EP0459983A1 - Antiatherosklerotische und antithrombotische 1-benzopyran-4-one und 2-amino-1,3-benzoxazin-4-one - Google Patents

Antiatherosklerotische und antithrombotische 1-benzopyran-4-one und 2-amino-1,3-benzoxazin-4-one

Info

Publication number
EP0459983A1
EP0459983A1 EP90900649A EP90900649A EP0459983A1 EP 0459983 A1 EP0459983 A1 EP 0459983A1 EP 90900649 A EP90900649 A EP 90900649A EP 90900649 A EP90900649 A EP 90900649A EP 0459983 A1 EP0459983 A1 EP 0459983A1
Authority
EP
European Patent Office
Prior art keywords
benzopyran
cpd
morpholinyl
methyl
phenyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP90900649A
Other languages
English (en)
French (fr)
Inventor
Ronald B. Gammill
Thomas M. Judge
Joel Morris
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Pharmacia and Upjohn Co
Upjohn 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 Pharmacia and Upjohn Co, Upjohn Co filed Critical Pharmacia and Upjohn Co
Publication of EP0459983A1 publication Critical patent/EP0459983A1/de
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
    • C07D265/22—Oxygen atoms
    • 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
    • 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
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present specification provides methods for use of pharmacologically active substances. Further the present specification provides novel compositions of matter and novel methods of their preparation.
  • Atherosclerosis in mammals is a disease characterized by the deposition of atherosclerotic plaque on arterial walls. While atherosclerosis exhibits many varied forms and consequences, typical consequences of atherosclerotic diseases include angina pectoris, myocardial infarction, stroke and transient cerebral ischemic attacks. Other forms of atherosclerotic diseases include certain peripheral vascular diseases and other ischemias (e.g., bowel and renal).
  • Atherosclerosis may be preventable or reversible.
  • Agents capable of preventing or reversing atherosclerosis are characterized as exhibiting antiatherosclerotic activity. Since serum lipids have a recognized association with atherogenesis, an important class of antiatherosclerotic agents are those with serum lipid-modifying effects. Serum lipids implicated in atherogenesis include serum cholesterol, serum triglycerides, and serum lipoproteins.
  • HDL's high density lipoproteins
  • LDL's low density lipoproteins
  • VLDL's very low density lipoproteins
  • HDL's are often referred to as alphalipoproteins
  • LDL's and VLDL's are referred to as betalipoproteins.
  • the enhancement of HDL levels is postulated to have direct antiatherosclerotic effects. See Eaton, R.P., J. Chron. Dis .31:131-135 (1978).
  • agents which reduce serum LDL's and serum VLDL's are also associated with antiatherogenic effects. See Haust, M.D., "Reaction Patterns of Intimal Mesenchyme to Injury and Repair in Atherosclerosis", Adv. Exp. Med. Biol. 43:3557 (1974), which postulates that serum LDL is a factor in atherosclerotic lesion formation.
  • 2-Aminochromones (4H-1-benzopyran-4-ones) are known in the literature.
  • the antiallergic activity of 2- aminochromones has been described in the literature by Mazzei, Balbi,
  • U.S. Patent 4,092,416 discloses various benzopyrone derivatives exhibiting anti-allergic activity, including 2- ⁇ 2- [4-(2-methoxyphenyl) -piperazinyl-1] -ethyl)- 5-methoxy-4-oxo-4H-1-benzopyran and 2- ⁇ 2-[4-(2-methoxyphenyl)- piperazinyl-1]-ethyl)-5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran.
  • JA-O25657 and JP-259603 descrive various 2-amino-3-carboxamide derivatives and 3-phenyl (optionally substituted)-2-aminochromone derivatives as useful as oncostatic and immunosuppressive agents.
  • 2-Amino-1,3-benzoxazin-4-ones are also known in the literature. Specifically, 2-morpholinyl-4H-1,3-benzoxazin-4-one (Cpd 98) and 8-methyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one (Cpd 84) are described in Netherlands patent application 6,412,966 (see also U.S. 3,491,092), and in the literature (Grigat, E., Putter, R., Schneider, K., Wedemeyer, K., Chem. Ber., (1964) 97, 3036).
  • This invention relates to compounds of the Formula I which are useful in association with a pharmaceutical carrier as antiatherosclerotic agents.
  • various compounds of the Formula I are useful in association with a pharmaceutical carrier as antiatherosclerotic agents.
  • various compounds of the Formula I are useful in association with a pharmaceutical carrier as antiatherosclerotic agents.
  • Formula I are useful inhibitors of cell proliferation and/or platelet aggregation.
  • X is N, or CZ where Z is H, C 1 -C 5 alkyl, amino (-NH 2 ) or a halogen atom; when X is CZ, Y is selected from the group consisting of
  • R 9 and R 10 being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R 9 and R 10 are not both hydrogen; (b) C 1 -C 12 alkyl; (c) phenyl optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl); (d)
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)], (e) -(CH 2 )npyridinyl or (f) wherein R 9 and R 10 , taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted
  • R 5 , R 6 , R 7 and R 8 being the same or different, are selected from the group consisting of hydrogen, C 1 -C 8 alkyl,
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)], -(CH 2 ) n naphthyl, -(CH 2 ) n pyridinyl,
  • Y is selected from the group consisting of
  • R 9 and R 10 being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R 9 and R 10 are not both hydrogen;
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl or- CO 2 (C 1 -C 4 alkyl)]
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl or- CO 2 (C 1 -C 4 alkyl)
  • 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1- piperazine optionally substituted with one or two members selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl,
  • R 5 , R 6 , R 7 and R 8 being the same or different, are selected from the group consisting of hydrogen, C 1 -C 8 alkyl,
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)], -(CH 2 ) n naphthyl, -(CH 2 ) n pyridinyl,
  • -CH CH(OCH 3 ) 2
  • n is 0-5, preferably 0 or one
  • p is 2-5, preferably 2 or 3;
  • q is 1-5, preferably 1 or 2;
  • X is preferably CZ where Z is H or C 1 -C 5 alkyl, more preferably H or methyl, most preferably H.
  • Y is preferably selected from the group consiting of -(CH 2 ) n NR 9 R 10 wherein R 9 and R 10 , taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of:
  • 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1- piperazine optionally substituted with one or two members selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, trifluoromethyl, -CH 2 O H ,- CO 2 H, -CO 2 CH 3 or -CO 2 CH 2 CH 3 .
  • Y is more preferably selected from the group consisting of
  • n 0 or 1 (most preferably 1) and R 9 and R 10 , taken together with N, form:
  • morpholine preferably 4-morpholine
  • phenyl optionally substituted with one or 2 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl
  • R 5 , R 6 , R 7 or R 8 is selected from:
  • R 15 is selected from C 1 C 5 alkyl, -(CH 2 ) n phenyl [phenyl optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, OH, trifluoromethyl or -CO 2 (C 1 -C 4 alkyl)], -(CH 2 ) n pyridin-1-yl or -(CH 2 ) p piperidin-1- yl], -(CH 2 ) n C(O)-(CH 2 ) n R 9 , -(CH 2 ) n C(O)O-(CH 2 ) p R 9 , -(CH) n C(O)O- (CH 2 ) p NR 9 R 10 , -(CH 2 ) n C(O)(CH 2 ) n NR 9
  • R 5 , R 6 , R 7 and R 8 are each hydrogen;
  • R 5 , R 6 , and R 8 are each hydrogen, and R 7 is selected from:
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl
  • -C ⁇ C-phenyl wherein phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl
  • phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 C 4 alkoxy, halo or trifluoromethyl
  • R 5 and R 6 are hydrogen, R 8 is hydrogen, halo or C 1 -C 5 alkyl, and R 7 is selected from: -O-(CH 2 ) n phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl),
  • -O-(CH 2 ) n pyridinyl (wherein pyridinyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl), -O-(CH 2 ) n naphthyl, -(CH 2 ) n phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl),
  • -(CH 2 )ppyridinyl (wherein pyridinyl is optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or trifluoromethyl), -(CH 2 ) p (1-piperidinyl), -(CH 2 )p(1-pyrrolidinyl) or -[(1-cyclohexyl-1H-tetrazol-5- yl)C 1 -C 4 alkoxy; or
  • R 5 , R 7 and R 8 are each hydrogen, and R 6 is
  • X is most preferably CH.
  • Y is most preferably 4-morpholinyl.
  • R 8 is preferably hydrogen or C 1 -C 5 alkyl, more preferably hydrogen or methyl.
  • the present invention includes the novel 2-amino(4H)-1-benzopyran-4-ones and 2-aminoalky1(4H)-1-benzopyran-4-ones of Formula I when X is CZ and the antiatherosclerotic utility of said compounds as well as the antiatherosclerotic utility of the known compounds of Formula I, including the 2-amino-1,3-benzoxazine-4-ones of Formula IB.
  • C i -C j indicates a carbon atoms content of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C 1 -C 3 alkyl refers to alkyl of 1-3 carbon atoms, inclucive, or methyl, ethyl, propyl, and isopropyl.
  • C 1 -C 4 alkyl is methyl, ethyl, propyl, or butyl, including isomeric forms thereof.
  • C 1 -C 6 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomeric forms thereof.
  • halo includes fluoro, chloro, bromo and iodo.
  • C 1 -C 8 alkylthiomethyl examples are methylthiomethyl, ethylthiomethyl, propylthiomethyl, butylthiomethyl, pentylthiomethyl, hexylthiomethyl, and heptylthiomethyl, and isomeric forms thereof.
  • C 1 -C 8 alkoxymethyl are methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentoxymethyl, butoxymethyl, pentoxymethyl, hexoxymethyl, and heptoxymethyl, and isomeric forms thereof.
  • heterocylic amines corresponding to heterocyclic amine rings according to -NR 9 N 10 are:
  • Examples of -O(CH 2 )p(N-methylpiperdin-3-yl) include (2-(N-methylpiperdin-3-yl)ethyl)oxy, (3-(N-methylpiperdin-3-yl)propy)loxy, (4-(N-methylpiperdin-3-yl)butyl)oxy.
  • Examples of -O-(CH 2 )pNR 9 R 10 include (2-(1-piperidinyl)ethyl)oxy, (2-(4-morpholinyl)ethyl)oxy, (2-(1-pyrrolidinyl)ethyl)oxy, (3-(N-methylpiperazinyl)propyl)oxy, (4-(N-ethyl-N-phenylamino)butyl)oxy, (5-(diethylamino)pentyl)oxy, (2-(4-benzylpiperazinyl)ethyl)oxy, and (3-(N,N-diisopropyl)propyl)oxy.
  • O-(CH 2 )pOR 15 examples include (2-methoxyethyl)oxy, (3- butoxypropyl)oxy, (4-phenoxybutyl)oxy, (2-benzyloxyethyl)oxy, (2-(2-(1-piperidinyl)ethoxy)ethyl)oxy and (3-(3-picolylmethoxy)propyl)oxy.
  • Examples of -(CH 2 ) n pyridinyl include 2-pyridyl, 3-pyridylmethyl and 4-pyridylethyl.
  • Examples of -(CH 2 ) n piperdinyl include 1-piperidinyl, 1-peiperidinylmethyl, 2-(1-piperidinyl)ethyl and 3-(1-piperidinyl)propyl.
  • Examples of -(CH 2 )qNR 9 R 10 include (1-piperidinyl)methyl, 2-(4-morpholinyl)ethyl, 3-(1-pyrrolindinyl)propyl and 4-(1-piperazinyl)butyl.
  • Examples of -(CH 2 ) n C(O)-(CH 2 ) n R 9 include acetyl, acetylmethyl, methylacetylmethyl, methylacetylethyl, phenylacetyl, phenylacetylmethyl, 2-(phenylacetyl)ethyl, 2-pyridylacetyl, 3-pyridylacetylmethyl, 3-(t-butylacetyl)propyl and 4- (ethylacetyl)butyl.
  • Examples of ⁇ (CH 2 ) n C(O)O- (CH 2 ) p Rg include carbomethoxy, carbomethoxymethyl, 2 -(carbomethoxy) ethyl, carbophenylmethoxy, carbophenylmethoxymethyl, 2-(carbo(3-pyridyl)methoxy)ethyl, carboethoxymethyl and 3-(carbopropoxy)propoxy.
  • Examples of -(CH 2 ) n C(O) (CH 2 ) n NR 9 R 10 include
  • Examples of -O-(CH 2 ) n C(O)-(CH 2 ) p R 9 include -O-(CH 2 )C(O)- (CH 2 )(CH 3 ), -O-C(O)-(CH 2 ) 2 (CH 3 ), -O-(CH 2 ) 3 C(O)-(CH 2 )phenyl,
  • Examples of -O-(CH 2 ) n C(O)O- (CH 2 ) p R 9 include -O-(CH 2 )C(O)O- (CH 2 )(CH 3 ), -O-C(O)O-(CH 2 ) 2 (CH 3 ), -O-(CH 2 ) 2 C(O)O-(CH 2 ) 3 (phenyl) and -O-(CH 2 ) 3 C(O)O-(CH 2 ) 2 (3-pyridyl).
  • Examples of -O-(CH 2 ) n C(O)-(CH 2 ) n NR 9 R 10 include -O-(CH 2 )C(O)- (CH 2 )N(CH 3 ) 2 , -O-C(O)-(CH 2 )(1-pyrrolidine), -O-(CH 2 )C(O)-(1- piperidine), -O-(CH 2 ) 2 C(O)-(CH 2 ) (1-N-methylpiperazine),
  • Examples of -N(R 9 ) (CH 2 ) n C(O)-(CH 2 ) n R 10 include -N(CH 3 )C(O)- (CH 3 ), -N(H)(CH 2 ) 2 C(O)-(CH 2 ) (phenyl), -N(H) (CH 2 )C(O) -(CH 2 ) 2 (3- pyridyl) and -N(CH 3 ) (CH 2 ) 3 C(O)-(CH 2 ) (CH 3 ).
  • Examples of -N(R 9 )- (CH 2 ) n C(O)O-(CH 2 ) n R 10 include
  • Examples of -N(R 9 ) (CH 2 ) n C(O)-(CH 2 ) n NR 9 R 10 include
  • Examples of -O-(CH 2 ) n phenyl include 2-(4- trifluoromethylphenyl)ethoxy, 4-chlorophenoxy, 4-fluorophenylmethoxy, 3-(4-methoxyphenyl)propoxy, 4-(2-methyl-4-fluorophenyl)butoxy, 2-(2-methoxyphenyl)ethoxy, 3-methoxyphenylmethoxy, 4-carbomethoxyphenylmethoxy, 2-(3,4-dichlorophenyl)ethoxy, 4-ethoxyphenylmethoxy, 3-(4-nitrophenyl)propoxy, 4-t-butylphenylmethoxy, 4-benzyloxyphenylmethoxy and 2-(3-triflouromethylphenyl)ethoxy.
  • Examples of -O-(CH 2 ) n pyridine include 2-pyridyloxy, 3-pyridylmethoxy and 2- (4-pyridyl)ethoxy.
  • Examples of -O(CH 2 ) n C(O)-(CH 2 ) n pyridine include -O(CH 2 )C(O)-(CH 2 )(2-pyridine), -O(CH 2 ) 3 C(O) - (CH 2 ) (3-pyridine) and -O(CH 2 ) 2 C(O) -(CH 2 )3(4-pyridine).
  • Examples of -O-(CH 2 ) n C(O)O-(CH 2 ) n pyridine include
  • Examples of -O(CH 2 ) n C(O) -N(R 9 ) (CH 2 ) n pyridine include
  • Examples of -O-(CH 2 ) n quinoxalinyl include 2-quinoxalinyloxy, 2-quinoxalinylmethoxy and 2-(2-quinoxalinyl)ethoxy.
  • Examples of -O-(CH 2 ) n quinolinyl include 2-quinolinyloxy, 2-quinolinylmethoxy and 2- (2-quinolinyl)ethoxy.
  • Examples of -O-(CH 2 ) n pyrazinyl include 2-pyrazinyloxy, 2-pyrazinyImethoxy and 2-(2-pyraziny1)ethoxy.
  • Examples of -O-(CH 2 ) n naphthyl include 1-naphthyloxy, 2-naphthylmethoxy and 2- (1-naphthyl)ethoxy.
  • Examples of -O-(CH 2 ) n C(O)- (CH 2 ) n naphthyl include -O-(CH 2 )C(O)-(CH 2 )(1-naphthyl), -O-(CH 2 )2C(O)-(CH 2 ) (2-naphthyl), -O-C(O)-(CH 2 )(1-naphthyl) and -O-(CH 2 )2C(O)-(CH 2 ) 2 (2-naphthyl).
  • Examples of -O-(CH 2 ) n C(O)O-(CH 2 ) n naphthyl include
  • Examples of -O- (CH 2 ) n C(O)NR 9 - (CH 2 ) n naphthyl include
  • Examples of - (CH 2 ) q -OH include hydroxymethyl , hydroxyethyl and hydroxybutyl .
  • Examples of (CH 2 ) q OC(O)R 9 include (CH 2 )OC(O)methyl , (CH 2 ) 2 OC(O) ethyl, (CH 2 ) 3 OC(O)phenyl, (CH 2 ) 4 OC(O) (3-pyridyl) and (CH 2 )OC(O)thiophene.
  • Examples of -(CH 2 ) q OC(O)-NR 9 R 10 include -(CH 2 )OC(O)-N(CH 2 ) 2 , -(CH 2 ) 2 OC(O)-N(ethyl) 2 , -(CH 2 ) 3 OC(O)-(1-pyrrolidine), -(CH 2 ) 4 OC(O)-(1-piperidine) and -(CH 2 )OC(O)-N-benzylamine.
  • Examples of -(1-cyclohexyl-1H-tetrazol-5-yl)C 1 -C 4 alkoxy, -[1-(C 1 -C 5 alkyl)-1H-tetrazol-5-yl]C 1 -C 4 alkoxy include -(1-cyclohexyl-1H-tetrazol-5-yl)methoxy, -(1-cyclohexyl-1H-tetrazol-5-yl)ethoxy, -[1-(methyl)-1H-tetrazol-5-yl]methoxy, -[1-(cyclopropyl)-1H-tetrazol-5-yl]ethoxy, -[1-(1-tert-butyl)-1H-tetrazol-5-yl]propoxy and -[1-(cyclopenyl)-1H-tetrazol-5-yl]methoxy.
  • Examples of -[1-(phenyl)-1H-tetrazol-5-yl]C 1 -C 4 alkoxy include -[1-(phenyl)-1H-tetrazol-5-yl]methoxy, -[1-(phenyl)-1H-tetrazol-5-yl]ethoxy, -[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]methoxy, -[1-(4-fluorophenyl)-1H-tetrazol-5-yl]propoxy.
  • Examples of -[1-(pyridinyl)-1H-tetrazol-5-yl]C 1 -C 4 alkoxy or -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C 1 -C 4 alkoxy include -[1-(2-pyridinyl)-1H-tetrazol-5-yl]methoxy, -[1-(3-pyridinyl)-1H-tetrazol-5-yl]ethoxy, -[1-(4-pyridinyl)-1H-tetrazol-5-yl]propoxy, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]methoxy, -[1-(1-phenylethyl)-1H- tetrazol-5-yl]ethoxy.
  • tertiary amines and aromatic heterocyclic amines of the subject specification and claims include the N-oxides thereof.
  • Pharmaceutically acceptable salts means salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate malate, succinate, tartrate, and the like. These salts may be in hydrated form.
  • the compounds of Formula I are all characterized by pronounced antiatherogenic activity, rendering these compounds useful in the treatment and prophylaxis of atherosclerosis.
  • Preferred antiatherosclerotic compounds include Compounds 2, 3, 19, 51, 72, 76, 84, 95, 96, 98, 112, 139, 163, 164, 171 and 204.
  • various compounds of Formula I are also potent inhibitors of cell proliferation and are contemplated as useful in the treatment of proliferative diseases such as cancer, rheumatoid arthritis, psoriasis, pulmonary fibrosis, scleroderma, cirrhosis of the liver and for the improved utilization of artificial prosthetic devices such as arterial grafts.
  • agents may also be useful in the prevention or treatment of obstruction or restenosis of arteries by subsequent administration of drug in cases such as by-pass surgery, coronary by-pass surgery, balloon angioplasty (and other procedures directed at re-establishing patency in occluded or partly occluded vessels, i.e atherectomy, laser or ultrasonic procedures), transplants, and post-thrombotic re-stenosis.
  • Compounds of Formula I which are inhibitors of cell proliferation are those active in the test procedure described in Pledger W.J., Stiles CD., Antniades H.N., Scher CD., [Proc. Natl. Acad. Sci (USA) (1977).
  • inhibitors of cell proliferation include Compounds 1-14; 16-17; 19-23; 25 and 26; 28; 30-34; 36-39; 42; 46-48; 51, 52; 54-56; 58-76; 81, 100-103; 105-112; 120-122; 125133; 135-145; 149; 155 and 156; 158-160; 163; 165 and 166; 171; 173180, 183-190, 193, 204, 206 and 207.
  • various compounds of Formula I are also inhibitors of ADP induced platelet aggregation and are useful in the prevention or treatment of thrombotic diseases and related complications by, for example, inhibition or reversal of platelet aggregation, or platelet adhesion or blood coagulation.
  • Compounds of Formula I which are inhibitors of platelet aggregation are those active in the test procedure described in Born, G.R., Cross M.J., J. Physiol., 168, p. 178 (1963).
  • Examples of inhibitiors of ADP induced platelet aggreation include: Compounds 23, 5-6, 9-11, 13, 20-22, 25-26, 28, 31-32, 34, 36-39, 31, 36-38, 5153, 56, 58-59, 63, 65, 69, 72-76, 80, 100, 102, 104, 106-107, 109113, 115, 116, 118, 120-123, 125-131, 133, 136-140, 147, 149, 154160, 162-167, 169, 171, 172, 178, 181-188, 192-198, and 207.
  • an oral route of administration either by conventional oral dosage forms or by mixture with food, represents the preferred method of their systemic administration.
  • these compounds may be administered by other convenient routes of administration whereby systemic activity is obtained.
  • These other routes of administration would include rectal, vaginal, subcutaneous, intramuscular, intravenous, and like routes.
  • an oral route of administration represents the preferred method of their systemic adminstration.
  • these compounds may be administered by other convenient routes of administration whereby systemic activity is obtained.
  • the patient or animal being treated must be given periodic doses of the drug in amounts effective to reduce serum and/or arterial cholesterol, and reduce arterial atherosclerotic lesion size (as determined by angiogram, ultrasound, NMR, etc.); or, by the irihibition or reversal of platelet aggregation, platelet adhesion or blood coagulation; or, by preventing arterial occlusion in vascular trauma associated with procedures such as by-pass grafts, coronary bypasses, angioplasty, post-thrombotic re-stenosis and transplants.
  • a compound of Formula I may be administered initially with higher succeeding doses until levels of serum and/or arterial cholesterol are favorably affected.
  • a compound of Formula I is administered initially at doses as low as about 0.01 mg/kg per patient per day, with increasing doses up to about 200 mg/kg per patient per day.
  • higher doses are also utilized to the extent patient tolerance permits further increases in dose.
  • each such dose may be about 50 mg/kg per patient per dose, or higher depending on tolerance.
  • Charts A-I herein describe various methods by which the compounds of Formula I are prepared. With respect to these Charts, X, Y, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above.
  • the compounds of Formula I are prepared by mixing the salicylic acid ester with the morpholine ynamine neat, or in an organic solvent, with stirring. After several minutes, a tertiary amine base, e.g. TEA (triethylamine), is added and the reaction stirred for a period of time.
  • TEA triethylamine
  • the product can be isolated by recrystallization or column chromatography.
  • the compounds of Formula I are prepared by reaction of a ortho-hydroxyacetophenone with an amideacetal, e.g., N,N-dimethylformamide dimethylacetal, to yield a vinylogous amide.
  • an amideacetal e.g., N,N-dimethylformamide dimethylacetal
  • a halogen Br, Cl, I or F
  • an organic solvent such as CHCI 3 or CHCN
  • Treatment of that halochromone with amines either neat or in the presence of organic solvents, then yields the desired 2-aminochromone.
  • the compounds of Formula I are prepared by treating a ortho-hydroxyacetophenone with carbon disulfide in the presence of base followed by treatment with acid which yields the 2-mercaptochromone. Treatment of the resulting mercaptan with the appropriate amine then affords the desired 2-aminochromone.
  • these compounds can be prepared by treatment of a o-hydroxy acetophenone with an iminium salt such as morpholine-4-phosgene iminium chloride, in the presence of boron trifluoride etherate. Subsequent hydrolysis and alkylation yields the desired compounds.
  • an iminium salt such as morpholine-4-phosgene iminium chloride
  • these compounds can be prepared by the treatment of an o-hydroxy acetophenone containing a trifluoromethyl sulfonate group with an iminium salt such as 4-morpholine dichloromethyleniminium chloride, in the presence of boron trifluoride etherate. Subsequent hydrolysis and alkylation yields the 2-aminochromone. Treatment of the 2-aminochromone with an acetylene in the presence of a palladium catalyst such as (bis)triphenylphosphine palladium dichloride and copper iodide yields a 2-aminochromone with a substituted acetylene. Hydrogenation of the acetylene yields the desired derivative.
  • an iminium salt such as 4-morpholine dichloromethyleniminium chloride
  • palladium catalyst such as (bis)triphenylphosphine palladium dichloride and a salt such as lithium chloride affords a 2- aminochromone substituted with an alkyl s ⁇ bstituent.
  • the compounds of formula I are prepared by treating 4-benzyloxy-2-hydroxy-3-methylacetophenone with sodium hydride, then ethyl ⁇ -methylthioacetate and finally acid to yield 7- benzyloxy-8-methyl-2-methylthiomethyl-4H-[1]-benzopyran-4-one.
  • Treatment of that compound with methyl iodide affords the corresponding 7-benzyloxy-8-methyl-2-iodomethyl-4H-[1]-benzopyran-4- one.
  • Treatment of that compound with the appropiate amine then afforded the compounds of formula I.
  • compounds of formula I can also be prepared by hydrogenation of a R 5-8 benzyloxy 2-amino-4H-1-benzopyran-4-one followed by alkylation of the resulting phenol as illustrated in chart I .
  • Part A Preparation of trichloroacetylmorpholine.
  • Morpholine (4.0 mL, 45 mmol) is dissolved in EtOAc (50 mL) and saturated K2CO3 (40 mL) added. The mixture is cooled in an ice bath and trichloroacetyl chloride (5.0 mL, 45 mmol) added drop-wise. The reaction is stirred for 20 min then diluted with EtOAc (200 mL) and washed with aq. K2CO3 (20 mL), water (2 X 50 mL) and brine (30 mL). The organic layer is dried over MgSO4. Rotary evaporation gives trichloroacetylmorpholine.
  • Part B Preparation of tricholorvinylmorpholine.
  • Trichloroacetylmorpholine (8.3 g, 36 mmol) is dissolved in toluene and triphenylphosphine (9.44 g, 36 mmol) added. The mixture is brought to reflux for 1.5 h, then cooled and solvent removed in vacuo. The residue is fractionally distilled at reduced pressure to give trichlorovinylmorpholine. BP - 85-7 oC, 20 mm Hg.
  • Part C Preparation of the morpholine ynamine.
  • Trichlorovinylmorpholine (5.50 g, 24.5 mmol) is dissolved in anhydrous ether (30 mL) under a nitrogen atmosphere. The mixture is cooled to -30oC and butyllithium (50 mL, 1.5 M, 75 mmol) added slowly, then the mixture is allowed to warm to 23 oC for 2 h. The mixture is cooled to -30 oC again and poured into cold 20 % ammonium hydroxide (20 mL), ether (50 mL) added and the solutions quickly separated.
  • the organic layer is filtered through anhydrous K2CO3 (5 cm) and concentrated in vacuo to a yellow orange oil that is fractionally distilled (0.9 mm Hg, BP - 53oC) to give the ynamine, 1-ethynyl morpholine, as a colorless oil (1.1 g, 40%).
  • Method A 3-Methoxy salicyl chloride (750 mg, 4 mmol) is dissolved in THF (4mL) and cooled to 0oC The morpholine ynamine (445 mg, 4.0 mmol) is dissolved in THF (4 mL) and then added dropwise to the cooled solution of the acid chloride. A white precipitate forms immediately and after stirring for 20 minutes, TEA (0.60 mL), 4.5 mmol) is added and the reaction temperature raised to 23°C After refluxing for 20 minutes the reaction is cooled to room temperature and the THF removed in vacuo.
  • Method B 3-Methoxy methyl salicylate (547 mg, 3.0 mmol) is dissolved in TEA (4.0 mL) and the morpholine ynamine (400 mg, 3.7 mmol) is added. The mixture is stirred for 48 h, then diluted with EtOAc (200 mL) and washed with water (5 X 20 mL), brine (30 mL) and dried (MgSO 4 ). Evaporation in vacuo affords 690 mg of crude product. Chromatography (silica gel [50 g]; 4% EtOH/CH 2 Cl 2 ) affords the desired product (160 mg; 20%).
  • Part B 2-(4-Morpholinyl)-3-nitro-4H-1-benzopyran-4-one (500 mg) is dissolved in EtOAc (30 mL). Palladium on carbon (10 %, 100 mg) is added under a nitrogen atmosphere. The mixture is fixed to a Parr hydrogenator at 30 psi for 4 hr, then filtered (Celite, 1 cm) and solvent removed in vacuo. The product is purified by flash chromatography (EtOAc) to give 3-Amino-2-(morpholinyl)-4H-1-benzopyran-4-one (419 mg, 94%). Mp 140-1oC; IR (mull) 2954, 2925, 2856,
  • Part A 3-(Dimethylamino)-1-(2-hydroxy-3-methyl-4-benzyloxyphenyl)-Propen-1-one.
  • Part B 3-Bromo-8-methyl-7-(phenylmethoxy)-[4H]-1-benzopyran-4-one.
  • the 3-bromochromone of Part B (1.0 g, 2.9 mmol) is dissolved in acetonitrile (35 mL). Anhydrous potassium carbonate is added (371 mg, 2.9 mmol). Then morpholine (0.252 mg, 2.9 mmol) is added dropwise. Stirring is begun and the reaction warmed to reflux for 36 h. The acetonitrile is removed in vacuo and the organic material is taken up in ethyl acetate. The organic phase is washed with water and brine then dried (MgSO 4 ). The solvent is removed in vacuo and the residue is chromatographed over silica gel ( CH 2 Cl 2 /Et 2 O; 2/1) to give two main fractions. The first contained a 3-amino substituted product.
  • Part B 3-(Dimethylamino)-1-(2-hydroxy-6-benzyloxyphenyl)-Propen-1-one
  • Part C 5-Benzyloxy-3-bromo-[4H]-1-benzopyran-4-one
  • the vinylogous amide of Part B (10.0 g, 33.6 mmol) is dissolved in CHCl 3 (150 mL) and cooled to 0°C Br 2 (5.38 g, 33.6 mmol) is added to the aforementioned solution in CHCI 3 (50 mL) dropwise over 10 minutes. After complete addition the reaction is diluted with H 2 O and vigorously stirred for 5 minutes. The organic layer is separated and washed with brine, dried (MgSO 4 ), and evaporated to give a dark red oil. Chromatography over silica gel (400 g) eluting with 1% CH 3 OH/CH 2 Cl 2 afforded, after recrystallization from EtOAc/Skelly-B, 4.76 g (42.8%) of the product.
  • the 5-benzyloxy-3-bromochromone of Part B (3.31g, 10.0 mmol) is dissolved in acetonitrile (50 mL). Anhydrous potassium carbonate (1.38g, 10.0 mmol) is added, then morpholine (1.02 mL, 11.0 mmol) is added. The mixture is heated to reflux for 72 h. The solvent is removed under vacuo and the residue is taken up in EtOAc (400 mL) and washed with water (3 X 50 mL) and brine (100 mL), then dried (MgSO*4). The solvent is removed in vacuo and the residue purified by flash chromatography (CHCI 3 /CH 3 OH, 99/1) giving three main fractions.
  • the second fraction contained a ring contracted product (0.60g, 33%).
  • Part A The 7,8-dimethoxy-3-bromochromone, R.B. Gammill, Synthesis (1979), p. 901, (3.42g, 12.0 mmol) is dissolved in acetonitrile (100 mL) and anhydrous potassium carbonate (1.66g, 12.0 mmol) is added. Morpholine (1.10 mL, 12.5 mL) is added dropwise and the reaction is warmed to reflux (82 C bath temperature) for 24 h. The acetonitrile is removed in vacuo, and the mixture is taken up in ethyl acetate (400 mL).
  • Part B The mixture of ring contracted and 2-morpholinyl chromone are rechromatographed (SiO 2 , CH 2 CI 2 /CH 3 OH, 98/2). The ring-contracted product is recrystallized from EtOH to give pale yellow crystals, Mp 180-181°C
  • Part A Preparation of 8-Methyl-7-(Phenylmethoxy)-2-mercapto-4H-1-benzopyran-4-one.
  • Potassium t-butoxide (65.5 g) is covered with 500 mL of benzene under nitrogen and that solution is placed in a water bath.
  • 4'- Benzyloxy-2'hydroxy-3'-methylacetophenone (50.0 g) and carbon disulfide (14.82 g) are dissolved in 500 mL of benzene and added dropwise to the potassium t-butoxide solution over a one hour period.
  • That mixture is poured into a separatory funnel and the organic layer discarded.
  • the aqueous is diluted with 300 mL of 20% H2SO4 and the solid that separated is collected on a filter and air dried to yield
  • Part B 8-Methyl-7-(phenylmethoxy)-2-mercapto-4H-1-benzopyran-4-one (2.0 g, 6.7 mmol), 1-(2-pyridyl)piperazine (1.19 g, 7.3 mmol) and TsOH (25 mg) is added to toluene and heated at reflux for 20 hours. The reaction temperature is lowered to room temperature and the toluene removed in vacuo. The resulting dark oil is diluted with EtOAc and the resulting crystals collected on a filter to afford 2.42 g of product. MP 148-9oC
  • the solid is taken up in 25ml acetonitrile in a 50ml one neck round bottom flask under nitrogen and the solution is cooled to 0 C.
  • the mixture is treated with 2.5ml water and the reaction is stirred for 48h as the cooling bath expired.
  • the acetonitrile is removed in vacuo and the residue is carefully diluted with 75ml 2:1 saturated sodium bicarbonate/sodium chloride.
  • the mixture is extracted with 4 X 35ml dichloromethane.
  • the combined organics are dried over magnesium sulfate and are concentrated in vacuo to an amber solid.
  • the precipitated material is collected by filtration and is dried in vacuo at 25 C to afford 569mg (87%) of phenol 39 (M.P. > 250 C) as a chalky grayish solid.
  • Second Alternate Part A 2',4'-Dihydroxy-3'-methyl-acetophenone (90% purity, 18.46g, 100 mmole) is suspended in 50ml diethylether in a 100ml one neck round bottom flask under nitrogen. The mixture is treated with boron trifluoride etherate (18.45ml, 150 mmole) and the reaction is stirred overnight at room temperature. The precipitated material is collected by filtration and the filter cake is washed well with fresh diethylether. The filtered material is air dried to afford 10.45g (47%) of difluoroboronate salt as a yellow solid.
  • the difluoroboronate salt (10.45g, 47 mmole) is combined with morpholine-4-phosgene iminium chloride (21.2g, 104 mmole) in 125ml 1,2-dichloroethane in a 250ml one neck round bottom flask under argon.
  • the reaction mixture is warmed to 70 C for 3h and is cooled to room temperature.
  • the orange-yellow precipitate is collected by filtration and is washed successively with 1,2-dichloroethane and diethylether to provide 25.3g of an orange solid.
  • the solid is suspended in 200ml acetonitrile in a 500ml one neck round bottom flask and the mixture is cooled to 0 C
  • the cooled mixture is treated with 20ml water and after stirring 20 min at 0 C, the reaction mixture is stirred overnight at room temperature.
  • the mixture is subsequently cooled to -33 C for 2h and the precipitated hydro chloride salt is collected by filtration and is washed with 125ml ice cold acetonitrile.
  • the filter cake is dried to provide 13.25g (69%) of the carbamate-chromone hydrochloride as a white solid.
  • the filtrate is concentrated in vacuo to an amber syrup.
  • the syrup is diluted with 100ml saturated sodium bicarbonate and the mixture is extracted with 4 X 50ml dichloromethane.
  • the combined organics are dried over magnesium sulfate and are concentrated in vacuo to a reddish oil which upon crystallization with ethylacetate yielded 875mg (5%) of carbamate-chromone as a yellow solid.
  • Hydrolysis of the carbamate-chromone as described in method B affords the desired phenol.
  • Part B 7-Hydroxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one (0.50g, 1.91mmol) is suspended in 15ml of acetonitrile. 1.3g of potassium carbonate is added followed by 0.39g (2.1mmol) of alphabromo-p-xylene. The mixture is refluxed for 5 hours. 0.04 g of additional alkylating agent is added and the mixture is refluxed for 2 hours. The cooled mixture is diluted with 5ml of water and filtered. The white solid is washed with water and dried. The solid is recrystallized from ethyl acetate to afford 0.59g (84%) of the product 48 (mp 167.5-168°C).
  • Cpd 44 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran- 4-one, Mp 224.5-225.5oC; Cpd 45 [(8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-7-yl)oxy) acetic acid lithium salt;
  • Cpd 54 7-[[4-(1,1-Dimethylethyl)phenyl]methoxy]-8-methyl-2- (4-morpholinyl)-4H-1-benzopyran-4-one, Mp 218.5-220oC;
  • Cpd 120 3,3-Dimethyl-1-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H- 1-benzopyran-7-yl]oxy]-butan-2-one mp. 197-198 Cpd 121 1-[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran- 7-yl]oxy]-propan-2-one mp. 206.5
  • Part A Potassium t-butoxide (134 g, 1.2 mole) is covered with benzene (1 L) in a flame dried round bottom flask equipped with an overhead stirrer, addition funnel, thermometer, and a nitrogen inlet. This suspension is maintained at 15°C. A solution of o-hydroxyacetophenone (54.4 g, 48.1 ml, 0.4 mole) and carbon disulfide (30.4, 24 ml, 0.4 mole) in benzene (700 ml) is slowly added over 1.3 hours, applying an ice bath periodically in order to maintain the temperature 18°C The slurry which forms is stirred at ambient temperature for one day.
  • reaction mixture is transferred to a separatory funnel containing water (4 L) and extracted with ether (4 x 250 ml) and EtOAc (3 x 250 ml).
  • ether 4 x 250 ml
  • EtOAc 3 x 250 ml
  • the aqueous layer is acidified with 10% H 2 SO 4 (1 L) and stirred at ambient temperature overnight.
  • the resulting solid is filtered off and dried in vacuo at 50°C overnight to yield 22.07 g of 2-mercapto-4H-1-benzopyran-4-one. Mp 207-8°C.
  • Tosic acid (0.4g, 2 mmol) is added to a solution of 2-mercapto- 4H-1-benzopyran-4-one (3.56 g, 20 mmol) and morpholine (2.44 g, 2.44ml, 28 mmol) in benzene (400ml). After refluxing for 4 hours, the reaction mixture is transferred to a separatory funnel containing EtOAc and water. Extracting with EtOAc (2x), washing with combined organic layers with water and brine, and filtering through sodium sulfate yields 4.56 of crude material after evaporation of the solvent.
  • the cyanoether is dissolved in acetonitrile (50 ,1), morpholine (1.43 g; 16.4 mmol) is added in 5 ml of acetonitrile and the reaction is stirred for two hours at room temperature. Crystals form and the reaction mixture is cooled to 0°C, and washed with cold acetonitrile to afford 1.65 g (40.8%).
  • Methyl salicylate 25 g, 0.164 M
  • BrCN 18.08 g, 0.172 M
  • dry acetone 500 mL
  • TEA 17.37 g, 0.172M
  • acetone 50 mL
  • a white precipitate separates from the solution.
  • the acetone is decanted and the precipitate washed with acetone.
  • the filtrate is concentrated in vacuo and used without further purification.
  • the above cyanoether (29.0 g, 0.164 M) is added to acetonitrile (300 mL) under an atmosphere of nitrogen.
  • 2',4'-Dihydroxy-3'methyl-propiophenone (7.21 g, 40 mmole) is suspended in 200ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen. The suspension is treated with diisopropylethylamine (6.97 ml, 40 mmole) and the solution is cooled to 0°C. Acetyl chloride (3.26 ml, 46 mmole), in 80 ml dichloromethane, is added slowly dropwise to the reaction mixture (1 h) at 0 C. The mixture is warmed to room temperature and is stirred 20 min.
  • the boron difluoride complex (1.05 g, 5.13 mmole) and 4-morpholine phosgene iminium chloride (1.25 g, 4.63 mmole) are combined in 12 ml 1,2-dichloroethanein a 25 ml one neck round bottom flask under nitrogen.
  • the reaction mixture is warmed to 60 C for 3 h.
  • the reaction is cooled to room temperature and the dichloroethane is removed in vacuo.
  • the residual oil is taken up in 12ml acetonitrile in a 25 ml one neck round bottom flask.
  • the mixture is warmed to 60°C, is diluted with 10 ml water, and is stirred for 5 min.
  • reaction mixture is immediately neutralized with 25 ml saturated sodium bicarbonate and the acetonitrile is removed in vacuo.
  • aqueous residue is extracted with 4 X 25 ml dichloromethane.
  • the combined organics are dried over magnesium sulfate and are concentrated in vacuo to afford 750mg (51%) of Cpd 173 as an orange solid.
  • the boron difluoride complex (prepared as in Part A above, 3.0 g, 11.1 mmole) is combined with 4-morpholine phosgene iminium chloride (2.5 g, 12.2 mmole) in 29 ml 1,2-dichloroethane in a 50 ml one neck round bottom flask under nitrogen.
  • the reaction mixture is warmed to 60°C for 3.5 h and is cooled to room temperature.
  • the dichloroethane is removed in vacuo and the oily residue is dissoved in 30 ml acetonitrile in a 100 ml one neck round bottom flask under nitrogen.
  • the solution is warmed to 60°C, is diluted with 25 ml water, and is stirred for 5 min.
  • the reaction mixture is immediately quenched with 30 ml saturated sodium bicarbonate and the acetonitrile is removed in vacuo.
  • the aqueous residue is extracted with 4 X 25 ml dichloromethane and the combined organics are dried over magnesium sulfate.
  • the dried organics are concentrated in vacuo to a yellow solid (2.82 g) which is dissolved in 30 ml methanol in 100 ml one neck round bottom flask under nitrogen.
  • the solution is diluted with 15 ml water and the mixture is treated with lithium hydroxide (800 mg, 19.1 mmole).
  • the reaction mixture is stirred Ih at room temperature.
  • 2',4'-Dihydroxy-3'methyl-acetophenone (11 g, 60.2 mmole) is suspended in 300 ml dichloromethane in a 1000 ml one neck round bottom flask under nitrogen.
  • the suspension is treated successively with pyridine (4.4 ml, 54 mmole) and N,N, dimethylamino-pyridine (730 mg, 6 mmole) and the solution is cooled to 0oC Triflic anhydride (11 ml, 66.2 mmole), in 1 X 100 ml dichloromethane, is added slowly dropwise to the reaction mixture (30 min) .
  • the reaction is stirred for 1 h at room temperature for 1 h and the mixture is washed with 2 X 200 ml 5% hydrochloric acid.
  • the organics are dried over magnesium sulfate and are concentrated in vacuo to a yellow oil.
  • the oil is distilled via kugelrhor under high vacuum (165 C) to provide 16.4 (91%) of triflate as a white solid.
  • the colorless solution is diluted with 10 ml saturated sodium bicarbonate and the acetonitrile is removed in vacuo.
  • the aqueous residue is extracted with 4 X 25 ml dichloromethane.
  • the combined organics are dried over magnesium sulfate and are concentrated in vacuo to a red solid.
  • the solid is recrystallized from ethyl acetate to afford 566 mg (45%) of chromonetriflate as an off white solid.
  • the suspension is treated successively with phenyl acetylene (100 ul, 0.91 mmole), bis (triphenylphosphine) palladium dichloride (14 mg, 0.02 mmole), and cuprous iodide (2 mg, 0.01 mmole).
  • the reaction mixture is warmed to 100-110°C overnight.
  • the reaction mixture is cooled to room temperature and is again treated successively with phenyl acetylene (100 ul, 0.91 mmole), bis (triphenylphosphine) palladium dichloride (14 mg, 0.02 mole), and cuprous iodide (2 mg, 0.01 mmole).
  • the reaction is heated to 110°C for 4 h and is cooled to room temperature.
  • the solid is suspended in 400 ml of acetonitrile, 40 ml of water is added and the mixture is stirred overnight at room temperature, heated at 50°C for 2 h and finally heated at 60°C for 30 min.
  • the solvent is evaporated and the material is taken up in methylene chloride/ saturated sodium bicarbonate.
  • the aqueous layer is extracted twice with methylene chloride and the combined organics are dried over magnesium sulfate. Evapora tion of the solvent and recrystallization from methanol gave 20.8 g (39%) of the chromone.
  • the mother liquors contained 5.8 g of crude product from which a second recrystallization yielded 0.7 g. mp. 201.5-202.5
  • the material is taken up in 20 ml of methanol and 10 ml of water and treated with 0.63 g (15 mmol) of lithium hydroxide. The mixture is stirred at room temperature for 30 min. The solvent is evaporated, the mixture is diluted with water and extracted twice with ethyl acetate. The aqueous layer is acidified to pH 6.1 qirh 5% hydrochloric acid and the solid is filtered, washed with ether and dried to afford 0.98 gt (71%) of the product.
  • Part A Sodium hydride (50% oil dispersion washed 3x in hexane, 23.2 g, 0.48 mol) is stirred in THF (195 ml) under nitrogen in a flame dried 2 1 three-necked round bottom flask equipped with an addition funnel and a condensor. A solution of the 2-hydroxyaceto phenone (25 g, 97.6 mmol) and ethyl ⁇ -thiomethyl- acetate (130.4 g, 123 ml, 0.9 mol) in THF (164 ml) is slowly dropped into the sodium hydride slurry. After about half of the reagent solution had been added the reaction is heated with a heating gun until the reaction had begun to reflux on its own.
  • Morpholine (0.21 g, 2.5 mmol) is added to a stirring solution of 7-phenylmethoxy-2-iodomethyl-8-methyl-4H-1-benzopyran-4-one (1.0 g, 2.5 mmol) and triethylamine (0.25 ml, 2.5 mmol) in CHCI 3 (12 ml). After stirring at ambient temperature for 2.5 h, the solvent is evaporated in vacuo. The residue is flash chromatographed (100 g silica gel, 50-100% Et0Ac/CH 2 Cl 2 , 45 ml fractions) to afford 0.72 g (79%) of the product. Recrystallization from ether afforded a white solid title product. MP 130-3°C
  • the catalyst is filtered off through a cintered glass funnel rinsing with EtOAc and MeOH. Evaporation of the solvent afforded

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Vascular Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyrane Compounds (AREA)
EP90900649A 1988-12-21 1989-12-15 Antiatherosklerotische und antithrombotische 1-benzopyran-4-one und 2-amino-1,3-benzoxazin-4-one Ceased EP0459983A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28779688A 1988-12-21 1988-12-21
US287796 1988-12-21

Publications (1)

Publication Number Publication Date
EP0459983A1 true EP0459983A1 (de) 1991-12-11

Family

ID=23104392

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90900649A Ceased EP0459983A1 (de) 1988-12-21 1989-12-15 Antiatherosklerotische und antithrombotische 1-benzopyran-4-one und 2-amino-1,3-benzoxazin-4-one

Country Status (8)

Country Link
EP (1) EP0459983A1 (de)
JP (1) JPH04502322A (de)
AU (1) AU634994B2 (de)
DK (1) DK118791A (de)
FI (1) FI912995A0 (de)
HU (2) HUT58310A (de)
RU (1) RU2118321C1 (de)
WO (1) WO1990006921A1 (de)

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525123B1 (de) * 1990-06-20 1997-09-17 PHARMACIA & UPJOHN COMPANY Antiatherosklerotische und antithrombotische 1-benzopyran-4-on- und 2-amino-1,3-benzoxazin-4-on-derivate
US5302613A (en) * 1990-06-29 1994-04-12 The Upjohn Company Antiatheroscleroic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones
US5252735A (en) * 1990-06-29 1993-10-12 The Upjohn Company Antiatherosclerotic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones
ES2079068T3 (es) * 1990-06-29 1996-01-01 Upjohn Co 2-amino-6-fenil-4h-piran-4-onas antiateroscleroticas y antitromboticas.
IL112764A0 (en) * 1994-03-18 1995-05-26 Ferrer Int New chromene derivatives
CA2182932A1 (en) * 1995-08-10 1997-02-11 Koju Watanabe Chromone derivative, process for preparing same and pharmaceutical composition
DE19850131A1 (de) * 1998-10-30 2000-05-04 Merck Patent Gmbh Chromenon- und Chromanonderivate
WO2000051992A1 (en) * 1999-03-04 2000-09-08 E.I. Du Pont De Nemours And Company Fused bicyclic oxazinone and thiazinone fungicides
GB9920910D0 (en) * 1999-09-03 1999-11-10 Indena Spa Novel chalcones
AU2001230426C1 (en) 2000-01-24 2006-06-22 Astrazeneca Ab Therapeutic morpholino-substituted compounds
DE10044091A1 (de) * 2000-09-07 2002-04-04 Merck Patent Gmbh Chromanonderivate
GB0119863D0 (en) 2001-08-14 2001-10-10 Cancer Res Campaign Tech DNA-PK inhibitors
GB0119865D0 (en) 2001-08-14 2001-10-10 Cancer Res Campaign Tech DNA-PK inhibitors
US7049313B2 (en) 2002-02-25 2006-05-23 Kudos Pharmaceuticals Ltd. ATM inhibitors
ATE471931T1 (de) 2002-04-17 2010-07-15 Cytokinetics Inc Verbindungen, zusammensetzungen und verfahren
WO2004006865A2 (en) 2002-07-17 2004-01-22 Cytokinetics, Inc. Compounds, compositions, and methods
NZ538420A (en) * 2002-08-16 2007-06-29 Kinacia Pty Ltd Inhibition of phosphoinositide 3-kinase beta
CN101260104A (zh) * 2002-08-16 2008-09-10 阿斯利康(瑞典)有限公司 抑制磷酸肌醇3-激酶β
CN100518740C (zh) * 2003-06-06 2009-07-29 阿里克斯股份公司 杂环化合物作为scce抑制剂的制药用途
EP1631295B1 (de) * 2003-06-06 2010-03-03 Arexis AB Verwendung von kondensierten heterozyklischen verbindungen als scce-hemmern zur behandlung von hautzuständen
DE602004026071D1 (de) 2003-08-13 2010-04-29 Kudos Pharm Ltd Aminopyrone und ihre verwendung als atm inhibitoren
ATE447957T1 (de) 2003-12-09 2009-11-15 Us Gov Health & Human Serv Verfahren zur unterdrückung einer immunantwort oder zur behandlung von proliferativen erkrankungen
RU2408596C2 (ru) 2004-09-20 2011-01-10 Кудос Фармасьютикалс Лимитед Ингибиторы днк-пк
WO2006085067A1 (en) 2005-02-09 2006-08-17 Kudos Pharmaceuticals Limited Atm inhibitors
AR053358A1 (es) 2005-04-15 2007-05-02 Cancer Rec Tech Ltd Inhibidores de adn - pk
WO2009038064A1 (ja) * 2007-09-19 2009-03-26 Institute Of Medicinal Molecular Design, Inc. Ｉ型１１βヒドロキシステロイド脱水素酵素阻害活性を有する複素環誘導体
CN102227420B (zh) * 2008-09-29 2015-06-24 西特里斯药业公司 作为沉默调节蛋白调节剂的喹唑啉酮、喹诺酮和相关的类似物
US8399460B2 (en) 2009-10-27 2013-03-19 Astrazeneca Ab Chromenone derivatives
US8530470B2 (en) 2011-04-13 2013-09-10 Astrazeneca Ab Chromenone derivatives
RU2468018C1 (ru) * 2011-10-06 2012-11-27 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Российский университет дружбы народов" (РУДН) Способ получения производных 4-оксо-4h-хроменов, содержащих винильную и енаминную группировки
TW201335151A (zh) * 2012-01-26 2013-09-01 Daiichi Sankyo Co Ltd 具有骨形成促進作用之色酮衍生物
WO2014030688A1 (ja) * 2012-08-24 2014-02-27 第一三共株式会社 鎖状側鎖を有するクロモン誘導体
JP6546098B2 (ja) 2013-03-04 2019-07-17 アストラゼネカ アクチボラグ 組み合わせ処置
CN108947952B (zh) * 2017-05-24 2021-09-21 中国医学科学院药物研究所 2-取代氨基-5-三氟甲基-8-硝基苯并（硫代）吡喃-4-酮类化合物及其制备方法和用途
CN108929329B (zh) * 2017-05-24 2020-12-11 中国医学科学院药物研究所 2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物
AR121719A1 (es) 2020-04-03 2022-06-29 Petra Pharma Corp Inhibidores alostéricos de cromenona del fosfoinosítido 3-quinasa (pi3k) para el tratamiento de enfermedades
CR20230517A (es) 2021-05-03 2023-11-28 Petra Pharma Corp Inhibidores alostéricos de cromenona del fosfoinosítido 3-quinasa (pi3k) para el tratamiento de enfermedades
AU2022282380B2 (en) 2021-05-27 2025-08-14 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (pi3k) for the treatment of cancer
TW202329930A (zh) 2021-09-30 2023-08-01 美商佩特拉製藥公司 用於治療疾病之磷酸肌醇3-激酶(pi3k)之異位色烯酮抑制劑

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0248420A2 (de) * 1986-06-04 1987-12-09 Daiichi Seiyaku Co., Ltd. Benzopyran-Derivate
EP0341104A2 (de) * 1988-04-06 1989-11-08 MERCK PATENT GmbH Substituierte flavonoide Verbindungen, ihre Salze, ihre Herstellung und die enthaltende Arnzeizusammensetzungen

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2205913A1 (de) * 1972-02-08 1973-08-16 Thiemann Chem Pharm Fab 2-amino-3-hydroxy-chromon-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
DE2555290A1 (de) * 1975-12-09 1977-06-16 Boehringer Mannheim Gmbh Neue benzopyron-derivate und verfahren zu ihrer herstellung
US4412071A (en) * 1982-05-17 1983-10-25 The Upjohn Company Antiatherosclerotic compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0248420A2 (de) * 1986-06-04 1987-12-09 Daiichi Seiyaku Co., Ltd. Benzopyran-Derivate
EP0341104A2 (de) * 1988-04-06 1989-11-08 MERCK PATENT GmbH Substituierte flavonoide Verbindungen, ihre Salze, ihre Herstellung und die enthaltende Arnzeizusammensetzungen

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MAZZEI M. ET AL.: "SYNTHESIS AND ANTI-PLATELET ACTIVITY OF SOME 2-(DIALKYLAMINO)CHROMONES", EUR. J. MED. CHEM., vol. 23, 1988, pages 237 - 242, XP023870168, DOI: doi:10.1016/0223-5234(88)90005-0 *
MORRIS J. ET AL.: "SYNTHESIS AND BIOLOGICAL EVALUATION OF ANTIPLATELET 2-AMINOCHROMONES", J. MED. CHEM., vol. 36, no. 14, 1993, pages 2026 - 2032, XP002218598, DOI: doi:10.1021/jm00066a012 *
See also references of WO9006921A1 *

Also Published As

Publication number Publication date
WO1990006921A1 (en) 1990-06-28
HU211339A9 (en) 1995-11-28
FI912995A7 (fi) 1991-06-19
JPH04502322A (ja) 1992-04-23
DK118791D0 (da) 1991-06-19
FI912995A0 (fi) 1991-06-19
AU4807190A (en) 1990-07-10
AU634994B2 (en) 1993-03-11
HU900394D0 (en) 1991-09-30
DK118791A (da) 1991-06-19
HUT58310A (en) 1992-02-28
RU2118321C1 (ru) 1998-08-27

Similar Documents

Publication Publication Date Title
AU634994B2 (en) Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones
US5703075A (en) Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones
WO1991019707A2 (en) Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones
EP0585913B1 (de) Kondensierte heterozyklische Verbindungen, deren Herstellung und Verwendung
CA2556653C (en) Tetrahydroquinolinones and their use as antagonists of metabotropic glutamate receptors
AU2002362385B2 (en) DNA-PK inhibitors
JPH069585A (ja) スルホンアミドエンドセリンアンタゴニスト
EP0489877B1 (de) Antiatherosclerotische und antithrombotische 2-amino-6-phenyl-4h-pyran-4-one
US4593092A (en) Class of spiro-linked pyrrolidine-2,5-diones
Chantegrel et al. Synthesis of [1] benzopyrano [3, 4-d] isoxazol-4-ones from 2-substituted chromone-3-carboxylic esters. A reinvestigation of the reaction of 3-acyl-4-hydroxycoumarins with hydroxylamine. Synthesis of 4-(2-hydroxybenzoyl) isoxazol-5-ones
IE913186A1 (en) 1,3-benzoxazine derivatives, their production and use
EP0505565B1 (de) Chinolinderivate, ihre herstellung und verwendung
EP1957475A1 (de) Chromenone und ihre verwendung als modulatoren von metabotropen glutamatrezeptoren
US5302613A (en) Antiatheroscleroic and antithrombotic 2-amino-6-phenyl-4H-pyran-4-ones
US4230850A (en) 3-Substituted-4-aminoalkoxy-5,6-condensed ring-2-pyranones
JP3724818B2 (ja) 縮合複素環化合物、その製造法および剤
JP3187837B2 (ja) 化合物
IE914343A1 (en) Benzoxazinone and benzothiazinone derivatives endowed with cardiovascular activity
WO2006037996A1 (en) Novel cyclic and acyclic propenones for treating cns disorders
CA2006306A1 (en) Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones
Graef et al. Synthesis of 6-phenyl substituted 2-formylnicotinates
RU2295521C2 (ru) Фотохромные оксазиновые соединения и способы их производства
US4591587A (en) Cyclopropyl pyridine compounds useful as calcium channel blockers
JPH09500878A (ja) 治療活性を有するベンゾキサジノン及びベンゾチアジノン
Awad et al. STUDIES ON THE VILSMEIER-HAACK REACTION. PART IV. SYNTHESIS AND REACTION OF SOME 3-METHY Ll-PHENYL-4-(ACETY L; IMINOACETYL AND THIOACETYL)-2-PYRAZOLIN-5-THIONE

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19910607

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE ES FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19930115

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: PHARMACIA & UPJOHN COMPANY

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 19980712