals administered in the treatment of diseases, are considered similar to lipid conjugates containing high molecular weight polymers. Other lipid conjugate derivatives of the present invention are glycerol-lipid moieties in which at least one of the two long chain alkyl groups at the C1 and C2 positions of the glycerol base is linked by an ether linkage or an alkyl linkage, rather than an ester linkage.

The present invention is further illustrated in the following examples of therapeutic compounds of lipid conjugates, their chemical preparation, their activity against diseases and methods of use as pharmacological compositions in the treatment of diseases.

Connections

In methods according to embodiments of the invention, the lipid conjugates administered to a patient comprise at least one lipid moiety covalently linked through a polar head atom to a monomeric or polymeric moiety (referred to herein as a conjugated moiety) of low or high molecular weight. Optionally, an optional linking group can be used to link the lipid-conjugated fragment to the monomeric or polymeric part. The conjugated moiety may be a low molecular weight carboxylic acid, a dicarboxylic acid, a fatty acid, a dicarboxylic fatty acid, acetylsalicylic acid, cholic acid, cholesteryl gemmisuccinate or a mono- or disaccharide, an amino acid or dipeptide, an oligopeptide, a mixture of tri-glycerides or di-glycerides, or such as repeating units of heparin, heparan sulfate, hyaluronic acid, chondroitin sulfate, dermatan, keratan sulfate or peptides Oka molecular weight or oligopeptide, polysaccharide poliglikana protein, glycosaminoglycans or mixture of glycoproteins. In a compositional aspect, high molecular weight phospholipid conjugates and related analogs are the subject of US Pat. No. 5,064,817, as well as the publications cited here.

In one embodiment of the invention, when the fragment of the conjugated carrier is a polymer, the ratio of covalently linked lipid fragments may be from one to

- 12 012138 one thousand lipid residues per polymer molecule, depending on the nature of the polymer and the reaction conditions used. For example, the relative amounts of starting materials or the length of the reaction time can be modified in order to obtain lipid-conjugated products with a high or low ratio of lipid residues to the polymer, as desired.

The term fragment refers to a chemical substance, otherwise corresponding to a chemical compound that has a valency corresponding to a covalent bond.

Examples of polymers that can be used as conjugated fragments for preparing lipid conjugates for use in the methods of this invention are physiologically acceptable polymers, including water-dispersible or soluble polymers of various molecular weights and various chemical species, mainly natural or synthetic polymers such as glycosaminoglycans, hyaluronic acid, heparin, heparin sulfate, chondroitin sulfate, chondroitin-6-sulfate, chondroitin-4-sulfate, kera tinsulfate, dermatinsulfate, plasma expanders including polyheline (Naetace1, a broken gelatin polypeptide crosslinked through urea bridges produced by Weipid), hydroxyethyl starch (He1ac1agsy, HE8) and extranes, food and medicinal celluloses, cellulose, carbohydrates, cellulose, carbohydrates, cellulose, carbohydrates, cellulose, ), polyamino acids, hydrocarbon polymers (e.g. polyethylene), polystyrenes, polyesters, polyamides, polyethylene oxides (e.g. polyethylene glycols, polycarboxyethylene glycol), gender vinylpyrrolidones, polysaccharides, alginates, assimilable gums (e.g., xanthan gum), peptides, injectable blood proteins (e.g., serum albumin), cyclodextrin, and derivatives thereof.

Examples of monomers, dimers and oligomers that can be used as conjugated fragments to produce lipid conjugates used in the methods of this invention can be mono- or disaccharides, carboxylic acid, dicarboxylic acid, fatty acid, dicarboxylic fatty acid, acetylsalicylic acid, cholic acid, cholesteryl gemmisuccinate and di- and trisaccharide monomer units of glycosaminoglycans, including heparin, heparan sulfate, hyaluronic acid, chondroitin, chondroitin-6-sulfate, hond oitin-4-sulfate, dermatin, dermatan sulfate, keratin, keratan sulfate or dextran.

In some cases, according to embodiments of the present invention, the monomers or polymers selected to produce lipid conjugates may themselves have selective biological activity. For example, heparin and hyaluronic acid are substances with a studied physiological effect. In the present invention, however, lipid conjugates formed from these substances as starting materials exhibit new and broader pharmaceutical activities than those that could be predicted from the administration of either heparin or hyaluronic acid that are not linked via a covalent bond phospholipids. It can be shown by standard comparative experiments, such as those described below, that phosphatidylethanolamine (PE) associated with carboxymethyl cellulose (referred to as CMPE, SMS-Reog CME), with hyaluronic acid (referred to as ΗΥΡΕ, NURE, Nua1-PE), heparin (denoted NERRE, NerRE, NERRE, NeraRE), with chondroitin sulfate A (denoted as C8APE, SkARE, SCARE), with polyheline (hemazzel) (denoted by NetRE, NEMPE) or with hydroxyethyl starch (denoted as NECRE, HEPPE) exceeds the range of activity values and in terms of activity climbed oh pharmacological activity of the free conjugates (polymers mentioned above, and the like). In fact, these latter substances are generally not considered useful in the methods of treating most of the diseases described here, and for special cases where their use is prescribed medically, such as ischemic vascular diseases, their concentration for use as a medicine is several orders of magnitude higher . Thus, the combination of a phospholipid, such as phosphatidylethanolamine or related phospholipids, which differ with respect to the polar head group, such as phosphatidylserine (P8), phosphatidylcholine (PC), phosphatidylinositol (P1) and phosphatidylglycerol (PC), leads to the creation of compounds with new pharmacological properties compared to the starting materials themselves.

The biologically active lipid conjugates described herein can have a wide range of molecular weights, for example, above 50,000 (up to several hundred thousand) when it is desired to retain lipid conjugates in the vascular system, and below 50,000 when it is desired to make the extravascular system a target. The only restriction on the molecular weight and chemical structure of the conjugated fragment is that it does not lead to a lipid conjugate lacking the desired biological activity, or does not lead to chemical or physiological instability to such an extent that the lipid conjugates are not used, like the drugs described here method of application.

In one embodiment, a compound in accordance with the invention is represented by the structure of general formula (A):

- 13 012138

(And where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000, where any bond between b, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (I):

Where

B ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K. ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Υ either absent or a spacer group having a length in the range of 2-30 atoms; and

X is either a physiologically acceptable monomer, dimer, oligomer or physiologically acceptable polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000, where, if Υ is absent, phosphatidylethanolamine is directly linked to X via an amide bond and, if Υ is a spacer, the spacer is directly linked to X via an amide or ester bond and to phosphatidylethanolamine via an amide bond.

Preferred compounds for use in the methods of the invention include one of the following as a conjugated fragment X: acetate, butyrate, glutarate, succinate, dodecanoate, diddecanoate, maltose, lactobionic acid, dextran, alginate, aspirin, cholate, cholesteryl hemmisuccinate, carboxy, hyaluronic acid, polyheline (hemazel), polyethylene glycol and polycarboxylated polyethylene glycol. The polymers used as starting materials for the production of PE conjugates can vary in molecular weight from 1 to 2000 kDa.

Examples of phosphatidylethanolamine (PE) fragments are analogs of a phospholipid in which a chain of two fatty acid groups is linked to the glycerol base of a phospholipid, of 2-30 carbon atoms in length, and in which these chains of fatty acids contain saturated and / or unsaturated carbon atoms. Instead of fatty acid chains, alkyl chains attached directly or via an ether linkage to the glycerol skeleton of a phospholipid are included in the present invention as PE analogues. According to the present invention, the most preferred PE moiety is dipalmitoylphosphatidylethanolamine.

Phosphatidylethanolamine and its analogs may be from various sources, including natural, synthetic and semi-synthetic derivatives and their isomers.

Phospholipids that can be used in place of the PE fragment are Ν-methylPE derivatives and their analogs linked by covalent bonding through the amino group of Ν-methyl-PE; Ν, Ν-dimethyl-PE derivatives and their analogues linked by covalent bonding through the amino group Ν, Ν-dimethyl-PE, phosphatidylserine (P8) and its analogues, such as palmitoyl stearoyl-P8, natural P8 from various sources, semi-synthetic P8, synthetic, natural and artificial P8 and their isomers. Other phospholipids suitable as conjugated fragments in this invention are phosphatidylcholine (RS), phosphatidylinositol (P1), phosphatidic acid and phosphatidylglycerol (RS), as well as their derivatives, including other phospholipids, lysophospholipids, phosphatidic acid, sphingomyomyelin, lysosphomyelielin, lysosphomyelielin, sphingosine.

For PE conjugates and P8 conjugates, a phospholipid is associated with conjugated monomeric

- 14 012138 or by polymer fragments through a nitrogen atom of a phospholipid head polar group, directly or through a spacer group. For RS, ΡΙ, and RS, a phospholipid is bound to conjugated monomeric or polymeric fragments via a nitrogen atom or one of the oxygen atoms of the head polar group directly or via a spacer group.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (II):

⁰ V

1C — c ^ -o — s-n

I _L

Kt — s — o — s-n o ό n-s-o-D n ό

Υ - Χ (Π) where

Κι is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Υ either absent or a spacer group having a length in the range of 2-30 atoms; and

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where, if Υ is absent, phosphatidylserine is directly bonded to X via an amide bond, and if Υ represents a spacer, the spacer group is directly bonded to X via an amide or ester linkage and bound to phosphatidylserine via an amide bond.

In yet another embodiment, the compound of the invention is | phosphatidylserine-U | p-X. where Υ is either absent or a spacer group having a length in the range of 2-30 atoms, X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan and η is a number from 1 to 1000, where phosphatidylserine can be associated with Υ or X, if Υ is absent, through the COO fragment of phosphatidylserine.

In another embodiment, the compound in accordance with the invention is represented by the structure of General formula (III):

(W) where

Κ ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ is either absent or is inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms; and

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between phosphatidyl, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (IV):

- 15 012138

αν) where

Κι is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-3 0 atoms; and

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In another embodiment, a compound in a round of general formula (V):

in accordance with the invention presents STRUCTURE II P O ’(V) where

K1 is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K2 is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms; and

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (VI):

О Н-С-0-Ρ-Ο-Ζ-Υ- Χ (UT) where

K ₁ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

- 16 012138

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In another embodiment, a compound in a round of general formula (VII):

in accordance with the invention presents structure (VII) where

B ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K. ₂ is either hydrogen, or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In one embodiment, conjugates of phosphatidylcholine (RS), phosphatidylinositol (P1), phosphatidic acid (RA), where Ζ is absent, and phosphatidylglycerol (RS) are defined in this invention as compounds of general formula (III).

In one embodiment of the present invention, Υ is absent. Non-limiting examples of suitable divalent groups forming an optional binding group (spacer) в, in accordance with embodiments of the invention, are a straight or branched chain alkylene, for example, of 2 or more, preferably 4-30 carbon atoms, -CO-alkylene-CO , -HH-alkylene-HH-, -CO-alkylene-HH-, -HH-alkylene-MHCO-alkylene-HH-, amino acid, cycloalkylene, where the alkylene in each example is straight or branched chain and contains 2 or more, preferably 2-30 carbon atoms in the chain, - (- О-СН ( H ₃₎ CH ₂ -) _x where x is an integer of 1 or more.

According to embodiments of the invention, in addition to the conventional phospholipid structure, similar derivatives for use in this invention are phospholipids modified at positions C1 or C2 to contain an ether or alkyl bond instead of an ester bond. In one embodiment, alkyl phospholipid derivatives and ether-based phospholipid derivatives are provided as illustrative examples.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (VIII):

N-s-Ο-Ρ-Ο-Ζ-Υ’-Χ (USH)

- 17 012138 where

Κι is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In another embodiment, a compound in a round of general formula (IX):

in accordance with the invention presents structural-C-O-P-O- Ζ— Υ · - X (IX) where

K1 is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K2 is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of general formula (1X3):

(Ka) where

K1 is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K2 is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of general formula (1X0):

- 18 012138

(B) where

K ₁ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (X):

Where

K ₁ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between phosphorylceramide, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XI):

N

I k.1 - s-he

H-C-ΝΗ-Υ • X o

but-s-n (XI) where

Κι is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ absent;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

- 19 012138 where, if Υ is absent, then sphingosyl is directly linked to X via an amide bond, and if Υ represents a spacer, the spacer group is directly linked to X and to sphingosyl via an amide bond, and to X via an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XII):

—'P (HP) where

K ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B is ceramide;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between ceramide, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XIII):

Is he

II I

Y1 - s-o-s-n & 2-S-O-S-N

II I,

About H-C-0-Ζ-Υ-Χ

I n

- “p (xx) where

TO; is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between diglycyril, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XIV):

Where

TO; is either hydrogen, or linear, saturated, monounsaturated, or poly

- 20 012138 a fixed alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the glycerolipid, Ζ, Υ and X is either an amide or an ester bond.

In another embodiment, the compound of the invention is represented by the structure of general formula (XV):

Where

K ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ is absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the glycerolipid, Ζ, Υ and X is either an amide or an ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XVI):

Where

K ₁ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound of the invention is represented by the structure of general formula (XVII):

- 21 012138

(Xvii) where

Κι is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound of the invention is represented by the structure of general formula (XVIII):

Where

Κι is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ2 is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either an amide or ester bond.

In another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XIX):

N

I

B.1— CH

I st ₂ - С-Н

H-C-0-Ζ-Υ-Χ

I with n-Ts (XIX) where

Κ ₁ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ2 is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and

- 22 012138 η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XX):

H I st.] - О-С-Н

K.2 — CH!

H-C-0-Ζ-Υ-Χ

I

B n’h (XX) where

Κι is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ ₂ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Y and X is either an amide or ester bond.

In yet another embodiment, the compound in accordance with the invention is represented by the structure of General formula (XXI):

Where

Κ ₁ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ ₂ is either hydrogen or a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ is absent or represents choline, phosphate, inositol or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either an amide or ester bond.

In one embodiment of the present invention, the glycosaminoglycan may be, inter alia, hyaluronic acid, heparin, heparan sulfate, chondroitin sulfate, keratin, keratan sulfate, dermatan sulfate or derivatives thereof.

