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US20060052613A1 - 1-alkyl-3-aminoindazoles - Google Patents

1-alkyl-3-aminoindazoles Download PDF

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Publication number
US20060052613A1
US20060052613A1 US10/539,423 US53942305A US2006052613A1 US 20060052613 A1 US20060052613 A1 US 20060052613A1 US 53942305 A US53942305 A US 53942305A US 2006052613 A1 US2006052613 A1 US 2006052613A1
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US
United States
Prior art keywords
phenyl
optionally substituted
ring
taken together
methoxyphenyl
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.)
Abandoned
Application number
US10/539,423
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English (en)
Inventor
Pete Delgado
Raymond Conrow
W. Dennis Dean
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.)
Alcon Inc
Original Assignee
Alcon Inc
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 Alcon Inc filed Critical Alcon Inc
Priority to US10/539,423 priority Critical patent/US20060052613A1/en
Assigned to ALCON, INC. reassignment ALCON, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CONROW, RAYMOND E., DEAN, W. DENNIS, DELGADO, PETER
Publication of US20060052613A1 publication Critical patent/US20060052613A1/en
Priority to US12/368,869 priority patent/US7799930B2/en
Abandoned legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • the present invention relates to 1-alkyl-3-aminoindazoles and preferably 1-(hydroxyalkyl)-3-aminoindazoles useful as intermediates for the preparation of 1-alkylindazoles.
  • Use of the 1-alkyl-3-aminoindazoles as intermediates avoids unwanted side products and results in enantiomerically pure final pharmaceutically active products.
  • Certain (aminoalkyl)indazoles are known to be useful for treating diseases of the central nervous system (WO 98/30548).
  • WO 02/098861 A1 and WO 02/098862 A1 disclose methods of preparation of (aminoalkyl)indazoles. Specifically, these applications disclose the conversion of 2-(hydroxyalkyl)aminobenzaldehydes to 1-(hydroxyalkyl)indazoles, which are useful intermediates for the preparation of 1-(aminoalkyl)indazoles.
  • the present invention overcomes the above mentioned problems and other drawbacks of the prior art by providing a method, capable of scaleup, to efficiently produce large quantities of 1-(aminoalkyl)indazoles. More specifically, the present invention provides a method of making 1-(aminoalkyl)indazoles in large quantities while avoiding large quantities of undesired isomers or by-products.
  • the present invention to relates to a method of making a 1-alkylindazole involving:
  • the present invention relates to a method of making a 1-(hydroxyalkyl)indazole involving:
  • the present invention relates to 1-alkyl-3-aminoindazoles. More particularly, the present invention relates to the use of 1-alkyl-3-aminoindazoles as intermediates for making 1-alkylindazoles.
  • a preferred embodiment of the present invention relates to 1-(hydroxyalkyl)-3-aminoindazoles, and particularly to the use of 1-(hydroxyalkyl)-3-aminoindazoles for making 1-(aminoalkyl)indazoles.
  • the 1-(aminoalkyl)indazoles that can be made following the methods of the present invention are preferably enantiomerically pure products which are preferably useful as pharmacologically active products such as in the treatment of glaucoma and/or are useful for lowering and controlling normal or elevated intraocular pressure.
  • the methods described herein avoid the problems associated with removal of acetic acid and are capable of scaleup to produce large quantities of material for formulation in pharmaceutical compositions.
  • 1-alkylindazoles can be produced by nitrosating a 2-alkylaminobenzonitrile, followed by reduction and cyclization, to form a 1-alkyl-3-aminoindazole. This aminoindazole can then be deaminated to form a 1-alkylindazole.
