JP2001518062A - Treatment of pulmonary fibrosis - Google Patents

Abstract

  (57) [Summary] Provided are compositions for treating pulmonary fibrosis and methods of using and making the compositions. The composition includes a quinazolinone derivative, preferably halofuginone. A preferred method of administration is by inhalation, preferably with a pharmaceutically acceptable carrier in the form of an aerosol.

Description

DETAILED DESCRIPTION OF THE INVENTION                              Treatment of pulmonary fibrosisField and background of the invention   The present invention relates to the treatment of pulmonary fibrosis, in particular quinazolinone derivatives such as halofuginone. It relates to the treatment of pulmonary fibrosis used.   Pulmonary fibrosis causes interstitial connective tissue to accumulate in the lungs, reducing lung function and gas exchange efficiency It is a chronic and incurable disease [S. Phan, New Strategies fo r Treatment of Pulmonary Fibrosis, 50 : 415-421, 1995]. Fibrous tissue increases the surface area of gas exchange in the lungs. It replaces more complex lung tissue with a pathological process that continuously reduces it. Lung fiber Syndrome often occurs after intervention such as bone marrow transplantation, radiation therapy and chemotherapy [N Agler, A. et al. Et al., Am. J. Respir. Crit. Care Med. , 154: 1082-1086, 1996]. Reasons given in more detail below Thus, the disease often results in death.   The etiology of pulmonary fibrosis involves the formation of fibrotic tissue in the lungs. The formation of fibrotic tissue is different It is characterized by a constantly high amount of collagen deposition. Collagen synthesis is another It is also involved in many pathological abnormalities. For example, systemic sclerosis, graft-versus-host disease (G VHD), primary and secondary diseases such as lung and liver fibrosis and various autoimmune diseases Clinical abnormalities and diseases associated with secondary fibrosis include normal tissue structure and function. Distinguished by excessive production of connective tissue that results in destruction. These diseases are excessive Best in terms of disruption of cell function, where severe collagen synthesis and deposition are the primary manifestations Can be interpreted. Key role of collagen in fibrosis impedes its accumulation Prompted the attempt to develop harmful medicines [K. I. Kivirikko, A nnals of Medicine, Vol. 25, pp. 113-126 ( 1993)].   Such medicaments are regulated by regulating the synthesis of procollagen polypeptide chains. Reduced or extracellular collagen fiber formation or accumulation of fibers with altered properties Can act by inhibiting certain post-translational processes that lead to either You. The Importance of Collagen to Maintain Tissue Integrity and Collagen for Various Diseases Unfortunately, despite the involvement of genogens, two to three types of synthesis of this protein Inhibitors are only available.   For example, cytotoxic drugs, e.g., slow collagen secretion into the extracellular matrix. Colchicine [D. Kershenobich et al. Engl. J. Me d., 318: 1709, 1988], and inhibition of important collagen metabolizing enzymes Agent [K. Karvonen et al. Biol Chem., 265: 8414, 1. 990]; J. Cunlife et al. Med. Chem., 35: 265. 2,1992] was used in an attempt to slow the growth of collagen-produced fibroblasts. [J. A. Casas et al., Ann. Rhem. Dis., 46: 763. 1987].   Unfortunately, none of these inhibitors are specific for collagen type No. Also, for example, Clq in the classical complement pathway, aceti of neuromuscular junction endplates Lecholinesterase, conglutinin and alveolar surfactant apoprotein Serious concerns about the deleterious consequences that interfere with the biosynthesis of other essential collagen molecules, such as I have a mind.   Other drugs that can inhibit collagen synthesis such as nifedipine and phenytoin Similarly, inhibiting the synthesis of other proteins blocks the collagen biosynthesis pathway. [T. Salo et al. Oral Pathol. Med., 19: 404. , 1990].   Collagen crosslinking inhibitors such as β-amino-propionitrile are also non-specific, , They can work as useful antifibrotic agents. Use them for a long time And elastin, another fiber connective tissue protein, is also crosslinked, Causes lathritic syndrome and elastosis Interfering with genesis. Furthermore, this collagen crosslinking inhibitory effect is secondary, and Overproduction of lagen must occur before its degradation by collagenase . Therefore, type-specific inhibitors of the synthesis of collagen itself have been identified as antifibrotic agents. Crab is required.   