In yet another embodiment, the glycosaminoglycan is a di- and trisaccharide unit of glycosaminoglycone monomers. In another embodiment, the chondroitin sulfate may be, inter alia, chondroitin-6-sulfate, chondroitin-4-sulfate, or a derivative thereof.

In one embodiment of the invention, glycosamine glycan sugar rings are intact. In another embodiment, the intact relates to closed. In another embodiment of the invention, intact refers to natural. In another embodiment of the invention, intact refers to non-destroyed.

In one embodiment of the present invention, the structure of the lipid or phospholipid in any compound of the invention is intact. In another embodiment, the natural structure of the lipid or phospholipid in any compound of the invention is preserved.

- 23 012138

In one embodiment of the invention, the compounds of the invention are biodegradable.

In one embodiment, the compound in accordance with the invention is represented by the structure of General formula (A):

b — Ζ — Υ - Χ (A) where

B is phosphatidyl;

Ζ is ethanolamine, where b and Ζ are chemically bonded, resulting in phosphatidylethanolamine; Υ absent;

X is hyaluronic acid; and η is a number from 1 to 1000; where any connection between phosphatidylethanolamine and hyaluronic acid is amide.

In one embodiment, the compound in accordance with the invention is represented by the structure of General formula (A):

(And where

B is phosphatidyl;

Ζ is ethanolamine, where b and Ζ are chemically bonded, resulting in phosphatidylethanolamine;

Υ absent;

X is chondroitin sulfate; and η is a number from 1 to 1000;

where any connection between phosphatidylethanolamine and chondroitin sulfate is amide.

In yet another embodiment, the invention provides a method of treating a patient suffering from asthma, comprising the step of administering to the patient any of the compounds of the invention, or a combination thereof, in an amount effective to treat a patient suffering from asthma. In another embodiment, the compounds of the invention include, but are not limited to, compounds represented by structures of general formulas: (A), (I), (II), (III), (1U), (Y), (U1), ( Y11), (USH), (IX), (Ka), (Kb), (X), (XI), (XII), (XIII), (ХЖ, (ХУ), (ХУ), (ХУП), (HUSH), (XIX), (XX), (XXI), (XXII), or any combination thereof, In yet another embodiment, the invention provides a method for preventing asthma in a patient.

In yet another embodiment, the invention provides a method of treating a patient suffering from rhinitis, comprising the step of administering to the patient any of the compounds of the invention, or a combination thereof, in an amount effective to treat a patient suffering from rhinitis. In yet another embodiment, the compounds of the invention include, but are not limited to, compounds represented by structures of general formulas: (A), (I), (II), (III), CB), (Y), (U), (UP), (USh), (IX), (Ka), (Kb), (X), (XI), (XII), (XIII), (ХЖ, (ХУ), (ХУ!), (ХУЛ ), (HUSH), (XIX), (XX), (XXI), (XXII), or any combination thereof .. In yet another embodiment, the invention provides a method for the prevention of rhinitis in a patient.

In yet another embodiment, the invention provides a method of treating a patient suffering from allergic rhinitis, comprising the step of administering to the patient any of the compounds of the invention, or a combination thereof, in an amount effective to treat a patient suffering from allergic rhinitis. In yet another embodiment, the compounds of the invention include, but are not limited to, compounds represented by structures of general formulas: (A), (I), (II), (III), (G (Y), (UT), (UP ), (УШ), (IX), (Ка), (КЬ), (X), (XI), (XII), (XIII), (ХЖ, (ХУ), (ХУЦ (ХУП), (ХУШ) , (XIX), (XX), (XXI), (XXII), or any combination thereof, In yet another embodiment, the invention provides a method for the prevention of allergic rhinitis in a patient.

In yet another embodiment, the invention provides a method of treating a patient,

- 24 012138 giving chronic obstructive pulmonary disease, comprising the step of administering to the patient any of the compounds of the invention, or a combination thereof, in an amount effective to treat a patient suffering from chronic obstructive pulmonary disease. In yet another embodiment, the compounds of the invention include, but are not limited to, compounds represented by structures of general formulas: (A), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Sha), (ΣΧΒ), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII ), (XVIII), (XIX), (XX), (XXI), (XXII) or any combination thereof. In yet another embodiment, the invention provides a method for preventing a patient with chronic obstructive pulmonary disease.

In yet another embodiment, the invention provides a method of treating a patient suffering from obstructive respiratory disease, comprising the step of administering to the patient any of the compounds of the invention, or a combination thereof, in an amount effective to treat a patient suffering from obstructive respiratory disease. In yet another embodiment, the compounds of the invention include, but are not limited to, compounds represented by structures of general formulas: (A), (I), (II), (III), (IV), (V), (VI) , (VII), (VIII), (IX), (Sha), (Kb), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), ( XVII), (XVIII), (XIX), (XX), (XXI), (XXII) or any combination thereof. In yet another embodiment, the obstructive respiratory disease is asthma. In yet another embodiment, obstructive respiratory disease is rhinitis. In yet another embodiment, the obstructive respiratory disease is allergic rhinitis. In yet another embodiment, the obstructive respiratory disease is a chronic obstructive pulmonary disease. In yet another embodiment, the invention provides a method for preventing asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease, obstructive respiratory disease, or combinations thereof in a patient.

Illustrative examples of preferred lipid conjugates for use in the methods of the embodiments of this invention are those in which lipid / phospholipid moieties are linked directly or indirectly through the linker moieties listed below.

- 25 012138

Phospholipid Spacer Polymer (m.m.) Abbreviation RE Dicarboxylic Acid + Diamine Polyheline (hemazel) (4-40 kDa) NEMRE; NetRE RE not Carboxymethyl cellulose (20-500 kDa) SMRE; SMS-RE RE not Hyaluronic acid (2-2000 kDa) ΗΥΡΕ (Nure) RE Dipalmitoya acid Hyaluronic acid (2-2000 kDa) ΗΥΡΕ- dipalmitoyl RE not Polyethylene glycol RE Υ Hydroxyethyl starch NEVER; Nezre RE Dicarboxylic Acid + Diamine Dextran (1-2000 kDa) £> exp RE not Dextran (1-2000 kDa) ϋβχΡΕ RE not Albumen RE not Alginate (2-2000 kDa) RE not Polyamino acid RE not Lactobionic acid RE not Aceti lsalits and lat RE not Cholesteryl gemmisuccinate RE not Maltose RE Υ not Cholic acid RE not Polycarboxylated floor ethylene glycol RE not Heparin (0.5-1 YukDa) NERRE; HEPE; Nerre Dimyristoyl- RE Υ various ϋΜΡΕ Dimyristoyl- RE Υ Hyaluronic acid NURMRE RZ Υ Half-gel (hemazel) RZ Υ Heparin RZ Υ Hyaluronic acid RS Υ Polyheline (hemazel) RS Υ Heparin RS Υ G haluronic acid ΡΙ Υ Polyheline (hemazel) ΡΙ Υ Heparin ΡΙ Υ Hyaluronic acid RS Υ Polyheline (hemazel) RS Υ G eparin RE Υ Chondroitin sulfate C8RE RE Υ Polyheline (hemazel) RS Υ Hyaluronic acid

In one embodiment, the compounds administered are NURE, C8LRE, CMPE, NetRE, NeZRE, EsxRE. Lz-PE and pharmaceutically acceptable salts thereof in combination with physiologically acceptable carriers or solvents. These polymers, if selected as conjugated fragments, can vary in molecular weight from 200 to 2,000,000 Da. Representatives of different molecular weights exhibit the desired biological effect, as shown in the section below.

- 26 012138

In addition to the compounds of the examples, further illustration of the compounds of this invention is presented in the section below.

New connections

Low molecular weight lipid conjugates in which the conjugated portion is a monomer, such as salicylate, bile acid or cholesteryl gemmisuccinate, or a di- or trisaccharide monomeric unit of polyglycosaminoglycan, such as heparin, heparan sulfate, chondroitin-6 sulfate, chondroitonic acid, 4-chondroitin, keratin, keratan sulfate, dermatin or dermatan sulfate have not been described previously. In accordance with embodiments of the invention, these new compounds exhibit a similar biological activity profile, as demonstrated below for other lipid conjugates, and have the general formula:

[phosphoatidylethanolamine-U] p-X [phosphatidylserin-U] p-X [phosphatidylcholine-Υ] p-X [phosphatidylinositol-U] p-X [phosphatidylglycerol-Υ] p-X [phosphatidic acid-Υ] p-X [ lysophospholipid-Υ] p-X [diadyl-glycerin-U] p-X [monoacyl-glycerol-Υ] p-X [sphingomyelin-U] p-X [sphingosine-Υ] p-X [ceramide-Υ] p-x where

Υ either absent or represents a spacer group, with a length in the range of 2-30 atoms;

X is a mono- or disaccharide, carboxylated disaccharide, mono- and dicarboxylic acids, salicylate, salicylic acid, aspirin, lactobionic acid, maltose, amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, di- or tripeptide, oligopeptide, trisaccharide, or di- or trisaccharide monomer unit of heparin, hep ansulfata, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, leatherette, dermatan sulfate, dextran, or hyaluronic acid; and η is the number of molecules of lipid fragments associated with the molecule of group X, where η represents a number from 1 to 1000.

In one embodiment of the present invention, low molecular weight phosphatidylethanolamine (PE) conjugates are defined above as compounds of formula (I), wherein:

B ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a mono- or disaccharide, carboxylated disaccharide, mono- and dicarboxylic acids, salicylate, salicylic acid, aspirin, lactic acid, maltose, amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, di- or tripeptide, oligopeptide, trisaccharide, or heparin di- or trisaccharide monomer unit, heparanza fata, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, leatherette, dermatan sulfate, dextran, or hyaluronic acid; and η is the number of molecules of lipid fragments associated with the molecule of group X, where η represents a number from 1 to 1000.

In one embodiment of the present invention, low molecular weight phosphatidylserine (P8) conjugates are defined above as a compound of formula (II), wherein:

IN! is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2 to 30 carbon atoms;

- 27 012138

Υ is absent or is a spacer group having a length in the range from 2 to 30 atoms;

X is a mono- or disaccharide, carboxylated disaccharide, mono- and dicarboxylic acids, salicylate, salicylic acid, aspirin, lactobionic acid, maltose, amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, di- or tripeptide, oligopeptide, trisaccharide, or di- or trisaccharide monomer unit of heparin, hep ansulfata, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, leatherette, dermatan sulfate, dextran, or hyaluronic acid; and η is the number of molecules of lipid fragments associated with the molecule of group X, where η represents a number from 1 to 1000.

In one embodiment of the present invention, phosphatidylcholine (PC), phosphatidylinositol (P1) and phosphatidylglycerol (PC) conjugates are defined above as compounds of formula (III), wherein

IN! is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range from 2 to 30 carbon atoms;

B ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2 to 30 carbon atoms;

Ζ is absent or represents inositol, choline or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a mono- or disaccharide, carboxylated disaccharide, mono- and dicarboxylic acids, salicylate, salicylic acid, aspirin, lactobionic acid, maltose, amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, di- or tripeptide, oligopeptide, trisaccharide, or di- or trisaccharide monomer unit of heparin, hep ansulfata, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, leatherette, dermatan sulfate, dextran, or hyaluronic acid; and η is the number of molecules of lipid fragments associated with the molecule of group X, where η is a number from 1 to 1000.

Examples of suitable divalent groups forming an optionally binding group Υ are a straight or branched chain alkylene, for example of 2 or more, preferably 4-18 carbon atoms, -CO-alkylene-CO, 4H-alkylene 4H-, -CO-alkylene- ΝΗ-, cycloalkylene, where the alkylene in each example is straight or branched chain and contains 2 or more, preferably 2-18 carbon atoms in the chain, - (-O-CH (CH ₃ ) CH ₂ -) _X , where x is an integer number from 1 or more.

In yet another embodiment, in addition to the conventional phospholipid structures, similar derivatives for use in this invention are phospholipids modified at the C1 or C2 positions so as to contain an ester or alkyl bond instead of an ester bond. These derivatives are given as examples here above by the general formulas (VIII) and (IX), where

B1 is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range from 2 to 30 carbon atoms;

B2 is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range from 2 to 30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ is absent or is a spacer group having a length in the range from 2 to 30 atoms;

X is a mono- or disaccharide, carboxylated disaccharide, mono- and dicarboxylic acids, salicylate, salicylic acid, aspirin, lactobionic acid, maltose, amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, di- or tripeptide, oligopeptide, trisaccharide, or di- or trisaccharide monomer unit of heparin, hep ansulfata, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, leatherette, dermatan sulfate, dextran, or hyaluronic acid; and η is the number of molecules of lipid fragments associated with the molecule of group X, where η is a number from 1 to 1000.

In yet another embodiment, similar low molecular weight derivatives for use in this invention are given as examples of general formulas (X), (XI) and (XII), where

B ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2 to 30 carbon atoms;

B2 is a linear, saturated, monounsaturated or polyunsaturated alkyl chain,

- 28 012138 having a length in the range from 2 to 30 carbon atoms;

Ζ is absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ is absent or is a spacer group having a length in the range of 2-30 atoms;

X is a mono- or disaccharide, carboxylated disaccharide, mono- or dicarboxylic acids, salicylate, salicylic acid, aspirin, lactobionic acid, maltose, amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, di- or tripeptide, oligopeptide, trisaccharide, or heparin di- or trisaccharide monomer unit, he aransulfata, keratin, keratin, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, leatherette, dermatan sulfate, dextran, or hyaluronic acid; and η is the number of molecules of lipid fragments associated with the molecule of group X, where η is a number from 1 to 1000.

