TWI299989B - Treatment of neuropathy - Google Patents

Description

1299989 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Invention Description (]) The present invention relates to cyclic guanosine 3,5,-monophosphate phosphate monoesterase type 5 (c G Μ P p D Ε 5 ) Inhibitors include, inter alia, the use of the compound sildenafil for the treatment of neurodegenerative diseases, especially for the treatment of diabetic neurodegenerative diseases. According to our international patent application W0 9 4/2 8 9 0 2 'we found that c G Μ PPD Ε 5 enzyme inhibitor compounds are powerful for the treatment of male erectile dysfunction (Μ ED, impotence) and female sexual disorders And an effective compound, which led to the development of the compound sildenafil (5-[2-ethoxy-5-(4-methyl-1 hexahydropyridylsulfonyl)phenyl]-1-methyl 3-3-n-propyl-1,6-dihydro-7 Η-pyrazolo[4,3-d]pyrimidin-7-one) (VIAGRATM), which proved to be significantly successful as the first of ED An effective oral therapeutic agent. Neurodegenerative diseases are a system that describes a course of neurological dysfunction. Many causes of neurodegenerative diseases affect both autonomic and peripheral nervous systems, such as metabolic disorders such as diabetes, hypothyroidism, and pyrrole osmosis; Toxic substances such as alcohol and some heavy metals and drugs; infections and inflammatory conditions such as leprosy and vasulitidis such as nodular polyarteritis and systemic lupus, as well as leukemia, lymphoma and other cancers, neurodegenerative diseases are also accompanied Genetic or hereditary disorders as well as amyloidosis or abnormal proteinemia. Specifically, neurodegenerative diseases are caused by the following systemic conditions, such as diabetes (often), uremia (sometimes), pleioplasmosis, hypoglycemia, vitamin deficiency, vitamin B 1 2 deficiency, severe The standard of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ (Please read the note on the back and fill out this page)

-4- 1299989 A7 B7 V. INSTRUCTIONS (2) Symptoms (sepsis), chronic liver disease, primary biliary cirrhosis, primary systemic amyloidosis, hypothyroidism, chronic obstructive pulmonary disease, limbs Hypertrophy, malabsorption (oral diarrhea, milky diarrhea), cancer (feeling), cancer (sensory motor), cancer (late), cancer (myelin loss), sputum IV infection, Lyme disease, Lymphopathy includes Hodgkin's disease, polycythemia vera, multiple myeloma (lytic), multiple myeloma (osteosclerosis or solitary plasmacytoma), benign monoclonal gamma globulin disease (IgA, IgG, and IgM) Or condensed globulinemia. In addition, neurodegenerative diseases are caused by drugs such as amiodarone (anti-arrhythmia), gold-thioglucose (anti-rheumatic drugs), cisplatin (anti-tumor drugs), and amphetamines (dermatological agents for example) Jatropha), Sodium sulphate (detoxification agent), hydralazine (hypotonic agent), isonicotinic acid, metronidazole (antiprotozoal), misionidazole (radioactive sensitizer), nido Nitofurantoin (urinary tract antibacterial agent), nucleoside phosphorylase analog (ddC, ddl, d4T) (antiretroviral), phenytoin (anticonvulsant), pyridoxine (vitamin), suramin ( Antineoplastic agents), taxol (antitumor drugs) or vincristine (antitumor drugs). In addition, neurodegenerative diseases are caused by environmental toxins such as acrylamide (flocculating agent/grouting agent), arsenic (herbicides/insecticides), diphtheria toxin, r-diketone six carbon, inorganic Lead, organic phosphate or strontium (rat poison). In addition, neurodegenerative diseases are caused by genetic disorders such as Charcot-Marie-Tooth (CM) disorders (1A, 16, 2, and 4), hereditary amyloid polyneuropathy, and hereditary sensory neurodegeneration. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210><297 mm) (please read the notes on the back and fill in the page)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed -5- 1299989 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed A7 _____ B7 V. Inventions (3) Diseases (Type I and II), Pyrrople Purple Neurodegenerative Disease, Genetics Sexually susceptible to stress paralysis, Fabry's disease, adrenal spinal neuropathy, Dejerine-Sottas neurodegenerative diseases (types A and B), Refsum's disease, telangiectasia ataxia, blood/3-lipoprotein deficiency, giant axis Neurodegenerative diseases, metachromatic white matter disorders, Frieddreich's ataxia. Neurodegenerative disease is one of the major causes of diabetes. There is no good treatment for its symptomatic treatment or prevention of continuous reduction of neurological function. The incidence of multiple neurodegenerative diseases is estimated to vary greatly in diabetes (5 % to 8). 0%), mainly because the definition of multiple neurodegenerative diseases and clinical narratives vary greatly. However, in American hospitals and community studies, the incidence rate is 20%. Diabetic neurodegenerative disease is an umbrella name that includes a variety of clinical types of neurodegenerative diseases, which fall into two major groups of local (mono-) and diffuse (multiple-) neurodegenerative diseases, diabetic neurodegenerative diseases. It is also a broad name that includes peripherals, skulls, and autonomic nerves that may be affected in diabetes. Neurodegenerative diseases of paratypic diabetes include diffusion variants including, for example, distal symmetry sensation/sensory motion of different clinical entities. Large/fixed fiber) multiple neurodegenerative diseases; autonomic neurodegenerative diseases involving dysfunction of the pupil, sweating, gastrointestinal tract (including stomach and gallbladder weakness, diarrhea), genitourinary dysfunction (including bladder and sexual dysfunction) and heart Vascular autonomic neurodegenerative disease, hypoglycemic unconsciousness is also a phenomenon of autonomic neurodegenerative disease. Localized diabetic neurodegenerative diseases include single neurodegenerative diseases and diverse single neurodegenerative diseases, spinal radiculopathy, plexus lesions and cranial neurodegenerative diseases. Chronic inflammatory myelin loss, multiple spinal radiculopathy can be applied to China National Standard (CNS) A4 Specification (210X297 mm) (Please read the notes on the back and fill out this page)

6- 1299989 A7 B7 V. INSTRUCTIONS (4) Department or diffuse, symmetric multiple neurodegenerative disease accounts for about 90% of clinical cases of diabetic polyneuropathy, and diabetic polyneuropathy includes especially symmetry Sensory motor multiple neurodegenerative disease, mainly affects the lower extremity of the lower extremity. The peripheral sensory neurodegenerative disease in diabetes may be acute or chronic. The acute multiple neurodegenerative disease usually follows the sudden change of metabolic state, and its characteristics are mainly It is a 'positive' sign of a few clinical phenomena, and usually resolves within 6 - 12 months. The sign of chronic polyneuropathy is similar to acute multiple neurodegenerative disease, but more gradually begins without sudden Factors, usually clinical, and can last for many years. According to the patent on nerves, diabetic neurodegenerative diseases can be classified into symmetric or asymmetrical neurodegenerative diseases, the former including distal sensory and sensorimotor neurodegenerative diseases, macrofibrous and fibrotic neurodegenerative diseases, distal fibrils Neurodegenerative diseases, insulin neurodegenerative diseases and chronic inflammatory myelin deprivation of multiple spinal radiculopathy (CIDP), asymmetric neurodegenerative diseases due to diabetes include single neurodegenerative diseases, diverse single neurodegenerative diseases, spinal radiculopathy, nerves Plexus lesions, cranial neurodegenerative diseases and spinal plexus lesions and asymmetric CIDP. Clinical diabetic neurodegenerative diseases can be classified as diffuse or local. Diffusion neurodegenerative diseases include: a) distal symmetrical sensory motor multiple neurodegenerative diseases of the following subtypes: i) primary fibrils, which are burning pain, excessive skin sensation, paresthesia, scalpel pain, loss of pain And temperature sensation, loss of visceral pain and foot ulcers; ii) primary large fiber phenomenon is the loss of vibration sensation, the size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the back Please fill out this page again)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1299989 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing, V. Inventions (5) Loss of proprioception, loss of reflex and slowing of nerve transmission speed; and iii). Type of mixing; And b) the following subtypes of autonomic neurodegenerative diseases: i) abnormal pupil function; ii) sweating dysfunction (perspiration disorder); ii 1) genitourinary dysfunction is a bladder dysfunction and reduces bladder variability Hygiene/incontinence/stagnation; iv) Sexual dysfunction including retrograde ejaculation, erectile dysfunction, defective lubrication (female); v) gastrointestinal dysfunction' phenomenon is gastroparesis, esophageal motility disorder, gallbladder weakness, diabetes Sexual diarrhea or constipation, urinary incontinence; or vi) hypoglycemic unawareness (adrenal neurodegenerative disease). c) Cardiovascular dysfunction, which is characterized by resting tachycardia, injury-induced vasodilation, injured venous artery reflex-related edema, or orthostatic hypotension. d) hypoglycemia is unconscious. Local neurodegenerative diseases include: a) single neurodegenerative disease b) diverse single neurodegenerative disease c) plexus lesion d) spinal nerve root disease e) cranial neurodegenerative disease f) limb neurodegenerative disease including proximal diabetic nephropathy Sexually transmitted diseases, multiple neurodegenerative diseases, the exact cause of the disease is still unclear and almost certain is multifactorial, involving genetic quality, metabolism and vascular abnormalities, and (please read the back of the note before you fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -8- 1299989 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (6) lack or confusion growth factor, peripheral nervous system There is no difference in the response to metabolic damage received in diabetes between type 1 and type 2 diabetes. It is recommended that two original types of diabetes may have similar clinical responses to treatment. So far, no test has been used for diabetes. Agents of neurodegenerative diseases are convincingly relieved of signs, and there is no advanced, established multiple neurodegenerative disease that can lead to the restoration of major axonal loss characteristics, requiring new and more effective therapies. W0 9 9/5 4 3 3 3 (not announced on the priority date) and the unpublished UK application GB 9 9 2 4 0 4 1.8 and GB99 24063 disclose substituted 5-(3-pyridyl)pyrazoles [4,3 - d]pyrimidin-7-one is used for the treatment of peripheral diabetic neurodegenerative diseases. Unpublished UK application GB-A-9924028.5 and GB0007345.2 disclose substituted 2-(3-pyridyl)-4a , 5-dihydroimidazo[5,1-f][1,2,4]triphthyl-4(3Η),-ketone for the treatment of peripheral diabetic neurodegenerative diseases, unpublished U Κ application GB9924020. 2 discloses the substituted 2-phenylindole-6-one or substituted 2-(3-pyridyl)phosphonium-6-one for the treatment of peripheral diabetic neurodegenerative diseases, all of which are excluded from the present invention for treatment Peripheral diabetic neurodegenerative disease. According to a first aspect, the present invention provides a pharmaceutical composition for treating a patient suffering from a neurodegenerative disease (preferably a diabetic polyneuropathy) comprising a therapeutically effective amount of a c G Μ PPD Ε 5 inhibitor, The condition is that the inhibitor is not i) substituted 5-(3-pyridyl)-pyrazolo[4,3 (please read the back of the note first and then fill out this page) clothing.

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This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) -9- 1299989 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (7) a d) pyrimidine b-7-ketone , ii) substituted 2-(3-pyridyl)-4a,5-dihydroimidazo[5,l-f][1,2,4]trin-4(311)-one, or iii a substituted 2-phenylindole-6-one or a substituted 2-(3-pyridyl)phosphonium-6-one for the treatment of peripheral diabetic neurodegenerative diseases. According to a second aspect, the present invention provides the use of a cGMP PDE5 inhibitor for the manufacture of a medicament for the treatment of a neurodegenerative disease, preferably a diabetic polyneuropathy, provided that the inhibitor is not i) substituted 5 - ( 3-pyridyl)-pyrazolo[4,3-d]pyrimidin-7-one, ii) substituted 2-(3-pyridyl)-4a,5-dihydroimidazo[5,1 f] [1,2,4]triphthyl-4(311)-one, or iii) substituted 2-phenylphosphonium-6-one or substituted 2-(3-pyridyl)fluorene-6 - Ketone, used to treat peripheral diabetic neurodegenerative diseases. The so-called neurodegenerative diseases include all of the above-mentioned types of neurodegenerative diseases, and the so-called neurodegenerative diseases are not limited to a specific cause, but include all the causes, especially the above reasons. Suitable inhibitors for use according to the invention include: pyrazoles disclosed in ΕΡ-Α - 0463756 [4,3 (please read the note on the back and fill out this page) • Clothing.

This paper scale applies to China National Standard (CNS) Α4 specification (210Χ297 mm) -10- 1299989 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (8) a d] pyrimidine-7-ketone, reveal Pyrazolo[4,3-d]pyrimidin-7-one in EP-A-0526004, disclosed in the published international patent application W〇9 3 / 0 6 1 0 4 pyrazolo[4,3 d] chewing d- 7-ketone, unexamined international patent application W〇9 3 / 〇7 1 4 9 isomerization pyrazolo[3,4-d]pyrimidin-4-one, disclosed in Announced International Patent Application No. / 93/12095, quinazolin-4-one, disclosed in the published international patent application W〇9 4 / 0 5 6 6 of pyrido[3,2-d]pyrimidine A 4-ketone, disclosed in the published international patent application W 0 9 4 / 0 0 4 5 3 嘌呤-6-ketone, disclosed in the published international patent application W〇98/49 1 66 pyrazolo[ 4,3 - d]pyrimidin-7-one, disclosed in the published international patent application W〇9 9 / 5 4 3 3 3 pyrazolo[4,3-d]pyrimidin-7-one, disclosed in EP- A - 0 9 9 5 7 5 1 pyrazolo[4,3-d]pyrimidin-4-one, pyrazolo[4,3-d] disclosed in the published international patent application WO 00/24745 Pyrimidine-7-one, a pyrazolo[4,3-d]pyrimidin-4-one disclosed in EP-A-09 9 5 7 0, a compound disclosed in the published international patent application WO 95/19978 The compound of the international patent application WO 99/ 2 4 3 3 3 and the compound disclosed in the published international patent application W〇9 3 / 0 7 1 2 4 are disclosed. Of course, the contents of the above-identified patent application, and in particular the general formula and the exemplified compounds thereof, are hereby incorporated by reference in their entirety. Preferred V-type phosphodiesterase inhibitors for use according to the invention include: (Please read the notes on the back and fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210X; 297 mm) -11 - 1299989 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (9) 5 — [2 — ethoxy 5- 5-(4-methyl-1 hexahydropyridylsulfonyl)phenyl]-1-indolyl-3-indolyl-1,6-dihydro-7-pyrazolo[4 , 3 - d]pyrimidin-7-one (West Danaf), which is also known as 1 [[3 -(6,7-dihydro-l-methyl-7-keto-3-propyl- 1H) -pyrazolo[4,3-d]pyrimidin-5-yl)-tetra-ethoxyphenyl]sulfonyl]-tetramethylpyridinolate (see EP-A-04637 5 6); 5-(2-ethoxy-5-norfosylethenylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d Pyrimidine-7-ketone (see EP-A-0526004) 9 3 -ethyl-5-[5 - (4-ethylhexaaminoindole-1-ylsulfonyl)- 2 -n-propoxybenzene 〕2-(pyridyl-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d] Pyrimidine-7-ketone (see W 0 98/49166); 3 -ethyl-5-[5-(4-ethylhexahydropyrazine-1) base 2-(2-methoxyB) Oxy) 吼 — -3 - yl) 2- 2 - (pyridine-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see W099) /54333 ); (+ ) — 3 —ethyl—5 —[5 —(4-ethylhexahydropyridinyl-1-ylsulfonyl)-2 —(2-methoxy-1(R) —methylethoxy)pyridin-3-yl]-2-yl- 2,6-dihydro-7 oxime-pyrazolo[4,3-d-pyrimidin-7-one, also known as 3- Ethyl 5- 5 -丨5 -[4-ethylhexahydro 11-p-mentyl-l-sulfonyl]-(Please read the back of the note before you fill out this page) Clothing.

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This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -12- 1299989 A7 B7 V. Description of invention (10) 2~([(ir) — 2 —Methoxy-1 monomethylethyl 〕oxy) (Please read the note on the back and fill out this page) 11 pyridine ~ 3 - 丨 2 2 - methyl - 2 , 6 - dihydro - 7 - 吡 - 哇 w [4, 3 - d Pyrimidine-7-ketone (see W099/54333); 5 —[2-ethoxy-5-(4-ethylhexahydropyrene-pyrene- 1 -ylindole) 1:1 ratio -3 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — {6—Ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-keto-2 Η-pyrazolo[4,3 — d]pyrimidin-5-yl]-3-pyridylsulfonylindole-4-ethylhexahydropyridin (see Example 1 below); 5 -[2 -isobutoxy-5-(4-B Hexylhydroquinone- 1 -yl fluorenyl)Q is more than 3 -D -3 -ethyl- 2 -(1 -methylhexahydro-d ratio b 4-(4-)- 2,6-dihydro-7H- π is a group of [4,3-d]pyrimidin-7-ketones (see Example 2 below); Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5 —[2—Ethoxy-5-(4-ethylhexahydropyrazine-1)-based π ratio π-determination 3-yl]-3-ethyl-2-phenyl- 2, 6 - dihydro-7 Η-pyrazolo[4,3-d]pyrimidin-7-one (see Example 3 below); (6R,12aR)-2,3,6,7,12,12 a-hexahydrogen —2 —Methyl-6—(3,4-methylenedioxyphenyl)—mouth-to-mouth and [2 ',1 ' : 6 ' 1] batch steep and [3 ' 4 — b] Oral-1,4-4-dione (IC 135), which is the compound of Examples 78 and 95 of the published international patent application WO 95/19978, and the compounds of Examples 1, 3, 7 and 8; This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -13- 1299989 A7 B7 V. Description of invention (n) 2 —[2—Ethoxy-5-(4-ethylhexahydroindole) a 1-sulfonyl)phenyl]-5-methyl-7-propyl-3 Η-mi And [5,1 - f] [1,2,4] ternone-4-ketone (vardenafil), also known as 1-[[3-(3,4-dihydro-5-methyl-4-ketone) Benzyl-7-propylimidazo[5,1-f]-as-three-till- 2-yl)- 4-ethoxyphenyl]sulfonyl]-4-ethylhexahydropyridinine The compounds of Examples 2 0, 19, 337 and 336 of the published international patent application WO 99/24433; and the compound of Example 1 of the published international patent application W〇93/07124 (EISAI); and from Rotella DP, J. Med. Chem., Compounds 3 and 14 of 2 0 0 0, 4 3, 1257. Other types of c GMP PDE 5 inhibitors which may be used in conjunction with the present invention include: 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3 (2H Pyridazinone; 1_[4 - [(1,3-benzo-dioxen-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4 tetrahydropyridine monocarboxylic acid Monosodium salt; (+) cis-5,6a,7,9,9a-hexahydro-2-[4-(trifluoromethyl)phenylmethyl-5-methylcyclopenta-4,5] Imidazo[2 ' 1 - b] 嘌 D let a 4 ( 3 Η ) ketone; furazlocillin; cis-2-cenhex-5-methyl-3,4,5,6 a,7, 8 ' 9,9a - octahydrocyclopenta[4,5]-imidazo[2.1-b]indole-4-one; 3-ethenyl-l-(2-chlorobenzyl)_2-propyl hydrazine a 6-carboxylate; 4 monobromo-5-(3-pyridyl-based paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the note on the back and fill out this page) 11

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed 14-1299989 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (12) Amino)-6-(3 -(4-chlorophenyl)propoxy —3 —(2 Η )pyridazinone; 1 —methyl—5 —( 5 -morpholine ethyl 2-n-n-propoxyphenyl)-3-n-propyl- 1,6- Dihydro-7-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzoindole-5-ylmethyl)amino]-6-chloro 2- 2 - quinoxalinyl] 4- 4 - hexahydro-steep citrate monosodium salt; Pharmaprojects No. 45 1 6 (Glaxo Wellcome); Pharmaprojects No. 505 1 (Bayer ); Pharmaprojects Ν〇 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer) And Sch-5 1 8 6 6. According to standard pharmaceutical practice, its toxicity, absorption, metabolism, pharmacokinetics, etc. can be easily determined by using literature methods to evaluate its efficacy and selectivity. The suitability of any specific c G Μ PPD Ε 5 inhibitor can be easily determined. G Μ PPD Ε 5 inhibitor I c 50 is at a concentration below 1000 nanomolar, more preferably below 50 nanomolar, and more preferably below 10 nanomolar . The IC50 of cGMP PDE5 inhibitors can be determined using established literature methods, such as disclosed in Ε P 0 4 6 3 7 5 6 - B 1 and EP052 6 004 - A1. The c GMP PDE 5 inhibitor used in the present invention is preferably selective for the PDE 5 enzyme, and the selectivity is preferably greater than PD E 3 ' is more suitable than PDE 3 and PDE 4, and the cGMP PDE 5 of the present invention is more suitable for inhibiting the paper. The scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

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-15- 1299989 A7 B7 V. INSTRUCTIONS (13) The selectivity of the agent is greater than 1 0 0, more preferably greater than 3 0 0 beyond P D E 3 and more preferably beyond PDE3 and PDE4. (Please read the notes on the back and fill out this page.) Those who are familiar with this art can easily determine the selectivity. For IC 5 0 P of PDE3 and PDE 4 enzymes, the established literature method can be used, see SA Ballard et al. Journal of Urology, 1 998, vol. 159, 2164-2171. Surprisingly, c G Μ P P D E 5 inhibitors such as sirnafford can be used to treat systemic neurodegenerative diseases, preferably via the mouth. The c G Μ P P D Ε 5 inhibitor can be administered alone, but in human medical care, it is usually administered in combination with a suitable pharmaceutical excipient diluent or carrier selected according to the desired mode of administration and standard pharmaceutical practice. For example, the c G Μ PPD Ε 5 inhibitor can be administered orally, subcutaneously or sublingually in the form of a tablet, capsule, pessary, expectorant, solution or suspension, which may contain a flavoring or coloring agent, For immediate, delayed, improved, or controlled release applications. The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycerin, and decomposers such as starch (more preferably corn) , potato or tapioca starch), sodium starch glycolate, sodium carboxymethylcellulose and certain complex strontium salts, and granulated binders such as polyvinylpyrrolidone, propyl methacrylate, Hydroxypropyl cellulose, sucrose, gelatin and gum arabic, in addition, may contain lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc. Solid compositions of a similar type may also be used as a dip in gelatin capsules. Preferred excipients herein include lactose, starch, cellulose, and milk sugar. The paper size applies to the Chinese National Standard (CNS) Α4 specification (210Χ297 -16- 1299989 A7 B7 V. INSTRUCTIONS (14) (Please read the note on the back and fill out this page) or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the present invention The c G Μ PPD Ε 5 inhibitor may incorporate a plurality of sweeteners or flavoring agents, coloring materials or dyes, emulsifiers and/or suspending agents and diluents such as water, ethanol, propylene glycol and glycerin, and mixtures thereof. c G Μ PPD Ε 5 inhibitors may also be administered parenterally, such as intravenously, arterial, peritoneal, intramuscular or subcutaneous, or may be administered via infusion techniques, for such parenteral administration, preferably in the form of a sterile aqueous solution. For use, which may contain other substances, such as sufficient salt or glucose to make the solution isotonic with blood. If necessary, the aqueous solution must be properly buffered (preferably from 3 to 9), under aseptic conditions Preparation of a suitable parenteral preparation can be accomplished by standard pharmaceutical techniques well known to those skilled in the art. The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed c G Μ PPD Ε 5 The dose of the inhibitor in this preparation will depend on its efficacy, but the expected range is from 1 to 5 〇 0 mg for up to three times a day, for Oral and parenteral to the patient, the daily dose of cGMP PDE5 inhibitor will usually be from 5 to 5 mg (in single or separate doses), in the case of West Danaf, preferably Dosages range from 1 〇 to 1 〇〇 mg, which can be used up to three times a day, but the precise dose will be determined by the physician and will depend on the age and weight of the patient and the severity of the symptoms. According to this, for example, a tablet or capsule of c G Μ PPD Ε 5 inhibitor may contain from 5 to 250 mg (for example, 1 〇 to 1 〇〇 mg) of active biochemical oral substance for one or two times or If necessary, the doctor will determine the most appropriate actual dose for any particular patient under any circumstances and it will vary with the age, weight and response of the patient. The above dose is the average paper size. Jiaxian County (CNS) Α4 specifications (21GX297 mm) · - -17- 1299989 A7 B7 V. Description of the invention (y example of the situation, of course, in some cases, the higher or lower dose range of the drug can be used, and this It will be included in the scope of the present invention. (Please read the notes on the back and fill out this page)

c G Μ P p D Ε 5 Inhibitors may also be administered intranasally or via inhalation and conveniently in the form of dry powder inhalers or aerosol spray formulations from pressurized containers, pumps, sprays or sprays and using suitable propellants For example, dichlorinated two-winning institute, dichlorofluorocarbonate, dichlorotetrafluoroethylene, and hydrofluoride, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3, 3 - heptafluoropropane, carbon dioxide or other suitable gas delivery, in the case of pressurized aerosol, the dosing unit will be determined by providing a valve to deliver the metered dose, pressurized container, pump, spray or sprayer can contain cGMP PDE5 A solution or suspension of the inhibitor, for example, using a mixture of ethanol and a propellant as a solvent, which may additionally contain a lubricating agent such as sorbitan trioleate, a capsule and a cartridge for inhalation or insufflation (cartridge) (Adopted, for example, from gelatin) can be formulated into a powder mixture containing a c GMP PDE 5 inhibitor and a suitable powder base such as lactose or starch. The Ministry of Economic Affairs Intellectual Property Office staff consumption cooperatives print aerosol or powder preparations preferably arranged so that each metered dose or "blowing" contains from 1 to 50 mg c G Μ PPD Ε 5 inhibitor for delivery to the patient's gas The total daily dose of the sol will range from 1 to 50 mg, which may be administered in separate doses or more often at separate doses throughout the day. Alternatively, the c G Μ P P D Ε 5 inhibitor can be administered in the form of a suppository or pessary. c G Μ PPD Ε 5 inhibitors can be applied topically in the form of colloids, water gels, lotions, solutions, lotions, ointments or powders, and cGMP PDE5 inhibitors can also be applied to the skin or transdermally, for example via the use of skin patches. . This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) -18- 1299989 Α7 Β7 V. Invention description (16) (Please read the note on the back and fill out this page) For topical application to skin , c G Μ PPD Ε 5 inhibitor can be formulated into a suitable ointment containing an inhibitor suspended or dissolved in, for example, a mixture containing one or more of the following: mineral oil, liquid petroleum jelly, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene a compound, emulsified mash and water, or it may be formulated into a suitable lotion or emulsion, suspended or dissolved, for example, in a mixture containing one or more of the following: mineral oil, sorbitan monostearate, polyethylene Alcohol, liquid paraffin, polysorbate oleate 60, residual wax ester oxime, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The c G Μ PPD Ε 5 inhibitor can also be used in combination with cyclodextrin, which is known to form inclusion and non-inclusion complexes with the drug molecule, and the formation of the drug-cyclodextrin complex can improve the solubility and dissolution rate of the drug molecule. , bioavailability and/or stability, the drug-cyclodextrin complex is generally suitable for most dosage forms and routes of administration, in addition to being directly complexed with the agent, the cyclodextrin can be used as an auxiliary additive, for example as a carrier. Agents, diluents or solubilizers, the most commonly used and suitable examples of α-, Θ- and r-cyclodextrin are disclosed in W〇一A — 9 1/1 1 1 72, W〇一 A — 94/02518 and W〇一A — 98/55148. The Ministry of Economic Affairs, the Intellectual Property Bureau, and the employee consumption cooperative are printed in humans. Usually, oral administration of c GMP PD Ε 5 inhibitor is the preferred route, and it is most convenient. In the case of patients suffering from swallowing or oral administration, the drug is poorly absorbed. It can be administered parenterally, sublingually or orally. The c G Μ PPD Ε 5 inhibitor may also be administered in combination with other active agents, and preferred agents include: compounds that modulate atrial natriuretic factor (also known as atrial natriuretic peptide), such as inhibitors of neutral endopeptidase; Suppression of bloody paper scales applicable to Chinese National Standard (CNS) Α4 specifications (210Χ297 mm) -19- 1299989 Α7 Β7 V. Description of invention (17) (Please read the note on the back and then fill out this page) Angiotensin-converting enzyme a compound such as ethoxybenzoic acid, and an inhibitor of binding of angiotensin-converting enzyme to a neutral endopeptidase such as omapatrilat; an angiotensin receptor antagonist such as losartan; a substrate for NO-synthesis enzymes such as L-arginine; a channel inhibitor such as amaptine (amlpdipine); an inhibitor of endothelial receptors and an inhibitor of endothelium-invertase; a cholesterol lowering agent such as Statins and fibrates; anti-platelet and anti-erythrocytic agents such as t PA, u PA, neo-dicoumarin, hirudin and other red blood cell inhibitors, heparin, thromboplastin activating factor Insulin sensitizers such as rezulin and hypoglycemic agents such as glipizide; L-D〇PA and carbidopa; acetylcholinesterase inhibitors such as Donets (donezipil) or steroidal; CZX 2 inhibitors printed by the Ministry of Economic Intelligence's employee property cooperatives; pregabalin: gabapentin; tricyclic antidepressants such as Amitriptyline hydrochloride; non-steroidal anti-inflammatory agents; and angiotensin-converting enzyme (ACE) inhibitors such as quinapril, better agents are: compounds that inhibit angiotensin-converting enzyme; angiotensin Receptor antagonist; substrate of N〇-synthase of endothelial receptor and inhibitor of endothelium-invertase; cholesterol lowering agent; and insulin sensitizer and hypoglycemic agent, especially insulin sensitizer and hypoglycemic agent . Of course, all the treatments mentioned herein include cure, alleviation and preventive treatment. The following examples of modulators are for illustrative purposes only and are not intended to limit the scope of the invention, and the active ingredient refers to a c G Μ P P D Ε 5 inhibitor. This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) -20- 1299989 A7 B7 V. Description of invention (18) Modulation 1 : (Please read the notes on the back and fill in this page) Tablets were prepared from the following ingredients: Sidanafu citrate (50 mg) mixed with cellulose (microcrystals), cerium oxide, stearic acid (smoke) and the mixture was compressed to form tablets. Modulation? ,: Preparation of intravenous preparations by mixing active ingredients (100 mg) and isotonic saline (1000 ml). The efficacy of c G Μ P P D Ε 5 inhibitors in the treatment of neurodegenerative diseases in patients can be demonstrated by the following clinical trials. This study was carried out using West Damnaf, but of course this study may be carried out with other c G Μ P P D Ε 5 inhibitors, such as one or more of the c G Μ P P D Ε 5 inhibitors listed above. The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed several males who showed positive signs of diabetic neurodegenerative disease, and then took the patient for 7 days without treatment to establish baseline information, including a series of pain surveys including the determination of the Pain Disability Index (PDI). (Excerpted from Tait et al 1990), Visual Analogue Scale (VAS) Pain Score and Verbal Evaluation of Pain Relief, then treated with Sidanaf (50 mg) or placebo every night for 1 day and immediately investigated the patient's pain The degree, followed by the patient's treatment period of 1 day, at this time the patient did not receive treatment, and then each patient received replacement therapy every night (that is, if they originally received the active agent, place a placebo, or vice versa) after 1 〇 Days, then immediately investigate the patient's pain level. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)~" -21 - 1299989 A7 B7 V. Invention description (19)

The Pain Disability Index (PDI) measures the overall pain associated with normal daily activities (ie, family responsibility for work, leisure, social activities, occupation, self-care, sleep) (scales from 0 to 0) 1 0), because the pain of diabetic neurodegenerative disease is often the most severe at night, an improved PDI survey to reflect this.

Visual Analogue Scale (VAS) The Pain Score is the average pain experienced during the survey. The patient's indication is determined on a continuous line from 0 (=no pain) to 100 (= most likely severe pain), dividing the pain into three categories: Surface pain (burning sensation, tingling sensation, etc.), deep pain (nails, needles, pain like electric shock, paralytic pain) and muscle pain (deep and fixed pain, pain like toothache, cramps, painful cramps) 0

The Verbal Evaluation of Pain Relief survey was performed by the patient indicating that the pain experienced in the past 10 days was completed at a scale of 0 to 6 relative to the baseline during the treatment period. The results showed a reduction in the degree of pain experienced in the patient, confirming the use of the c G Μ P P D Ε 5 inhibitor for this condition. Moreover, an improved uncontrolled report of pain signs has been accepted in patients with diabetic polyneuropathy who received a 50 mg single dose of Stanford. Example 1 2 -(Methoxy B)-5-[2-Ethoxy-R-(4-Ethylhexa-l-ylsulfonyl)pyridine-3-yl]-3 Ethyl paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page), *ιτ

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 22 - 1299989 A7 B7 V. Description of Invention (2〇) —2,6 — 一氤一 7 Η —Pyrazole ί 4,3 - d-one

〇Me

(Please read the note on the back and then fill out this page.) The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative will print the product of the following steps i) (〇. 〇7 5 mM), trimethyl decyl) potassium amide ( 298 mg, 1.50 mmol. Acidic ethyl ester (73 μl, 0.75 mmol) heated in a sealed container of ethanol (1 0 ° C in a closed vessel at 120 ° C for 12 hours, but after the mixture Distribute in ethyl acetate and sodium bicarbonate aqueous solution, and separate the layers, dry the organic layer (M g S〇4) and evaporate the gel on vacuum gel with dichloromethane:methanol (9 8 : 2 ) as a stream wash After purification of the crude product by column chromatography, the title compound 161 mg, 値·· C, 5 3 · 1 8 ; Η, 6 · 4 8 ; N,1 8 - 1 C23H33N7〇5S.0.20C2H5C〇2CH3 Theory値C,5 3.2 1 ; Η, 6·49 ;Ν, 18.25 U (CDC13) : 1 . Ο 3H,t), 1.40 (3H,t),1.5 8(3H, ,2.41(2H,q) ,2.57 (4H,m), 3. This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) Double (and vinegar liter) will be cold liquid, in tube experiment 4; 4 ( t ) 0 8 -23 - 129998 9 A7 B7 V. INSTRUCTIONS (21) (2H, q), 3.14 (4H, m), 3«3〇(3H' s )'3.92(2H,t) , 4.46(2H,t) ' 4.75(2H , q), 8.62 (lH, d), 9.04 ( lH, d), 10.61 (lH, s); LRMS : m / z 520 (M + l) + ; melting point 161 - 1 6 2 t:. Material a) acridine-2-amine a 5-sulfonic acid (please read the back of the note first and then fill out this page)

MM

〇 = S = 〇OH Order 2-aminopyridine (80 g, 0.85 mol) added to fuming sulfuric acid (320 g) in 30 minutes and the resulting easily heated at 140 °C After 4 hours, after cooling, the reaction was poured into ice (2 g) and the mixture was further stirred in an ice/salt bath for 2 hr, and the obtained suspension was filtered, and the solid was applied with ice water (200 ml) The ice-cold IMS (200 ml) was rinsed and dried under suction to give the title compound as a solid 111.3 g; LRMS: m/z 17 5 ( Μ + 1 ) + b ) A 3 - y stinky 5 - sulfonic acid paper scale applicable to China National Standard (CNS) A4 specification (210x297 mm)

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives -24 - 1299989 A7 B7 V. Description of invention (22) nh2 νΛ^/Βγ

V o=s=o

OH bromine (9 9 g, 0 · 6 2 mol) was added dropwise over 1 hour to a hot solution of the product from step a) (1.08 g, 0.62 mol) in water (600 mL) After the completion of the addition, the reaction was allowed to cool, the reaction mixture was cooled, and the obtained mixture was filtered, and then evaporated to dryness to afford the title compound 5 3. 4 g; (DMS 〇d6, 300 MHz): 8.08 (1H, s) , 8 · 1 4 ( 1 Η, s ); LRMS: m/z 253 (M) +. c) mouth spit a fixed 3 - bromine - 2 - atmosphere - 5 - sulfonium chloride

Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (please read the notes on the back and fill in this page) 0=?=0

CI A solution of sodium nitrite (7.6 g, 1 1 0 0 0 mol) in water (30 ml) was added dropwise to the product from step b) (2 5 · 3 g, 100.0 mmol) Ear) ice-cold solution in aqueous hydrochloric acid solution (115 ml, 20%), keep the temperature below 6 °C, stir the reaction at 0 °C for 30 minutes, then stir at room temperature for another hour, under reduced pressure The following standards for the reaction paper are applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -25- 1299989 A7 B7 V. Description of the invention (23) The compound is evaporated and the residue is dried under vacuum at 70 °C. 7 hours, a mixture of this solid, phosphorus pentachloride (3 0 · gram ' 14 4 mM) and phosphonium chloride (1 ml, 10. 8 millimolar) was heated at 1 2 5 ° C After cooling for 3 hours, the reaction mixture was poured into ice (1 g) and the obtained solid was filtered, rinsed with water, and the product was dissolved in dichloromethane and dried (

<RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; d) 3 -Bromo-2-chloro-5-(4-ethylhexahydropyridin-1-sulfonyl)pyridine (Please read the note on the back and fill out this page)

The Ministry of Economic Affairs' Intellectual Property Office staff consumption cooperative printed 1 hexahydropyrrolidine (1 1.3 ml, 8 9.0 mmol) and triethylamine (12.5 ml, 89.0 mmol) in dichloromethane ( A solution of 10.5 ml) was added dropwise to an ice-cold solution of the product from step c) (23.0 g, 79.0 mmol) in dichloromethane (1 50 ml) and the reaction was stirred at 0 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residual brown oil was applied to silica gel with methylene chloride: a paper size applicable to the Chinese National Standard (CNS) A4 specification (210×297 mm) &quot; ~ -26- 1299989 A7 _______ B7 V. Inventive Note (24) Alcohol (9 9 : 1 to 97:3) was purified by column chromatography as a gradient eluting to give the title compound as an orange solid: 14.5 g; 5 (CDC13, 300MHz) : 1.05 (3H,t) '2*42(2H,q) ,2.55(4H,m), 3.12 (4H,m) ,8.24(1H,s), 8. 6 7 ( 1 H,s ) . e) —3 —Bromo,..2—Ethoxy-5—(4—7, a certain six-puppet-pigment-1 di-based 碏-base) mouth ratio ti (please read the notes on the back and fill in the form) Page)

The Ministry of Economic Affairs Intellectual Property Office staff consumption cooperative printed the product from step d) (6.6 0 g, 1 7.9 mmol) and sodium ethoxide (6.09 g, 8 9.55 mmol) in ethanol (100 ml) The mixture was heated under reflux for 18 hours and then cooled. The reaction mixture was concentrated under reduced pressure.mjjjjjjjjjjjjjjjjj The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organic layer solution was dried (M g S 〇 4 ) and evaporated under reduced pressure to give the title compound as a brown solid. Standard (CNS) A4 size (210 X 297 mm) -27 - A7 1299989 _ B7 ---^----------- V. Description of invention (25) 6·4ΐ gram, experiment: C,41.27 ;Η,5·33 ; N, 1 1.1 1 ; Ci3H2〇BrN3〇3S Theory 値C,4 1.3 5 ;Η,5.28;Ν,1〇·99%; $ (CDC13,300MHz) : 1.06 ( 3H,t) 'l.48(3H,t), 2.42(2H,d), 2.56 (4H,m),3.09 (4H,m), 4.54(2H,q) ,8.10(lH,s), 8.46 (lH, s) ; LRMS: m/z 378, 3 8 〇 ( M + 1 ) +. f) pyridine 2-ethoxy-5-(4-ethylhexafluoropyridinyl)--3-carboxylic acid ethyl ester (please read the back of the note first and then fill out this page)

The Ministry of Economic Affairs’ Intellectual Property Office employee consumption cooperative will print the product from step d) (6·40 g, 1 6 · 9 2 mmol), triethylamine (12 ml, 8 6 · 1 mmol) and The mixture of hydrazine (triphenylphosphine) palladium (0) in ethanol (60 ml) was heated at 1 ° C and 200 psi of one of the carbon oxide pressure for 18 hours, then cooled, and the reaction mixture was concentrated under reduced pressure. And the residue on the silicone with methylene chloride on the paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) -28- 1299989 A7 B7 __ five, invention description (26) •• methanol (1 0 0 ········································ 1.39(3H,t), 1.45(3H,t), 2.40(2H,q),2·54(4Η,γπ), 3.08(4H,m),4.38(2H,q), 4.55(2H,cj) , 8.37 (lH, s), 8 · 6 2 ( 1 H, s ); LRMS: m/z 372 (M + l) +. g) Pyridine 2 -ethoxy-5-(4-ethylhexa-pyrene-one-one capped ore-based)-3-decanoic acid (please read the notes on the back and fill out this page)

n^V^oh Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing V ·0=Γ0

Stir the mixture of the product of step f) (4·96 g, 13.35 mmol) and aqueous sodium hydroxide (25 ml of '2 equivalents of '50.0 mmol) in ethanol (25 ml) at room temperature. After 2 hours, the reaction mixture was concentrated to half volume under reduced pressure, washed with diethyl ether and applied to the Chinese National Standard (CNS) A4 size (210×297 mm) -29- 1299989 A7 B7. It is acidified to p Η 5 with 4 equivalents of hydrochloric acid, and the organic extract of the hydrazine is dried with dichloromethane (3×30 ml) (please read the notes on the back and fill in the form) page)

Mg S 〇 4) and evaporated under reduced pressure to give the title compound as a brown solid, 4.02 g; 5 (DMS 〇d6, 3 〇〇 MHz): 1.18 (3H, t), 1·37 (3H, t), 3 · 08 (2H, q ), 3.17-3.35 (8H, m), 4.52 (2H, q ), 8.30 (1H, s), 8.7 〇 (1H, s). h) 4 — 〔2—Ethoxy-5-(4-ethylhexahydrod-d-butan-1-ylsulfonyl)pyridin-3-carbamamine-1]-1H-3

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 3 - ethyl - 1 - pyrazole - 5 -carboxamide (W 〇 9849166) (9.2 g, 59.8 mmol) in N, N - dimethyl A solution of guanamine (60 ml) was added to the product from step g) (2 1.7 g, 6 2.9 mmol), 1-hydroxybenzotriazole hydrate (10.1 g, 66.0 mmol) and triethyl A solution of amine (13.1 5 ml, 94.3 mmol) in dichloromethane (240 ml), this paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -30- 1299989 A7 _B7_ V. Description of invention ( 28) (Please read the note on the back and fill out this page) Add 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1 3 · 2 6 g, 6 9 · 2 mmol; and the solution was stirred at room temperature for 6 hours, the dichloromethane was evaporated under reduced pressure, and the residual solution was poured into ethyl acetate (40 mL). The sodium aqueous solution (40 ml) was washed, and the obtained crystalline precipitate was filtered, washed with ethyl acetate and dried under reduced pressure to give a standard. Compound white powder 22 g; 5 (CDC13+1 drop DMS 〇d6): 〇.96 (3H, t), 1.18 (3H, t), 1.50 (3H, t), 2.2 5- 2.56 (6H, m) , 2.84( 2H,q), 3.00(4H,m), 4.70(2H,q) ' 5.60( 1H,bi*. s) , 6.78(lH,br.s) ,8.56 (1H, d) , 8.76 ( lH,d), 10.59 (lH,s), 12.10-12.30 (1H, s ) ;LRMS:m/z4 80(M+l)+〇i ) 2 —methyl chloride B 4 —[2-B Oxygen-5-(4-Ethyl hexahydropyrimidin-1-ylsulfonyl)pyridine-3-a certain carbamide]-upper quinone-3-ethylpyrazole-5-carbamamine Ministry of Economy Intellectual Property Bureau employee consumption cooperative printing - ruler Zhang - paper standard standard I home country one country I use I suitable S Ν

- Μ 7 7 9 2 X 31 1299989 A7 B7 V. Description of the invention (2g) Add 1-bromo-2-methoxyethane (1.7 2 mmol) to the product from step h) (750 mg) , 1 · 5 6 mM) and a solution of carbonic acid planer (1.1 2 g, 3.4 4 mmol) in N,N-dimethylformamide (15 ml), and the solution is at 60 After stirring at ° C for 18 hours, the cooled mixture was distributed in water and ethyl acetate and the layers were separated. The organic layer was dried (M g S ◦ 4 ), concentrated under reduced pressure and azeotroped with toluene to give a solid. This product was recrystallized from diethyl ether to give the title compound as a white solid. And 2 = isobutoxy-5 - (4-ethoxylated - 1 - a vibrating base) mouth ratio P疋-3 -yl] -3 ~ Zj S ~~ (1 - A certain hexahydro AiT .:_4_-_ base) - 2 2 g - dihydrogen: Ui - carbazino [4, hd] pyrimidine-7-ketone (please read the notes on the back and fill out this page) Printed by employee consumption cooperatives

Exhibition N - the product from the following step b) (90 mg, q 1 5 6 mM), bis(dimethyl oxalate) potassium amide (1 56 mg, 〇 · 78 mmol) and acetic acid A mixture of ethyl ester (14 mg, 0.156 mmol) in isopropanol (12 ml) was heated in a closed container of i 3 〇 &lt; t. The paper scale was applicable to the Chinese National Standard (CNS) A4 specification (210X297) PCT)

-32 - 1299989 A7 B7 V. INSTRUCTIONS (3〇) (Please read the note on the back and fill out this page) 6 hours, pour the cooled reaction mixture into saturated aqueous sodium bicarbonate (60 ml) and use The ethyl acetate (60 ml) was extracted, and the combined organic extracts were dried (M g S 〇 4 ) and evaporated under reduced pressure to give a colloid, methylene chloride: methanol: 0.88 ammonia (92.6: 6 .6 : 0 · 6 ) Purification of the crude product by column chromatography as a stream washing liquid gave the beige compound of the title compound 3 6 mg, 5 (CDC1 3): 1 · 0 1 ( 3 Η, t ),1 · 1 2 ( 6 Η,d ),1·39 (3H,t), !·94 (2H, m), 2.15 (2H, m), 2.22-2.44 (6H, m), 2.55 (6H , m), 3·〇2 (4H,m),3·14 (4H,m), 4.22 (1H,m),4·43 (2H,d), 8.60 dH,d),9.00 (1H,d ), 10.54 (1H, s). The starting material of the grade should be a) -2_- (1 - Di-terpenyl-based hexachloro-peri- sylphate-specific s- 4-yl) - 4 - Γ 2 - ethoxyl-5 - ( 4 - ethyl hexahydro DU: D Well defeated -^ - 3 - a certain amino-based amine -3 - ethyl late 哗 -5 - a