Such a type-specific collagen synthesis inhibitor is used in rice to treat fibrosis disorders. It is disclosed in U.S. Pat. No. 5,449,678. This specific inhibitor has the formula : (Where R₁Is hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower A member of the group consisting of alkoxy, R_TwoIs a member of the group consisting of hydroxy, acetoxy and lower alkoxy And R_ThreeIs a member of the group consisting of hydrogen and lower alkenoxy-carbonyl. ) A pharmaceutically effective amount of a pharmaceutically active compound and a pharmaceutically acceptable salt thereof. Composition. Of this group of compounds, halofuginone is particularly effective for such treatments. It turned out to be fruitful.   U.S. Pat. No. 5,449,678 states that these compounds provide scleroderma and GVHD. It is disclosed that it is effective for treating fibrosis disorders such as fibrosis. Furthermore, WO application No. 96 / 06616 is effective for treating these compounds calstenosis Disclose that. These two abnormalities are due to the excess amount of halofuginone inhibited Associated with Lagen deposition. Restenosis occurs in the lumen of the affected vessel , Characterized by smooth muscle cell proliferation and extracellular matrix accumulation against vascular injury [Choi et al., Arch. Surg., 130: 257-261, 1 995]. One characteristic of such smooth muscle cell proliferation is a normal contractile phenotype. Of the phenotype to the created phenotype. Type I collagen is Has been shown to support the phenotypic alteration that can be blocked by Non [Cho i et al., Arch. Surg., 130: 257-261, 1995; U.S. Patent No. 5,449,678].   However, due to the in vitro effects of halofuginone, its in vivo effects are necessarily It is not predictable. For example, Halofuginone is disclosed in US Pat. No. 5,449. No. 678, Collagen-type synthesis in bone chondrocytes Is inhibited in vitro. However, chickens treated with halofuginone have It has not been reported to have an increased rate of destruction and its effects are not seen in vivo. Is not shown. Therefore, the exact in vivo behavior of halofuginone is It is not always possible to predict exactly from Nbittro's research.   In addition, halofuginone or other related quinazolinones are associated with pulmonary fibrosis. The ability to block or inhibit pathological processes has been described in one document [Nagler , A. Et al., Am. J. Respir. Crit. Care Med., 154: 1082-1086, 1996], but the prior art does not know otherwise. Not been. Halofuginone specifically inhibits the synthesis of type I collagen Although shown to be effective, such inhibition would otherwise be a treatment for pulmonary fibrosis. Has not been shown otherwise to be effective. Available treatment options currently available It has significant side effects and is usually available to slow or stop the progression of fibrosis. In fact, pulmonary fibrosis has a high mortality rate because it is not effective [Nagler, A .; La , Am. J. Respir. Crit. Care Med., 154: 1082 -1086, 1996]. For example, steroids, penicillamine, colchicine, Luquilizing agents, non-steroidal anti-inflammatory drugs, antioxidants and immunosuppressants It has been shown to be largely ineffective in slowing or stopping the progression of the disease ing. Most other drugs such as protease inhibitors and cell adhesion factors Is nonspecific and has potentially dangerous side effects. As mentioned above, Various inhibitors of the process of genogen production have been tried against pulmonary fibrosis, Had a specific effect [S. H. Phan in Lung Cell B iology, D.E. Edited by Massaro, Marcel Dekker, New York, 1989, p. 907-979].   Thus, collagen synthesis, deposition or cross-linking in an attempt to treat pulmonary fibrosis Simply administering a known in vitro inhibitor is not effective. Obviously, non Specific delay or cessation of fibrotic disease without specific or adverse side effects A new treatment for this incurable disease is needed to stop it.   