In another embodiment, similar low molecular weight derivatives for use in this invention are given as examples of general formula (XIII), wherein:

K ₁ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range from 2 to 30 carbon atoms;

K ₂ is a linear, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range from 2 to 30 carbon atoms;

Ζ absent, or represents choline, phosphate, inositol or glycerol;

Υ is absent or is a spacer group having a length in the range from 2 to 30 atoms;

X is a mono- or disaccharide, carboxylated disaccharide, mono- or dicarboxylic acids, salicylate, salicylic acid, aspirin, lactobionic acid, maltose, amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, di- or tripeptide, oligopeptide, trisaccharide, or heparin di- or trisaccharide monomer unit, he aransulfata, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, leatherette, dermatan sulfate, dextran, or hyaluronic acid; and η is the number of molecules of lipid fragments associated with the molecule of group X, where η is a number from 1 to 1000.

In yet another embodiment, related low molecular weight derivatives of the invention may be given as examples of general formulas (A), (I) to (XXI), wherein in one embodiment of the present invention, X is covalently linked to a lipid. In yet another embodiment, X is covalently linked to a lipid via an amide bond. In yet another embodiment, X is covalently linked to a lipid via an ester linkage. In yet another embodiment, the lipid is phosphatidylethanolamine. In yet another embodiment, the CAS may be, inter alia, chondroitin sulfate. In yet another embodiment, the conjugates are biodegradable.

In one embodiment, the invention provides a glycosaminoglycan (CAC) compound covalently linked to a lipid to provide a compound having preferred therapeutic properties.

In yet another embodiment, the CAC compound is covalently linked to a lipid via an amide bond. In yet another embodiment, the CAC compound is covalently linked to the lipid via an ester linkage. In yet another embodiment, the lipid may be, inter alia, phosphatidylethanolamine. In yet another embodiment, the CAS may be, inter alia, chondroitin sulfate. In yet another embodiment, the conjugates are biodegradable.

SAS of the cell surface plays a key role in protecting cells from various damaging agents and processes, such as reactive oxygen species and free radicals, endotoxins, cytokines, invasions of promoting enzymes and agents that cause and / or facilitate the destruction of the intercellular matrix and basement membrane, cell permeability leukocyte extravasation and infiltration, chemotaxis, etc. In addition, SAS of the cell surface protects cells from bacterial, viral and parasite infections and other exposing effects on the cell and the subsequent penetration of microorganisms. Enriching the cell surface of the CAS in this way will help protect the cell from the damaging process. Thus, in one embodiment, the PbA2 inhibitors were conjugated to CAC or CAC-like molecules. In yet another embodiment, these lipid conjugates provided multidirectional protection against various damaging effects and effectively attenuated diseases where cellular protection against damage by biochemical mediators was required.

In another embodiment, the CAC-like molecules may be, inter alia, negatively charged molecules. In yet another embodiment, CAC-like molecules can

- 29 012138 can be, among other things, salicylate derivatives. In another embodiment, the CAS-like molecules may be, inter alia, dicarboxylic acid.

Getting connections

The preparation of certain high molecular weight lipid conjugates is the subject of US Patent Application Serial Number 5064817, which is incorporated herein by reference in its entirety. These synthetic methods are repeated below and are considered as acceptable as obtaining low molecular weight, i.e. lipid conjugates containing monomers and dimers as conjugating fragments, with modifications to the procedure that are completely obvious to a qualified person.

When the parent compound selected by the conjugation moiety has a substituent that is reactive or may be reactive with the substituent in the parent lipid compound, the conjugated carrier moiety can be coupled directly to the lipid molecule (s) to form a lipid conjugate. When this is not the case, the bifunctional binding starting material can be used to link the two molecules indirectly.

Lipid conjugates are prepared by linking a polar conjugate, i.e., a monomer or polymer, directly or indirectly to the Pb moiety, in accordance with the general reaction schemes described in US Pat. No. 5,064,817.

For example, dicarboxylic acids of various lengths can be used as spacers for the acylated PE used as a precursor for the PE conjugate. These acids may be associated with natural, semi-synthetic or synthetic PE.

For example, PE can be linked indirectly to aminodextran, as described in US Pat. No. 5,064,817.

Polymers with carboxylic acid groups, such as polyamino acids, carboxymethyl cellulose or polymers to which fatty acids can be linked, can be coupled directly to PE according to the scheme described in US Pat. No. 5,064,817.

It is clear that these examples are taken only as an illustration and cannot be construed as limiting the invention, as many modifications in reagents and methods may be possible for a person skilled in this field. Based on the wide range of pharmacological properties exhibited by lipid conjugates, it appears that the compounds encompassed by the formulas [-XXI, in addition to those explicitly described above, have the same valuable biological activities that show usefulness in the methods of treating the diseases described below.

In one embodiment, the invention provides a method for producing a compound represented by the structure of general formula (A):

_Ε _-Ζ · —Υ-Χ

- -’p (A) where

B is a lipid or phospholipid;

Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any connection between Ε, Ζ, Υ and X is either amide or ester, including, inter alia, the stages:

binding of b to Ζ;

binding of Ζ to Υ;

binding of Υ to X;

where, if Ζ is absent, then непосредственно is directly associated with Υ, if Υ is absent, then Ζ is directly associated with X, and if Υ and Ζ are absent, then b is directly associated with X, thereby obtaining a compound represented by the structure of general formula (A )

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (I):

- 30 012138

Where

Κι represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Υ either absent or represents a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or physiologically acceptable polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where, if Υ is absent, phosphatidylethanolamine is directly linked to X via an amide bond, and if Υ is a spacer group, the spacer group is directly linked to X via an amide or ester bond, and linked to phosphatidylethanolamine via an amide bond, including, inter alia, phosphatidylethanolamine binding steps with Υ; and binding Υ to X;

if Υ is absent, phosphatidylethanolamine is directly bound to X, thereby obtaining a compound represented by the structure of general formula (I).

In one embodiment, the phosphatidylethanolamine is a chemical moiety represented by the structure of the general formula:

where Κι and К _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (II):

Rut

K. ϊ-ο— S — N

I

K ₂ - s — О-С-Н О Н СОО

Н-С-О-1? —О-С — С — Ν — Υ - Χ ¹ 1 ¹ | I

N O ’n n n

Ν— Υ — X (P) where

Κ1 is an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ ₂ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or physiologically acceptable polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where, if Υ is absent, phosphatidylserine is directly linked to X via an amide bond, and if Υ is a spacer group, the spacer group is directly linked to X via an amide or ester bond and linked to phosphatidylserine via an amide bond, including, inter alia, phosphatidylserine binding steps with Υ and

- 31 012138 binding of Υ to X;

if Υ is absent, phosphatidylserine is directly bound to X, thereby obtaining a compound represented by the structure of general formula (II).

In one embodiment, the phosphatidylserine is a chemical moiety represented by the structure of the general formula

О Н к, —ОА-Н ¹ 1

Na — c — o — snono soo6 nA — oA — oA ~ A — Νn ά - A A A where Κι and K _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (III)

η (Ш) where

Κι represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ2 is an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between phosphatidyl, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding phosphatidyl to Ζ;

binding of Ζ to Υ;

binding Υ to X;

if Ζ is absent, phosphatidyl bind directly to Υ, if Υ is absent, Ζ bind directly to X, if Υ and Ζ are absent, phosphatidyl bind directly to X, thus obtaining a compound represented by the structure of general formula (III).

In one embodiment, the phosphatidyl may be a chemical moiety represented by a structure of the general formula

IT

Κι — th — ϋ-ά-n I ₂ —C — ο-ό-n o Y n-s-o-o-oA And where Κ1 and Κ2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (IV)

(Iv)

- 32 012138 where

K ₁ is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any connection between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of: binding the phospholipid to Ζ;

binding of Ζ to Υ;

binding of Υ to X;

if Ζ is absent, the phospholipid is bound directly to Υ, if Υ is absent, Ζ is bound directly to X, and if Υ and Ζ are absent, the phospholipid is bound directly to X, thereby obtaining a compound represented by the structure of general formula (IV).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

N

K! —6-N

Yu-S-O-S-N about n4-oL-on where K ₁ and K _{2 are} defined here.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (V)

in (V) where

K ₁ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms.

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X represents a physiologically acceptable monomer, dimer, oligomer or polymer, wherein X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the phospholipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

if Ζ is absent, the phospholipid is bound directly to Υ, if Υ is absent, Ζ is bound directly to X, and if Υ and Ζ are absent, the phospholipid is bound directly to X, thereby obtaining a compound represented by the structure of general formula (V).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

- 33 012138

Ο Η ^ -Β-ο-έ-ι η η ₂ —CH-ο

Η-έ-ο - ^ - ο ά 6 where Ρ | and Β _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (VI) n

I —o-s-n to ₂ -s-o-s-n o and v

About H-C-Ο-Ρ-Ο-Ζ-Υ-X

I n

I Oh ’(VI) where

B ₁ is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B ₂ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the phospholipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the phospholipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the phospholipid binds directly to X, thereby obtaining the compound represented by the structure of general formula (VI).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

H, —o-s-n * I n ₂ –s-α-s-n o ΰ n-s-o-AoI I where B ₁ and B _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (VII)

(Vii) where

B ₁ is an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B ₂ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

- 34 012138

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the phospholipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the phospholipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the phospholipid binds directly to X, thereby obtaining the compound represented by the structure of general formula (VII).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

Oh N u-ϊ-ο-έ-Η]

Cd — oh, □

H-C-O-1-OI I where K and K _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (VIII)

Mr. '

I

B-1 — C-H

I

K ₂ —C-No

III

H-C-Ο-Ρ-Ο-Ζ-Υ II

ΗΟ-

(USH) where

K represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, series, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the phospholipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the phospholipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the phospholipid binds directly to X, thereby obtaining the compound represented by the structure of general formula (VIII).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

N

H1-6-n

Kg — sn about

H-C-O - & - Ok cg where K and K _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (IX)

- 35 012138

Where

Κ ₁ is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K ₂ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and n is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the phospholipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the phospholipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the phospholipid binds directly to X, thereby obtaining the compound represented by the structure of general formula (IX).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

where P | and K _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (IX; ·!)

Where

Κι is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ ₂ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and n is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the phospholipid to Ζ;

binding of Ζ to Υ;

- 36 012138 binding of Υ to X;

where, if Ζ is absent, the phospholipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the phospholipid binds directly to X, thereby obtaining the compound represented by the structure of general formula (Ka).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

where Κ1 and Κ2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (K)

Where

Κ1 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ2 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Y is either absent or is a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the phospholipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the phospholipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the phospholipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the phospholipid binds directly to X, thus obtaining the compound represented by the structure of general formula (Kb).

In one embodiment, the phospholipid may be a chemical moiety represented by a structure of the general formula

where Κ1 and Κ2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (X)

- 37 012138 where

Κ ₁ is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ ₂ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000; where any bond between ceramide phosphoryl, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of ceramide phosphoryl binding to Ζ; binding of Ζ to Υ; binding Υ to X; where, if Ζ is absent, phosphoryl ceramide is bonded directly to Υ, if Υ is absent, Ζ is bonded directly to X, and if Υ and Ζ are absent, phosphoryl ceramide is bonded directly to X, thereby obtaining a compound represented by the structure of general formula (X).

In one embodiment, the phosphoryl ceramide may be a chemical moiety represented by a structure of the general formula

where Κ1 and Κ2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XI) (XI) where

Κ ₁ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where, if Υ is absent, sphignosyl is directly linked to X via an amide bond, and if Υ is a spacer group, the spacer group is directly linked to X and sphingosyl via an amide bond and to X via an amide or ester bond, including but not limited to sphingosyl with Υ;

binding Υ to X;

where, if Υ is absent, sphingosyl bind directly to X, thereby obtaining a compound represented by the structure of general formula (XI).

In one embodiment, the sphingosyl may be a chemical moiety represented by a structure of the general formula

N

I d1 - C-OH n-s-ynNO-S-N

I n

where Κ1 is defined above.

- 38 012138

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XII)

N

Oh Κί — s-he II I

K.2 — s-in-s-n

H-C-O-2-Υ-Χ (HP) where

K.1 represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K2 is an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B is ceramide;

Ζ either absent or represents ethanolamine, serine, inositol, choline or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between ceramide, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of linking ceramide with Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, ceramide is bonded directly to Υ, if Υ is absent, Ζ is bonded directly to X, and if Υ and Ζ are absent, the ceramide is bonded directly to X, thereby obtaining a compound represented by the structure of general formula (XII).

In one embodiment, the ceramide may be a chemical moiety represented by a structure of the general formula

Ξ

I

О Κί-С-ОН ^{11 1} “Ka-S-YN-S-N n — s — o—

I n

where K1 and K2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XIII) ’OH

II I

Κι— С-О-С-Н * I к ₂ —с-о-с-н

II I

About H-C-0-Ζ-Υ-Χ

I n

- -4c (ХШ) where

K1 represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

K2 is an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between diglyceryl, Ζ, Υ and X is either amide or ester,

- 39 012138 comprising, inter alia, the steps of diglyceryl binding to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, diglyceryl bind directly to Υ, if Υ is absent, Ζ bind directly to X, and if Υ and Ζ are absent, diglyceryl bind directly to X, thus obtaining the compound represented by the structure of general formula (XIII).

In one embodiment, diglyceryl may be a chemical moiety represented by the structure of the general formula

IT

And 1

Κι-С-О-С-Н

H ₃ —C — O — 6 — H ¹¹ 1 O H — C — OI n

where Κ ₁ and K _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XIV)

N y-1 — O — C — H c — C — O — C — N

II I

О Н-С-Ο-Ζ-Υ'-Χ I н (XIV) where

Κ ₁ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ ₂ represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the glycerolipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of linking the glycerolipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the glycerolipid is bonded directly to Υ, if Υ is absent, Ζ is bonded directly to X, and if Υ and Ζ are absent, the glycerolipid is bonded directly to X, thereby obtaining a compound represented by the structure of general formula (XIV).

In one embodiment, the glycerolipid may be a chemical moiety represented by a structure of the general formula

N

Y! —O-S-N

K _g —C — O — C — H

II I О Н-С-Он where Κ ₁ and К _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XV)

- 40 012138

(Xv) where

C) represents an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B ₂ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the glycerolipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of linking the glycerolipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the glycerolipid is bound directly to Υ, if Υ is absent, Ζ is bound directly to X, and if Υ and Ζ are absent, the glycerolipid is bound directly to X, thereby obtaining a compound represented by the structure of general formula (XU).

