TWI242431B - Pharmaceutical compositions for treating pulmonary diseases - Google Patents

Abstract

This invention relates to a pharmaceutical composition for treating pulmonary diseases such as chronic obstructive pulmonary disease or asthma, comprising a phosphodiesterase 4 inhibitor and an anti-inflammatory corticosteroid.

Description

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1242431 A7 ^ ~ --------------- V. Description of the invention (1) Field of the invention The present invention relates to preventing or reducing the occurrence of lung disease symptoms. Compositions and methods for treating or reducing the severity of lung disease. In particular, the present invention relates to a composition and method for treating a lung disease regulated by phosphoenzyme 4 (brain 4), which comprises administering a pDE45 inhibitor and an anti-inflammatory corticosteroid. BACKGROUND OF THE INVENTION It is very difficult to identify novel therapeutic agents for treating lung diseases. In fact, the development of this disease is related to many intermediaries. Therefore, it seems unlikely that the 10 effects of the single-intermediate would have a significant effect on all three symptoms of chronic asthma. The method of "intermediate" is to regulate the cell activity on disease pathology. One of the methods is to increase the S content of CAMP (adenine nucleoside ring 3, 5, monophosphate). Framed AMP is a wide range The second 15th courier of hormonal intermediary biological responses, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When appropriate agonists bind to specific cell surface receptors Can activate adenine nucleotide cyclase, accelerate the conversion of Mg + and ATp into cAMP. Mounting AMP can regulate most (if not all) cells have 20 pathological activities of allergic asthma. As mentioned above, increasing cAMP will produce Beneficial effects include: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) inhibition of neutrophil neutrophil degranulation, 4) inhibition of basophilic neutrophil degranulation, and 5) inhibition of monocytes White blood cells and macrophages are activated. Therefore, activating adenine nucleotide cyclase or inhibiting phosphodiester This paper is in accordance with China National Standard (CNS) A4 (210 X 297) ) _ N ϋ n ϋ tn «-1-0, I xm ·· I Hitomi (Please read the precautions on the back before filling out this page) 1242431 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs 2) The compounds of the enzyme should be able to effectively inhibit the improper activation of airway smooth muscle and various inflammatory cells. The main cellular mechanism for deactivating cAMP is to use one or more cyclic nucleotide phosphodiesterases of the isoenzyme family ( PDE) hydrolyzes the 3, -phosphate diester bond. 5 It has been shown that significant cyclic nucleotide phosphodiesterase (PDE) isoenzyme (pde4) can break down c AMP in airway smooth muscle and inflammatory cells. [T〇rphy Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents'1 in New Drugs for Asthma, Barnes ed. IBC Technical Services Ltd., 1989]. Studies have shown that inhibition of this enzyme 10 not only produces airway smooth muscle relaxation but also inhibits hypertrophy. Cells, basophils, and neutrophils are de-granulated, along with inhibition of monocyte and neutrophil activation. In addition, when the adenine nucleotide cyclase activity in When hormones or autacoid increase, pDE 4 inhibition

Agents have significantly beneficial effects, as well as in vivo. Therefore, pDE 15 4 inhibits the effective prostaglandin £ 2 and prostacyclin (activator of adenine ribonuclease cyclase) content of T in the lung. This compound will provide a unique approach to the treatment of bronchial asthma with significant therapeutic advantages among the currently available medicaments. In addition, many etiologies of lung diseases include multiple mediators, so they are suitable for combined treatment. In the present invention, pDE 4 inhibitors are used to treat lung diseases with anti-inflammatory corticosteroids (especially delivered by inhalation). This composition is particularly useful in the treatment of chronic obstructive pulmonary disease (copD) or asthma. Summary of the invention -------------------- Order · ^ ---- (Please read the precautions on the back before filling out this page) -4- 1242431 Ministry of Economy Wisdom Printed by the Property Agency Staff Consumer Cooperative

