WO1998043642A1 - Treatment for pulmonary fibrosis - Google Patents
Treatment for pulmonary fibrosis Download PDFInfo
- Publication number
- WO1998043642A1 WO1998043642A1 PCT/IL1997/000115 IL9700115W WO9843642A1 WO 1998043642 A1 WO1998043642 A1 WO 1998043642A1 IL 9700115 W IL9700115 W IL 9700115W WO 9843642 A1 WO9843642 A1 WO 9843642A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- halofuginone
- group
- pulmonary fibrosis
- compound
- pharmaceutically acceptable
- Prior art date
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- 0 *C1[C@](*N(C=Nc2c3cccc2)C3=O)N(*)CCC1 Chemical compound *C1[C@](*N(C=Nc2c3cccc2)C3=O)N(*)CCC1 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Definitions
- the present invention relates to the treatment of pulmonary fibrosis and, in particular, to the treatment of pulmonary fibrosis with quinazolinone derivatives such ' as Halofuginone.
- Pulmonary fibrosis is a chronic and incurable disease in which interstitial connective tissue accumulates in the lungs, reducing lung functionality and efficiency of gas exchange [S. Phan, New Strategies for Treatment of Pulmonary Fibrosis, 50:415-421, 1995].
- the fibrotic tissue replaces more complex pulmonary tissue in a pathological process which progressively reduces the surface area for gas exchange in the lungs.
- Pulmonary fibrosis often follows such therapeutic interventions as bone marrow transplantation, radiotherapy and chemotherapy [Nagler, A. et al, Am. J. Respir. Crit. Care Med., 154: 1082-1086, 1996]. For reasons given in greater detail below, the disease is frequently fatal.
- the pathogenesis of pulmonary fibrosis includes the formation of fibrotic tissue in the lungs.
- the formation of fibrotic tissue is characterized by the deposition of abnormally large amounts of collagen.
- the synthesis of collagen is also involved in a number of other pathological conditions.
- clinical conditions and disorders associated with primary or secondary fibrosis such as systemic sclerosis, graft-versus- host disease (GVHD), pulmonary and hepatic fibrosis and a large variety of autoimmune disorders, are distinguished by excessive production of connective tissue, which results in the destruction of normal tissue architecture and function.
- GVHD graft-versus- host disease
- pulmonary and hepatic fibrosis and a large variety of autoimmune disorders
- cytotoxic drugs have been used in an attempt to slow the proliferation of collagen-producing fibroblasts [J.A. Casas, et al., Ann. Rhem. Dis., 46: 763, 1987], such as colchicine, which slows collagen secretion into the extracellular matrix [D. Kershenobich, et al, N. Engl. J. Med., 318: 1709, 1988], as well as inhibitors of key collagen metabolism enzymes [K. Karvonen, et al., J. Biol Chem., 265: 8414, 1990]; C.J. Cunliffe, et al., J. Med. Chem., 35:2652 ,1992].
- Collagen cross-linking inhibitors such as ⁇ -amino- propionitrile, are also nonspecific, although they can serve as useful anti-fibrotic agents. Their prolonged use causes lathritic syndrome and interferes with elastogenesis, since elastin, another fibrous connective tissue protein, is also cross-linked. In addition, the collagen cross-linking inhibitory effect is secondary, and collagen ove ⁇ roduction has to precede its degradation by collagenase. Thus, a type-specific inhibitor of the synthesis of collagen itself is clearly required as an anti-fibrotic agent.
- Such a type-specific collagen synthesis inhibitor is disclosed in U.S. Patent No. 5,449,678 for the treatment of a fibrotic condition.
- This specific inhibitor is a composition with a pharmaceutically effective amount of a pharmaceutically active compound of a formula:
- R is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy;
- R is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and R is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; as well as pharmaceutically acceptable salts thereof.
- Halofuginone has been found to be particularly effective for such treatment.
- U.S. Patent No. 5,449,678 discloses that these compounds are effective in the treatment of fibrotic conditions such as scleroderma and GVHD.
- WO Application No. 96/06616 further discloses that these compounds are effective in treating restenosis.
- the two former conditions are associated with excessive collagen deposition, which can be inhibited by Halofuginone.