In one embodiment, the glycerolipid may be a chemical moiety represented by a structure of the general formula

IT

Kg-B-0-έ-Η

K.2 — O — C — n ns-oI n

where B1 and B2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XUT)

η (XVI) where

B1 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B2 is an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or represents choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the lipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the lipid is bound directly to Υ,

- 41 012138 if Υ is absent, Ζ is bound directly to X, and if Υ and Ζ are absent, the lipid is bound directly to X, thereby obtaining a compound represented by the structure of general formula (XVI).

In one embodiment, the lipid may be a chemical moiety represented by a structure of the general formula

N

Я1— (4 — n Kg-s-a-4-n □ Н-С-ОI n

I where Κι and К _{2 are} defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XVII)

O H <1 I

Β.Ι — s-o-s-n

Kg — C — H

NS-Ο-Ζ-Υ4-Χ

I n

(Xvii) where

Κι is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Κ2 is an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or constitutes choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and n is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the lipid to Ζ; binding of Ζ to Υ; binding Υ to X;

where, if Ζ is absent, the lipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the lipid binds directly to X, thereby obtaining a compound represented by the structure of general formula (XVII).

In one embodiment, the lipid may be a chemical moiety represented by a structure of the general formula

Is he

K1 — ιϋ-ο-s-n

K2 — cn H - ^ - O1 and where Κ3 and Κ2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XVIII)

N

K, —O — C — H to ₂ ——— st

I

H-C-0-Ζ-Υ-Χ where (ΧνΐΠ)

- 42 012138

B1 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B ₂ represents either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or constitutes choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the lipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the lipid is bonded directly to Υ, if Υ is absent, Ζ is bonded directly to X, and if Υ and Ζ are absent, the lipid is bonded directly to X, thereby obtaining a compound represented by the structure of general formula (XVIII).

In one embodiment, the lipid may be a chemical moiety represented by a structure of the general formula

H!

Κχ — o-s-i (

In _2- O — S-N n-s-οι n

where B1 and B2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XIX)

N

B] - CH to ₂ - s ι: h

I> - n

H-C-0-Ζ-Υ-Χ (HC) where

B1 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B2 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or constitutes choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any connection between the lipid, Ζ, Υ and X is either amide or ester, including, inter alia, the stages:

lipid binding to Ζ;

binding of Ζ to Υ;

binding of Υ to X;

where, if Ζ is absent, the lipid is bonded directly to Υ, if Υ is absent, Ζ is bonded directly to X, and if Υ and Ζ are absent, the lipid is bonded directly to X, thereby obtaining a compound represented by the structure of general formula (XIX).

In one embodiment, the lipid may be a chemical moiety represented by a structure of the general formula

- 43 012138

Η

Κι — C — Η

Κ ₂ —C — Η

HC-OI

Η where B1 and B2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XX)

(XX) where

B1 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B2 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or constitutes choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of binding the lipid to Ζ;

binding of Ζ to Υ;

binding Υ to X;

where, if Ζ is absent, the lipid is bonded directly to Υ, if Υ is absent, Ζ is bonded directly to X, and if Υ and Ζ are absent, the lipid is bonded directly to X, thereby obtaining a compound represented by the structure of general formula (XX).

In one embodiment, the lipid may be a chemical moiety represented by the structure of general formula n

I

Κι — о-с-н н ₂ —С-Н н-С-ΟΙ н

where B1 and B2 are defined above.

In yet another embodiment, the invention provides a method for producing a compound represented by the structure of general formula (XXI) n I K, —CH

I

K ₂ -O — CH

Η-Ο0-Ζ-Υ - Χ (XXI) where

B1 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

B2 is either hydrogen or an unbranched, saturated, monounsaturated or polyunsaturated alkyl chain having a length in the range of 2-30 carbon atoms;

Ζ either absent or constitutes choline, phosphate, inositol or glycerin;

Υ either absent or a spacer group having a length in the range of 2-30 atoms;

X is a physiologically acceptable monomer, dimer, oligomer or polymer, where X is a glycosaminoglycan; and

- 44 012138 η is a number from 1 to 1000;

where any bond between the lipid, Ζ, Υ and X is either amide or ester, including, inter alia, the steps of linking the lipid to Ζ;

binding of Ζ to Υ;

binding of Υ to X;

where, if Ζ is absent, the lipid binds directly to Υ, if Υ is absent, Ζ binds directly to X, and if Υ and Ζ are absent, the lipid binds directly to X, thereby obtaining a compound represented by the structure of general formula (XXI).

In one embodiment, the lipid may be a chemical moiety represented by a structure of the general formula:

H I Ng — CH

K ·? —O · ^- —C— I ns-oI n

where Κι And K _{2 are} defined above.

In yet another embodiment, binding according to the invention can be accomplished by removing a water molecule, thereby forming an amide or ester bond. In yet another embodiment, binding may be performed in the presence of a detergent. In yet another embodiment, the binding may be induced by ultrasonic irradiation.

In yet another embodiment, any binding method of the invention can be accomplished by removing a water molecule, thereby forming an amide or ester bond. In yet another embodiment, binding may be performed in the presence of a detergent. In yet another embodiment, the binding may be induced by ultrasonic irradiation.

In yet another embodiment of the invention, the compound of the present invention can be obtained by a coupling method by removing a water molecule, thereby forming an amide or ester bond. In yet another embodiment, a compound of the present invention can be prepared by a coupling method in the presence of a detergent. In yet another embodiment, the compound of the present invention can be obtained by a method of binding induced by ultrasonic irradiation.

In one embodiment, the binding of phosphatidylethanolamine and chondroitin sulfate is carried out in the presence of a detergent. In another embodiment, the detergent may be, inter alia, ΌΌΑΒ. Of course, any other suitable detergent may be used.

In one embodiment, the binding of phosphatidylethanolamine and hyaluronic acid is induced by ultrasound.

Methods for treating diseases based on Pb conjugates

In one embodiment, the lipid conjugates described herein can be used to treat a disease by exhibiting at least one of their many pharmacological activities, including mitigating or preventing tissue damage that occurs during a pathological disease state, by stabilizing cell membranes; limiting oxidative damage to cells and blood components; restriction of cell proliferation, cell extravasation and (tumor) changes in the nature of cell migration; suppression of the immune response; or mitigating physiological responses to stress resulting in elevated chemokine levels. The therapeutic properties of these compounds are clearly demonstrated in the use of animal models of a single disease in which it is desirable to use drugs. Patients to whom lipid or Pb conjugates can be administered have experience of symptoms of the disease or a risk of disease or experience relapses or exacerbations of the disease. The effectiveness of these compounds in the cellular and animal models of diseases is described below in the examples.

The combination of lipids, such as but not limited to phosphatidylethanolamine and phosphatidylserine, with additional monomeric or polymeric fragments, is thus a practical area for the production of new drugs for medical purposes, provided that the resulting chemical composition exhibits the desired number of pharmacological properties. In the cases described here, the various biological actions and efficacy in relation to diseases exhibited by the compounds far exceed the properties expected from the use of the starting materials themselves, administered alone or in combination. However, it will probably be proven that Pb conjugated compounds, alone or in combination, are valuable drugs in adapting to methods of treating diseases other than the conditions specifically described herein.

- 45 012138

In one embodiment, the invention provides a method of treating a patient suffering from a disease similar to asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease, obstructive respiratory disease, chlamydial infection, impaired cell proliferation of smooth muscles, metastatic cancer, colitis, Crohn's disease or other forms damage to the intestinal mucosa, cardiovascular diseases, atherosclerosis, stroke of the central nervous system tissue, diffuse sclerosis, contact dermatitis, psoriasis, cell proliferative disorders, sepsis, acute respiratory distress syndrome, autoimmune diseases, hemolysis, HIV infection or conjunctivitis.

In one embodiment, the invention provides a method of treating a patient suffering from asthma, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In yet another embodiment, the invention provides a method for preventing asthma in a patient, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In yet another embodiment, the invention provides a method of treating a patient suffering from allergic rhinitis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In yet another embodiment, the invention provides a method for the prevention of allergic rhinitis in a patient, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In yet another embodiment, the invention provides a method of treating a patient suffering from chronic obstructive pulmonary disease, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In one embodiment, the invention provides a method for the prevention of chronic obstructive pulmonary disease in a patient, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In yet another embodiment, the invention provides a method of treating a patient suffering from obstructive respiratory disease, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In yet another embodiment, the invention provides a method for preventing obstructive respiratory disease, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer.

In yet another embodiment, the invention provides a method of treating a patient in need of antioxidant therapy, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating the patient, in need of antioxidant therapy.

In yet another embodiment, the invention provides a method of treating a patient in need of anti-ΤΝΕ therapy, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thus performing treatment of a patient in need of anti-ΤΝΕ therapy.

In yet another embodiment, the invention provides a method of treating a patient suffering from impaired cell proliferation of smooth muscles, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thus performing treatment of a patient suffering from a disorder associated with cell proliferation of smooth muscles.

In yet another embodiment, the invention provides a method of treating a patient after vascular catheterization, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating the patient after carried out catheterization of blood vessels.

In yet another embodiment, the invention provides a method of treating a patient,

- 46 012138 giving metastatic cancer, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from metastatic cancer.

In yet another embodiment, the invention provides a method for treating a patient suffering from colitis, Crohn's disease and other forms of damage to the intestinal mucosa, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer thus treating a patient suffering from damage to the intestinal mucosa, including colitis or Crohn’s disease.

In yet another embodiment, the invention provides a method of treating a patient suffering from a cardiovascular disease, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating the patient suffering from cardiovascular disease.

The present invention provides a method of treating a patient suffering from atherosclerosis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from atherosclerosis.

In yet another embodiment, the invention provides a method of treating a patient suffering from a stroke of tissue of the central nervous system, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby providing treatment a patient suffering from a stroke in the tissue of the central nervous system.

In yet another embodiment, the invention provides a method of treating a patient suffering from multiple sclerosis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from multiple sclerosis.

In yet another embodiment, the invention provides a method of treating a patient suffering from contact dermatitis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from contact dermatitis.

In yet another embodiment, the invention provides a method of treating a patient suffering from psoriasis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from psoriasis .

In yet another embodiment, the invention provides a method of treating a patient suffering from a cell proliferative disorder, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating the patient, suffering from cell proliferative disorder.

In yet another embodiment, the invention provides a method of treating a patient suffering from sepsis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from sepsis .

In yet another embodiment, the invention provides a method of treating a patient suffering from ΆΚΌ8, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from ΆΚΌ8 .

In yet another embodiment, the invention provides a method of treating a patient suffering from an autoimmune disease, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from autoimmune disease.

In yet another embodiment, the invention provides a method of treating a patient suffering from hemolysis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from from ge

- 47 012138 Molise.

In yet another embodiment, the invention provides a method of treating a patient undergoing tissue transplantation or rejecting an allograft, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby providing treatment a patient who has undergone tissue transplantation or allograft rejection.

In yet another embodiment, the invention provides a method of treating a patient suffering from HIV infection, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from HIV infection.

In yet another embodiment, the invention provides a method of treating a patient suffering from conjunctivitis, including, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from conjunctivitis .

In yet another embodiment, the invention provides a method for extracorporeal tissue preservation, comprising, inter alia, the step of adding to the tissue preparations or organs an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby increasing the viability of tissue preparations or organs outside the patient donor.

In yet another embodiment, the invention provides a method of treating a patient suffering from an infection caused by Syuatouph, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating the patient suffering from an infection caused by SYATuF.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from asthma.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the prevention of asthma in a patient.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from allergic rhinitis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the prevention of allergic rhinitis in a patient.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the treatment of a patient suffering from chronic obstructive pulmonary disease.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the prevention of chronic obstructive pulmonary disease in a patient.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the treatment of a patient suffering from obstructive respiratory disease.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the prevention of obstructive respiratory disease in a patient.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient in need of antioxidant therapy.

In yet another embodiment, the invention provides the use of lipid or phosphate.

- 48 012138 folipid fragment associated with a physiologically acceptable monomer, dimer, oligomer or polymer, in the preparation of a pharmaceutical composition for the treatment of a patient in need of anti-β therapy.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from a disorder associated with smooth muscle cell proliferation.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the treatment of a patient undergoing vascular catheterization.

In yet another embodiment, the invention provides the use of a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from metastatic cancer.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from damage to the intestinal mucosa, including, but not limited to, colitis or Crohn’s disease.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from a cardiovascular disease.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from atherosclerosis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the treatment of a patient suffering from a central nervous system stroke.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from multiple sclerosis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from contact dermatitis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from psoriasis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from a cell proliferative disorder.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from sepsis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from ΆΚΌ8.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from an autoimmune disease.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from

- 49 012138 hemolysis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the treatment of a patient undergoing tissue transplantation or allograft rejection.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from HIV infection.

In yet another embodiment, the invention provides the use of a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from conjunctivitis.

In yet another embodiment, the invention provides the use of a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition to increase the viability of tissue preparations or organs outside a patient donor.

In yet another embodiment, the invention provides the use of a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for the treatment of a patient suffering from SYATUS infection.