Thus inhibiting disease development without unwanted non-specific or toxic side effects There is a well-recognized need for pulmonary treatment, and having such treatment is high Will bring significant advantages.Summary of the Invention   Halofuginone may be involved in other mechanisms, but probably Inhibits the pathophysiological processes of pulmonary fibrosis by inhibiting type I synthesis It was unexpectedly discovered that it could be inhibited by vivo. Collagen tie Inhibition of peptide synthesis has been reported as a plausible mechanism, while Limiting to a mechanism is neither desirable nor necessary. Because shown below Data reveals efficacy of halofuginone as an inhibitor of pulmonary fibrosis in vivo This is because   According to the teachings of the present invention, (Where R₁Is hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and low A member of the group consisting of R_TwoIs a member of the group consisting of hydroxy, acetoxy, and lower alkoxy. And R_ThreeIs a member of the group consisting of hydrogen and lower alkenoxy. Group with And a pharmaceutically effective amount of a compound that is a member of their pharmaceutically acceptable salts. A combination for treating pulmonary fibrosis, combined with a biologically acceptable carrier Success Things are provided.   According to a further preferred embodiment of the invention, the compound is preferably halofugino It is. The composition is preferably a pharmaceutically acceptable carrier for the compound. Have Most preferably, the composition is administered to lung tissue, for example as an aerosol Is done.   According to another embodiment of the present invention, (Where R₁Is hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and low A member of the group consisting of_TwoIs hydroxy, acetoxy and A member of the group consisting of lower alkoxy, and R_ThreeIs hydrogen and lower alk A member of the group consisting of nonoxy-carbonyl. ) And their pharmacy A pharmaceutically effective amount of a compound that is a member of a pharmaceutically acceptable salt. A method for producing a medicament for treating pulmonary fibrosis, comprising the step of placing in a carrier. Provided.   According to yet another embodiment of the present invention, (Where R₁Is hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and low A member of the group consisting of_TwoAre hydroxy, acetoxy, and And a member of the group consisting of_ThreeIs hydrogen and lower It is a member of the group consisting of kenoxy-carbonyl. ) And their pharmaceutically acceptable Administering to the subject a pharmacologically effective amount of the pulmonary fibrosis in the subject. A method of treatment is provided.   Here, the term "subject" refers to a human or lower animal to which halofuginone has been administered. Means The term "patient" means a human subject. The term "pulmonary fibrosis" It refers to a fibrosis disorder of the subject's lungs or respiratory tract. The term "treatment" refers to pulmonary fibrosis Once it has occurred, it substantially disrupts the pulmonary fibrosis process from the beginning, And slowing or stopping the progression of pulmonary fibrosis.   Hereinafter, the term “oral administration” refers to administration by mouth, buccal for absorption by the gastrointestinal tract. Administration, including but not limited to sublingual administration.   Compositions for oral administration include powders or granules, suspensions in aqueous or non-aqueous media. Or a solution, a packet, a capsule or a tablet. Thickeners, diluents, seasonings, Dispersing aids, emulsifiers or binders may be desirable.   The term "parenteral administration" refers to intravenous infusion or intraperitoneal, subcutaneous, or intramuscular Administration including, but not limited to, injection.   Preparations for parenteral administration may contain buffers, diluents and other suitable additives. Sterile aqueous solution, but is not limited thereto.   “Halofuginone,” a specific quinazolinone derivative, is referred to throughout this specification. It is understood that other quinazolinone derivatives may be used instead. I want to. These derivatives have the formula: (Where R₁Is hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower A member of the group consisting of alkoxy, R_TwoIs hydroxy, acetoxy and low A member of the group consisting of_ThreeIs hydrogen and lower alkeno A member of the group consisting of xy-carbonyl. ) And pharmaceutically acceptable salts thereof Having.   