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WO2001083429A1 - Derives d'aniline - Google Patents

Derives d'aniline Download PDF

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Publication number
WO2001083429A1
WO2001083429A1 PCT/JP2001/003721 JP0103721W WO0183429A1 WO 2001083429 A1 WO2001083429 A1 WO 2001083429A1 JP 0103721 W JP0103721 W JP 0103721W WO 0183429 A1 WO0183429 A1 WO 0183429A1
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WO
WIPO (PCT)
Prior art keywords
compound
agent
mixture
added
headache
Prior art date
Application number
PCT/JP2001/003721
Other languages
English (en)
Japanese (ja)
Inventor
Toshio Honda
Toshihiko Makino
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU2001252648A priority Critical patent/AU2001252648A1/en
Publication of WO2001083429A1 publication Critical patent/WO2001083429A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to an aniline derivative having an inhibitory effect on nitric oxide synthase (nitricoxidedesynthaise, NOS).
  • NOS there are at least three types of NOS isoforms.
  • NNOS type 1
  • eNOS type 3
  • iNOS type 2
  • iNOS type 2
  • iNOS type 2
  • iNOS type 2
  • iNOS type 2
  • ipopolysaccharide LPS
  • isourea derivatives isothiourea derivatives, or guanidine derivatives are described in WO95 / 09619, WO96Z09286, WO96Z18608, WO98 / 42667, WO99 / No. 23069, and the like.
  • An object of the present invention is to provide an aniline derivative having NOS inhibitory activity and useful as a medicament.
  • Another object of the present invention is to provide an aniline derivative having a selective inhibitory activity on nNOS and useful as a medicament.
  • an aniline derivative having a specific structure that is, an isourea derivative, an isothiourea derivative, or a guanidine derivative has an excellent NOS inhibitory action.
  • the present inventors have found that they have, or have a strong nNOS inhibitory activity, or have a selective inhibitory activity on nNOS, and completed the present invention based on such findings.
  • the present invention also provides a medicine, a NOS inhibitor, a selective nNOS inhibitor, or a therapeutic agent for cerebrovascular disease containing the above compound. Furthermore, the present invention provides various disease states containing the above compound, which can be expected to have therapeutic effects by selectively inhibiting nNOS, for example, head trauma, spinal injury, pain, Parkinson's disease, Alzheimer's disease, convulsions And a therapeutic agent for morphine tolerance or dependence.
  • the “NOS inhibitor” refers to a compound having an inhibitory effect on at least one isoform of three N ⁇ S isoforms.
  • the “n NS selective inhibitor” has a weak effect on eNOS and iNOS among three isoforms of NOS and has a selective inhibitory effect on nNOS.
  • the compounds included in the present invention show good NOS inhibitory activity or good nNOS-selective inhibitory activity, as described in the test examples described later.
  • the types of cerebrovascular disease include cerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack (TIA), cerebral edema, and cerebral infarction.
  • Subtypes of cerebral infarction include atherothrombotic infarction, lacunar infarction, or cardiogenic embolism.
  • the target pain types include, for example, headache.
  • subtypes of headache include migraine, tension-type headache, or cluster headache or chronic paroxysmal headache.
  • the compounds in the compound group (1) may have tautomers depending on the surrounding environment of the compounds, and these tautomers are all included in the present invention.
  • the pharmaceutically acceptable salt of the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and hydroiodic acid.
  • salts with organic acids such as formic acid, acetic acid, fumaric acid and tartaric acid.
  • the compound of the present invention or a salt thereof may be a suitable excipient, scavenger, lubricant, preservative, disintegrant, buffer, binder, stabilizer, wetting agent, emulsifier, coloring agent, flavor or fragrance.
  • scavenger lubricant
  • preservative disintegrant
  • buffer binder
  • stabilizer wetting agent
  • emulsifier coloring agent
  • coloring agent flavor or fragrance.
  • administration is mainly by intramuscular or intravenous injection There is expected.
  • oral administration may be considered.
  • the dose of the compound of the present invention or a salt thereof depends on the patient's body type, age, physical condition, and degree of disease. Although it can be selected as appropriate depending on the time elapsed after the onset, etc., it is expected to be 0.01 to 100 mg O body per day. In general, even if the same dose is administered, the blood concentration may vary greatly from patient to patient, so it is ideal to determine the optimal dose of the drug for each patient while monitoring the blood concentration of the drug. It is.
  • an effective amount of the main component is dissolved in distilled water for injection, and if necessary, an antioxidant, a stabilizer, a solubilizing agent, a buffer, a preservative, and the like are added. After complete dissolution, filtration, filling, sealing, and sterilization by a high-pressure steam sterilization method or a dry heat sterilization method can be performed to obtain an injection.
  • an aqueous solution in which the main component is dissolved in distilled water for injection may be lyophilized by an ordinary method.
  • mannitol may be used as an excipient that can be easily lyophilized.
  • sugars such as inositol, lactose, maltose, and sucrose, or sugar alcohols, or glycine and the like, and then freeze-dried in the usual manner to prepare the preparation.
  • Example 1a In order to show the usefulness of the present invention, test results on the inhibitory effects of the compounds included in the compound group (1) on various NOS are shown in Test Examples.
  • Example 1a Example 1a
  • Example 9a To a solution of the compound (1.94 g) obtained in Example 9a in methanol (30 ml) was added sodium hydroxide (1.04 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified by adding 2N hydrochloric acid, and extracted with chloroform. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the obtained residue were added t-butyl alcohol (20 ml), diphenylphosphoric azide (1.80 g) and triethylamine (66 Omg), and the mixture was heated and stirred at 90 for 18 hours.
  • Tiophosgene (0.028 ml) was added dropwise to a solution of (9 Omg) in methylene chloride (8 ml), and the mixture was stirred at room temperature for 5 minutes. 28% aqueous ammonia solution (4m
  • Example 8b Using the compound obtained in Example 8b, t-butyl N- (5-amino-2-methoxyphenylmethyl) -N- (3-phenylpropyl) carbamate was prepared in the same manner as in Example lb. Obtained. The title compound was obtained in the same manner as in Example 13a using the obtained compound.
  • Example 1d A mixture of the compound (72 mg) obtained in Example 1d and trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. After dissolving the residue in ethanol, a 1,4-dioxane solution of hydrogen chloride (4N) was added, and the mixture was stirred at room temperature for 2 minutes, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate, and the aqueous layer was lyophilized to give the title compound quantitatively.
  • a crude enzyme sample of nNOS was prepared by the following procedure. Untreated male Sprague Daw 1 ey (SD) rats (body weight 300-400 g) were decapitated, the whole brain was quickly removed, and the cerebral cortex was collected on ice. Next, a 5-fold volume of a 50 mM Tris-HC1, ImM DTT (pH 7.4) solution was added, homogenized for 3 minutes, and centrifuged at 1,000 X g for 10 minutes. The obtained supernatant was centrifuged at 100,000 ⁇ g for 60 minutes, and the soluble cytoplasmic fraction of the finally obtained supernatant was used as a crude enzyme preparation of nNOS.
  • a crude enzyme sample of eNOS was prepared by the following procedure. ⁇ Pulmonary artery vascular endothelial cell line (CPAE) was cultured in MEM medium containing 20% FBS. A few days later, this was detached from the flask with a 0.25% trypsin, ImM EDTA solution, added with an appropriate amount of FBS, and centrifuged at 1,000 rpm for 10 minutes. An appropriate amount of a phosphate buffer solution containing no calcium and magnesium (; H7.4) was added to the cells in the sediment, and the mixture was centrifuged at 1,000 rpm for 10 minutes.
  • CPAE Pulmonary artery vascular endothelial cell line
  • a crude enzyme preparation of iNOS was prepared by the following procedure.
  • LPS (1 Omg / kg) was intraperitoneally administered to the rats, and after 6 hours, the rats were perfused with 1 OUZml of heparin-containing saline, and the lungs were removed. Then, a 5-fold dose of a 5 OmM Tris-HC1, ImM DTT (pH 7.4) solution was added, homogenized for 3 minutes, and centrifuged at 1,00O Xg for 10 minutes. The obtained supernatant was then centrifuged at 100, OOOXg for 60 minutes, and the soluble cytoplasmic fraction of the finally obtained supernatant was used as a crude enzyme sample of iNO.S.
  • NO S activity is one of the substrate L- [3 H] is one of the reaction products from arginine L- [3 H] was measured by quantifying the amount of conversion into citru 1 1 ine (B rain Edema IX, 60, p 285- 288, 1994;. Neur or epo rt 6, 154 1—1545, 1995).
  • the reaction solution was 100 nM L— [ 3 H] arginine, crude enzyme preparation (10-30 zg / ml protein), 1.25 mM Ca C12, 1 mM EDTA, 10 g / m 1 calmodu lin, ImM NADPH, 100 M tet ahyd r ob i op terine, 10 ⁇ , ⁇ FAD, 10 U FMN, 5 OmM Tr is—HC 1 (pH 7.4), to which the compound of the present invention or A control compound was added.
  • the reaction was started by addition of L- [3 H] arginine, after 10 minutes the ink Yubeshiyon at 37 ° C, 5 OmM Tr is -HC l (pH5. 5), ImM E DTA was added 2 ml, placed in an ice To stop the reaction.
  • the reaction solution cation exchange resin column (Dowex AG50WX- 8, Na + fo rm, 3. 2ml) through a substrate L- [3 H] arginine remaining unreacted and is the reaction product L-[3 H ] Citru 1 1 ine was separated. And this eluate, further a certain amount of distilled water
  • the eluate obtained through the column to Minipaiaru were collected L- [3 H] cit ru l 1 i ne. Thereafter, scintillator was added and the radioactivity was measured by liquid core guides laser Chillon counter to quantify L- [3 H] citru 1 1 ine.
  • nNOS and eNOS were determined by subtracting the activity detected in the absence of CaC12 and calmodulin from the activity detected in the presence of CaCl2 and calmodulin.
  • the activity of iNOS was detected in the absence of CaCl2 and calmodulin.
  • the protein concentration in the crude enzyme preparation was determined using a Microassay kit manufactured by Piolad. All experiments were performed in duplicate.
  • Table 18 shows the IC50 value (concentration required for 50% activity inhibition) of the test compound for each NOS isoform and the ratio of each IC50 value as an index indicating selectivity. Further, in Table 19, when using a test compound 10_ 6 M, and displays the inhibitory activity against NN_ ⁇ S or e NO S in the above reaction conditions. Table 18
  • the compound of the present invention has an excellent NOS inhibitory action.
  • the compound of the present invention has a strong nNOS inhibitory activity or a selective inhibitory effect on nN ⁇ S, and various disease states in which a therapeutic effect can be expected by selectively inhibiting nNOS, such as cerebral blood It is useful as a therapeutic agent for vascular disorders, head trauma, spinal injury, pain, Parkinson's disease, Alzheimer's disease, convulsions, morphine resistance or dependence.
  • the compound of the present invention can be expected to have a sufficiently excellent effect as compared with existing NOS inhibitors, or can be expected to have a clinically useful effect.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule (A), des tautomères de ces derniers, ou des sels pharmaceutiquement acceptables des deux, qui présentent une activité inhibitrice de NOS et qui sont des médicaments utiles dans le traitement de différentes maladies.
PCT/JP2001/003721 2000-04-28 2001-04-27 Derives d'aniline WO2001083429A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001252648A AU2001252648A1 (en) 2000-04-28 2001-04-27 Aniline derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-129725 2000-04-28
JP2000129725 2000-04-28

Publications (1)

Publication Number Publication Date
WO2001083429A1 true WO2001083429A1 (fr) 2001-11-08

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WO (1) WO2001083429A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718671B2 (en) 2003-07-10 2010-05-18 Achillion Pharmaceuticals, Inc. Substituted arylthiourea derivatives useful as inhibitors of viral replication
EP4057003A1 (fr) * 2021-03-12 2022-09-14 Universidad de Castilla la Mancha Détection sélective d'anion de sulfate à l'aide de fluorophores guanylés

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996018608A1 (fr) * 1994-12-12 1996-06-20 Chugai Seiyaku Kabushiki Kaisha Derives d'aniline a activite inhibant la monoxyde d'azote synthase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996018608A1 (fr) * 1994-12-12 1996-06-20 Chugai Seiyaku Kabushiki Kaisha Derives d'aniline a activite inhibant la monoxyde d'azote synthase
WO1996018607A1 (fr) * 1994-12-12 1996-06-20 Chugai Seiyaku Kabushiki Kaisha Derive d'aniline inhibant la synthase du monoxyde d'azote

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718671B2 (en) 2003-07-10 2010-05-18 Achillion Pharmaceuticals, Inc. Substituted arylthiourea derivatives useful as inhibitors of viral replication
EP4057003A1 (fr) * 2021-03-12 2022-09-14 Universidad de Castilla la Mancha Détection sélective d'anion de sulfate à l'aide de fluorophores guanylés
WO2022189677A1 (fr) * 2021-03-12 2022-09-15 Universidad De Castilla-La Mancha Détection sélective d'anion sulfate à l'aide de fluorophores guanylé

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Publication number Publication date
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