WO1992011252A1 - Composes anti-inflammatoires - Google Patents

Composes anti-inflammatoires Download PDF

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Publication number
WO1992011252A1
WO1992011252A1 PCT/US1991/009126 US9109126W WO9211252A1 WO 1992011252 A1 WO1992011252 A1 WO 1992011252A1 US 9109126 W US9109126 W US 9109126W WO 9211252 A1 WO9211252 A1 WO 9211252A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
lower alkyl
compound
phenyl
propyl
Prior art date
Application number
PCT/US1991/009126
Other languages
English (en)
Inventor
Stevan Wakefield Djuric
Donald John Fretland
Stella Siu-Tzyy Yu
Original Assignee
G.D. Searle & Co.
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 G.D. Searle & Co. filed Critical G.D. Searle & Co.
Publication of WO1992011252A1 publication Critical patent/WO1992011252A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • LTB 4 Leukotriene D 4 and C 4
  • LTB 4 leukotriene B 4
  • LTD 4 and LTC 4 are associated with smooth muscle contraction and contract guinea pig ileum, human and guinea pig bronchi and human pulmonary artery and vein.
  • LTB is associated with neutrophil stimulation and is characterized by chemotaxis, aggregation and degranulation. LTB 4 is believed to be an important mediator of inflammation. High levels of LTB 4 are detected in rheumatoid arthritis, gout, psoriasis, and inflammatory bowel disease. Thus antagonists of LTB 4 are useful in the therapy of such diseases.
  • Gastroenterolocrv. 1985: f$8. : 580-7 discusses the role of arachidonic acid metabolites in inflammatory bowel disease.
  • the prior art generally describes the above compounds as LTD 4 antagonists for use as anti-allergy compounds or as antagonists of SRS-A, the slow reacting substance of anaphylaxis.
  • compounds of Formula I are selective LTB 4 antagonists useful in treating inflammatory diseases.
  • R represents lower alkyl of 1 to 6 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or -(CH ) m -R 3 wherein R 3 represents cycloalkyl of 3 to 5 carbon atoms and m is 1, 2 or 3;
  • R- L is -CONH 2 or - C - NHS0 2 R 2 wherein R 2 is lower alkyl, phenyl, unsubstituted or substituted with lower alkyl.
  • n is an integer from 2 to 5.
  • LTB 4 leukotriene B 4
  • LTD 4 leukotriene D
  • This invention encompasses the compounds of Formula I as previously described.
  • Preferred embodiments of the present invention are compounds of the Formula la, and the stereoisomers and pharmaceutically acceptable salts thereof.
  • R is propyl, 2-propenyl or cyclopropylmethyl, and R n is
  • Scheme 1 illustrates a specific embodiment of the method for preparing compounds of the invention.
  • the biological activity of the compounds of this invention was determined by the following test procedures.
  • Neutrophils were purified from venous blood of normal human donors using standard techniques of dextran sedimentation, centrifugation on Ficoll-paque® (Pharmacia) or Histopaque® sterile solution (Sigma) and hypotonic lysis of erythrocytes (Boyum, A. , Isolation of Leukocytes from Human Blood: Further Observations. Scand. J. Lab. Clin. Invest.. 21 (Suppl. 97) : 31, 1968) . The purity of isolated neutrophils was >95%.
  • Neutrophil degranulation was determined by measuring the release of myeloperoxidase activity into the incubation medium. Neutrophils (3 x 10 6 ) in 1 ml HBSS solution were preincubated with cytochalasin B(5 ⁇ g) at 37°C for 5 minutes, followed by preincubation with test compounds for 7 minutes. Neutrophils were then incubated for 2 to 20 minutes with LTB 4 (5 x 10 ⁇ 8 M) to induce degranulation. Following incubation, samples were centrifuged and myeloperoxidase was extracted from the cell pellets by sonication in phosphate buffer containing 0.4% Triton X-100. Triton X-100 was.
  • Myeloperoxidase activity released into the supernatant was expressed as the percent of the average total activity (pellet plus supernatant) .
  • Neutrophils (4 - 6X10 6 ) in lml Hanks' balanced salt solution containing 10 mM HEPES buffer (HBSS) , pH 7.4 and 30 ⁇ M nordihydroguaiaretic acid were incubated with 0.6xl0 ⁇ 9 M ( 3 H) LTB 4 in the presence or absence of test compounds.
  • the incubation was carried out at 0°C for 45 minutes and terminated by adding 5ml of ice-cold HBSS followed by rapid filtration of incubation.mixture under vacuum through GF/C glass fiber filters. The filters were further washed with 10ml HBSS and radioactivity was determined.
  • Specific binding was defined as the difference between total binding and nonspecific binding which was not displaced by 10 ⁇ 7 M unlabeled LTB 4 . All data refer to specific binding.
  • HBSS HBSS
  • 3 X 10 ⁇ 8 M LTB 4 in the presence of absence of test compound.
  • cells from the lower well were lysed and nuclei counted in a Model S- Plus-IV Coulter Counter. Percent inhibition was calculated from cell counts corrected for random migration by subtracting the mean of the HBSS control.
  • the compounds of this invention can be administered in a number of dosage forms.
  • a preferred method of delivery would be oral or in such a manner so as to localize the action of the inhibitor.
  • the compounds could be injected directly into the affected joint.
  • the compounds could also be administered in oral unit dosage forms such as tablets, capsules, pills, powders or granules. They may be introduced intraperitoneally, subcutaneously, or intramuscularly using forms known to the pharmaceutical art. Topical application in the form of salves and ointments are useful for treating psoriasis. Regardless of the route of administration selected, the compounds are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.
  • IC 50 is the effective concentration needed to cause 50% inhibition.
  • the compounds of this invention can be administered in a number of dosage forms.
  • a preferred method of delivery would be oral or in such a manner as to localize the action of the antagonist.
  • the compounds could be ' -iected directly into the affected joint.
  • the compounds could also be administered in oral unit dosage forms such as tablets, capsules, pills, powders or granules. They may be introduced intraperitoneally, subcutaneously, or intramuscularly using forms known to the pharmaceutical art.
  • Topical application in the form of salves and art Topical application in the form of salves and ointments is useful for treating psoriasis. Regardless of the route of administration selected, the compounds are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.
  • a unit dosage of a compound of the invention would contain from about 50 mg to about 500 mg of the active ingredient with from about 70 mg to about 300 mg preferred.
  • the dosage regimen for antagonism of LTB by the compounds of this invention is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the mammal, the particular disease and its severity, the route of administration and the particular compound employed.
  • An ordinarily skilled physician or veterinarian will readily determine and prescribe the effective amount of the compound to prevent or arrest the progress of the condition. In so proceeding, the physician or veterinarian could employ or use relatively low dosages at first, subsequently increasing the dose until a maximum response is obtained.
  • a dosage range of l to 25 mg/kg of body weight is administered to patients in need of treatment for inflammatory conditions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention se rapporte à des composés représentés par la formule (I) et aux stéréoisomères et sels pharmaceutiquement acceptables de ces composés. Dans la formule (I), R représente un alkyle inférieur de 1 à 6 atomes de carbone, un alcényle inférieur de 2 à 6 atomes de carbone, ou -(CH2)m-R3 où R3 représente un cycloalkyle de 3 à 5 atomes de carbone et m est égal à 1, à 2 ou à 3; R¿1? représente -CONH2 ou α où R2 représente un alkyle inférieur, un phényle, non substitué ou substitué par un alkyle inférieur, ou β; et n représente un nombre entier compris entre 2 et 5. Ces composés servent d'agents anti-inflammatoires pour traiter notamment les troubles intestinaux d'origine inflammatoire, les arthrites rhumatoïdes, la goutte, l'asthme et le psoriasis.
PCT/US1991/009126 1990-12-19 1991-12-11 Composes anti-inflammatoires WO1992011252A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US629,919 1984-07-11
US62991990A 1990-12-19 1990-12-19

Publications (1)

Publication Number Publication Date
WO1992011252A1 true WO1992011252A1 (fr) 1992-07-09

Family

ID=24525019

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/009126 WO1992011252A1 (fr) 1990-12-19 1991-12-11 Composes anti-inflammatoires

Country Status (4)

Country Link
AU (1) AU9134991A (fr)
IE (1) IE914409A1 (fr)
PT (1) PT99833A (fr)
WO (1) WO1992011252A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995033742A1 (fr) * 1994-06-08 1995-12-14 G.D. Searle & Co. Antagonistes de la leucotriene b¿4?

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0150447A2 (fr) * 1984-01-06 1985-08-07 G.D. Searle & Co. Dihydrobenzopyrannes 2-carboxylates substitués

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0150447A2 (fr) * 1984-01-06 1985-08-07 G.D. Searle & Co. Dihydrobenzopyrannes 2-carboxylates substitués

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 103, no. 19, issued 1985, November 11, (Columbus, Ohio, USA), G.D. SEARLE et al. "Benzopyran antimetabolites", *
CHEMICAL ABSTRACTS, vol. 110, no. 25, issued 1989, June 19, (Columbus, Ohio, USA), ST.W. DJURIC et al. "Continuous method for pro- duction of 2-alkoxy-3,4-di- hydropyrans", *
CHEMICAL ABSTRACTS, vol. 111, no. 17, issued 1989, October 23, (Columbus, Ohio, USA), N. COHEN et al. "3,4-Dihydro-2H-1-benzopyran- -2-carboxylic acids and related compounds as leuko- triene antagonists", *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995033742A1 (fr) * 1994-06-08 1995-12-14 G.D. Searle & Co. Antagonistes de la leucotriene b¿4?

Also Published As

Publication number Publication date
AU9134991A (en) 1992-07-22
IE914409A1 (en) 1992-07-01
PT99833A (pt) 1992-12-31

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