BRIEF DESCRIPTION OF THE DRAWINGS The invention will be better understood with reference to the following drawings and examples, in which the features are fully understood. Although described in connection with specific embodiments, the present invention is not limited to these particular embodiments. It is not intended to be. On the contrary, the invention as defined in the appended claims. Is intended to cover all alternatives, modifications and equivalents included in the scope of ing. Thus, the following drawings and examples, including preferred embodiments, are illustrative of the invention. The purpose of the present invention is to specifically explain the application, the details of which are given as examples and of the present invention. It is provided for the purpose of illustration of the preferred embodiment only, Procedures and the most useful and easily understood description of the principles and conceptual features of the present invention; It should be understood that they have been introduced to provide what seems to be possible.BRIEF DESCRIPTION OF THE FIGURES   The present invention will now be described by way of the accompanying drawings, which are shown by way of example only.   FIG. 1 shows the effect of halofuginone on hydroxyproline concentration in rat lung. It is a graph which shows a result.   FIG. 2 shows the effect of halofuginone on protein concentration in rat lung It is a graph.   FIG. 3 shows halof versus hydroxyproline / protein ratio in rat lung. It is a graph which shows the effect of Guinon.   FIG. 4 is a graph showing the effect of halofuginone on DNA levels in rat lung. It is rough.   FIGS. 5A and 5B show histologically stained bleomycin-treated rats. 2 shows a section of a lung taken away.Description of the preferred embodiment   As described in the examples below, halofuginone is involved in another mechanism. But probably by inhibiting collagen type I synthesis Remember that the pathological process of pulmonary fibrosis can be inhibited in vivo It was discovered without. In fact, regardless of the specific mechanism, the data shown below Reveals in vivo efficacy of halofuginone in inhibiting pathological progression of pulmonary fibrosis It is clearly shown.   Such a discovery is unexpected for three reasons. First, Halofugi Non in vitro behavior does not exactly correspond to its in vivo behavior. No. This was observed in vivo and in vitro using bone chondrocytes. This can be shown by the distinct effect of lofuginone. US Patent No. 5,449,6 As shown in No. 78, halofuginone is a collagen type I in chondrocytes. Inhibits synthesis of in vitro. However, chickens treated with Halofuginone Has not been reported to have an increased rate of bone destruction, and its effects are Indicates that it cannot be seen. Thus, the correct in vivo behavior of halofuginone Is not always exactly predictable from in vitro studies.   Second, other inhibitors of collagen synthesis, deposition and cross-linking may be used in the treatment of pulmonary fibrosis. Inhibition of collagen production alone, which has not been proven effective, is a cure for pulmonary fibrosis. It is insufficient to determine the success or failure of treatment. Therefore, c New finding that lofuginone can successfully suppress pulmonary fibrosis in vivo Regular and non-trivial.   For example, Nagler's reference [Nagler, A. et al. Et al., Am. J. Respi r. Crit. Care Med., 154: 1082-1086, 1996]. Apart from the prior art, the prior art shows that halofuginone is useful for treating pulmonary fibrosis in vivo. Did not teach something. In addition, halofuginone and related compounds in the lungs The ability to slow or stop the progression of fibrosis is new and nonobvious. Imbi Given the differential response to halofuginone found in toro and in vivo For example, it is not expected to show such a capability in vivo.   The present invention will be more readily understood from the following illustrative examples and figures. C Although only Lofginone is mentioned, the teaching content is incorporated herein by reference. Other quinazos described and claimed in U.S. Pat. No. 3,320,124, incorporated herein by reference. Note that the linone derivatives are believed to have similar properties.   The present invention is also applicable to the treatment of pulmonary fibrosis with quinazolinone-containing compounds such as halofuginone. Related. Compositions using specific pharmaceutical preparations and methods using these compounds This will be described below.   