- Restenosis is characterized by smooth muscle cell proliferation and extracellular matrix accumulation within the lumen of affected blood vessels in response to a vascular injury [Choi et al, Arch. Surg., 130:257-261, 1995].
- smooth muscle cell proliferation is a phenotypic alteration, from the normal contractile phenotype to a synthetic one.
- Type I collagen has been shown to support such a phenotypic alteration, which can be blocked by Halofuginone [Choi et al, Arch. Surg., 130: 257-261, 1995; U.S. Patent No. 5,449,678].
- Halofuginone inhibits the synthesis of collagen type I in bone chrondrocytes in vitro, as demonstrated in U.S. Patent No. 5,449,678.
- chickens treated with Halofuginone were not reported to have an increased rate of bone breakage, indicating that the effect is not seen in vivo.
- the exact behavior of Halofuginone in vivo cannot always be accurately predicted from in vitro studies.
- Halofuginone or other related quinazolinone to block or inhibit pathological processes related to pulmonary fibrosis has only been shown in one reference [Nagler, A. et al, Am. J. Respir. Crit. Care Med., 154: 1082-1086, 1996], but is not otherwise known in the prior art.
- Halofuginone has been shown to have a specific inhibitory effect on the synthesis of type I collagen, such inhibition has not been otherwise shown to be efficacious in the treatment of pulmonary fibrosis.
- pulmonary fibrosis has a high mortality rate, as currently available therapeutic options have significant side effects and are not generally efficacious in slowing or halting the progression of the fibrosis [Nagler, A.
- Halofuginone can also inhibit the pathophysiological process of pulmonary fibrosis in vivo, possibly by inhibiting collagen type I synthesis, although another mechanism or mechanisms could also be responsible. While inhibition of collagen type I synthesis is proposed as a plausible mechanism, it is not desired to be limited to a single mechanism, nor is it necessary since the in vivo data presented below clearly demonstrate the efficacy of Halofuginone as an inhibitor of pulmonary fibrosis in vivo.
- composition for treating pulmonary fibrosis including a pharmaceutically effective amount of a compound in combination with a pharmaceutically acceptable carrier, the compound being a member of a group having a formula:
- R is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy;
- R- is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy
- R_ is a member of the group consisting of hydrogen and lower alkenoxy; and pharmaceutically acceptable salts thereof.
- the compound is preferably Halofuginone.
- the composition preferably includes a pharmaceutically acceptable carrier for the compound. Most preferably, the composition is administered to lung tissue, for example as an aerosol.
- a method of manufacturing a medicament for treating pulmonary fibrosis including the step of placing a pharmaceutically effective amount of a compound in a pharmaceutically acceptable carrier, the compound being a member of a group having a formula: wherein:
- R. is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; -R ⁇ is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy, and R ⁇ is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; and pharmaceutically acceptable salts thereof.
- a method for the treatment of pulmonary fibrosis in a subject including the step of administering a pharmaceutically effective amount of a compound having a formula:
- R j is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; - ⁇ is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and R-, is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; and pharmaceutically acceptable salts thereof.
- the term "subject” refers to the human or lower animal to whom Halofuginone was administered.
- patient refers to human subjects.
- pulmonary fibrosis refers to any fibrotic condition in the lungs or respiratory tract of the subject.
- treatment includes both substantially preventing the process of pulmonary fibrosis from starting and slowing or halting the progression of pulmonary fibrosis once it has arisen.
- oral administration includes, but is not limited to, administration by mouth for absorption through the gastrointestinal tract, buccal administration and sublingual administration.
- compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, capsules or tablets. Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable.
- parenteral administration includes, but is not limited to, administration by intravenous drip or intraperitoneal, subcutaneous, or intramuscular injection.
- Formulations for parenteral administration may include but are not limited to .
- sterile aqueous solutions which may also contain buffers, diluents and other suitable additives.
- R. is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy; ⁇ is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and j is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; and pharmaceutically acceptable salts thereof.
- FIG. 1 is a graph of the effect of Halofuginone on hydroxyproline concentration in rat lung
- FIG. 2 is a graph of the effect of Halofuginone on protein concentration in rat lung
- FIG. 3 is a graph of the effect of Halofuginone on hydroxyprolineYprotein ratios in rat lung
- FIG. 4 is a graph of the effect of Halofuginone on DNA levels in rat lung and
- FIGS. 5A and 5B show histologically-stained sections of lung from bleomycin- treated rats.