In one embodiment, treatment requires controlling the expression, production, and activity of phospholipase enzymes. In yet another embodiment of the invention, the treatment requires controlling the production and / or action of lipid mediators. In another embodiment, treatment requires mitigating damage to glycosaminoglycans (AOs) and proteoglycans. In yet another embodiment, the treatment requires controlling the production and action of oxidizing agents, oxide radicals, and nitric oxide. In yet another embodiment, the treatment requires antioxidant therapy. In yet another embodiment, the treatment requires controlling the expression, production and action of cytokines, chemokines, adhesive molecules, or interleukins. In yet another embodiment, the treatment requires the protection of lipoproteins from damaging agents. In yet another embodiment, the treatment requires controlling cell proliferation. In yet another embodiment, treatment requires controlling angiogenesis and vascularization of organs. In yet another embodiment, the treatment requires inhibition of invasion promoting enzymes. In yet another embodiment, the treatment requires control of cell invasion. In yet another embodiment, the invasive cells are white blood cells. In yet another embodiment, the invasive cells are cancer cells. In yet another embodiment, the treatment requires monitoring leukocyte activation, adhesion, or extravasation. In yet another embodiment, the treatment requires mitigation of ischemia or reperfusion injury. In yet another embodiment, the treatment requires inhibition of lymphocyte activation. In yet another embodiment, the treatment requires protection of the blood-brain barrier. In yet another embodiment, the treatment requires monitoring the production of neurotransmitters and their action. In yet another embodiment, the treatment requires controlling spasm of the blood vessels and airways. In yet another embodiment, treatment requires extracorporeal tissue preservation.

In one embodiment, the lipid mediator is a glycerolipid. In yet another embodiment, the lipid mediator is a phospholipid. In yet another embodiment, the lipid mediator is a sphingolipid. In yet another embodiment, the lipid mediator is sphingosine. In yet another embodiment, the lipid mediator is ceramide. In yet another embodiment, the lipid mediator is a fatty acid. In yet another embodiment, the lipid mediator is arachidonic acid. In yet another embodiment, the lipid mediator is an eicosanoid derived from arachidonic acid. In yet another embodiment, the lipid mediator is a platelet activating factor (PAE). In yet another embodiment, the lipid mediator is a lysophospholipid.

In one embodiment, the damaging agent is phospholipase. In yet another embodiment, the reactive species are oxygen species (ΚΘ8). In yet another embodiment, the damaging agent is free radicals. In yet another embodiment, the damaging agent is a lysophospholipid. In yet another embodiment, the damaging agent is a fatty acid or derivative thereof. In yet another embodiment, the damaging agent is hydrogen peroxide. In yet another embodiment, the damaging agent is a phospholipid. In yet another embodiment,

- 50 012138 of the damaging agent is an oxidizing agent. In yet another embodiment, the damaging agent is a cationic protein. In yet another embodiment, the damaging agent is streptolysin. In yet another embodiment, the damaging agent is a protease. In yet another embodiment, the damaging agent is hemolysin. In yet another embodiment, the damaging agent is sialidase.

In one embodiment, the invasion promoting enzyme is collagenase. In yet another embodiment, the invasion promoting enzyme is matrix metalloproteinase (MMP). In yet another embodiment, the invasion promoting enzyme is heparinase. In yet another embodiment, the invasion promoting enzyme is heparanase. In yet another embodiment, the invasion promoting enzyme is hyaluronidase. In yet another embodiment, the invasion promoting enzyme is gelatinase. In yet another embodiment, the invasion promoting enzyme is chondroitinase. In yet another embodiment, the invasion promoting enzyme is dermatanase. In yet another embodiment, the invasion promoting enzyme is keratanase. In yet another embodiment, the invasion promoting enzyme is a protease. In yet another embodiment, the invasion promoting enzyme is lyase. In yet another embodiment, the invasion promoting enzyme is hydrolase. In yet another embodiment, the invasion promoting enzyme is a glycosaminoglycan-degrading enzyme. In yet another embodiment, the invasion promoting enzyme is a proteoglycan-degrading enzyme.

In one embodiment, the physiologically acceptable monomer is salicylate. In yet another embodiment, the physiologically acceptable monomer is salicylic acid. In yet another embodiment, the physiologically acceptable monomer is aspirin. In yet another embodiment, the physiologically acceptable monomer is a monosaccharide. In yet another embodiment, the physiologically acceptable monomer is lactobionic acid. In yet another embodiment, the physiologically acceptable monomer is glucuronic acid. In yet another embodiment, the physiologically acceptable monomer is maltose. In yet another embodiment, the physiologically acceptable monomer is an amino acid. In yet another embodiment, the physiologically acceptable monomer is glycine. In yet another embodiment, the physiologically acceptable monomer is a carboxylic acid. In yet another embodiment, the physiologically acceptable monomer is acetic acid. In yet another embodiment, the physiologically acceptable monomer is butyric acid. In yet another embodiment, the physiologically acceptable monomer is dicarboxylic acid. In yet another embodiment, the physiologically acceptable monomer is glutaric acid. In yet another embodiment, the physiologically acceptable monomer is succinic acid. In yet another embodiment, the physiologically acceptable monomer is a fatty acid. In yet another embodiment, the physiologically acceptable monomer is dodecanoic acid. In yet another embodiment, the physiologically acceptable monomer is didodecanoic acid. In yet another embodiment, the physiologically acceptable monomer is bile acid. In yet another embodiment, the physiologically acceptable monomer is cholic acid. In yet another embodiment, the physiologically acceptable monomer is cholesteryl gemmisuccinate.

In one embodiment, the physiologically acceptable dimer or oligomer is a dipeptide. In yet another embodiment, the physiologically acceptable dimer or oligomer is a disaccharide. In yet another embodiment, the physiologically acceptable dimer or oligomer is a trisaccharide. In yet another embodiment, the physiologically acceptable dimer or oligomer is an oligosaccharide. In yet another embodiment, the physiologically acceptable dimer or oligomer is an oligopeptide. In yet another embodiment, the physiologically acceptable dimer or oligomer is a di- or trisaccharide glycosaminoglycan unit. In yet another embodiment, the physiologically acceptable dimer or oligomer is hyaluronic acid. In yet another embodiment, the physiologically acceptable dimer or oligomer is heparin. In yet another embodiment, the physiologically acceptable dimer or oligomer is heparan sulfate. In yet another embodiment, the physiologically acceptable dimer or oligomer is keratin. In yet another embodiment, the physiologically acceptable dimer or oligomer is keratan sulfate. In yet another embodiment, the physiologically acceptable dimer or oligomer is chondroitin. In yet another embodiment, the invention

A physiologically acceptable dimer or oligomer is chondroitin sulfate. In yet another embodiment, the physiologically acceptable dimer or oligomer is chondroitin-4-sulfate. In yet another embodiment, the physiologically acceptable dimer or oligomer is chondroitin-6-sulfate. In yet another embodiment, the physiologically acceptable dimer or oligomer is dermatin. In yet another embodiment, the physiologically acceptable dimer or oligomer is dermatan sulfate. In yet another embodiment, the physiologically acceptable dimer or oligomer is dextran. In yet another embodiment, the physiologically acceptable dimer or oligomer is polyheline (Hematzel). In yet another embodiment, the physiologically acceptable dimer or oligomer is alginate. In yet another embodiment, the physiologically acceptable dimer or oligomer is hydroxyethyl starch (Getastartch). In yet another embodiment, the physiologically acceptable dimer or oligomer is ethylene glycol. In yet another embodiment, the physiologically acceptable dimer or oligomer is carboxylated ethylene glycol.

In yet another embodiment, the physiologically acceptable polymer is glycosaminoglycan. In yet another embodiment, the physiologically acceptable polymer is hyaluronic acid. In yet another embodiment, the physiologically acceptable polymer is heparin. In yet another embodiment, the physiologically acceptable polymer is heparan sulfate. In yet another embodiment, the physiologically acceptable polymer is chondroitin. In yet another embodiment, the physiologically acceptable polymer is chondroitin-4 sulfate. In yet another embodiment, the physiologically acceptable polymer is chondroitin-6-sulfate. In yet another embodiment, the physiologically acceptable polymer is keratin. In yet another embodiment, a physiologically acceptable polymer is keratan sulfate. In yet another embodiment, the physiologically acceptable polymer is dermatin. In yet another embodiment, the physiologically acceptable polymer is dermatan sulfate. In yet another embodiment, the physiologically acceptable polymer is carboxymethyl cellulose. In yet another embodiment, the physiologically acceptable polymer is cextran. In yet another embodiment, the physiologically acceptable polymer is polyheline (Hematzel). In yet another embodiment, the physiologically acceptable polymer is alginate. In yet another embodiment, the physiologically acceptable polymer is hydroxyethyl starch (Getastartch). In yet another embodiment, the physiologically acceptable polymer is polyethylene glycol. In yet another embodiment, the physiologically acceptable polymer is polycarboxylated polyethylene glycol.

In one embodiment, the lipid or phospholipid moiety is a phosphatidic acid. In yet another embodiment, the lipid or phospholipid moiety is an acylglycerol. In yet another embodiment, the lipid or phospholipid moiety is monoacylglycerol. In yet another embodiment, the lipid or phospholipid moiety is diacylglycerol. In yet another embodiment, the lipid or phospholipid moiety is triacylglycerol. In yet another embodiment, the lipid or phospholipid moiety is sphingosine. In one embodiment, the lipid or phospholipid moiety is sphingomyelin. In yet another embodiment, the lipid or phospholipid moiety is ceramide. In yet another embodiment, the lipid or phospholipid moiety is phosphatidylethanolamine. In yet another embodiment, the lipid or phospholipid moiety is phosphatidylserine. In yet another embodiment, the lipid or phospholipid moiety is phosphatidylcholine. In yet another embodiment, the lipid or phospholipid moiety is phosphatidylinositol. In yet another embodiment, the lipid or phospholipid moiety is phosphatidylglycerol. In yet another embodiment, the lipid or phospholipid fragment is an ether phospholipid derivative or an alkyl phospholipid derivative.

In one embodiment, the invention provides a method of treating a patient suffering from a disease, wherein treating the disease requires controlling phospholipase A2 activity; controlling the production and / or action of lipid mediators, such as eicosanoids, platelet activation factor (PAE) and lysophospholipids; mitigating damage to the cell surface of glycosaminoglycans (CAC) and proteoglycans; controlling the production of oxygen radicals and nitric oxide; protection of plasma cells, tissues and lipoproteins from damaging substances such as reactive oxygen species (K.O8) and phospholipases; antioxidant therapy; antiendotoxin tera

- 52,012,138 FDI; control of cytokine, chemokine and interleukin production; controlling cell proliferation, including smooth muscle cells, endothelial cells and skin fibroblasts; controlling angiogenesis and vascularization of organs; inhibiting invasion promoting enzymes such as collagenase, heparinase, heparanase and hyaluronidase; control cell invasion; monitoring leukocyte activation, adhesion and extravasation; mitigation of ischemic / reperfusion injury; inhibition of lymphocytic activation; controlling spasm of blood vessels and respiratory tract; protection of the blood-brain barrier; controlling neurotransmitter (dopamine) products and actions (acetylcholine); extracorporeal tissue preservation or any combination thereof.

In one embodiment of the invention, the term control means inhibiting the production and action of the above factors in order to maintain their activity at a normal basic level and inhibit their activation in pathological conditions.

In one embodiment, the physiologically acceptable monomer is selected from salicylate, salicylic acid, aspirin, monosaccharide, lactobionic acid, maltose, amino acid, glycine, carboxylic acid, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate; or where the physiologically acceptable dimer or oligomer is a dipeptide, disaccharide, trisaccharide, oligopeptide or di- or trisaccharide monomeric unit of heparin, heparan sulfate, keratin, keratan sulfate, chondroitin, chondroitin-6-sulfate, chondroitrin-dermatin-dermatin-4-dermatin-dermatin-4 hyaluronic acid; or where the physiologically acceptable polymer is glycosaminoglycan, polyheline (hemestsel), alginate, hydroxyethyl starch (getastartch), polyethylene glycol, polycarboxylate, polyethylene glycol, chondroitin-6-sulfate, chondroitin-4-sulfate, keratin, heparaman sulfate, hepatosulfate , dextran or hyaluronic acid.

In one embodiment, the lipid moiety is any one of phosphatidic acid, acylglycerol, monoacylglycerol, diacylglycerol, triacylglycerol, sphingosine, sphingomyelin, chondroitin-4-sulfate, chondroitin-phosphonidylate, yl-phospholidin-ylatedin, phosphonidylate, yl-phospholidin-ylated, an ether or alkyl derivative thereof, and a physiologically acceptable monomer or polymer moiety is any of aspirin, lactobionic acid, maltose, glutaric acid, polyethylene glycol, carboxymethyl cellulose, heparin, dextran, hemacell, hetastart or hyaluronic acid.

In one embodiment, the present invention provides the use of a lipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer in the manufacture of a pharmaceutical composition for treating a patient suffering from asthma, allergic rhinitis, chronic obstructive pulmonary disease, obstructive respiratory disease, colitis, Crohn’s disease stroke of the central nervous system, multiple sclerosis, contact dermatitis, psoriasis, cardiovascular disease, including prophylaxis for invasive procedures, invasive cell proliferative disorders, antioxidant therapy, hemolytic syndromes, sepsis, acute respiratory distress syndrome, tissue graft rejection syndromes, autoimmune disease, viral infection, and hypersensitive conjunctivitis.

In yet another embodiment, the present invention provides the use of a pharmaceutical composition according to the present invention for treating a patient suffering from asthma, allergic rhinitis, chronic obstructive pulmonary disease, obstructive respiratory disease, colitis, Crohn’s disease, central nervous system stroke, multiple sclerosis, contact dermatitis, psoriasis, cardiovascular disease, including prophylaxis for invasive procedures, invasive cell proliferative disorders a, antioxidant therapy, hemolytic syndromes, sepsis, acute respiratory distress syndrome, tissue transplant rejection syndromes, autoimmune disease, viral infection and hypersensitive conjunctivitis, where the composition is formulated for administration topically, orally, nasally, in an aerosol, intravenous, intraocular, intraarterial, ways or in suppositories.

In yet another embodiment, the invention provides a method of treating a patient suffering from an intestinal disease, comprising, inter alia, the step of administering to the patient an effective amount of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, thereby treating a patient suffering from intestinal disease.

In yet another embodiment, the invention provides the use of a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer, in the manufacture of a pharmaceutical composition for treating a patient suffering from an intestinal disorder.

In yet another embodiment, the invention provides a method of treating a patient suffering from a disease associated with the production and / or action of lipid mediators and / or impaired glycosaminoglycans (AOs).

In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from an intestinal disease, comprising, inter alia, a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In one embodiment, an intestinal disease may be, inter alia, a disease associated with the production and / or action of lipid mediators and / or impaired glycosaminoglycans (AOs).

In one embodiment, the intestinal disease can be, inter alia, Crohn’s disease, ulcerative colitis, immuno-inflammatory intestinal damage, drug enteropathy, ischemic-induced intestinal damage, or any combination thereof.

In one embodiment, the physiologically acceptable monomer may be, inter alia, salicylate, salicylic acid, aspirin, monosaccharide, lactobionic acid, glucuronic acid, maltose, amino acid, glycine, carboxylic acid, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesteryl gemmisuccinate, or where a physiologically acceptable dimer or oligomer may be among other things, a dipeptide, disaccharide, trisaccharide, oligosaccharide, oligopeptide or di- or trisaccharide monomer unit of glycosaminoglycans, hyaluronic acid, heparin, heparan sulfate, keratin, keratan sulfate, chondroitin sulfonitro-sulfonitrate, 4-chondroitin sulfonitrate dermatan sulfate, dextran, polyhelin, alginate, hydroxyethyl starch, ethylene glycol or carboxylated ethylene glycol, or where the physiologically acceptable polymer may be, inter alia, glycosaminoglycan, hyaluronic acid slot, heparin, heparan sulfate, chondroitin, chondroitin sulfate, keratin, keratan sulfate, leatherette, dermatan sulfate, carboxymethylcellulose, dextran, polizhelinom, alginate, hydroxyethyl starch, polyethylene glycol, polyethylene glycol or a polycarboxylate.

In yet another embodiment, the physiologically acceptable polymer may be, inter alia, hyaluronic acid.

In yet another embodiment, the physiologically acceptable polymer may be, inter alia, chondroitin sulfate.

In yet another embodiment, the lipid or phospholipid moiety can be, but is not limited to, phosphatidic acid, acylglycerol, monoacylglycerol, diacylglycerol, triacylglycerol, sphingosine, sphingomyelin phosphonylidene phosphonylidene phosphonylidene phosphonylidene, phosphate, phosphonylidene phosphonylidene, phosphate, phosphonylidene phosphonylidene, phosphate; .

In yet another embodiment, the phospholipid moiety may be, inter alia, phosphatidylethanolamine.

Dosage and route of administration

The methods of this invention can be adapted to the use of therapeutic compositions containing lipid conjugates in mixtures with conventional excipients, i.e. a pharmaceutically acceptable organic or inorganic carrier suitable for parenteral, enteral (i.e., oral) or topical administration that do not impair the action of the active compounds. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, saline solutions, alcohols, gum arabic, vegetable oil, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, white paraffin, glycerin, alginate, hyaluronic acid, collagen, aromatic oil, fatty acid, monoglycerides and diglycerides, fatty acid esters of pentaerythritol, hydroxymethyl cellulose, polyvinylpyrrolidone, etc. Pharmaceutical preparations can be sterilized and, if desired, mixed with excipients, i.e., lubricants, preservatives, stabilizers, moisturizers, emulsifiers, salts that affect osmotic pressure, buffers, dyes, fragrances and / or flavors, etc. . which do not impair the action of the active substances. They can also be combined as desired with other active substances, for example, vitamins.

In one embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from sepsis, comprising a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from asthma, comprising a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

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In yet another embodiment, the invention provides a pharmaceutical composition for the prophylaxis of asthma in a patient, comprising a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from allergic rhinitis, comprising a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for the prophylaxis of allergic rhinitis in a patient, comprising a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from chronic obstructive pulmonary disease, comprising a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for the prevention of chronic obstructive pulmonary disease in a patient, comprising a lipid or phospholipid fragment linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from obstructive respiratory disease, comprising a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for the prevention of obstructive respiratory disease in a patient, comprising a lipid or phospholipid moiety linked to a physiologically acceptable monomer, dimer, oligomer or polymer; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from asthma, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the invention provides a pharmaceutical composition for the prevention of asthma in a patient, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from allergic rhinitis, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the invention provides a pharmaceutical composition for the prophylaxis of allergic rhinitis in a patient, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from chronic obstructive pulmonary disease, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the invention provides a pharmaceutical composition for the prevention of chronic obstructive pulmonary disease in a patient, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the invention provides a pharmaceutical composition for treating a patient suffering from obstructive respiratory disease, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the invention provides a pharmaceutical composition for the prevention of obstructive respiratory disease in a patient, comprising any of the compounds of the invention, or any combination thereof; and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the compounds of the invention include, but are not limited to, compounds represented by structures of general formulas: (A), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Sha), (Kb), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII ), (XVIII), (XIX), (XX), (XXI), (XXII) or any combination of them.

Although the examples presented here describe the use of Pb conjugates for subcutaneous, intraperitoneal, or topical administration, the success of the described provides good reasons to suggest that other routes of administration or combinations with other pharmaceutical preparations may be at least successful. Route of administration (e.g., local, parenteral,

- 55 012138 enteral, intravenous, vaginal, inhalation, intranasal (spray), suppositories or oral) and the dosage regimen is determined by qualified clinicians based on factors such as the exact nature of the condition being treated, the severity of the condition, age and general physical condition of the patient and etc.

In general, the doses used for the above purposes will be different, but effective for the manifestation of the desired therapeutic effect. As used herein, the term “pharmaceutically effective amount” means an amount of a compound of formulas A and I-XXI that will cause the desired alleviation of the symptoms or signs of the disease in a patient. Doses used for any of the above purposes will generally be from 1 to about 1000 mg per kg body weight (mg / kg), administered one to four times daily or by continuous IV infusion. When the compositions are dosed for topical application, they will generally be in a concentration range of 0.1 to about 10% w / v, administered 1-4 times per day.

As used above, the term “pharmaceutically acceptable carrier” means any composition that is safe and which provides the desired delivery by the desired route of administration of an effective amount of at least one compound of the present invention. Essentially, all of the above compositions of the present invention are thus designated as pharmaceutically acceptable carriers. This term also means the use of buffered compositions, where the pH is maintained at a particular desired level, in the range from pH 4.0 to pH 9.0, in accordance with the stability of the compounds and by administration.

Injectable sterile solutions, in particular oily or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories, are particularly suitable for parenteral use. Ampoules are generally accepted unit dosage forms.

For inhalation use, in particular for the treatment of airway obstruction or blockage, solutions or suspensions of the compounds are mixed and aerosolized or nebulized in the presence of a suitable suitable carrier.

For topical application, in particular for the treatment of skin diseases such as contact dermatitis or psoriasis, a mixture of compounds with conventional creams or sustained release patches are acceptable.

For enteral administration, in particular, tablets, dragees, solutions, drops, suppositories or capsules are suitable. Syrup, elixir or the like. may be used where a sweetened solvent is used. As indicated, suppositories or enemas may be the recommended route of administration.

Slow or directed release compositions can be formulated, for example, liposomes or compositions where the active compound is protected by a differentially destructible coating, for example, microencapsulation, multiple membranes, etc. It is also possible to lyophilize new compounds and use the obtained lyophilisates, for example, for the manufacture of injection products .

Thus, the present invention provides the use of lipid conjugates in various dosage forms suitable for aerosol, rectal, vaginal, conjunctival, intravenous, intraarterial and sublingual routes of administration.

It must be taken into account that the actual preferred amounts of the active compound in a particular case will vary according to the particular compound employed, in particular according to the formulated composition, the method of use and the particular site and organism to be treated. Dosage for administration to a patient can be determined using generally accepted considerations, for example, by routine comparison of various activities of the compounds and a known agent, i.e. through a prescribed, generally accepted pharmacological protocol.

Without further study, it is believed that a person skilled in the art will be able, using the preceding description, to fully apply the present invention. The following preferred specific embodiments are, therefore, construed as merely illustrative and not limiting the rest of the disclosure in any way.

Examples

The main abbreviations used in the examples are listed below:

HA = hyaluronic acid

NURE = dipalmitoylphosphatidylethanolamine (PE) conjugated with HA (also designated as NURE, Nua1RE)

C8L = chondroitin sulfate A

C8LRE = PE conjugated to C8L (also designated as SkRE, SkARE)

SMS = carboxymethyl cellulose

CMPE = PE conjugated with SMS

NERRE = PE conjugated to heparin (also referred to as NERRE, NERRE)

EEUR = PE conjugated to dextran

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AcRE = PE conjugated with aspirin

NetPE = PE conjugated with polyheline (hemazzel)

Nuemre = dimyristoyl PE bound to HA

The examples demonstrate the usefulness of lipid conjugates in the prevention and treatment of diseases, as presented in patent application PCT / i805 / 06591, filed March 2, 2005, application I8, serial number 10/989606, filed November 17, 2004, and application I8, serial number 10/989607, filed November 17, 2004, which are incorporated into this description by reference in its entirety.

Example 11. Obstructive respiratory disease

Lipid conjugates are effective in treating obstructive respiratory disease. This is demonstrated in asthma in experiments 1-8, described below. In asthma, obstruction of air flow is due to airway obstruction, which is the result of constriction and obstruction of the lumen of the blood vessels of the lungs. One widespread experimental system for studying airway constriction serves to induce contraction of smooth muscle drugs isolated from the airways in the absence and presence of a drug. Another widespread study of the anti-asthma effect of a drug is the use of live animals that have asthma. This disease is present in animals that have been sensitized with an antigen and which can be observed when asthmatic breathing occurs and stops using plethysmography.

In experiments 1.1-1.3, a muscle preparation (tracheal rings) was isolated from rats and in experiments 1.4-1.5 from guinea pigs. Muscle contraction is measured by attaching the muscle to a strain gauge that works similar to a spring. Induction of contraction appears when an asthmatic substance such as endothelium-1 (ET), acetylcholine (AeCH) is introduced.

Experiment 1.1. Isolated rat tracheal rings (in linear order) were immersed in Krebs-Hanselet buffer (pH = 7.4) and connected to a voltage sensor. ET-1 was added at the final concentration, as indicated, and the contraction of the tracheal ring was determined by a change in the applied force to the voltage sensor (Fig. 1.1A). Then, the highest concentration of ET was used in the study of lipid conjugates to inhibit smooth muscle contraction. In this experiment (Fig. 1.1B), rat tracheal rings were incubated with a NURE lipid conjugate at the indicated concentration for 1 h. ET-1 was then added at a final concentration of 1 μM, and the ring contraction was determined as in Experiment 1.1A. Each data represents an average of ± 8.Ό. four separate experiments (4 rats).

Experiment 1.2. Rat tracheal rings were incubated with 3 μM NURA or only hyaluronic acid (HA) for 1 h. ET-1 was then added at a final concentration of 1 μM (empty columns) or 10 μM (filled columns), and the ring contraction was determined as in the experiment 1.1 (Fig. 1.2).

Experiment 1.3. Similar to experiment 1.2, but a reduction in tracheal ring was induced with 10 µM Acetylcholine (AcC’11). as shown in FIG. 1.3.

Experiment 1.4. Tracheal rings of guinea pigs (in linear order), immersed in Ringer's solution, were connected to an instrument that measures the length of the chain of rings. CMPE or HEPPE were added to the bath 1 h before stimulation of contraction or with the help of Cr1a1i8a (goh (type II) enzyme or endothelin-1, as shown (Table 1.1).

Table 1.1. Inhibition of contraction of the tracheal rings using SMPE and NERRE

Stimulant Lipid conjugate % inhibition Phospholipase (0.5 μm / ml) (cGoEaFiz asgoh type II) CMRE (10 μm) 100 ± 0.3 Histamine (20 μM) CMRE (10 μm) 69 + 0.1 Histamine (20 μM) NERRE (15 μM) 56 ± 0.05 Endothelin-1 (100 nM) CMRE (10 μm) 92 ± 1,1

Experiment 1.5. Guinea pig tracheal rings were incubated with or without CMPE for 30 minutes before stimulation. The medium was collected after 30 minutes and RFE ₂ and TXB ₂ were determined by radioimmunoassay (Table 1.2). (pb = below the determination threshold.)

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Table 1.2. Inhibition of the production of RFE ₂ and TXB ₂ tracheal tissue using CMPE

Stimulant SMRE pce ₂ (ng / ml) tkhv ₂ (ng / ml) Histamine (40 μM) - 5.1 5,6 Histamine (40 μM) 10 μM η.ά. 1, 75

Experiment 1.6-1.8 demonstrates the ability of lipid conjugates to exert their pharmacological effects on live animals. The following procedures were performed in these experiments.

Male rats Schgeb Wgo \ pack No. r \ yau (4 weeks old) obtained from Nag1an. USA used in this study. All protocols are approved by the Animal Safety Committee of the University of Negeu.

Asthma induction

Asthma was induced in rats by sensitization with albumin (ΟνΑ, 81dta-Veyouo1, Israel) according to the previously described protocol (33): on day O, the rats received one subcutaneous injection of 1 mg of ΟνΑ + aluminum hydroxide (200 mg / ml in 0.9% Ναί'Ί) (81dta-Veyouo1, Israel) and an intraperitoneal injection of 1 ml containing 6x10 ⁹ killed by heating bacteria Boche1e11a Reg1i8818 (Rayeig Mapeeh, France). Repeated bronchial allergization was carried out from 14 days every other day for 1 month by inhalation of ΟνΑ (1 mg / ml in 0.9% saline solution) for 5 minutes each time in a 20 L box connected to an ultrasonic nebulizer (L8 230 8-box νί1Κικιι \ Ό 8ig b1, France).

Treatment

Rats were divided into 4 therapeutic groups:

1. Non-sensitized and not receiving treatment, used as a simple control;

2. Sensitization + allergization with and without treatment, used as a positive control;

3. Sensitization + allergization with ΟνΑ and treatment with lipid conjugates (NURE), or subcutaneous injection (8C), or inhalation, after each allergization (NURE);

4. (in terms of experiments) - Sensitization + allergization with ΟνΑ and treatment with 8C injection of 300 mcg dexamethasone before each allergization (ΟνΑ / Ex). The ΟνΑ / ΟνΑ group received 1 ml of saline before each allergization.

