Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; 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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• 2003
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