Although the etiology of pulmonary fibrosis is not fully understood, animal models of the disease Development is successful. Pulmonary fibrosis is induced in rats by parenteral administration of bleomycin Led. Interestingly, bleomycin is used as a chemotherapeutic [Nagler, A .; Et al., Am. J. Respir. Crit. Care Me d., 154: 1082-1086, 1996]. As mentioned above, chemotherapy is Is one of the causes of pulmonary fibrosis. Therefore, the bleomycin model Available directly or specifically for treatment-induced idiopathic pulmonary fibrosis; It is a more general example of the etiology of the disease.   Pulmonary fibrosis induced by bleomycin is associated with inflammation of the lower respiratory tract, interstitial edema and lung Characterized by inflammation of alveollar injury. This capillary damage is then This results in the entry of di, mast cells and inflammatory cells into the alveolar space. Then increase Proliferation and activation of failed fibroblasts is associated with increased interstitial deposition and increased collagen type I. And fibrosis [Nagler, A. et al. Et al., Am. J. Respir. Cr it. Care Med., 154: 1082-1086, 1996]. Therefore, As in bleomycin-induced and other types of pulmonary fibrosis Fibrosis suppression depends on the delay or cessation of the pathological processes that lead to the production of fibrotic tissue. Exist.   Therefore, compounds intended to suppress pulmonary fibrosis lead to the deposition of fibrotic tissue The above blurs about their ability to slow or stop the pathological process Must be tested in an in vivo model, such as the omycin model. Like that Examples of experiments include collagen tying as described in more detail in Examples 1-3 below. The test was performed for Halofuginone, a pu I synthesis inhibitor.   Furthermore, once a very clear and effective compound is found, Agents and routes of administration must be elucidated for maximum efficacy of treatment. Made like that The agent and the route of administration will effectively absorb and transport the compound to the desired site of treatment. On the other hand, non-specific side effects caused by the systemic distribution of the compound are minimized. It must be small. Quinazolinone-containing compounds such as halofuginone The following specific examples illustrate these formulations and routes of administration for Examples 4 to 6 are shown.                                 Example 1 Effects of halofuginone on biochemical markers in rat lung   Experimental methods for in vivo studies and specific biochemical markers in lung tissue Specific effects of Halofuginone are shown below. Basically, Halofuginon is a bleo Inhibits increased collagen levels induced by mycin, which translates into diverse biochemistry Marked by marker. The specific experimental method is as follows.   Eighty male Sabra rats weighing 350-400 g were placed in 4 And divided into soups. The first group was a control group without any injections. No. The second group received intraperitoneal injections of bleomycin at 5 mg / kg body weight for 7 consecutive days Was. The third group received an intraperitoneal injection of halofuginone at a total dose of 5 mg per rat. Performed every second day for the duration of the experiment. The fourth group is bleomycin and halo Separate intraperitoneal injections of fuguinone with the above doses in separate syringes after a two hour interval I went in.   All rats were fed a constant diet and had free access to drinking water. Rat weight And food intake were monitored over the entire experimental period. 10 animals from each group Rats were sacrificed after 4 and 6 weeks with an overdose of pentobarbital. Kill the lungs Rats were removed and washed with phosphate buffered saline. One lung with liquid nitrogen Immediately frozen and lyophilized for analysis of hydroxypurine concentration. Dried All lower right lobes were weighed, finely ground and homogenized with distilled water. Next, set The fabric was boiled for 30 minutes in distilled water. After cooling and centrifuging, extract the tissue residues, It was subjected to a second cycle of the boiling and centrifugation process. The two supernatants are then pooled and Coats were taken for hydroxyproline concentration and protein level analysis.   Hydroxyproline was added to the aliquot with 6N HCl at 138 ° C. for 3 hours. After being subjected to acid hydrolysis, the Stemmann and Stalder assay [H . Stephenmann, and K.C. Stalder, Clin. Chim. Ac ta, 18: 267-273, 1967]. Dry tissue weight results It is shown in FIG. 1 as micrograms of hydroxyproline per 1 mg amount. Tan Protein levels were determined by the Bradford assay [M. Bradfor d, Analyt. Biochem., 72: 248-254, 1976]. Hid The roxyproline / protein ratio was determined from samples taken from the same aliquot.   