Two methods of treatment for NURE were used: 1. Rats received an 8C injection of 1 ml of saline containing 15 mg of NURE (with about 1 mg / ml body fluid = 20 μM) 2. Rats freely placed in a 20 liter box connected to an ultrasound inhaler, inhaled NURE as follows: 5 ml 1 mg / ml NURE was aerosolized in a 20 L box, thus diluting NURE to 0.25 μg / ml aerosol. The respiratory rate of the rat was 120 breaths / min, with a tidal volume of about 1 ml, thus ventilation reached 120 ml / min. If all inhaled Nure were absorbed in 5 minutes (600 ml were inhaled), the maximum absorbed NURE would be 120 μg.

In method 1, all groups (5 rats each) were treated and allergized as described above on days 14, 16, 18 and 20, and pulmonary function (RemN) was determined on day 20 before and 5 minutes after allergization (ΕΑΒ).

In method 2, each group (10 rats each) was treated and allergized from 14 days, every other day, to 45 days. Pulmonary function (RemN) was determined 20 days before and 5 minutes and 8 hours after allergization, which corresponds to an early and late asthmatic reaction (ΕΑΒ and ΕΑΒ, respectively).

Evaluation of bronchospasm

Rats were freely placed in a chamber plethysmograph (Vihso E1ek1goshsk Shs., Tgou, No. Uogk, υδΑ) connected to a pneumotachometer (ЕМКА ТесЬм ^^ ек, Туре 0000) at one end and with a 10 ml bottle at the other end. The pneumotachometer was connected to the preamplifier (model MAX2270, Vihso E1ekyoshsk). The analog signals from the amplifier were converted into a digital signal using an ΑΌ card (LRM-16, No. 1yug1a1 ShkOiteShk, ΛυδΙιη, Texak, υδΑ). Evaluation of bronchospasm was expressed as an increased pause (Reg111). Peηk = (РΕΕ / РIΕ) * ((Te-Т ^) / Т ^), where PEЕ = peak expiratory flow, РГЕ = peak inspiratory flow, Te = expiratory time, Tg = relaxation time = time to reduce pressure to 36% of total pressure in the box during exhalation.

Broncho-alveolar lavage (YOU)

On day 45, rats were euthanized by bleeding through the abdominal aorta under anesthesia by intraperitoneal injection of pentobarbital sodium (100 mg / kg). Rats were tracheotomized and cannulated through the trachea. Broncho-alveolar lavage (ΒΑΕ) was collected by repeated lung washes with 5 ml of physiological saline with a total volume of 50 ml.

Assessment of airway pathology

After collecting ΒΑΕ, the lungs were removed and filled with 4% buffered formaldehyde at a pressure of 20 cm-NJ. Lobar sections of the lungs were obtained and embedded in paraffin. Histological environment

- 58 012138, 3 microns thick were excised and stained with hematoxylin and eosin to evaluate interstitial and peribronchial inflammation and thickening of the smooth muscle of the respiratory tract. Other sections were filled with trichrome to assess subepithelial fibrosis (basement membrane) and PA8 to assess epithelial cell mucosal metaplasia.

Histological morphometry of the structural changes in the airways was performed using the TshadeG computer program (MH Veshekba I8L) in 3 randomly selected sections from each mouse. Quantification of peribronchial cell infiltrates in the airway tissue was successfully performed by counting the number of these cells in the 50 μm region under the airway epithelium in sections stained with hematoxylin and eosin. Cells were expressed as the number per millimeter of the thickness of the basal membrane of the respiratory tract, which was evaluated by tracking the basement membrane in calibrated digital images (43). Morphometric analysis of L8M and masses of the basement membrane to identify their thickening was performed as described previously (44). Briefly, airway measurements were made by tracking digital images of interest. Images of airway structures were subsequently evaluated. All airways were evaluated by the following morphometric parameters: the thickness of the epithelium of the basal membrane of the airways (Lb) and the L8M region on sections stained with eosin, hematoxylin and the blue color of the basement membrane of sections stained with trichrome. L8M cells or a thickening of the basement membrane were normalized to Lb squares (in ncm ² ) to correct for differences in the size of the airways. Only large (> 2000 μm Lb) and average airway sizes (1000-2000 μm Lb) were selected, since it was shown that the most significant pathological changes occur in these airways.

Expression of 8PBA ₂ Protein in Lung Tissue: Proteins were determined in homogenized lung tissue (100 μg protein) using standard XUeChemLb1o1. Specific polyclonal antibodies against anti-8PBA ₂ (8ap1a Cgik) are diluted 1: 500 (v / v) in ΊΒ8Τ buffer + 0.1% V8L. An immune response was determined by increased chemoluminescence (EC).

Cysteinyl Leukotriene (SuhT)

The level of CKbT was assessed in VL using a kit for direct enzyme immunoassay (HA) according to the manufacturer's instructions (Lshegayat Ryagshas1a B1o (ec1g and K). The specificity of the kit was 100% for LTC4, 100% for L4, 70% for LET4. was from 0 to 48 pg.

Cell culture — cells isolated from VL were suspended in EMEM with an additional 10% fetal calf serum (HS8) and added to a ⁶ -well plate in the amount of 10 ⁶ cells / well. Cells were incubated for 2 hours at 37 ° C, then non-adherent cells were removed by washing with PB8. Adhesive cells were resuspended in EMEM supplemented with 10% PC8 in an amount of 10 ⁶ cells / well and incubated for 48 hours. The culture medium was then collected and analyzed to determine biochemical markers.

The production of nitric oxide - N0, the production of BAB by a macrophage culture was determined by assessing their level in the culture medium using the Specc e) a1 photometric method. (45).

ΤΝΓα Production: The ΤΝΡα BAB production of macrophage culture was determined in the culture medium using radioimmunoassay kits (K1A) (Ategkyat-Ryagataa, IK).

Statistical analysis

All data are expressed as mean ± 8EM. One-way AN0VA analysis was used to compare therapeutic groups. The paired comparison image was performed using the ΤikeuKgateg Η8Ό test (p = 0.05). Where necessary, data were logarithmized prior to analysis to a stable deviation. In all analyzes, P <0.05 was considered statistically significant.

Statistics

Statistical analysis was performed using software (SV-8ΤAΤ, Oupa1shs M | sgo5u51et 811ueg 8rppd ME, I8A). An abnormality analysis (AN0VA) was used to analyze the difference in results between therapeutic groups. The Τikeu test was used to compare between therapeutic groups. A value of p <0.05 was considered as a significant difference.

Experiment 1.6 demonstrates that 8C administration of lipid conjugates significantly alleviates ΟVA-induced bronchospasm (Fig. 1.4, bronchospasm was induced in ΟVA-sensitized rats by 0VA inhalation and was expressed in Repey, evaluated before and 5 minutes after allergization. Each value represented is is an average of ± 8EM for 10 rats, statistical significance: a - P <0.01; b, c - P <0.05), reduces the expression of phospholipase secretion (Fig. 1.5, Fig. depicts HUeChemp L1o1 and the corresponding density measurement & PbA ₂ in pulmonary homogenization those rats with ΟVA-induced asthma treated as shown.In panel B, for each enzyme, the density values were normalized to an appropriate control) and prevents the production of bronchospastic lipid mediators cysteinyl leukotrienes (Fig. 1.6, broncho-alveolar lavage (BAB) was collected from killed experimental animals, and SuKET levels were determined by E [A. as described in the methods. Each value presented represents an average of ± 8EM for 10 rats. Stats

- 59 012138 static reliability: a, b - P <0.01. There is no significant difference between Nure treated and native rats).

Experiment 1.7 (aerosol administration of NURE) demonstrates that treatment of asthmatic rats by inhalation of lipid conjugates protects rats from sensitizing ΟνΑ, since treatment significantly reduces ΑνΑ-induced bronchospasm in both early and late asthmatic reactions (Fig. 1.7, bronchospasm, expressed as percent change RSPN was induced in ΟνΑ-sensitized rats by inhalation of ΟνΑ and measured before allergization and 5 minutes and 8 hours after allergization. 8EM for 10 rats. Two experiments were performed for the FIR. 5 rats were included in each group in the first experiment. The same experiment was repeated with 10 rats in each group, which were then used to determine ΕΑΚ. Combined statistical analysis for ΕΑΚ gave p <0.01 between asthmatic and NUR-treated rats; there is no significant difference between NUR-treated and native or Όχ-treated groups. For ΕΑΚ, p <0.01 between asthmatic and NUR-treated; there is no significant difference between NURPE-treated and native or Όχ-treated groups), inhibits the production of CKbT, a strong bronchospastic lipid mediator (Fig. 1.8, broncho-alveolar lavage (C) was collected from killed rats and CKBT level was determined by EM. Each the presented value is an average of ± 8EM for 10 rats. P <0.01 between asthmatic and NUR-treated rats; there is no significant difference between NUR-treated and native groups) and nitric oxide (ΝΟ), a characteristic smooth muscle cell constrictor (f Ig 1.9, macrophages collected from ΒΑΌ different groups were cultured without further treatment with NURE or Όχ, and ΝΟ the product was determined as described in the methods. Each value represents an average of ± 8EM for 10 rats. The level of ΝΟ decreased when comparing asthmatic and native rats, both by means of NURE, p <0.001 and p <0.001, respectively, and by Όχ p <0.001 and p <0.001, respectively). This therapy also prevented asthma-associated inflammation, which was manifested by preventing inflammatory cell infiltration and remodeling of the airways (Fig. 1.10, the rats were inhaled ΟνΑ every other day for 30 days. For Nure treatment, the rats were inhaled with NURE aerosol for 5 min prior to each allergization, the rats were euthanized on day 45. A — hematoxylinoeosin staining to determine inflammatory cell infiltration and changes in the thickness of smooth muscle cells ( Α8Μ). B - staining of the connective tissue (collagen) with stone trichrome to determine the change in the thickness of the basement membrane. C - staining with the Schiff base of periodic acid (ΡΑ8) to determine the metaplasia of the mucous membrane of the epithelial cells of the respiratory tract. 1, 2, 3 and 4 depict native tissues, asthmatic, Nure-treated and Όχ-treated rats, respectively, and Fig. 1.11) and production of ΤΝΡ-alpha by pulmonary macrophages (Fig. 1.12, macrophages collected from ΒΑΌ different groups were cultured as described in the methods. Each value presented represents an average of ± 8EM for 10 rats. p <0.01 between asthmatic and NUR-treated rats. There is no significant difference between Nurechenny, native and Όχ-treated rats).

Experiment 1.8, in which NURE was given as an aerosol only prior to allergization to rats that were sensitized with ΟνΑ (NURE was not given during sensitization as in Experiment 1.7), demonstrates that inhalation of lipid conjugates is effective in preventing allergen-induced bronchospasm in subjects already suffering from asthma when inhalations are performed prior to allergization (ΟνΑ) (Fig. 1.13, ΟνΑ-sensitized asthmatic rats are inhaled with dispersed Nure (1 mg / ml) for 5 min or with dispersed phi with saline solution 30 minutes later, they were stimulated with ΟνΑ inhalation (1 mg / ml) for 5 minutes, CSP was evaluated before treatment (control) and 5 minutes after each inhalation.Each presented value represents an average of ± 8EM for 5 rats. *, **, p <0.05), and the reverse development of bronchospasm (induction of bronchodilation), when inhalation was carried out after allergization. FIG. 1.14: ΟνΑ sensitization of asthmatic rats was induced by inhalation of ΟνΑ (1 mg / ml) for 5 min. 30 minutes later, they were treated by inhalation with dispersed NURE (1 mg / ml) or dispersed saline for 5 minutes. CSP was evaluated before (control) and after allergization and treatment. Each value presented represents an average of ± 8EM for 5 rats. *, p <0.05.

These experiments demonstrate that lipid conjugates can be used to treat obstructive respiratory disease, reduce airway constriction through a variety of mechanisms, including spasm inhibition and decrease obstructive airway infiltration.

Example 2. Antioxidant Therapy

Lipid conjugates are effective in preventing oxidative damage. This is demonstrated in experiments 2.1-2.3. The harmful effects of peroxide free radicals on living tissue are known as oxidative damage. When the cell membrane is the target of such a damaging process, the result is membrane dysfunction and instability.

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Oxidative damage to blood proteins, in particular blood lipoproteins, leads to their increased accumulation in vascular cells, thus causing atherogenesis. In fact, oxidative cell damage is the main component of the process of maturation or aging.

Oxidative damage to proteins or cell membranes is generally examined by exposure to tissue with hydrogen peroxide produced by the enzyme glucose oxidase (CO) in the absence or presence of additional membrane destabilizing substances, such as PBA ₂ , or by exposure to divalent cations, such as copper.

Experiments 2.1-2.3 demonstrate the ability of lipid conjugates to protect cells from oxidative damage, as believed by the retention of arachidonic acid and intracellular substances of low molecular weight by cells.

Experiment 2.1 .:

Confluent SCM (green monkey cub epithelial cells) were labeled with ³ narachidonic acid. Cells were treated with CMPE for 30 min before treatment with CO and PBA ₂ (0.5 units / ml) (Fig. 2.1).

Experiment 2.2.

BCM cells were labeled with ³⁵ AO ₄ overnight. Cells were washed ΌΜΕΜ (containing 10 mg / ml VZA) 4 times with RVZ. The cells were then incubated in ΌΜΕΜ with the addition of CO (producer H ₂ O ₂ ) for 90, and the culture medium was collected and ³⁵ W radioactivity was counted. For the treatment of CMPE, the cells were incubated with CMPE, with the indicated concentration, for 30 minutes before the introduction of CO. Each value represented is an average of ± 8ΕΜ for 5 repetitions. * p <0.005, ** p <0.001 (Fig. 2.2).

Experiment 2.3.