- Halofuginone can also inhibit the pathological process of pulmonary fibrosis in vivo, possibly by inhibiting collagen type I synthesis, although another mechanism or mechanisms could also be responsible. Indeed, irrespective of the specific mechanism, the data presented below clearly demonstrate the efficacy of Halofuginone in vivo for inhibition of the pathological progression of pulmonary fibrosis.
- Halofuginone in vitro does not exactly correspond to its behavior in vivo. This can be demonstrated by the differential effect of Halofuginone observed with bone chondrocytes in vivo and in vitro. Halofuginone inhibits the synthesis of collagen type I in chrondrocytes in vitro, as demonstrated in U.S. Patent No. 5,449,678.
- chickens treated with Halofuginone were not reported to have an increased rate of bone breakage, indicating that the effect is not seen in vivo.
- the exact behavior of Halofuginone in vivo cannot always be accurately predicted from in vitro studies.
- Halofuginone would be useful in the treatment of pulmonary fibrosis in vivo.
- the ability of Halofuginone, and related compounds, to slow or halt progression of fibrosis in the lungs is both novel and non-obvious. The demonstration of such an ability in vivo is particularly unexpected, given the differential responses seen in vitro and in vivo to Halofuginone.
- the present invention is of a treatment for pulmonary fibrosis with quinazolinone- containing compounds such as Halofuginone. Both compositions with specific pharmaceutical formulations and methods of using these compounds are described below.
- quinazolinone- containing compounds such as Halofuginone.
- Both compositions with specific pharmaceutical formulations and methods of using these compounds are described below.
- Pulmonary fibrosis has been induced in rats by the parenteral administration of bleomycin.
- bleomycin is used as a chemotherapeutic agent [Nagler, A. et al, Am. J. Respir. Crit. Care Med., 154: 1082-1086, 1996].
- chemotherapy is one of the causes of pulmonary fibrosis in patients.
- the bleomycin model is directly and specifically applicable to idiopathic, medication-induced pulmonary fibrosis, as well as being more generally exemplary of the pathogenesis of pulmonary fibrosis.
- Bleomycin-induced pulmonary fibrosis is characterized by inflammation of the lower respiratory tract, interstitial edema and alveolar capillary damage. This capillary damage in turn results in the infiltration of macrophages, mast cells and inflammatory cells into the alveolar space. Subsequently, enhanced fibroblast proliferation and activation result in increased interstitial deposition of collagen type I and fibrosis [Nagler, A. et al., Am. J. Respir. Crit. Care Med., 154: 1082-1086, 1996]. Thus, inhibition of fibrosis, as in both bleomycin-induced and other types of pulmonary fibrosis, depends upon the slowing or halting of the pathological process leading to the production of fibrotic tissue.
- Halofuginone inhibited bleomycin-induced increased collagen levels, as demonstrated by a variety of biochemical markers.
- the specific experimental method used was as follows. Eighty male Sabra rats weighing from 350-400 g were divided into four groups of
- the first group was a control group which did not receive any injections.
- the second group received intraperitoneal injections of bleomycin, 5 mg/kg body weight, for seven consecutive days.
- the third group received intraperitoneal injections of Halofuginone, 5 mg per rat, every other day for the entire experimental period.
- the fourth group received separate intraperitoneal injections of bleomycin and Halofuginone at the above dosages in separate syringes following a two hour interval.
- All rats were given a regular diet and received drinking water ad libitum. The weight and food intake of the rats were monitored during the entire experimental period. Ten rats from each group were killed after 4 and 6 weeks with an overdose of pentobarbital. The lungs were removed from the killed rats and washed with phosphate- buffered saline. One lung was immediately frozen in liquid nitrogen and lyophilized for the analysis of hydroxyproline concentration. The entire dried right lower lobe was weighed and finely minced and homogenized in distilled water. The tissue was subsequently boiled in distilled water for 30 minutes. After cooling and centrifugation, the tissue residue was subjected to a second cycle of the extraction, boiling and centrifugation process. Both supernatants were then pooled, and aliquots were taken for the analysis of hydroxyproline concentration and protein levels.