A7 V. Description of the invention (3), this article is about a method for treating mammalian lung disease, which depends on the patient's administration of an effective amount of PDE4-specific inhibitory sword and the amount of sterol resistance. Inflammatory medicines, wherein the medicines can be administered simultaneously or separately and continuously, and the continuous medicines can be medicines with close or prolonged time. The first feature of Ben Sheming is about a kind of adjuvant for the treatment of mammalian lung disease, which includes an effective amount of a PDE4-specific inhibitor, an effective amount of a solid anti-inflammatory agent, and a pharmaceutically acceptable Excipients. DETAILED DESCRIPTION OF THE INVENTION The combination therapy of the present invention comprises the administration of an anti-inflammatory agent of a PDE4 inhibitor and a steroid 'to prevent the occurrence of lung disease or to treat existing symptoms. The compounds may be co-administered in each dosage form. Or two different formulations (which can be the same or different) can be used together. To clarify, the two drugs may each be an oral preparation, or one of them may be an oral preparation and the other an inhalant, or both may be inhaled dosage forms. He can be used at the same time. Or they can be administered at close or prolonged time, for example, one drug is administered in the morning and the second drug is administered in the evening. The composition can be used for prevention or after the onset of symptoms. In some examples, the composition can be used to prevent the progression of lung disease or to inhibit the failure of functions such as lung function. The PDE4-specific inhibitor of the present invention can be any known compound or PDE4 inhibitor that inhibits the PDE4 enzyme, and is only an inhibitor of pDE4, but not a compound that inhibits other PDE family members and PDE4. 1. This paper size applies to China National Standard (CNS) A4 (210 X 297 public love)

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1242431 A7 V. Description of the invention (4) Generally, the PDE4 binding agent is suitable, and its combination of the high affinity between pDE4 catalyzed form and rollpram is divided by pDE4 catalyzed form The proportion of KM with low affinity binding between rollpram) is about V 0 · m or greater than oi. 5 PDE inhibitors (such as theophylline and pentoxyfyllln) used to treat inflammation and as bronchodilators, can inhibit PDE isoenzymes in all tissues. These compounds have side effects because they are non-selective Inhibits all 5 PDE isoenzymes in all tissues. The compound can effectively treat the target disease condition, but also has adverse effects. If the adverse effects can be avoided or minimized, it will be useful in treating some Increasing the effect of overall treatment in disease conditions. For example, clinical studies of the selected PDE 4 inhibitor roHpram, which is an antidepressant, have shown that it has the activity to treat mental disorders and the effect to produce the moon bowel For example, heartburn, nausea, and vomiting. In this disclosure, the low-affinity binding rule is referred to as the low-affinity binding site of cAMP, which is called the low-affinity binding site (ude 4). Other forms of high-affinity binding catalytic sites are called "high-affinity" binding sites (HPDE 4). This term, HPDE4, should not be related to human PDE4 herein '' hPDE4 ,, Confusion. The initial experiment was to establish a [3H] -rollpram binding assay. Its -0 details are shown in Example 1 below. In order to determine whether the same gene product has high affinity binding activity and low affinity binding Activity, the yeast was transformed using known methods and fermented to express recombinant PDE 4 after 6 hours of fermentation. Western blotting analysis using antibodies against PDE 4 revealed that the performance of PDE 4 increased over time and grew in growth 3 Hour-6- This paper size is applicable to China National Standard (CNS) A4 specifications (210 x 297. I love fjing first read the precautions on the back and then this page) Order JI —----- line

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1242431 A7 * — '---- — ___________ V. Description of Invention (5) One of them reached the maximum value. In addition, more than 90% of the immunological reaction products were located in the supernatant of the yeast hydrolysate and speed centrifugation (10,000 x g). [3H] R-㈠-larpram binding and PDE activity were monitored with protein performance. The coexistence of PDE 4 activity and the binding activity of rllopram showed that these two functions exist in the same gene product. Western blot analysis found similar results. More than 85% of rolipipan (r0iipram) inhibited pDE activity and [H] -laripon (r0Hpram) binding activity existed in the yeast supernatant. Floor. Overall, §, this system represents most of the recombinant pDE 4 (4) and HPDE 4 with only small strata. Therefore, inhibition of recombinant PDE 4 catalyzed / tongue properties is mainly due to the effect of compounds on LpDE 4. Therefore, the activity of inhibiting pDE 4 catalysis can be used as an index of the compound's efficacy against LpDE 4. The effectiveness of the compound on HPDE4 can be evaluated by examining its ability to compete with [3H] R_lipram (rlipram). To develop SARs analysis, two assay systems were used to determine the potency of selected compounds against low and high affinity rolipram binding sites. Use standard compounds to establish experimental results. It is expected that some compounds will compete more strongly with [3H] _radolip (rOHpram) than other sites on the rolipram high affinity binding site. The efficacy of the other is low-affinity binding agent rolipram 20 mouth. Because SAR is not associated with high-affinity binding and low-affinity binding, SAR inhibits the binding of still-affinity [3H] _rolipram because the SAR binds to low-affinity lipan (r. Hpram) binding site. We have just known that human mononuclear leukocytes reconstituted PDE 4 (hPDE 4) and its inhibitory -7- This paper size applies the Chinese National Standard (CNS) A4 specification (21〇χ 297)-(Please read the precautions on the back first (More on this page) Order -------- Line

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5. Description of the invention (6) There are at least two forms of interaction between the interactions of the preparation. The interpretation of such observations 疋 hPDE 4 has two significant forms. One form binds with high affinity to rohpram and denbufyl Une, while the other form binds to such compounds with low affinity. The preferred PDE4 inhibitor of 5 is used in the present invention, which has a favorable therapeutic ratio, that is, the compound can favorably inhibit the enzyme form of cAMP catalytic activity that binds to rollpram with low affinity, thereby reducing the inhibitory enzyme Side effects of high affinity and sexual binding to rolipram. Another way of saying this is that the better compound binds 1C50 of the catalytic form of pDE 4 10 with high affinity to rallipram divided by PDE 4 that binds to low affinity with ronapram The proportion of the IC50 in the catalytic form is about 0. or more. The standard printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs can be further improved. The ic50 ratio of the PDE4 inhibitor is about 0.1 or greater than 0.1; the ratio is 1 nanomolar concentration [3H]. Combination of rolipram with high affinity The ICw value of competitive binding of the PDE4 15 form of rolipipram and the use of 1 micromolar concentration [3h] -cAMP as a substrate to inhibit low affinity binding (Rolipram) The ratio of IC50 values of the catalytically active form of PDE4. For a further retrospective explanation of this test, see the joint application US Application 08/4 56274, filed May 31, 1995, which is incorporated herein by reference in its entirety, for a deeper understanding of the practice of the present invention. Examples of suitable PDE4 inhibitors are: (RH +)-l_ (4,, yl) -4-[(3-cyclopentyloxy) _4_methoxyphenyl] _2_tonrolidone; (R )-(+)-l- (4-bromofluorenyl) -4-[(3-cyclopentylmethoxymethoxyphenyl] -2-place This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 1242431 A7 B7 V. Description of the invention (7) Slightly burned ketone; 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '-[N2-cyano-S -Methyl isothioureido] henyl) -2-p to 4 ketone; cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane; μcarboxylic acid]; 5cis- [4-cyano-4- (3-cyclopropylmethoxy-4-monofluoromethoxyphenyl) cyclohexyl-1-ol] ο

5 1X Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 (Magic-(+)-[4- (3_cyclopentyloxy_4_methoxyphenyl), pyrrolidine · 2_subunit] Ethyl acetate; (S)-(-)-[4- (3-Cyclopentyloxy-4-methoxyphenyl), pyridine_2_ylidene] ethyl acetate. The best PDE 4 The inhibitor has an iCw ratio of more than 0.05, and particularly preferred compounds have a ratio of more than 1.0. The preferred compound is ciscyanocyclopentyloxy-4-methoxyphenyl) cyclohexane small carboxylic acid, 2 _Methoxycarbonylcyano-4- (3-cyclopropylmethoxy-4difluorofluorenyloxyphenyl) cyclohexane 4-ketone, and cis- [4-cyano-4- (3-cyclo Propylmethoxy-4 difluoromethoxyphenyl) cyclohexane-1 -ol], can preferentially bind to low affinity binding sites when binding such compounds, with an IC5G ratio of 0.1 or More than 〇1. U.S. Patent 5,552,438 (issued September 3, 1996) has described such compounds. This patent and its disclosed compounds are incorporated herein by reference. It is disclosed in US Pat. No. 5,552,438 that the specific compound is cis-4-cyano 4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-carboxylic acid, and salts and esters thereof. Class, prodrug or physical form. Astra (Hofgen? N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P 98)) -9-