To demonstrate the ability of lipid conjugates to inhibit the oxidation of blood lipoproteins. ΕΌΌ (0.1 μM) was incubated in the absence and in the presence of various concentrations of ΗΥΓΕ or HA at 37 ° C. At time zero, 5 μM CuCl ₂ was added to the dispersions, and the mixture was continuously monitored for the content of oxidation products at 245 nm (Fig. 2.3). Absorption at 245 (units of optical density, OO) is given as a function of time (8c1shCheg s1 a1., Egee KaLsa1 Βίο1 Μβά 24; 12941303, 1998).

These experiments demonstrate that the administration of lipid conjugates is effective in the prevention of tissue damage caused by oxidative stress (associated with the production of free radicals and hydrogen peroxide) through a variety of mechanisms, including inhibition of lipoprotein oxidation, as well as their absorption, inhibition of arachidonic acid release and maintaining cellular integrity membranes (inhibition of CAS destruction), including red blood cell membranes.

Example 3. Pulmonary injury / acute respiratory distress syndrome (AKO8)

In acute respiratory distress syndrome (AKO8), which is usually caused by bacterial endotoxins (L8, LTA), high production of damaging mediators, in particular neutrophil-attracting chemokines and cytokines, is produced by endothelial cells of pulmonary microvasculature ΑΜνΕί. '). To demonstrate the ability of lipid conjugates to control the production of these damaging substances, ΌΜνΈ ^ were exposed to LB8 (endotoxin of gram-positive bacteria) and LTA (endotoxin of gram-negative bacteria) in the absence and presence of lipid conjugates, and the subsequent production of cytokines and adhesive molecules was studied.

In turn, the endothelial cells of the human pulmonary microvessels (ΕΜνΈ ^) were purchased from S'ePZuCheth Ketadep, Segtapu, at passage 4. Cells were uniformly seeded at a density of 5,000 cells ^- ™ ² in T25 flasks and maintained according to the manufacturer's specifications in ΕCΜ-ΜV. Assessment of ΜVΜC was based on positive staining for the absorption of acetylated L0B, factor νΐΠ-associated with antigen and expression of PECAM (ΟΌ31), as well as negative staining for smooth muscle alpha actin. In each experiment, the viability of LB8- and LTA-stimulated or NURPE-treated ^ VVC was investigated by trypan blue staining. The production and expression of mRNA of cytokines and adhesive molecules was determined as described in US application serial number 10/989606, filed November 17, 2004, which is incorporated herein by reference.

The production of chemokines ΕNΑ-78, Cgo-α, and GE-8 secreted into the culture medium stimulated with ΕΜνΕΟ was evaluated by BUZA in accordance with the manufacturer's instructions.

To isolate RNA and carry out the polymerase chain reaction (PCR) by CT-RAC, the confluent ^ ΜVΕC were stimulated with the medium as a control or LB8 (1 μg / ml) or LTA (10 μg / ml) in the presence or absence of NURE (10 μM ) Total RNA was isolated using trisol reagent in accordance with the manufacturer's instructions. Each RNA preparation was digested with DNase to remove possible impurities of genomic DNA. 1 μg of total RNA was reverse transcribed using Ziregrespr! ΤΜ II Rgeatr1Shsa (ju

- 61 012138 wii with manufacturer's instructions. Amplification of 0.5 μl of cDNA was carried out in a total volume of 2.5 μl containing 19.6 pmol of each chemokine primer, 5 mM άΝΤΡ, 2.5 units. Polymerase Tad, 10 mM Tp8 HC1, 7.5 mM KC1, 1.5 mM MdC1 ₂ . PCR reactions were initiated at 94 ° C for 3 min, followed by 30 amplification cycles, each consisting of: 94 ° C for 1 min, 58 ° C for 1 min, 72 ° C for 2 min. At the end of amplification cycles, the products were incubated for 10 min at 72 ° C. Control samples were created either with the exception of cDNA synthesis, or without the addition of cDNA. PCR products were divided into 1% agar. Real-time PCR: 500 ng of total RNA of each sample was added for reverse transcription to cDNA for real-time PCR analysis using a set of 181 8! Tap ΌΝΑ 8Up е 818 K К according to the manufacturer's instructions (Cosye). cDNA was diluted in 20 μl of OEPC-treated water. DNA chains were generated by PCR amplification of gene products, purification and quantitative analysis by spectrophotometry. Real-time PCR products, such as cDNA samples and DNA strands, are formed in a total volume of 25 μl in the presence of 2 μl of the reaction mixture Bsch11 ss1eg-Eab! 8! Ag1 аз Maz! Eg 8UBK CGEEpB 0.5 μM gene-specific primers and 4 mM MDS1 ₂ . Standard curves were obtained for all chemokines. PCR productivity was analyzed by the slope of the standard curves, and is between 90 and 100%. The concentration of chemokine cDNA was calculated by linear regression analysis for all standard curves and adjusted for a single level of SAREN. At least five reproductive experiments have been performed.

Adhesive molecules K.AM-1 and p-selectin are determined by fluorescently activated cell sorters (EAC8); the confluent Ρ-ΜνΕΟ was stimulated with the medium as a control, or LB8 (1 μg / ml) or LTA (10 μg / ml) in the presence or absence of NUPE (10 μM). Subsequently, the cells were harvested by T / E, washed repeatedly, and monoclonal antibodies directed against the endothelial adhesive molecules of UAM-1 and P-selectin were added at a 1:20 dilution over 30 minutes at 4 ° C. In addition, unstimulated or stimulated cells were harvested as described and preincubated for 20 min with NOPE (10 μM) and anti-TB4 monoclonal antibodies. Cells were washed and incubated with anti-mouse P (ab ') 2, MTS conjugated secondary antibodies. After washing, the cells were examined by EAC8 scanning.

ΝΡκΒ expression was determined by analysis of the electrophoretic mobile shift (EM8A); the confluent ^ ΜVΕC was incubated overnight in a stock medium containing 0.01% B8A. Then they were stimulated or not for various time periods with the help of EP8, HS-1 or T№-a in the presence or absence of NURE and the corresponding nuclear extracts were obtained. Oligonucleotides containing the ΝΡκΒ consensus sequence (5'-AST TCA CCC CAC TTT CCC ACC C-3 '), DNA was labeled to a specific activity> 5x10 ⁷ cpm / μg. ΝΡκΒ-binding was carried out in 10 mM HEPE8, (pH = 7.5), 0.5 mM EETA, 70 mM KCl, 2 mM ΌΓΓ, 2% glycerol, 0.025% No.-40, 4% Iso11, 0.1 M PM8E , 1 mg / ml B8A and 0.1 μg / ml poly άί / ys in a total volume of 20 μl. Nuclear extracts (10 μg) were incubated for 30 min at room temperature in the presence of 1 ng of labeled oligonucleotide. DNA-protein complexes were separated on 5% non-denatured polyacrylamide gels by electrophoresis in a low-ionized buffer and visualized by autoradiography. Specific shear bands are demonstrated by the addition of cold ΝΡκΝΡ or C consensus sequences using anti-p65 antibodies for super-shift.

Experiment 3.1 demonstrates that lipid conjugates are effective in suppressing endotoxin-induced production and expression of ^ -8, ^NΑ-78 and Cgo-α chemokines RNA and their mRNA expression, as shown in FIG. 3.1, 3.2 and 3.3.

Experiment 3.2 demonstrates that lipid conjugates are effective in suppressing the expression of adhesive molecules of YuAM-1 and E-selectin (Fig. 3.4).

Experiment 3.3 demonstrates that lipid conjugates are effective in suppressing the expression of ΝΡκΒ, a transcription factor that increases in the endotoxin-induced state of damage (Fig. 3.5).

The obtained results additionally demonstrate the therapeutic usefulness of lipid conjugates in the treatment of AKE8 and pulmonary damage, as well as other diseases having common mechanisms, such as peritonitis, renal failure, organ transplantation, etc.

Example 4. The study of toxicity

Experiment 4.

The following compounds were tested: NURE, CMPE, C8APE and NerRE. Compounds were administered as P injections in a single dose of 1000, 500 or 200 mg / kg body weight. Toxicity was evaluated after a week by determining mortality, body weight, hematocrit, blood counts (red blood cells and white blood cells) and visual examination of internal organs after opening. Data were compared with control untreated mice. Each dose was applied to a group of 3 mice. No significant changes in the above criteria induced by treatment with these compounds were observed, except for NerRE, which caused bleeding.

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Non-toxicity of lipid conjugates is shown in table. 4.1 and tab. 4.2, representing the results obtained for Nure in studies of acute (4.1) and (4.2) delayed toxicity.

Table 4.1. Acute toxicity

Dose Nure (mg / kg body weight) Body weight (g) Pic 10 x ⁶ willow X 10 ³ Hematocrit 0,0 (the control) 21.9 ± 0.2 22.6 + 0.3 10.7 ± 0.4 9.3 ± 0.3 45.0 ± 0.5 250 22.1 ± 0.4 23.1 + 0.6 11.4 + 0.1 7.7 + 0.2 43.3 + 0.7 500 21.4 + 0.3 22.3 ± 0.4 11.5 ± 0.3 8.1 ± 1.3 44.7 + 2.3 1000 21.7 + 0.2 22,110,2 10,910,4 7,410.6 40.3 ± 0.7

FAC = red blood cells. ABC = white blood cells. Each value represented is an average of ± 8EM.

To study the delayed toxicity of NURE, a group of 6 mice received a dose of 100 mg NURE / kg body weight administered by 1P injection 3 times a week for 30 weeks (a total of 180 mg per mouse, weighing 20 g). Toxicity was evaluated as for table. 4.1. There is no mortality and no significant changes induced by this treatment compared to healthy untreated mice (see table. 4.1), as shown in table. 4.2.

Table 4.2. Results after 30 weeks

Body mass (g) CEFAJ ⁶ IVSHU ³ Hematocrit % Control (untreated rats) 39.5 ± 3.1 10.9 ± 0.8 9.3 + 0.6 45.0 ± 0.8 Well processed rats 39.0 + 2.7 11.7 ± 0.7 8.1 + 15 43.4 ± 4.9

Example 5. Synthesis procedures

The procedures below are examples of the synthesis of various specific lipid conjugate variants and can be modified in accordance with the desired compositions (for example, changing the molar ratio between lipid / phospholipid and CAC or CAC size).

I. NURE = phosphatidylethanolamine (PE) -linked hyaluronic acid.

A. Truncated Hyaluronic Acid (HA)

Dissolve 20 g of HA in 12 L of water, add 200 mg of EtO ₄ -7H ₂ O, dissolved in 20 ml of water, add 400 ml of H ₂ O ₂ (30%), stir for 1.5 hours. Filter through 30 kDa. ΕίΙΐΓοη . Lyophilized. Yield: 16 g of truncated HA.

B. Conjugation with PE (per 1 g)

Receiving:

1. 10 g of HA are dissolved in 500 ml of ME8 buffer, 0.1 M, pH = 6.5.

2. 1.0 g of PE is dissolved in 500 ml of t-ViOH with 100 ml of H ₂ O.

Two solutions are mixed, 1 g of HOBT and 10 g of EES are added. It is treated with ultrasound in an ultrasonic bath for 3 hours. The excess of free PE (both EES and HOBT) is removed by extraction into the organic phase (by adding chloroform and methanol to obtain the ratio C / M / H ₂ O: 1/1/1). The aqueous phase is separated by means of a separation funnel. Repeat this step twice. For final purification from reagents, they are filtered through a Είΐίτοη membrane (30 kDa) and lyophilized.

Yield: approximately 8 g.

II. C8APE = PE-linked chondroitin sulfate A (C8A)

Receiving:

1. 10 g of C8A are dissolved in 1.2 L of ME8 buffer, 0.1 M, pH = 6.5.

2. 1 g of PE is dissolved in 120 ml of chloroform / methanol: 1/1. Add 15 ml of detergent (IIAI).

Mix 1 with 2, with stirring, add 1 g HOBT and 10 g EES. continuing to mix thoroughly for at least a day. The excess of free PE (both EES and NOVT) is removed by extraction into the organic phase (by adding chloroform and methanol to obtain

- 63 012138 solutions of chloroform / Ме0Н / Е1: 0Н / Н ₂ 0: 1/1 / 0.75 / 1). The aqueous phase is separated by means of a separation funnel. Repeat this step twice. Filter through a Είΐίτοη membrane (30 kDa) and lyophilize. To remove traces of ΌΌΆΒ, 1 g of dry product is dissolved in 100 ml of water and 100 ml of MeOH and purified by ion exchange using GK120 resin. Dialyzed (to remove MeOH) and lyophilized.

Yield: approximately 8 g.

Unexpected results show that the ultrasonic treatment used in the synthesis of NURE is the best substitute for detergent when mixing the aqueous and lipid phases. The use of ultrasonic treatment methods simplifies the synthesis and improves the purification of the product.

Specialists in this field it is clear that the present invention is not limited to what is specifically shown and described above in this description, and that there are numerous modifications, all of which fall within the scope of the present invention. To a greater extent, the scope of the invention is defined by the claims below.

Claims (8)

CLAIM 1. The compound represented by the structure of General formula (A) b — Ζ —- Υ-Χ - - * p (A) where b is a lipid or phospholipid; Ζ is either absent or is ethanolamine, serine, inositol, choline or glycerin; Υ either absent or a spacer group having a length in the range of 2-30 atoms; X is a physiologically acceptable monomer, dimer, oligomer or polymer, and η is a number from 1 to 1000, for the treatment or prevention of allergic rhinitis or chronic obstructive pulmonary disease. 2. The compound according to claim 1, where X is a polysaccharide. 3. The compound of claim 2, wherein said polysaccharide is carboxymethyl cellulose. 4. The compound according to claim 2, where the specified polysaccharide is a glycosaminoglycan. 5. The compound according to claim 4, where the specified glycosaminoglycan is hyaluronic acid. 6. The compound according to claim 4, where the specified glycosaminoglycan is heparin. 7. The compound according to claim 1, where b is phosphatidylethanolamine. 8. The compound of claim 7, wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine.