CA2340250A1 - Process for preparing regiospecific substituted pyrazine isomers - Google Patents

Process for preparing regiospecific substituted pyrazine isomers Download PDF

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CA2340250A1
CA2340250A1 CA002340250A CA2340250A CA2340250A1 CA 2340250 A1 CA2340250 A1 CA 2340250A1 CA 002340250 A CA002340250 A CA 002340250A CA 2340250 A CA2340250 A CA 2340250A CA 2340250 A1 CA2340250 A1 CA 2340250A1
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Kelley L. Ford
Shyamal I. Parekh
Anthony R. Haight
Wenke Li
Weijiang Zhang
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to a process of producing specific isomers of substituted pyrazine compounds, substituted thieno[b]pyrazine, substituted pteridins, compounds, and derivatives thereof. The regiospecific substituted pyrazine compounds are useful in the preparation of pharmaceuticals, including compounds useful in treating benign prostatic hyperplasia.

Description

PROCESS FOR PREPARING
REGIOSPECIFIC SUBSTITUTED PYRAZINE ISOMERS
This application is a continuation-in-part of US application serial number 09/136,983, filed August 20,1998, incorporated herein by reference.
Background of the Invention s US 4,990,630 to Sato et al discloses a process for reacting a 2,3-diamino-3-phenylthioacrylonitrile compound with a symmetric 1,2-dicarbonyl compound to produce a symmetric pyrazine compound. A limitation of this process is that it cannot produce unsymmetrical pyrazine compounds with predictable regiospecificity.
The present invention relates to a process of producing specific isomers of to substituted pyrazine compounds, substituted thieno[b]pyrazine, substituted pteridins, compounds, and derivatives thereof. The regiospecific substituted compounds are useful in the preparation of pharmaceuticals, including compounds useful in treating benign prostatic hyperplasia.
~s Detailed Description of the Invention For the purposes of this disclosure, the term 'regiospecific' as used herein, is defined as the formation of one isomer of a compound in greater quantity than other isomers.
The terms "loweralkyl" or "alkyl" as used herein refer to straight or branched chain 2o alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl,
2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, 2s tetrahydronaphthyl, naphthyridinyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl
3 PCT/US99/19044 and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl and carboxamide.
to The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
In one embodiment of the present invention shown in Scheme I, a 2, 3-diaminocompound (1) wherein A is nitrile and B is -SR wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl.
Compound 1 is may be reacted with an ketone compound (2) wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl to produce a regioselective substituted pyrazine compound (3) in the presence of excess acid and a solvent. R3 and R4 are independently selected from the group consisting of of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring 2o with the oxygen atoms to which they are attached.
HZN A + O OR3 RZ N\ A + N\ A
R~ --OR N B
4 Scheme I
2s In a preferred embodiment of the present invention as shown in Scheme 2, 2, diamino-3-phenylthioacrylonitrile (5) wherein R1 is phenyl, is reacted with a ketone compound (2) wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, to produce a regioselective substituted pyrazine compound (6) in the presence of excess acid and a solvent. R3 and R4 are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached. The reaction proceeds in the presence of excess acids in a solvent s to produce a regioselective substituted pyrazine isomer (6) over isomer (7).

~OR3 R2 N~ + N' CN
R2 >
i Scheme 2 ~o In a more preferred embodiment of the present invention as shown in Scheme 3, 2, 3-diamino-3-phenylthioacrylonitrile (8) is reacted with 2, 2-diethoxyacetophenone (9) in the presence of excess acids in a solvent to produce a regiospecific substituted pyrazine isomer ( 10) over isomer ( 1 I ).
I-~N CN O ~ CN
+ OC~C~ ~ I N CN I N
N S OCh~CI-~ ~ N S
8 ~ \ \ I ~ N S/ \ ~ ~ ll / \
to ~/
~s Scheme 3 Solvents suitable for the present invention include, but are not intended to be limited to alkanol solvents. Alkanol solvents include, but are not intended to be limited to, 2o methanol, ethanol, propanol, isopropanol, butanol, and isobutanol. Acids suitable for the present invention include, but are not intended to be limited to, carboxylic acids and halogenated carboxylic acids. Suitable halogenated carboxylic acids include, but are not SUBSTITUTE SHEET (RULE 26) intended to be limited to trifluoroacetic acid, tribromoacetic acid, trichloroacetic acid, and the like.
Another embodiment of the present invention, as shown in Scheme 4, includes the formation of substituted thieno[b]pyrazines. Substituted thieno[b]pyrazines may be prepared by reacting Compounds (12) and (13) with a thioglycolate ester in the presence of a base. Bases suitable for the reaction include, but are not limited to, tertiary amines such as triethylamine and diisopropylethylamine. The substituted thieno[b]pyrazines may be prepared by first preparing the pyrazine sulfone (13) from the substituted pyrazine and reacting the pyrazine sulfone with a thioglycolate ester in the presence of a base such as, but not limited to, a tertiary amine as described above or in the presence of an inorganic base including, but not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
The sulfone may be prepared by reacting compound (10) with a carboxylic peracid, including, but not limited to, metachloroperbenzoic acid, peracetic acid and the like. The t s sulfone may also be prepared by reacting compound ( 10) with a peracid generated in situ from sodium perborate and an acid selected from the group consisting of carboxylic acids and halogenated carboxylic acids. Examples of carboxylic acids and halogenated carboxylic acids including, but not limited to, acetic acid, chloroacetic acid, dichloroacetic acid, and the like.
Scheme 4 / /
N CN I CN I CN
I ~ NaB03 ~ I Nw ~ I N\
N S

12 / \ 13 ~ \
HS(CH2)"C(O)ORs Base /

~N~ /"CO2R5 S

The resulting sulfone (13) may be reacted with a thioglycolate ester of the formula HS(CH2)nC(O)ORS wherein n=1-10 and RS is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl, in the presence of a tertiary amine base and a co-solvent. Co-solvents suitable for the invention include, but are not limited to methanol, s ethanol, and isopropanol. Bases suitable for the invention include, but are not limited to tertiary amines such as triethylamine and diisopropylethylamine, and the like or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium biocarbonate.
Substituted pyrrolo[b]pyrazines are prepared by reacting a sulfone with io H2NCH2C02R6 where R6 is alkyl in the presence of a base as described above.
Substituted pteridins may be prepared by reacting a sulfone with imidines such as H2NCR7NH where R7 is selected from the group consisting of hydrogen alkyl, aryl, or arylalkyl in the presence of a base. Bases suitable for the invention include, but are not limited to alkylamines such as triethylamine, diisopropylethylamine, diisopropylamine, is and the like, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium bicarbonate.
The following examples are intended to be illustrative of the present invention and not limiting in scope.
2o Example 1
5-phenyl-2-phenylthiopyrazine-3-carbonitrile To a suspension of 2,3-diamino-3-phenylthioacrylonitrile toluenesulfonic acid (8 grams (g), 22 millilmoles (mmol)), and triflouroacetic acid (14.8 g, 130 mmol) in isopropanol (100 milliliters (mL)) was added 2,2-diethoxy-acetophenone (4.2 g, zs mmol). The mixture was stirred for 24 hours (h) at ambient temperature before adding 80mL water. The slurry was stirred for 1 h and the solid filtered and washed with 50 mL
of 50% aqueous isopropanol to yield after drying, 4.25g (73%) of S-phenyl-2-phenylthiopyrazine-3-carbonitrile. 1H NMR (CDCI3) 8 8.9 (s, IH), 8.0-7.9 (m, 2H), 7.7-7.6 (m, 2H), 7.59-7.45 (m, 6H).
6 Example 2 5-phenyl-2-phenvlsulfin~pyrazine-3-carbonitrile A slurry of 5-phenyl-2-phenyl-thiopyrazine-3-carbonitrile, (2.89 g) in acetic acid (40 mL) was heated to 45-50 °C and sodium perborate monohydrate (2.5 g) was added in two portions over IO minutes. The slurry was stirred at 45-50°C for 2.5 h, cooled to ambient temperature, and water (50 mL) was added. The slurry was filtered, washed with water ( 100 mL) and dried to give S-phenyl-2-phenylsulfinylpyrazine-3-carbonitrile (2.82 g, 88%). 1 H NMR (DMSO) b 9.67 (s, 1 H), 7.97 (m, 2H), 7.78-7.62 (m, 6H).
to Example 3 phenyl-2-phenylsulfonylpyrazine-3-carbonitrile 3-Chloroperoxy benzoic acid (mCPBA) (8.9 g, 52 mmol) was added into a solution of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile (Sg, l7mmol) in methylene chloride (100m1) at <6°C and this was stirred at room temperature for 18 h.
Methanol (100 mL) ~s was added and this was concentrated to 100 ml and repeated once more. The solid that formed was filtered and washed with methanol (20 ml) to give 4.5 g (yield 80%) of 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile, mp 222-224°C. 1 HNMR
(CDCI3 ) 8 (ppm) 9.19 (s,lH)8.21 (dd, 2H, J1 =BHz, J2=2.SHz), 8.08 (dd, 2H, J1=8 Hz, J2=3Hz),
7.73 (dt, 2H, J1=8, J2 =2.SHz), 7.6, (m, SH). 13C NMR(DMSO-d6) 8(ppm).
IR(ICBr) 20 3125, 3070, 2250, 1555, 1325, 1160, 730. HRMS(FAB) Calculated m/z for M+H
C17H12N3O2S 322.0650, Observed m/z 322.0652.
Example 4 Alternative synthesis of 5-uhenvl-2-phenvlsulfonvluvrazine-3-carbonitrile 2s A slurry of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile (SOg), and chloroacetic acid (176 g) in acetic acid (530g) was heated to 45-55°C for approximately 24 hours. The mixture was cooled to ambient temperature, and 500 mL of water was added. The slurry was filtered, washed with 300 mL of water and dried to give 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (48.3 g, 91 %).

Example 5 Thienopyrazine formation To a suspension of 85% S-phenyl-2-phenylsulfonyl-pyrazine-3-carbonitrile, 15%
5-phenyl-2-phenylsulfinylpyrazine-3-carbonitrile (3.2 g 10 mmol), and diisopropylethyl s amine (2.58 g, 20 mmol) in 47 mL ethanol was added methylthioglycolate (1.06 g, 10 mmol). This was stirred at 20°C for 1 h and then 55°C for 7 h.
Then methylthioglycolate (0.18 g, 0.17 mmol) and heated to SS°C for 4 h. After cooling to 5°C. The solid was filtered, washed with methanol ( 10 mL) and dried to give 2.4 g (84% yield) 4.

(CDCI 3) b 9.09 (dd, 2H, JI=8, J2=2 Hz), 7.53 (m, 3H), 6.27 (br s, 2H), 3.393 (s, 3H).
to I3C NMR (CDCI3) 8 165.30, 153.78, 149.19, 145.47, 142.34, 140.30, 136.06, 129.25, 129.11, 127.02, 51.87. MS(CI) 286 (M+1).
Example 6 Preparation of 3-amino-2-ethoxvcarbonyl-5-phenylpvrrolo[blp ry azine is To 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (1.0 g, 3.1 mmol)), and glycine ethyl ester hydrochloride (0.43 g, 3.1 mmol) in tetrahydrofunan ( 15 mL) was added diisopropylethylamine (1.62 mL, 9.3 mmol). The mixture was heated at reflux for 24 h then anhydrous sodium carbonate (0.49 g, 4.65 mmol) was added. The mixture was refluxed for an additional 10 h before its solvent was removed in vacuo. The residue was 2o purified by flash chromatography (90% ethyl acetate/10% heptane) to give, after removing solvents, 0.54g (62%). 1H NMR (CDC13): 8 1.34 (d, J= 6.8 Hz, 3H}, 4.31 (q, J=
6.8 Hz, 2H), 4.33 (s, 2H), 5.85 (s,lH), 7.49 (rn, 3H), 7.91 (m, 2H), 8.7I (s, 1H).
Example 7 2s Preparation of 4-amino-6-phen~pteridin To S-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (I.0 g, 3.1 mmol)), and formamidine acetate (0.32 g, 3.1 mmol) in tetrahydrofuran ( 1 SmL) was added diisopropylethylamine ( 1.62 mL, 9.3 mmol). The mixture was heated at relux for 24 h then anhydrous sodium carbonate (0.49 g, 4.65 nunol) was added. The mixture was 3o refluxed for an additional 3 h before its solvent was removed in vacuo. The residue was
8 purified by flash chromatography (90% ethyl acetate/10% heptane) to give, after removing solvents, 0.52 g (78%). 1 H NMR (DMSO-d6): 87.68 (m, 3H), 8.59 (m, 2H), 8.72 (s, 1 H), 8.85 (s, 1 H), 8.95 (s, 1 H), 9.85 (s, 1 H).
s Example 8 Preparation of 4-amino-1-meth~phenylpteridin To 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (1.0 g, 3.1 mmol)), and acetamidine hydrochloride (0.29 g, 3.1 mmol) in tetrahydrofuran (15 mL) was added diisopropylethyl-amine (1.62 mL, 9.3 mmol). The mixture was heated at reflux for 3 h ~o then anhydrous sodium carbonate (0.49 g, 4.65 mmol) was added. The mixture was refluxed for an additional 7 h before its solvent was removed in vacuo. The residue was purified by flash chromatography (50% ethyl acetate/50% heptane) to give, after removing solvents, 0.63 g (89%). 1H NMR (DMSO-d6): 8 2.60 (s, 3H), 7.64 (m, 3H), 8.31 (s, 1H), 8.42 (s, 1 H), 8.56 (m, 2H), 9.76 (s, 1 H).

Claims (29)

Claims:

We claim:
1. A process for producing a regiospecific substituted pyrazine isomer compound of the formula comprising reacting a 2,3,-diaminocompound of the formula wherein A is nitrile and B is -SR wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl with a ketone compound of the formula wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, R3 and R4 are independently selected from the group consisting of of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached, in the presence of excess acid and a solvent..
2. A process of claim 1 wherein said acid is selected from the group consisting of carboxylic acids and halogenated carboxylic acids.
3. A process of claim 1 wherein said solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and butanol and isobutanol.
4. A process of claim 2 wherein said acid is a halogenated carboxy acid.
5. A process of claim 4 wherein said halogenated carboxy acid is selected from the group consisting of trifluoroacetic acid, tribromoacetic acid, and trichloroacetic acid.
6. A process of claim 3 wherein said solvent is isopropanol.
7. A process of claim 1 wherein said 2,3-diamino compound is 2, 3-diamino-3-phenylthioacrylonitrile and said ketone compound is 2, 2-diethoxyacetophenone to produce regiospecific 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile.
8. A process for producing a substituted thieno[b]pyrazines of the formula by reacting a sulfoxide compound of the formula or a sulfone compound of the formula with a thioglycolate ester in the presence of a base.
9. A process of claim 8 wherein said base is selected from the group consisting of tertiary amines and inorganic bases.
10. A process of claim 9 wherein said tertiary amine is selected from the group consisting of triethylamine and diisopropylethylamine.
11. A process of claim 9 wherein said inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
12. A process of claim 8 wherein a co-solvent is added.
13. A process of claim 12 wherein said co-solvent is selected from the group consisting of methanol, ethanol, and isopropanol.
14. A process of claim 8 wherein said sulfone compound may be prepared by reacting a compound of the formula with a carboxylic peracid, selected from the group consisting of, metachloroperbenzoic acid and peracetic acid.
15. A process of claim 8 wherein said sulfone compound is prepared by reacting a compound of the formula with a peracid generated in situ from sodium perborate and a acid selected from the group consisting of carboxylic acids and halogenated carboxylic acids.
16. A process of claim 15 wherein said carboxylic acid is acetic acid.
17. A process of claim 15 wherein said halogenated carboxylic acid is selected from the group consisting of chloroacetic acid and dichloroacetic acid.
1~. A process of claim 14 wherein a co-solvent is added.
19. A process of claim 18 wherein said co-solvent is selected from the group consisting of methanol, ethanol and isopropanol.
20. A process of claim 15 wherein a co-solvent is added.
21. A process of claim 20 wherein said co-solvent is selected from the group consisting of methanol, ethanol and isopropanol.
22. A process of claim 8 wherein said sulfone or sulfoxide compound is reacted with a thioglycolate ester of the formula HS(CH2)nC(O)OR5 wherein n=1-10 and R5 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl, in the presence of a base.
23. A process of claim 21 wherein said base is selected from the group consisting of tertiary amines and inorganic bases.
24. A process of claim 22 wherein said tertiary amine is selected from the group consisting of triethylamine and diisopropylethylamine.
25. A process of claim 21 wherein said inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
26. A process for preparing a substituted pyrrolo[b]pyrazines are prepared by reacting a sulfone with H2NCH2CO2R6 where R6 is alkyl in the presence of a base as described above.
27. A process of claim 25 wherein said base is selected from tertiary amines such as triethylamine and diisopropylethylamine, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium bicarbonate.
28. A process for preparing a substituted pteridins may be prepared by reacting a sulfone with imidines such as H2NCR7NH where R7 is selected from the group consisting of hydrogen alkyl, aryl, or arylalkyl in the presence of a base.
29. A process of claim 27 wherein said base is selected from tertiary amines such as triethylamine and diisopropylethylamine, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium bicarbonate.
CA002340250A 1998-08-20 1999-08-20 Process for preparing regiospecific substituted pyrazine isomers Abandoned CA2340250A1 (en)

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US13698398A 1998-08-20 1998-08-20
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US8115000B2 (en) 2006-06-22 2012-02-14 Mallinckrodt Llc Pyrazine derivatives and uses thereof in renal monitoring
US8664392B2 (en) 2004-12-23 2014-03-04 Medibeacon, LLC Pyrazine derivatives for bioconjugation
US8778309B2 (en) 2004-12-23 2014-07-15 Medibeacon Llc Fluorescent pyrazine derivatives and methods of using the same in assessing renal function
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DE3768479D1 (en) * 1986-08-13 1991-04-11 Nippon Soda Co 2,3-DIAMINOACRYLONITRILE DERIVATIVES.
CH681226A5 (en) * 1990-05-02 1993-02-15 Firmenich & Cie Prepn. of unsymmetrical alkyl-pyrazine(s) - by thermal cyclisation of new oximino-aza:diene(s)
US5597823A (en) * 1995-01-27 1997-01-28 Abbott Laboratories Tricyclic substituted hexahydrobenz [e]isoindole alpha-1 adrenergic antagonists

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US8778309B2 (en) 2004-12-23 2014-07-15 Medibeacon Llc Fluorescent pyrazine derivatives and methods of using the same in assessing renal function
US9114160B2 (en) 2004-12-23 2015-08-25 Medibeacon, LLC Pyrazine derivatives and uses thereof in renal monitoring
US9480687B2 (en) 2004-12-23 2016-11-01 Medibeacon, Inc. Pyrazine derivatives and uses thereof in renal monitoring
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USRE47413E1 (en) 2004-12-23 2019-06-04 Medibeacon, Inc. Pyrazine derivatives and uses thereof in renal monitoring
US8115000B2 (en) 2006-06-22 2012-02-14 Mallinckrodt Llc Pyrazine derivatives and uses thereof in renal monitoring
US9216963B2 (en) 2006-06-22 2015-12-22 Medibeacon Inc. Pyrazine derivatives with extended conjugation and methods of using the same in optical applications
US10370362B2 (en) 2006-06-22 2019-08-06 Medibeacon Inc. Pyrazine derivatives with extended conjugation and methods of using the same in optical applications

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