Hydroxyproline is an amino acid present in collagen in relatively large amounts And is used as an indicator of the overall level of collagen in a particular tissue. So the figure As shown in Figure 1, bleomycin was killed 4 or 6 weeks later. Apparently, hydroxyproline levels (and thus collagen levels) Le) caused a significant increase. This increase was completed by treatment with Halofuginone. Totally inhibited. However, in rats that did not receive bleomycin, Halofuginone administration did not cause changes in hydroxyproline concentration . Therefore, the effect of halofuginone is simply the variation in hydroxyproline concentration. It was to inhibit omycin-induced increase.   FIG. 2 is a graph showing the effect of halofuginone on protein concentration in rat lung. is there. Again, bleomycin was found to be in the lung protein of animals killed after 4 or 6 weeks. Caused a significant increase in quality level. Halofuginone is the lung of an animal killed 4 weeks later Once again completely inhibited the bleomycin-induced increase in No such inhibition was seen in tissues taken from animals killed after 6 weeks .   FIG. 3 shows halof versus hydroxyproline / protein ratio in rat lung. It is a graph which shows the effect of Guinon. Again, bleomycin treatment was observed in rat lungs. Caused a significant increase in the hydroxyproline / protein ratio and increased It was shown that protein synthesis was mainly due to increased protein synthesis. Halofugi Non reduces this ratio to the level found in tissue taken from control rats. Was. Thus, apparently, halofuginone is not induced by bleomycin in rat lungs. The increased levels of induced collagen synthesis were completely inhibited. But halo Fuginone alone has no appetite-decreasing effect in rats, and the effect of halofuginone is It was shown to be specific for inhibiting gen synthesis.                                 Example 2 Effect of Halofuginone on DNA Level   Experimental method for the effect of halofuginone on DNA levels in rat lung and The results are shown. Basically, a significant decrease in DNA levels is induced by bleomycin Was done. However, this reduction was abolished by Halofuginone. The experimental method is It is as follows.   Lung tissue from four groups of rats was stopped when its preparation was at the time of lyophilization of the tissue Prepared as described in Example 1 except as noted. The amount of DNA in dry lung tissue is B urton's method [K. Burton, Meth. Enzymo I., XII-B: 163-166, 1968]. Results per mg of dry tissue weight Are shown in FIG. 4 as micrograms of DNA.   As shown in FIG. 4, bleomycin was killed at 4 or 6 weeks in rats. Caused a significant decrease in DNA levels in lung tissue taken from Halofuginone Eliminated this decrease in DNA levels in bleomycin-treated rats, Effect on DNA levels in rats not treated with bleomycin I had no fruit.   Previous in vitro studies using cultured fibroblasts have shown that bleomycin has It was shown to reduce DNA levels in these cells soon [Nagler, A. Et al., Am. J. Respir. Crit. Care Med., 154: 1 082-1086, 1996]. Therefore, this effect of bleomycin was Matches well with the fruit. Halofuginone's ability to eliminate this bleomycin-inducing effect Overall Of bleomycin for inhibition of experimental fibrosis processes and DNA levels May be associated with both corresponding inhibitions of the effect. Involved in the mechanism Halofuginone, DN in mice not treated with bleomycin Specific elimination of this bleomycin-inducing effect without altering A levels .                                 Example 3 Effects of halofuginone on tissue and morphology of rat lung   Rats were treated as described in Example 1 and then sacrificed. Further details in this embodiment Take one lung for biochemical analysis and combine the others as described in detail. Taken for woven tests. Histological examination showed that bleomycin had spread pneumonia Induces certain morphological changes in rat lung, such as and thickened alveolar walls. I made it clear. Halofuginone prevents these changes from happening, The air space of the usual appearance was brought. The experimental method is as follows.   Lungs taken for histological examination were fixed with Carnoy after removal from rats Placed in the preparation. Next, the lung fixed with Carnoy was buried in paraffin, A 6 mm thick tissue section cut from the apex, middle and lower extremities of the left lung did. Next, these sections were cloned into a monoclonal antibody against rat mast cell chymase. Incubate with antibody and use alkaline phosphater to detect antibody And hematoxylin-eosin for morphological determination. Was.   