- Hydroxyproline was determined by subjecting the aliquots to acid hydrolysis with
- Hydroxyproline ⁇ protein ratios were determined from samples taken from the same aliquot. Hydroxyproline is an amino acid which is present in relatively large amounts in collagen, and therefore serves as an indicator for the overall level of collagen in a particular tissue.
- bleomycin clearly caused a significant increase in hydroxyproline concentration, and therefore of collagen levels, in the lungs of rats sacrificed after 4 or 6 weeks. This increase was completely inhibited by treatment with Halofuginone.
- administration of Halofuginone to rats which were not given bleomycin did not cause any change in hydroxyproline concentration. Therefore, the effect of Halofuginone was simply to inhibit the bleomycin-induced increase in hydroxyproline concentration.
- Figure 2 is a graph of the effect of Halofuginone on protein concentration in rat lung. Again, bleomycin caused a significant increase in protein levels in the lungs of animals sacrificed after 4 or 6 weeks. Halofuginone again completely inhibited this bleomycin-induced increase in protein levels in the lungs of animals sacrificed after 4 weeks, although no such inhibition was seen in tissue taken from animals sacrificed after
- Figure 3 is a graph of the effect of Halofuginone on hydroxyproline ⁇ protein ratios in rat lung.
- bleomycin treatment caused a significant increase in the hydroxyprolineYprotein ratio in rat lung, indicating that the increased protein synthesis was largely due to increased collagen synthesis.
- Halofuginone reduced this ratio to the level seen in tissue taken from control rats.
- Halofuginone completely inhibited the increased levels of collagen synthesis induced by bleomycin in the lungs of rats.
- Halofuginone alone did not demonstrate an anorectic effect in rats, indicating that the effect of Halofuginone is specific for inhibition of collagen synthesis.
- Example 2 Effect of Halofuginone on DNA Levels
- Lung tissue from four groups of rats were prepared as described in Example 1 , except that the preparation stopped at the lyophilization of the tissue.
- DNA in the dried lung tissue was determined by the method of Burton [K. Burton, Meth.
- bleomycin caused a significant reduction in levels of DNA in lung tissue taken from rats which were sacrificed at 4 or 6 weeks.
- Halofuginone abolished this reduction of DNA levels in bleomycin-treated rats, yet had no effect on the level of DNA in non-bleomycin-treated rats.
- the Carnoy-fixed lung was then embedded in paraffin and histologic sections, 6 mm thick, were then cut from the apex, central portion - and lower end of the left lung. These sections were then incubated with monoclonal antibodies to rat mast cell chymase, and were stained with alkaline phosphatase to detect the antibodies, and with hematoxylin-eosin for determination of mo ⁇ hological features.
- Figures 5A and 5B show the resulting stained sections of lung from bleomycin- treated rats.
- the tissue shown in Figure 5A was from a rat treated with bleomycin alone and sacrificed after 6 weeks. Diffuse pneumonitis and thickened alveolar walls can clearly be seen, showing the extensive mo ⁇ hological changes caused by the bleomycin- induced process of fibrosis. No such changes can be seen in Figure 5B, which shows lung tissue taken from a rat treated with both Halofuginone and bleomycin. Instead, airspaces with substantially normal mo ⁇ hology can be seen. Clearly, the effects of
- Halofuginone are specific for the prevention of the mo ⁇ hological changes produced during the pathological process of fibrosis.
- Halofuginone can be administered to a subject in a number of ways, which are well known in the art. Although a number of routes of administration are possible, such as oral or parenteral administration, the most preferred route of administration for the treatment of pulmonary fibrosis is by inhalation, either through the nose, mouth or both.
- inhalation would permit direct exposure of the affected tissue to the pharmaceutical composition containing Halofuginone or another quinazolinone derivative.
- Second, such direct exposure would minimize systemic abso ⁇ tion, thus minimizing any potential side effects. Inhalation for drug delivery to the lungs is thus more comparable to topical application on the skin in terms of systemic exposure.
- Third, direct exposure would minimize the amount of
- Halofuginone would be delivered to the tissue to be treated. Indeed, if the dose given to the rats (5 mg per kg) is extrapolated to an average human subject, about half a gram would be required, which is a large amount for administration and could potentially reduce patient compliance. Fourth, direct exposure could be particularly important for subjects with significant fibrotic tissue already present in the lungs, as this tissue does not contain the normal structure of the capillary network, potentially reducing the ability of the blood vessels to deliver Halofuginone to the tissue to be treated. Fifth, inhalation of pharmaceutical compositions allows for a rapid onset of therapeutic effect. Finally, other routes of administration could prove inconvenient for various reasons.