&gt;τ (The Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperation, Du Nan printing, adding sodium hydride (6 4 mg, 60% dispersion in mineral oil, liquid, 1.6 mmol) to the product from step 1) of Example 1. (^4 ^ millimu ear) in tetrahydrofuran (1 〇 ml) solution, and the solution is disturbed for 1 ,, add 4 -[(methylsulfonyl)oxy]-hexammine paper scale for China National Standard (CNS) A4 Specification (210X 297 mm) -33- 1299989 A7 B7 V. Description of Invention (31) T-butyl pyridinecarboxylate (W〇9 3 1 9 0 5 9 ) (1.60 mmol) The reaction mixture was stirred at 60 ° C for 3 days, and the cooled mixture was distributed in ethyl acetate and sodium hydrogencarbonate aqueous solution and the liquid layer was separated, and the aqueous layer was extracted with ethyl acetate, and the combined organic solution was dried ( M g S 0 4 ) and evaporating under reduced pressure, and the residue was purified by column chromatography eluting with EtOAc (EtOAc) 3 10 mg, 5 (〇〇(:13): 1.02 (31〇, 1.23(311,1), 1.49 (9H, s), 1.57 (3H, m), 1.93 (2H, m)5 2.16 (2H, m), 2.4 0 (2H, q), 2.54 (4H, m), 2.82-2.97 (4H, m), 3.10 (4H, m), 4.30 (3H, m), 4.79 (2H, q), 5.23 (1H, s) , 6.65 (1H, s), 8.63 (1H, d), 8.82 (lH, d), 10.57 (1H, s). (Please read the notes on the back and fill out this page)

, 1T Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, printed b) 4 -[2-ethoxy-5-(4-ethylhexachloro-p-pyridyl-1-ylsulfonyl)pyridin-3-ylformamidine Amino]-3-metal- 2 - (

Trifluoroacetic acid (1.5 ml) was added to a solution of the product from step a) above (320 mg, 0.48 mmol) in dichloromethane (2 mL). Hour, the reaction mixture was evaporated under reduced pressure and the residue was thoroughly dried with diethyl ether and dried under vacuum. The paper size was applied to the Chinese National Standard (CNS) A4 specification (210X 297 mm) — -34 - 1299989 A7 B7 , after the invention (32), a white solid was obtained, and formaldehyde (2 17 μL, 37% aqueous solution, 2·90 mmol) was added to a solution of the intermediate amine in dichloromethane (8 mL). The solution was stirred vigorously for 30 minutes, acetic acid (8 8 μl, 1.6 9 mmol) was added, and the solution was stirred for another 30 minutes, then sodium triethoxysulfonium hydride (1 6 9 mg, 0.8 0) was added. The mixture was stirred at room temperature for 16 hours, and the reaction mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate.

Mg S〇4) and evaporated under reduced pressure, using dichloromethane: methanol: 0.88 ammonia (9 1 · 7 5 : 7 · 5 : 0 · 7 5 ) as a flow washing liquid through the column Purification of the residue by chromatography to give the title compound: EtOAc, EtOAc (EtOAc, EtOAc, EtOAc, EtOAc , m), 2.25-2.45 (7H, m), 2.54 (4H, m), 2_91 (2H, q), 2.99-3.16 (6H, m), 4.08 (1H, m), 4.78 (2H, q), 5.11 (1H, br.s), 6.65 (1H, br.s), 8.63 (1H, d), 8.83 (1H, d), 10.53 (1H, s) ° Example 3 5 — [ 2 — Ethoxygen a -5 - (4 - ethyl six gas mouth than brown - 1 - base sulfhydryl) acridine a 3-base] a 3 - B - 2 - phenyl - 2, 6 -

, a gas of 7 Η — sitting in the eye and [4, 3 - d].密口定一7 — S This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

, 1T

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1299989 A7 B7 V. Invention description (33)

N Add pyridine (0 · 1 mL, 1 · 0 8 mmol) to the product from the following step a) (25 0 mg, 0.54 mmol), copper (II) acetate monohydrate (145 mg, 0.72) a mixture of phenylboronic acid (132 mg, 1.08 mmol) and 4 angstrom molecular sieve ester (392 mg) in dichloromethane (5 mL), and the reaction was stirred at room temperature for 4 days. Filtration and evaporation of the filtrate under vacuum. The crude product was purified by column chromatography eluting with methylene chloride: methanol: hexanes &lt;RTI ID=0.0&gt; The hexane was triturated, and the obtained solid was filtered and purified from crystals eluted from EtOAc EtOAc EtOAc (EtOAc) ), 1.60 (3H, t), 2.42 (2H, q), 2·58 (4H, m), 3.10 (2H, q), 3.17 (4H, m), 4.76 (2H, q), 7.40 (1H, m),7·51 (2H,m), 7.80 (2H,d),8·67 (1H,d),9.16 (1H,s),10·90 (1H,s); LRMS: m/z 538 (M+l)+. Preparation of starting materials; a) 5 — —Ethoxy-5 — ( 4 —Ethyl hexahydroindole _ 1 2 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (please first Read the notes on the back and fill out this page)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed -36 - 1299989 A7 B7 V. Description of Invention (34) Based on J-Et Turtle II) - 3 - B - 2, fi - Dioxin - Pyrimidine - 7-ketone

NN (please read the note on the back and fill out this page) Add bis(trimethyldecyl) potassium amide (8.28 g, 41.6 mmol) to the product from step 1 of step 1 (i 〇·〇克, 2 〇·8 毛•吴耳) and ethyl acetate (2 ml, 20 mmol) solution in ethanol (160 ml) and heat the reaction mixture in a sealed container of 12 for 12 hours The cooled mixture was evaporated under reduced pressure and purified by column chromatography using dichloromethane:methanol: 〇·8 8 ammonia (9 5 ·· 5 : 〇· 5 ) as a washing liquid. The title compound was obtained in the title compound 3 · 7 5 g, 5 (CDCh): 1.03 (3 Η, t), 1·42 (3Η, t) 1·60 (3H, t), 2.42 (2H, q), 2·58 (4H,m),3·02 (2H,q),3 l6 (4H,m),4.78 (2H,q),8.66 (1H,d),9·08 (1H,d),11·〇〇 (1Ή s), 1 1.05- 1 1.20 ( 1H, br· s); LRMS: m/z 462 (M+l)+. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm), 11

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives • 37-

Claims (1)

1299989 A8 B8 C8 D8 4:.' Application for Patent Scope Attachment 2A: Patent Application No. 9 1 1 24370 Application for Chinese Patent Application Replacement December 20, 1996 Revision 1 · A combination of neurodegenerative diseases, including sildenafil and Gabapentin. 2 - A combination for treating a neurodegenerative disease comprising a sirnabide and a pregabalin 药学3 - a pharmaceutical composition for treating a neurodegenerative disease, comprising sirnavir and gaba butyl. 4. A pharmaceutical composition for treating a neurodegenerative disease comprising sirnavir and hydrazine. The pharmaceutical composition according to claim 3, wherein the neurodegenerative disease is diabetic polyneuropathy. Hr———IIΦ------IT------f (please read the «Precautions on the back and fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print this paper scale for China Standard (CNS) A4 specification (210X297 mm)