WO1994012503A1 - Remede contre l'hypertension pulmonaire - Google Patents

Remede contre l'hypertension pulmonaire Download PDF

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Publication number
WO1994012503A1
WO1994012503A1 PCT/JP1993/001757 JP9301757W WO9412503A1 WO 1994012503 A1 WO1994012503 A1 WO 1994012503A1 JP 9301757 W JP9301757 W JP 9301757W WO 9412503 A1 WO9412503 A1 WO 9412503A1
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WO
WIPO (PCT)
Prior art keywords
atom
formula
hydrogen atom
c0ch
compound
Prior art date
Application number
PCT/JP1993/001757
Other languages
English (en)
Japanese (ja)
Inventor
Masahiko Oka
Kiyotomo Seto
Original Assignee
Nissan Chemical Industries, Ltd.
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 Nissan Chemical Industries, Ltd. filed Critical Nissan Chemical Industries, Ltd.
Publication of WO1994012503A1 publication Critical patent/WO1994012503A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a method for treating pulmonary hyper-JflDE, which is characterized by using a viranobenzoxadiazole derivative as an active ingredient, and to a pharmaceutical, which is characterized by containing them as an active ingredient.
  • Patents 327127 and Amerili Patent 4900752 disclose that pyranoben zooxadiazole derivatives have a strong K-channel activating effect, and that circulatory system such as high JfilflE disease, angina pectoris, arrhythmia, etc. It discloses the possibility of being used to treat disorders, but does not mention the possibility of treating pulmonary bleeding.
  • High pulmonary jfiLE disease is defined as a mean pulmonary artery pressure of 25 ramHg or higher and occurs when there is a sustained increase in pulmonary arterioles or pulmonary veins.
  • the cause of the onset is not always clear, and there is no fundamental treatment method.
  • administration of diuretics and vasodilators Or oxygen inhalation is performed.
  • surgical procedures such as simultaneous cardiopulmonary transplantation have been performed.
  • Ca ++ antagonists such as difudipine, ACEP and harmful drugs such as captopril, and vasodilators such as hydralazine are used.
  • the selectivity for the pulmonary artery is low, and it often does not respond. Disclosure of the invention
  • the present inventors have intensively searched for a compound capable of treating pulmonary hypertension. Was completed.
  • the compound according to the present invention has the general formula (I)
  • a 0H or 0C (0) CH 8 - n X n (X denotes a fluorine atom, a chlorine atom, a bromine atom, methylcarbamoyl group or a methoxy group, n represents an integer of 0-3 )
  • B means a bond;
  • B means a hydrogen atom or, together with A, means a bond
  • R 1 is a hydrogen atom and R 2 represents a hydrogen atom
  • C (Z) CH 8 - n X n (Z means an oxygen atom or a sulfur atom.)
  • C (Z) NHCH 8 - means n X n ;
  • R 1 is not a hydrogen atom
  • R 1 and R 2 are joined together (m means 4 or 5), (CH ⁇ iXZ), N (R 5 ) (CH 2 ) 2 C (Z ) (R 5 represents a hydrogen atom or a methyl group.) Or (CH 2 ) m -Z) or (CH 2 ) m - 20 C (Z);
  • R 3 and R 4 are the same as or different from each other, and each represents a hydrogen atom or a ⁇ alkyl group, or R 3 and R 4 are taken together and are substituted with an alkyl group. 1,4-butylene or 1,5-pentylene. Or a salt capable of forming a compound represented by the formula (1), which is an acceptable salt, and details of its production method are described in Japanese Patent No. 327127 and Patent No. 4900752 ⁇ . It is described in.
  • the compound used in the present invention has an asymmetric center and has optical isomers, and the present invention also includes these optical isomers.
  • the method for producing optical isomers is disclosed in US Pat. No. 5,097,037 and EP 409165.
  • An object of the present invention is to provide a method for treating pulmonary hypertension, which comprises using, as an active ingredient, a compound represented by the general formula (I) or a salt thereof when a salt can be formed. And a pharmaceutical characterized by containing them as an active ingredient.
  • the medical products mentioned here include oral preparations such as tablets and syrups, as well as parenteral preparations such as ointments, creams, lotions, pastes, jellies, gels, mousses, and aerosols.
  • the content of the compound of the formula (I) is 0.005% to 10%, preferably 0.05% to 3%, and the application amount is 1% O.OOlmg to 100rag, preferably 0.0Lmg to: lOmg, applied once or several times a day, but may be increased or decreased taking into account the patient's symptoms, weight, age, sex, etc.
  • R 1 when R 1 is a hydrogen atom, R 2 is preferably C0CH 8 , C0CH 2 CH 8 , C0CH 2 F, COCFs, C0CH 2 C1, C0NHCH 3 , and when R 1 is other than a hydrogen atom, Is the combination of R 1 and R 2 --(CH 2 ) 8 C0-,-(CH 2 ) 4 C0-,-(CH 2 ) 80 C0-, -NH (CH 2 ) 2 C0-,- (CH 2 ) 4 -,-(CH 2 ) 5- and the like are preferable.
  • R 8 and R 4 are preferably an alkyl group, and particularly preferably a methyl group and an ethyl group. Particularly preferred compounds include compounds represented by the following formulas (11), (III) and (IV).
  • FIG. 1 shows the mean pulmonary artery pressure when a compound represented by the formula (III) (NIP-121) and a typical Ca ++ antagonist, diphedipine (formula V), were administered.
  • test examples and prescription examples are shown, but the present invention is not limited to these examples.
  • FIG. 1 shows the results of the compound (NIP-121) represented by the formula (III) and nifidipine (formula V), which is a typical Ca ++ antagonist.
  • NIP-121 showed a clear mean pulmonary artery hypotensive effect at a dose of 10 / zgAg or higher, but diphediopine did not show a decrease even at a dose of 1,000 / igkg.
  • the compound of the present invention has a strong t3 ⁇ 40 ⁇ JfiLffi action.
  • the upper part was mixed by a conventional method to obtain 0.1% aerosol. Availability ⁇ ⁇

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne un remède contre l'hypertension pulmonaire contenant un ingrédient actif comprenant un composé représenté par la formule générale (I) ou, s'il peut former un sel, un sel pharmaceutiquement acceptable dudit composé, ledit composé et son sel présentant une puissante résistance à l'hypertension pulmonaire ainsi qu'une toxicité réduite, ce qui leur permet d'être utile dans le traitement de l'hypertension pulmonaire. Dans ladite formule (I), A représente OH ou OC(O)CH3-nXn (où X représente fluor, chlore, brome, méthyle ou méthoxy, et n représente un nombre entier de 0 à 3), ou bien A peut être combiné avec B pour représenter un liaison; B représente hydrogène ou peut être combiné avec A pour représenter une liaison; quand R1 représente hydrogène, R2 représente hydrogène, C(Z)CH¿3-n?Xn (où Z représente oxygène ou soufre) ou bien C(Z)NHCH3-nXn; quand R?1¿ ne représente pas hydrogène, R1 et R2 sont combinés pour représenter (CH¿2?)m (où m représente 4 ou 5), (CH2)m-1 C(Z), N(R?5)(CH¿2)2C(Z) (où R5 représente hydrogène ou méthyle), (CH¿2?)m-2NHC(Z) ou bien (CH2)m-2OC(Z); et R?3 et R4¿, qui peuvent être identiques ou différents, représentent chacun hydrogène ou alkyle C¿1?-C4, ou bien R?3 et R4¿ sont combinés pour représenter 1,4-butylène ou 1,5-pentylène qui peuvent être chacun substitués par alkyle C¿1?-C4.
PCT/JP1993/001757 1992-12-03 1993-12-02 Remede contre l'hypertension pulmonaire WO1994012503A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4324445A JPH06172173A (ja) 1992-12-03 1992-12-03 肺高血圧症治療剤
JP4/324445 1992-12-03

Publications (1)

Publication Number Publication Date
WO1994012503A1 true WO1994012503A1 (fr) 1994-06-09

Family

ID=18165897

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001757 WO1994012503A1 (fr) 1992-12-03 1993-12-02 Remede contre l'hypertension pulmonaire

Country Status (2)

Country Link
JP (1) JPH06172173A (fr)
WO (1) WO1994012503A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04290876A (ja) * 1990-11-26 1992-10-15 E R Squibb & Sons Inc ベンゾジアゾロ類似体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04290876A (ja) * 1990-11-26 1992-10-15 E R Squibb & Sons Inc ベンゾジアゾロ類似体

Also Published As

Publication number Publication date
JPH06172173A (ja) 1994-06-21

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