- Halofuginone could be given in aerosolized form from a pneumatic or ultrasonic nebulizer, for example.
- Halofuginone could be suspended in micronized form in a fluorocarbon propellant solvent and delivered in metered doses from a pressurized canister.
- most of the propellant solvent is lost through flash evaporation and replaced by moisture in the respiratory tract, leading to the deposition of hydrated micronized particles.
- both of these methods rely upon deposition of the free form of Halofuginone to the respiratory tract.
- liposome-based aerosols for drug delivery.
- aerosols examples are given in PCT Application No. WO 86/01714.
- Halofuginone would be trapped in the liposomes, which would then be suspended in an aqueous solution, and delivered by a nebulizer or other metered-dose system.
- Further examples of drug delivery by inhalation are described in U.S. Patent No. 5,340,587.
- dosing is dependent on the severity of the symptoms and on the responsiveness of the subject to Halofuginone. Persons of ordinary skill in the art can easily determine optimum dosages, dosing methodologies and repetition rates.
- Halofuginone has been shown to be an effective inhibitor of pulmonary fibrosis.
- the following example is an illustration only of a method of treating pulmonary fibrosis with Halofuginone, and is not intended to be limiting.
- the method includes the step of administering Halofuginone, in a pharmaceutically acceptable carrier as described in Example 4 above, to a subject to be treated.
- Halofuginone is administered according to an effective dosing methodology, preferably until a predefined endpoint is reached, such as the absence of further progression of pulmonary fibrosis in the subject.
- Examples of types of pulmonary fibrosis for which such a treatment would be effective include, but are not limited to, pulmonary fibrosis following such therapeutic interventions as bone marrow transplantation, radiotherapy and chemotherapy.
- Other examples include pulmonary fibrosis caused by contact with injurious chemicals, inflammation, neoplasms, toxic substances, auto-immune diseases, vasculitis, trauma, post-surgical effects, genetic disorders, scleroderma, viral diseases such as cytomegalovirus, lung transplants, burns, congenital malformations and chemical compounds like monocrotaline.
- Halofuginone is synthesized in accordance with good pharmaceutical manufacturing practice. Examples of methods of synthesizing Halofuginone, and related quinazolinone derivatives, are given in U.S. Patent No. 3,338,909. Next, Halofuginone is placed in ' a suitable pharmaceutical carrier, as described in Example 4 above, again in accordance with good pharmaceutical manufacturing practice.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002285350A CA2285350A1 (en) | 1997-03-31 | 1997-03-31 | Treatment for pulmonary fibrosis |
AU20420/97A AU737094B2 (en) | 1997-03-31 | 1997-03-31 | Treatment for pulmonary fibrosis |
PCT/IL1997/000115 WO1998043642A1 (en) | 1997-03-31 | 1997-03-31 | Treatment for pulmonary fibrosis |
JP52550097A JP2001518062A (en) | 1997-03-31 | 1997-03-31 | Treatment of pulmonary fibrosis |
EP97908480A EP0991411A4 (en) | 1997-03-31 | 1997-03-31 | Treatment for pulmonary fibrosis |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IL1997/000115 WO1998043642A1 (en) | 1997-03-31 | 1997-03-31 | Treatment for pulmonary fibrosis |
Publications (1)
Publication Number | Publication Date |
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WO1998043642A1 true WO1998043642A1 (en) | 1998-10-08 |
Family
ID=11061990
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IL1997/000115 WO1998043642A1 (en) | 1997-03-31 | 1997-03-31 | Treatment for pulmonary fibrosis |
Country Status (5)
Country | Link |
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EP (1) | EP0991411A4 (en) |
JP (1) | JP2001518062A (en) |
AU (1) | AU737094B2 (en) |
CA (1) | CA2285350A1 (en) |
WO (1) | WO1998043642A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6440445B1 (en) | 1996-09-30 | 2002-08-27 | Brigham & Women's Hospital | Methods and compounds for treatment of abnormal uterine bleeding |
JP2003508489A (en) * | 1999-09-09 | 2003-03-04 | ハダジツト・メデイカル・リサーチ・サービシズ・アンド・デベロツプメント・カンパニー・リミテツド | Improve wound healing |
EP2114409A2 (en) * | 2007-01-21 | 2009-11-11 | Agricultural Research Organization | Composition and method for treating or preventing skeletal muscle fibrosis |
AU2013270622B2 (en) * | 2007-01-21 | 2016-05-19 | Agricultural Research Organization | Composition and method for treating or preventing skeletal muscle fibrosis |
US10155742B2 (en) | 2012-01-13 | 2018-12-18 | President And Fellows Of Harvard College | Halofuginol derivatives and their use in cosmetic and pharmaceutical compositions |
US11708353B2 (en) | 2018-06-08 | 2023-07-25 | The General Hospital Corporation | Inhibitors of prolyl-tRNA-synthetase |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5449678A (en) * | 1994-01-11 | 1995-09-12 | Agricultural Research Organization, Ministry Of Agriculture | Anti-fibrotic quinazolinone-containing compositions and methods for the use thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6028075A (en) * | 1997-02-11 | 2000-02-22 | Pines; Mark | Quinazolinone containing pharmaceutical compositions for prevention of neovascularization and for treating malignancies |
-
1997
- 1997-03-31 EP EP97908480A patent/EP0991411A4/en not_active Ceased
- 1997-03-31 CA CA002285350A patent/CA2285350A1/en not_active Abandoned
- 1997-03-31 WO PCT/IL1997/000115 patent/WO1998043642A1/en active Application Filing
- 1997-03-31 JP JP52550097A patent/JP2001518062A/en not_active Ceased
- 1997-03-31 AU AU20420/97A patent/AU737094B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5449678A (en) * | 1994-01-11 | 1995-09-12 | Agricultural Research Organization, Ministry Of Agriculture | Anti-fibrotic quinazolinone-containing compositions and methods for the use thereof |
Non-Patent Citations (1)
Title |
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See also references of EP0991411A4 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6440445B1 (en) | 1996-09-30 | 2002-08-27 | Brigham & Women's Hospital | Methods and compounds for treatment of abnormal uterine bleeding |
JP2003508489A (en) * | 1999-09-09 | 2003-03-04 | ハダジツト・メデイカル・リサーチ・サービシズ・アンド・デベロツプメント・カンパニー・リミテツド | Improve wound healing |
EP2114409A2 (en) * | 2007-01-21 | 2009-11-11 | Agricultural Research Organization | Composition and method for treating or preventing skeletal muscle fibrosis |
EP2114409A4 (en) * | 2007-01-21 | 2010-09-01 | Agricultural Res Org | Composition and method for treating or preventing skeletal muscle fibrosis |
US8410120B2 (en) | 2007-01-21 | 2013-04-02 | Mark Pines | Composition and method for treating or preventing skeletal muscle fibrosis |
AU2008206643B2 (en) * | 2007-01-21 | 2013-09-19 | Agricultural Research Organization | Composition and method for treating or preventing skeletal muscle fibrosis |
US9023859B2 (en) | 2007-01-21 | 2015-05-05 | State Of Israel, Ministry Of Agriculture, Agricultural Research Organization | Composition and method for treating or preventing skeletal muscle fibrosis |
AU2013270622B2 (en) * | 2007-01-21 | 2016-05-19 | Agricultural Research Organization | Composition and method for treating or preventing skeletal muscle fibrosis |
US10155742B2 (en) | 2012-01-13 | 2018-12-18 | President And Fellows Of Harvard College | Halofuginol derivatives and their use in cosmetic and pharmaceutical compositions |
US11708353B2 (en) | 2018-06-08 | 2023-07-25 | The General Hospital Corporation | Inhibitors of prolyl-tRNA-synthetase |
Also Published As
Publication number | Publication date |
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EP0991411A1 (en) | 2000-04-12 |
AU2042097A (en) | 1998-10-22 |
EP0991411A4 (en) | 2000-05-31 |
CA2285350A1 (en) | 1998-10-08 |
JP2001518062A (en) | 2001-10-09 |
AU737094B2 (en) | 2001-08-09 |
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