Figures 5A and 5B show stained sections of lungs from bleomycin-treated rats. You. The tissue shown in FIG. 5A was treated with bleomycin alone and killed 6 weeks later. From the public. Spread pneumonia and thickened alveolar walls are clearly visible Morphology caused by fibrosis process induced by bleomycin It shows the target change. Such a change was observed in both halofuginone and bleomycin. 5B, which shows lung tissue taken from rats treated with. Instead, an air space having a substantially normal form can be seen. Khalov Guinone's effects prevent morphological changes made during the pathological process of fibrosis And clearly specific.                                 Example 4 Formulations suitable for Halofuginone administration   Halofuginone can be administered to a subject in a number of ways well known in the art. it can. Various administration routes such as oral and parenteral administration are possible, The most preferred route of treatment is by inhalation, either nose, mouth or both . This is preferred for a number of reasons. First, inhalation is Halofuginone or other The affected tissue directly against a pharmaceutical composition containing the quinazolinone derivative of Would be possible. Second, such direct exposure is systemic Minimizing absorption and minimizing potential side effects. Therefore, the transportation of drugs to the lungs Inhalation is more comparable to topical application to the skin in terms of systemic exposure You. Third, direct exposure should treat virtually all halofuginones Minimize the amount of halofuginone needed for treatment because it will be sent to the tissue . In fact, the dose given to rats (5 mg / kg) was extrapolated to the average human subject Then about 1/2 gram is required, which is large for administration and potentially Will reduce the compliance of the elderly. Fourth, direct exposure already exists in the lungs Can be particularly important for patients with significant fibrotic tissue. Because this group The weave does not have the normal structure of the capillary network and has a halo to the tissue to be treated. This is because it potentially reduces the ability of the blood vessels to transport fuginone. Fifth, Inhalation of the pharmaceutical composition allows for a rapid onset of the therapeutic effect. Finally, other routes of administration Could prove inconvenient for a variety of reasons. For example, in the above experiment Intraperitoneal delivery by infusion is inconvenient for regular administration of halofuginone . The efficacy of oral halofuginone has not been confirmed in rats and lower animals , Has never been tested in humans. In addition, patients receiving chemotherapy Chemotherapy causes severe nausea and cough in some human subjects Oral administration is quite problematic. Therefore, administration of Halofuginone by inhalation Avoid many of these problems on other routes.   For administration by inhalation, halofuginone can be administered, for example, with an air nebulizer or an ultrasonic nebulizer. Could be administered in the form of an aerosolized formulation. Or, and preferably, haloff Guinone is suspended in ultrafine form in a fluorocarbon propellant solvent and the Can be transported in a pressurized metal container. After aerosolization, the propellant solvent Most are lost due to instantaneous evaporation and replaced by moisture in the respiratory tract This leads to the deposition of granular particles. However, both of these methods release halofuginone. It relies on deposition into the respiratory tract of the shape.   An alternative and preferred method is to use liposomal aerosols for drug delivery. And Examples of such aerosols are described in PCT application WO 86/01714. It is shown. Halofuginone is trapped in liposomes and then converted to an aqueous solution. It will be suspended and transported by metal containers or other metered dose systems. Further A specific example of drug delivery by inhalation is described in US Pat. No. 5,340,587. ing.   Regardless of the route of administration, the dosage depends on the severity of the symptoms and It depends on the responsiveness. Persons skilled in the art can easily determine optimal dosage, administration method and repetition rate. Can be determined.                                 Example 5 How to treat pulmonary fibrosis   As mentioned above, halofuginone has been shown to be an effective inhibitor of pulmonary fibrosis. Was. The following examples are merely illustrative of how Halofuginone treats pulmonary fibrosis. It is not intended to be limiting.   The method is performed in a pharmaceutically acceptable carrier as described in Example 4 above. Administering halofuginone to the subject to be treated. Halofuginone is preferred Or until a predetermined endpoint is reached, such as a lack of further progression of pulmonary fibrosis in the subject. And is administered by an effective administration method.   Examples of the types of pulmonary fibrosis for which such treatments are effective include bone marrow transplantation, radiation therapy Pulmonary fibrosis following treatment intervention after chemotherapy and chemotherapy, but not limited to No. Other examples include contact with harmful drugs, inflammation, tumors, toxic substances, autoimmune diseases , Vasculitis, trauma, postoperative effects, genetic disease, scleroderma, cytomegalovirus Chemical compounds such as Ruth's disease, lung grafts, burns, congenital malformations and monocrotaline Pulmonary fibrosis caused by the disease.                                 Example 6 Process for producing a drug containing halofuginone   The following is a specific example of a method for producing halofuginone. First, Halofuginone Is synthesized in accordance with valid pharmaceutical manufacturing practice. Specific examples of the synthesis of halofuginone And related quinazolinone derivatives are shown in U.S. Pat. No. 3,338,909. . The halofuginone was then replaced with the above example, again according to a legitimate pharmaceutical manufacturing practice. Place in a suitable pharmaceutical carrier as described in 4.   The above description is intended to serve as an example, and may contain many other examples. It will be appreciated that embodiments are possible within the spirit and scope of the invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 211: 32 C07D 211: 32 239: 90) 239: 90) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, HU IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT , RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, UZ, VN (72) Inventor Naigler Arnon Israel Jerusalem 74381 Sedrot Herzl 46

Claims (1)

[Claims] 1. The following formula: Wherein R ₁ is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; R ₂ is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy And R ₃ is a member of the group consisting of hydrogen and lower alkenoxy.) And a pharmaceutically effective amount of a compound that is a member of a pharmaceutically acceptable salt thereof. A composition for treating pulmonary fibrosis in combination with a carrier. 2. The composition of claim 1, wherein said composition is Halofuginone. 3. The composition of claim 1, further comprising a pharmaceutically acceptable carrier for said compound. 4. 4. The composition of claim 3, wherein said pharmaceutically acceptable carrier allows the composition to be administered as an aerosol. 5. The following formula: Wherein R ₁ is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; R ₂ is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy And R ₃ is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl.) And a pharmaceutically effective amount of a compound that is a member of a pharmaceutically acceptable salt thereof. A method for producing a medicament for treating pulmonary fibrosis, comprising the step of placing in an acceptable carrier. 6. 6. The method of claim 5, wherein said carrier allows said compound to be administered as an aerosol. 7. The method of claim 5, wherein the compound is halofuginone. 8. The following formula: Wherein R ₁ is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; R ₂ is a member of the group consisting of hydroxy, acetoxy and lower alkoxy; And R ₃ is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl.) And a pharmaceutically effective amount of a pharmaceutically acceptable salt thereof. How to treat fibrosis. 9. 9. The method according to claim 8, wherein said compound is halofuginone. 10. 9. The method of claim 8, wherein said compound further has a pharmaceutically acceptable carrier. 11. 11. The method of claim 10, wherein the pharmaceutically acceptable carrier allows the composition to be administered as an aerosol.