This paper size is in accordance with Chinese National Standard (CNS) A4 (21 × 297 mm) 1242431 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (8) AWD-12-281; 9-Benzyl Adenine derivative, called NCS-61 3 (INSERM); D-4418 in Chiroscience and Schering-Plough; benzodiazepine PDE4 inhibitor, called CI-1018 (PD-168787; Parke-Davis / Wamer -Lambert); Benzo-5 dipermene derivatives were disclosed by Kyowa Hakko in WO 9916766; Napp (Landells? LJ et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393), V-11294A; roflumilast (CAS reference No 162401-32-3) and Byk-Gulden revealed blah 10 (pthalazinone) (WO 9947505); or T-440 Compounds, (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther 51998? 284 (1): 162). Any or all of the above compounds are beneficial to the methods described herein. Many of the specific compounds in the above literature do not have common names or trade names, 15 are described in the joint application US patent application USSN 862,083 dated October 30, 1992; USSN 862, 11 1 dated October 30, 1992 USSN 862,030 application date October 30, 1992; and USSN 862,114 application date October 30, 1992 or subsequent applications or priority of one or more US patents. The full text of each application or related patent is hereby incorporated by reference as a reference in this case. The steroid agents used in the present invention are prodrugs of oral and inhaled corticosteroids with anti-inflammatory activity. Examples of steroids are methylprednisolone, prednisone, dexamethasone, fluticasone, beclomethasone, butazone-10- (Please read first (Notes on the back are on this page) m Order -------- line

This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 1242431 A7 B7 V. Description of the invention (9) (budesonide), flunisolide, mometasone furoate, and to Triamcinolone acetonide. Methylprednisone and prednisone are oral and injectable anti-inflammatory corticosteroids; they are available from many manufacturers and pharmaceutical companies. Beclomethasone 5 dipropionate is sold by Glaxo Wellcome under the names Beconase⑧ and Beconase AQ⑧ in the form of an aerosol inhalation. Fluticasone propionate is sold by Glaxo Wellcome under the name Flonase (R). Triamcinolone acetonide is a nasal spray and aerosol sold under the name Nasacort⑧ by 10 Rhone-Poulenc Roher. Flunisolide is a nasal solution that is sold by Roche Laboratories under the names Nasalide® and Nasarel ™. Dexamethasone is a sodium spargar salt and is sold by Medeva Pharmaceuticals, Inc. under the name Dexacortm. Nasal formulations of mometasone furoate as a monohydrate 15 are sold under the name Nasonex® by Schering Corp. Budesonide is another inhaled corticosteroid used to treat lung disease. It is a powder that is placed in a turbohaler device and sold under the name Pulmicort Turbohaler (c) by Astra Pharmaceuticals, L.P. All medicines and nasal preparations or oral or injectable formulations can be found in the 1999 edition of the 20 Doctor's Desk References (PDR), published by Medical Economics Corporation, Inc, of New Jersey, USA, and available at ht tp: / / www. tomescps · com / fraMain · asp? Mnu = 0 and found on the website of Zhihexiji. In addition, Table I also lists the corticosteroids that are currently under development and can be used in the present invention. -11- This paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before this page) Order -------- line

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 1242431 V. Description of the invention (10) Table I Inhaled corticosteroids company disease symptoms mometasone furoate Schering-Plough Asthma SAR rofleponide AstraZeneca Asthma ciclesonide B k-Gulden / Recordati Asthma butixocort Propionate Warner-Lambert / 3M Asthma / Rhinitis RPR-106541 Rhone-Poulenc Rorer Asthma ST-126 SSP / Torii Asthma (Please read the precautions on the back first and then this page) The best combination treatment is one or More dexamethasone, fluticasone, beclomethasone, budesonide, flunisolide 5, mometasone furoate, And triamcinolone acetonide and cis-4-cyano-4- (3-cyclopentyloxy-4 methoxyphenyl) cyclohexyl-1-propanoic acid, Cilomalast (Ariflo⑧ ) Commissioned. The preferred treatment is the simultaneous administration of a steroid inhaler and an oral dosage form of the acid, where each drug is administered once or twice daily. Regarding the administration of acid 10, the best controlled oral tablets are controlled release. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. The two active agents can be considered for use at the same time, or very close. In addition, one drug can be administered in the morning and the other drug can be administered in the evening. Or another way, one medicine can be administered twice a day and the other medicine can be administered once a day (co-administration is selected once at the time of twice daily administration, or 15 places respectively). Preferably, the two drugs are co-administered at the same time. The activated compounds of the present invention and their pharmaceutically acceptable salts can be adjusted into oral syrups, tablets, capsules, controlled release preparations, or lozenges. Syrup preparations are generally suspended in a compound or a salt-containing liquid carrier. -12- This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 5 5. Description of the invention (U) liquid or Solution composition 'such as: ethanol, arachis oil, salamander oil, sweetener flavoring or coloring water. If the composition is in the form of a lozenge, any pharmaceutically acceptable carrier for the preparation of body can be used. Examples of the carrier include magnesium stearate, zeolite, talc, gelatin 'arabin, stearic acid, starch, lactose, and m. The composition is recorded as «, any routine encapsulation procedure is appropriate, such as Hard gelatin capsule shell for the above carrier. If the composition is made into a soft gelatin shell capsule, any medically acceptable carrier for wound dispersions or suspensions can be used. For example: water soluble gum, cellulose, petrolates or oils, incorporated into soft gelatin Capsule shell. 10 15. Representative parenteral compositions are formed by the solution or suspension of the compound or by the presence of g-free water-soluble or water-insoluble phosphonium salt, depending on the enteral-acceptable oils, For example: polyethylene glycol, polypyrrolidone, lecithin, peanut oil or sesame oil. Representative inhalable compositions are solutions, suspensions or emulsions, which can be administered in the form of a dry powder or in the form of an aerosol using conventional propellants such as fluorinated fume "(such as trichlorofluoromethane). Preferably, the PDE4 inhibitor composition is in the form of a unit dose, such as a capsule. The preferred steroid is a metered aerosol dose, and the metered dry: a terminal inhaler or a nasal spray. Wooden knife 20, the tongue component can be administered daily Use 1 to 6 times to fully exert the desired activity. Preferably, the active ingredient is administered about once or twice a day, more preferably twice a day. This compound is used to treat asthma caused by exercise (Eia) , Asthma (PIA) and asthma caused by cold (CIA) (the above are slow L wood inlets, > / -13- This paper size applies to China National Standard (CNS) A4 specifications (21〇297) (Centi) 1242431 A7 B7 V. Description of the invention (u) and interstitial symptoms) to combat suspicious irritants. Preferably, the compound is used as a long-term treatment. As for the dosage of the drug, it is believed that the dosage of the PDE4 inhibitor is adult Between 1 and 200 micrograms per day. Steroids According to the label put into use. 5

Example 1-Binding assay of gallate diesterase with rolipram Example 1A The isolated low-affinity forms of human mononuclear leukocytes PDE 4 and hrPDE (human recombinant PDE4) were determined. Therefore, a standard assay can be used to evaluate the activity of PDE 4 catalysis using 1 μl 10 Molar concentration [3H] cAMP as a substrate (Torphy et al ·, J. of Biol. Chem., Vol · 267, No. 3 pp 1798-1804, 1992) The activity of the compound against the low affinity form PDE 4. [3H] -rolipram (specific activity of 5.6 Ci / Mol). Except for the final cAMP solution modified into: 50 mmoles of trimethylolaminomethane HCl (pH7.5) '5 mmoles of MgCl2, 50 μmoles of 5'-AMP and 1 nanomoles of [ Other than 3H] -rolipram, the standard measurement conditions are the same as the published PDE measurement conditions (Torphy et al., J. of Biol. Chem., Vol. 267, No. 3 ρρΠ98-18〇4 , 1992). The measurement was performed at 30 ° C for 1 hour. Stop the reaction and use the Brandel Cell Collector to separate the bound ligand from the free ligand. Competition for high-affinity binding sites was evaluated using conditions measuring low-affinity PDE activity, and the expected [3H] cAMP did not appear. -14- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1242431 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (l3) Example 1B Measurement of Phosphodiesterase PDE activity was measured using [3H] cAMP SPA or [3H] cGMP SPA enzyme assay (described above, Amersham Life Sciences). The reaction was performed in a 96 5 well microtiter plate at room temperature. 0.1 ml of the reaction buffer solution contained (final concentration): 50 millimolar concentration of trimethylolaminomethane-HCl, pH 7.5, 8.3 millimolar Concentration MgCl2, 1.7 millimolar concentration EGTA, [3H] cAMP or [3H] cGMP (approximately 2000 dpm / pico Morse), enzymes and various concentrations of inhibitors. The measurement was performed for 1 hour and 50 microliters of 10 SPA yttrium silicate beads were added in the presence of zinc sulfate to terminate the reaction. Shake the titration plate and let stand for 20 minutes at room temperature. Scintillation spectroscopy was used to evaluate the formation of the radiolabeled product. [3H] R_liplipram binding assay 15 The [3H] R_liplipram binding assay was performed by a method modified from Schneider and coworkers, see Nicholson, et al. Trends Pharmacol. Sci., Vol. 12, ρρ · 19-27 (1991) and McHale et al. Mot. Pharmacol., Vol. 39, 109_113 (1991). The binding site of RR-ralipram to PDE4 can be found in Torphy et 20 al ·, Mol. Pharmacol ·, Vol. 39, ρρ · 376- 384 (1991). Therefore, the combined competition of [3H] R-rolipram provides non-independent evidence of the effectiveness of PDE4 inhibitors against unlabeled competitors. Measured in 0.5 microliters of buffer solution, containing (final concentration) · 50 millimolar concentration of trihydroxyamidoaminomethane HC1, pH 7.5, 5 millimolar concentration of MgCl2, 0.05% bovine serum -15- ( (Please read the notes on the back before this page)

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Claims (1)

1242431 as B8 C8 A pharmaceutical composition for treating lung diseases, comprising an effective amount of PDE4 inhibiting anti-inflammatory corticosteroids. And 2. The pharmaceutical composition according to item 1 of the application, wherein the PDE4 inhibitor is cis-4-cyano-4- (3-cyclopentyloxy-4-methoxybenzyl) cyclohexanecarboxylic acid And the steroids are selected from the group consisting of: dexamethasone, fluticasone, beclomethasone, budesonide, flumsollde, and modason. metas〇ne) furoate, and triamcinolone acetonide. (Please read the notes on the back before filling this page) Printed on the paper by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) V. ,, "Equivalent value χ, > 1242431 Patent Female Treasure Case No. 89173039 Seven Application Date -------- Examples, Π, " Case No. \ 2 Category ^ f P ^ Jv 〇ROC ratoit Application No.89123039 Chinese manual amendment page 1, 2 and 2-1-Attachment (I) Amended Pages 1. 2 and 2 ~ l of the Chinese Specification-Encl. (I) (submitted by May 26, the Republic of China) (Subqg ^ ted on May 26, 2005) Printed by the Consumers' Cooperative Bureau of the Central Bureau of Standards, Ministry of Economic Affairs _ Cloud 1 Patent Specification—Invention A, new name% Chinese pharmaceutical composition for treating pulmonary diseases English Pharmaceutical Composition for treating pulmonary diseases Name 1. Peter Goodeellow 2. Richard Nieman 3. Richard Soder • Torph Theodore J. Torphy-invention-k nationalities 1., 2. are both British 3. created for Americans \ S ----- residence, residence 1. Harlow, Essex, UK Third Avenue, Harlow, Essex CM1 9 5 AW, UK 2. 715 St. Andrews Road, Philadelphia, PA 19117? USA 3. 715 Andrew Road, Philadelphia, North Penn. USA 3. 823 Mt. Pleasant Road, Bryn Mawr , PA 19010, USA Name (name) SmithKline Beecham Corporation Nationality US III. Applicant's Residence and Residence (Agency) One Franklin Plaza No. 1 Franklin Plaza, Faraday, PA, USA , Philadelphia, Pennsylvania 19103, United States of America Representative Name --- --- Stuart R. Suter '...-_, J prep f T ^ l \ A Λ XCI 1 L ·. / ^. _ .1 * 1 AAA _ ▲ eight, · yw, * -u gutter 0 Yang) eight 4 specifications (210 \ 297 mm) 009528LHT (9SMICOR) red form-connection 1} 1} 1242431 A7 B7 five 1. Description of the Invention 1 (ROC Patent Application No. 89123039, Chinese Patent Application No. 89230039, Amendment to the Chinese Manual, pages 16-20-Attachment (I) Amended Pages 16-20 of the Chinese SDecification-EncU (Submitted on January 3, 1994 ) (Submitted on January 3, 2005) Albumin, 2 mM Micromolar concentration [3H] R-rolipram (5.7 x 104 dpm / picomol) and various concentrations of non-radioactive inhibitors were performed at 30 ° C for 1 hour. Add 2.5 ml of ice-cold reaction buffer solution (without [3H] -R-rolipram) to stop the reaction and quickly filter through Whatman GFB filter membrane soaked with 0.3% 5 polyethyleneimine (Brandel cells Harv esters). The filter was washed with 7.5 ml of ice buffer solution, dried, and counted by liquid scintillation spectroscopy. Example 2 Cilomalast / Low-Dose Inhaled Corticosteroid 10 (ICS), Dose Range Study Study Design: • This is phase IIB, a randomized, placebo-controlled, dose range study, including for minor / Patients with moderate asthma undergo a single-blind placebo test for one week, a double-blind treatment phase for 6-weeks, and a follow-up phase for one week. 15 · Study population: Eligible male or female patients, aged 18 to 70, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, mild to moderate asthma, and using low-dose inhaled corticosteroids (not greater than 500 micrograms of beclomethasone dipropionate / day or equivalent is not enough to control. Patients were screened for 50% and 180% FEV 1 and 80%, and the reversibility of the / 5-2 agonist was 20 12% or more based on the prediction of height, age, gender, and ethnicity. The patient's generalized symptom score must be 6 or more over the 4 days prior to the random basic visit. The sample size was 300 evaluable patients. • Cilomalast is 5 mg, 10¾g, 15¾g, twice daily for 6 weeks. -16 · This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) A7 B7 1242431 V. Description of Invention 1 () • Although the average dose of ICS is 652 micrograms, patients with a median value of 500 micrograms Beclomethasone equivalent. • Primary end point: changes in the clinical expiratory volume (FEV 1) of the trough from baseline to endpoint in 1 second, changes in clinical FEV I per week, and changes in 4 hours after the first double-blind dose of 5 drugs . • Secondary endpoint: use of rescue medication and symptoms after overnight. • Tertiary endpoints: clinical forced vital capacity (FVC), clinical peak expiratory flow rate (PEFR), 25-75% (FEF25-75) and 75% (FEF75) forced expiratory flow, PEER variation of gas therapy PEFR for sexual and gas therapy, with an overall symptom score. Evaluation Criteria Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Measurement of primary efficacy, which is defined as the change in the clinical expiratory volume (FEV 1) of the air collection trough from baseline to endpoint within 1 second. The 15-week clinical FEV 1 changes in double-blind treatment and the clinical FEV 1 changes 4 hours after the first double-blind medication were also analyzed. Variables for secondary efficacy are inhaled / aerosolized stone-2 agonists used and asthma symptoms overnight. The variable factors of the third effect are forced vital capacity (FVC), clinical peak expiratory flow rate (PEFR), 25-75% (FEF25-75) and 75% (FEF75) forced expiratory flow 20 volume, gas PEER variability of therapy, PEFR of gas therapy, generalized symptom score (composite score of overnight, morning, and overall white asthma), morning asthma, overall daytime asthma, inhaled corticosteroids, cough, asthma, shortness of breath / Thoracic tightness, rate of asthma exacerbation, and overall physician and patient assessment. -17- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) A7 B7 1242431 V. Description of the invention 4) Research results: The endpoint ITT analysis showed that 15 mg Cilomalast BID compared with placebo There is no statistical improvement in the gas collecting tank FEV! (0.16 L; 5 P == 0.062). • The endpoint ITT analysis showed that the gas collecting tank FEV1 was a dose-dependent response. The right excludes the ICS dose> 500 micrograms of Beka. Beclamethasone, but patients receiving 15 mg of cilomalast BID showed significant improvement in the air trap FEVK0.21 L; ρ = 〇 · 〇33) 1. Support for Cilomalast ) Evidence of 15 mg BID includes 4-hour FEV !, residential PEFR, FEF25_75, and overall assessment scores for physicians and patients. Example 3 15 Cilomalast / High-Dose Inhaled Corticosteroid (ICS) Study Study Design: • Patients with mild, moderate asthma, DB, PC, DR > 800 micrograms beclomethasone Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs • West Romana ((^ 1〇11 ^ 1 & 8〇 ((〇 之 剂It is 5, 10, and 15 mg twice every 20 days for 4 weeks. • 2 week test. • Primary end point: air trap clinical FEV !. • Secondary end point. • PEFR, symptoms, PEFR variability in the morning. , Evening PEFR, clinical PEFR, FEF25-75, FEF75, rescue drugs used. -18- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X297 mm) Α7 Β7 1242431 V. Description of invention 1 () Research Results: ITT analysis showed no clinically significant changes in the clinical air trap FEV in any dose group. 5 • No dose order was observed at the grade end point. • 800 micrograms of ICS (0.16 L; p = 0.009) patients were excluded. The 10-mg Cilomalast BID repeated measurement analysis shows that the gas collecting tank FEV 1 is statistically improved. • The dose range of ICS (beclamethasone) is 100 to 4000 micrograms, 10 is 1136 micrograms on average. • Support 10 The evidence for the effective dose of milligrams of Cilomalast BID is also derived from the superior values of the 4-hour clinical FEV !, clinical FVC, and PEER. • No dose-response relationship was measured. before The research described is similar. Ministry of Economic Affairs, Intellectual Property Bureau, Employee Consumer Cooperative, printed Table 1. Comparison of Compounds in Selected Studies. Allergen Stimulation Study Comparative Data: Allergen Stimulation Study Ariflo 15 亳 g bd Singulaire Ultair ICS 800µg budesonide B2% LAR Maximum reduction (treatment Effect) * 1.3 12.3 10.7 22.9 +6.9 LAR Maximum Reduced Protection% No 36.4 30.8 32 No Reduced LAR i% AUC (Treatment 3.5 63.5 42.4 Not Made -19- This paper size applies the Chinese National Standard (CNS) A4 specification (21〇 χ297 public love) A7 B7 1242431 V. Description of the invention) Effect) Protection of AUC LAR% No 56.9 42.6 Not illustrated: The data of Cilomalast are from ICS analysis of patients with asthma < 652 micrograms. Data for montelukast (MT), budesonide (BDP), and both are from a single study examining the effects of Singulair on inhaled corticosteroids. 5 Singulair SBA. There were significant differences between the placebo (Pbo) and study groups. Although there were improvements in the placebo group in the study of Cilomalast, it was concluded that Cilomalast was better than Singulair when low-dose ICS was added. 10 The foregoing description and examples are intended to illustrate, but not to limit, the invention. For the scope of patents claimed by the inventor in this case, please refer to the scope of patent application below. Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -20- This paper size applies to China National Standard (CNS) A4 (210x297 mm)