  • R is a C 2 to C 12 (hydroxy)alkyl group optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, OR 5 , OC( ⁇ O)R 5 , OC( ⁇ O)OR 5 , N(R 5 ) 2 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , or with one or more F atoms;
  • R is a C 2 to C 6 (hydroxy)alkyl optionally substituted with phenyl, OR 5 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , or with one or more F atoms;
  • the nitrosation can be carried out on a 2-hydroxyalkyl)aminobenzonitrile, followed by reduction and cyclization, to form a 1-(hydroxyalkyl)-3-aminoindazole.
  • This 1-(hydroxyalkyl)-3-aminoindazole can then be deaminated to form a 1-(hydroxyalkyl)indazole.
  • the steps of nitrosation/reduction-cyclization and deamination are carried out using a readily removable solvent.
  • Preferred solvents for use in the methods of the present invention include tetrahydrofuran and methanol.
  • This 1-(hydroxyalkyl)indazole can then be further reacted to form a desired 1-(aminoalkyl)indazole which is preferably enantiomerically pure and is preferably a pharmaceutically active product.
  • the 1-(hydroxyalkyl)indazole can be reacted with a sulfonyl halide or sulfonic anhydride to form a corresponding sulfonic ester.
  • This sulfonic ester can be reacted with a metal azide to yield a 1-(azidoalkyl)indazole which in turn is reacted with a hydrogen source and a catalyst to yield a 1-(aminoalkyl)indazole.
  • the hydrogen source is preferably ammonium formate and the catalyst is preferably palladium on charcoal in the presence of an organic solvent, such as ethanol.
  • the 2-(hydroxyalkyl)aminobenzonitrile has the formula
  • R is a C 2 to C 12 alkyl group substituted with at least one OH group and optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, OR 5 , OC( ⁇ O)R 5 , OC( ⁇ O)OR 5 , N(R 5 ) 2 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , or with one or more F atoms;
  • R 1 , R 2 , R 3 and R 4 are independently H, F, Cl, Br, CF 3 , OH, OR 5 , OC( ⁇ O)R 5 , OC( ⁇ O)OR 5 , N(R 5 ) 2 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , NO 2 , CN, N 3 , SH, S(O) n R 5 , C( ⁇ O)R 5 ,
  • R is a C 2 to C 6 alkyl group substituted with at least one OH group and optionally substituted with phenyl, OR 5 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , or with one or more P atoms;
  • R 1 , R 2 , R 3 and R 4 are independently H, F, Cl, CF 3 , OR 5 , OC( ⁇ O)R 5 , OC( ⁇ O)OR 5 , N(R 5 ) 2 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , NO 2 , CN, C( ⁇ O)R 5 , COOR 5 , CON(R 5 ) 2 , C 1 to C 6 alkyl optionally substituted with phenyl, C( ⁇ O)R 5 , COOR 5 , CON(R) 2 , CN, OR 5 , OC( ⁇ O)R 5 ,
  • the 2-alkylaminobenzonitrile which is used in the methods of the present invention can be prepared by any number of reaction schemes.
  • the 2-alkylaminobenzonitrile can be formed by reacting a 2-fluorobenzonitrile with an alkylamine in an organic solvent.
  • the alkylamine is a hydroxyalkylamine and the product is a 2-(hydroxyalkyl)aminobenzonitrile.
  • a 2-fluorobenzonitrile can be reacted with 1-amino-2-propanol in the presence of an organic solvent to yield the desired 2-(2-hydroxypropyl)aminobenzonitrile.
  • reaction schemes can be used to form the desired starting 2-alkylaminobenzonitrile.
  • Those skilled in the art in view of the present invention, can form a variety of starting 2-alkylaminobenzonitriles for purposes of the present invention.
  • the nitrosation can be accomplished by the addition of at least one organic nitrite or inorganic nitrite preferably in the presence of at least one organic solvent.
  • suitable nitrites include, but are not limited to, tert-butyl nitrite, isobutyl nitrite, isoamyl nitrite or sodium nitrite.
  • Preferred solvents include, but are not limited to, ethers, and a more preferred solvent is tetrahydrofuran. Combinations or mixtures of two or more nitrites can be used. This would also be true with respect to the other reactants in that combinations or mixtures of various reactants can be used.
  • the intermediate nitrosamine is treated with a reducing agent in the presence of an organic solvent to effect reduction with concurrent cyclization, affording a preferred 1-(hydroxyalkyl)-3-aminoindazole.
  • a reducing agent is zinc, and the reduction is carried out in the presence of an acidic salt such as ammonium acetate or ammonium chloride.
  • the organic solvent is tetrahydrofuran or methanol, or a mixture of tetrahydrofuran and methanol.
  • R is a C 2 to C 12 (hydroxy)alkyl group optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, OR 5 , OC( ⁇ O)R 5 , OC( ⁇ O)OR 5 , N(R 5 ) 2 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , or with one or more F atoms;
  • R is a C 2 to C 6 (hydroxy)alkyl group optionally substituted with phenyl, OR 5 , N(R 5 )C( ⁇ O)R 5 , N(R 5 )C( ⁇ O)OR 5 , or with one or more F atoms;
  • the deamination of the I-(hydroxyalkyl)-3-aminoindazole can be accomplished by reaction according to general procedures known in the art as described, for example, in March (1992).
  • the deamination is accomplished by treatment of the 1-(hydroxyalkyl)-3-aminoindazole with an organic nitrite in the presence of a hydride source and an organic solvent.
  • suitable organic nitrites include, but are not limited to, tert-butyl nitrite, isobutyl nitrite, and isoamyl nitrite.
  • the hydride source is preferably hypophosphorous acid or sodium hypophosphite. Most preferably the hydride source is hypophosphorous acid.
  • the organic solvent may be an alcohol, such as methanol or ethanol, in which case the solvent can also function as a hydride source. Generally, the organic solvent is methanol.
  • desired indazoles such as 1-(aminoalkyl)indazoles can be formed.
  • the present invention essentially prevents the formation of unwanted isomers thus resulting in improved yields and a process that is less expensive.
  • the process of the present invention can start with a racemic 2-(hydroxyalkyl)aminobenzonitrile, or can start with an (R)- or (S)-enantiomerically enriched 2-(hydroxyalkyl)aminobenzonitrile.
  • the process of the present invention permits great flexibility in the starting 2-(hydroxyalkyl)aminobenzonitrile, which further permits great flexibility in forming various desired indazoles such 1-(aminoalkyl)indazoles.
  • the indazoles which can be formed using the methods of the present invention are useful in, for instance, treating glaucoma and/or lowering or controlling elevated intraocular pressure.
  • the preferred process of the present invention uses a 2-alkylaminobenzonitrile in which the alkyl group is substituted by at least one OH group.
  • the ability to have an OH group in such a reaction sequence is a great benefit and unexpected since those skilled in the art might expect that the OH group would not survive further processing.
  • the method of the present invention allows formation of the desired indazole without the need for a protecting group on the hydroxy substituent.
  • the present invention permits the formation of various desirable indazoles, which previous to the present process, were quite difficult to form.
  • compositions and/or methods disclosed and claimed herein can be is made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve similar results. All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US10/539,423 2002-12-23 2003-12-19 1-alkyl-3-aminoindazoles Abandoned US20060052613A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/539,423 US20060052613A1 (en) 2002-12-23 2003-12-19 1-alkyl-3-aminoindazoles
US12/368,869 US7799930B2 (en) 2002-12-23 2009-02-10 1-alkyl-3-aminoindazoles

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US43638502P 2002-12-23 2002-12-23
PCT/US2003/040370 WO2004058725A1 (en) 2002-12-23 2003-12-19 1-alkyl-3-aminoindazoles
US10/539,423 US20060052613A1 (en) 2002-12-23 2003-12-19 1-alkyl-3-aminoindazoles

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/368,869 Division US7799930B2 (en) 2002-12-23 2009-02-10 1-alkyl-3-aminoindazoles

Publications (1)

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US20060052613A1 true US20060052613A1 (en) 2006-03-09

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Family Applications (2)

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US10/539,423 Abandoned US20060052613A1 (en) 2002-12-23 2003-12-19 1-alkyl-3-aminoindazoles
US12/368,869 Expired - Fee Related US7799930B2 (en) 2002-12-23 2009-02-10 1-alkyl-3-aminoindazoles

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US12/368,869 Expired - Fee Related US7799930B2 (en) 2002-12-23 2009-02-10 1-alkyl-3-aminoindazoles

Country Status (12)

Country Link
US (2) US20060052613A1 (ko)
EP (1) EP1578729A4 (ko)
JP (1) JP2006514651A (ko)
KR (1) KR20050086927A (ko)
CN (1) CN100361977C (ko)
AU (1) AU2003303477A1 (ko)
BR (1) BR0317665A (ko)
CA (1) CA2509833A1 (ko)
MX (1) MXPA05006851A (ko)
PL (1) PL376084A1 (ko)
WO (1) WO2004058725A1 (ko)
ZA (1) ZA200504719B (ko)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070072920A1 (en) * 2005-09-23 2007-03-29 Alcon, Inc. Phenylethylamine analogs and their use for treating glaucoma
US20070135430A1 (en) * 2003-11-26 2007-06-14 Dantanarayana Anura P Substituted furo[2,3-g]indazoles for the treatment of glaucoma
US20070293475A1 (en) * 2006-06-20 2007-12-20 Alcon Manufacturing Ltd. Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6960579B1 (en) 1998-05-19 2005-11-01 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
TW593302B (en) 2001-12-20 2004-06-21 Alcon Inc Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
JP2006511556A (ja) 2002-12-13 2006-04-06 アルコン,インコーポレイテッド 新規のベンゾピラン類似体及び緑内障の治療のためのそれらの使用
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
US7338972B1 (en) 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
AR046890A1 (es) 2003-12-15 2005-12-28 Alcon Inc [1,4] oxazino [2,3-g] indazoles sustituidos para el tratamiento del glaucoma.
WO2006062839A1 (en) 2004-12-08 2006-06-15 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma
CN102372675B (zh) * 2010-08-14 2013-12-18 王娜 6-氯-4-碘吲唑及其制备方法与应用
DE102015012050A1 (de) * 2015-09-15 2017-03-16 Merck Patent Gmbh Verbindungen als ASIC-Inhibitoren und deren Verwendungen

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3133081A (en) * 1964-05-12 J-aminoindazole derivatives
US3681382A (en) * 1969-02-07 1972-08-01 Ciba Geigy Corp 3-aminoindazoles
US3725431A (en) * 1970-09-23 1973-04-03 Ciba Geigy Corp 1-aralkyl-3-aminoindazoles
US3963739A (en) * 1972-09-30 1976-06-15 Dynamit Nobel Aktiengesellschaft 3-Amino-4,5,6-trichloro-7-nitriloindazoles

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1770649A1 (de) * 1968-06-15 1971-11-11 Bayer Ag Substituierte 3-Amino-indazole
JP3560986B2 (ja) * 1997-01-13 2004-09-02 山之内製薬株式会社 5―ht2c受容体作用薬及びアミノアルキルインダゾール誘導体
AU2002310224B2 (en) 2001-06-01 2007-06-07 Alcon, Inc. Methods of making indazoles
WO2002098861A1 (en) * 2001-06-01 2002-12-12 Alcon, Inc. Methods of making 1-(2-aminopropyl)-6-hydroxyindazole

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3133081A (en) * 1964-05-12 J-aminoindazole derivatives
US3681382A (en) * 1969-02-07 1972-08-01 Ciba Geigy Corp 3-aminoindazoles
US3725431A (en) * 1970-09-23 1973-04-03 Ciba Geigy Corp 1-aralkyl-3-aminoindazoles
US3963739A (en) * 1972-09-30 1976-06-15 Dynamit Nobel Aktiengesellschaft 3-Amino-4,5,6-trichloro-7-nitriloindazoles

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070135430A1 (en) * 2003-11-26 2007-06-14 Dantanarayana Anura P Substituted furo[2,3-g]indazoles for the treatment of glaucoma
US20090012291A1 (en) * 2003-11-26 2009-01-08 Alcon, Inc. SUBSTITUTED FURO[2,3-g]INDAZOLES FOR THE TREATMENT OF GLAUCOMA
US7476687B2 (en) 2003-11-26 2009-01-13 Alcon, Inc. Substituted furo[2,3-g]indazoles for the treatment of glaucoma
US20070072920A1 (en) * 2005-09-23 2007-03-29 Alcon, Inc. Phenylethylamine analogs and their use for treating glaucoma
US20070293475A1 (en) * 2006-06-20 2007-12-20 Alcon Manufacturing Ltd. Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma

Also Published As

Publication number Publication date
CN1732157A (zh) 2006-02-08
EP1578729A1 (en) 2005-09-28
PL376084A1 (en) 2005-12-12
EP1578729A4 (en) 2007-08-29
MXPA05006851A (es) 2005-08-16
US20090149659A1 (en) 2009-06-11
KR20050086927A (ko) 2005-08-30
CN100361977C (zh) 2008-01-16
BR0317665A (pt) 2005-11-29
CA2509833A1 (en) 2004-07-15
JP2006514651A (ja) 2006-05-11
WO2004058725A1 (en) 2004-07-15
ZA200504719B (en) 2006-08-30
AU2003303477A1 (en) 2004-07-22
US7799930B2 (en) 2010-09-21

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AS Assignment

Owner name: ALCON, INC., SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DELGADO, PETER;CONROW, RAYMOND E.;DEAN, W. DENNIS;REEL/FRAME:017248/0459

Effective date: 20050603

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE