WO2004110991A2 - PROCESS FOR IMIDAZO[4,5-c]PYRIDIN-4-AMINES - Google Patents

PROCESS FOR IMIDAZO[4,5-c]PYRIDIN-4-AMINES Download PDF

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WO2004110991A2
WO2004110991A2 PCT/US2004/016833 US2004016833W WO2004110991A2 WO 2004110991 A2 WO2004110991 A2 WO 2004110991A2 US 2004016833 W US2004016833 W US 2004016833W WO 2004110991 A2 WO2004110991 A2 WO 2004110991A2
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carbon atoms
compound
formula
alkyl
moiety contains
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Kyle J. Lindstrom
Luke T. Dressel
Jason D. Bonk
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3M Innovative Properties Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Abstract

A process and intermediates for preparing 1H-imidazo[4,5-c]pyridin-4-amines are disclosed. The process includes providing a 7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine and converting a 7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine to a 1H-imidazo[4,5-c]pyridin-4-amine.

Description

PROCESS FOR MIDAZO[4,5-c]PYRIDIN-4- AMINES
FIELD This invention relates to processes for preparing lH-imidazo[4,5-c]pyridin-4- amines and to intermediates for use in preparing lH-imidazo[4,5-c]pyridin-4-amines.
BACKGROUND There has been a major effort in recent years to prepare and find compounds that modulate the immune system. Certain lH-imidazo[4,5-c]pyridin-4-amine compounds useful as immune response modifiers and methods for their preparation are described, for example, in U. S. Patent Nos. 5,446,153; 5,494,916; 5,644,063; 6,525,064; 6,545,016; and 6,545,017, in International Publication No. WO 02/46194, and in U.S. Patent Publication No. 2004/0010007. However, despite these developments, there is a continuing need for useful, alternative processes and intermediates for preparing immune response modifying 1H- imidazo[4,5-c]pyridin-4- amines.
SUMMARY It has now been found that lH-imidazo[4,5-c]pyridin-4-amine compounds of the
Formula I
Figure imgf000002_0001
I and pharmaceutically acceptable salts thereof, wherein Ri is selected from hydrogen; CΗRxRy wherein Rx is hydrogen and Ry is selected from alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRZRZ wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms;
R2 is selected from hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; and R3 and R4 are independently selected from hydrogen and alkyl of one to five carbon atoms, can be prepared by a process comprising the steps of: providing a compound of Formula VII
Figure imgf000003_0001
VII wherein R\, R , R3, and Rt are as defined above; reacting the compound of Formula VII with triphenylphosphine to provide an N-triphenylphosphinyl compound of Formula VIII
Figure imgf000003_0002
VIE; and hydrolyzing the N-triphenylphosphinyl compound of Formula VIII to provide a compound of Formula I. In other embodiments, lH-imidazo[4,5-c]pyridin-4-amine compounds of the
Formula la
Figure imgf000004_0001
la and pharmaceutically acceptable salts thereof, wherein Rja is selected from hydrogen and CHRxRy wherein Rx is hydrogen and Ry is selected from alkyl or cyclic alkyl containing one to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms;
R2a is selected from hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; and
R and R4 are independently selected from hydrogen and alkyl of one to five carbon atoms, can be prepared by a process comprising the steps of: providing a compound of Formula Vila
Figure imgf000004_0002
VHa wherein Rla, R2a, R3, and R4 are as defined above; reductively removing the tetrazolo ring from the compound of Formula Vila to provide a compound of the Formula la.
In some embodiments the above processes further comprise the step of isolating the compound of Formula I, the compound of Formula la, or pharmaceutically acceptable salts thereof.
In another aspect this invention provides intermediate compounds of the Formulas IV- VII, described below, which are useful in the preparation of the compounds of Formula I and la, for example, in the processes described herein. As used herein, the terms "alkyl", "alkenyl", and the prefix "alk-" are inclusive of straight chain and branched chain groups.
The terms "comprising" and variations thereof do not have a limiting meaning where these terms appear in the description and claims. The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION Reaction Scheme I illustrates one embodiment of the invention where R1; R2, R3 and R4 are as defined above.
In step (1) of Reaction Scheme I a 2,4-dichloro-3-nitropyridine of Formula II is reacted with an amine compound of formula R!NH , wherein R\ is as defined above, to provide a 2-chloro-3-nitropyridine of Formula III. In some embodiments the compound of formula R!NH2 is selected from 2-hydroxy-2-methylpropylamine, 2-methylpropylamine, and H-butylamine. The reaction may be carried out in an inert solvent such as N,N- dimethylformamide or dichloromethane in the presence or in the absence of a base such as triethylamine at a reduced temperature, or at an elevated temperature up to the reflux temperature of the solvent. For example, the reaction can be carried out by adding the amine to a solution of a compound of Formula II in a suitable solvent such as N,N- dimethylformamide in the presence of a tertiary amine such as triethylamine at a reduced temperature, e.g., about 0 °C. The product can be isolated from the reaction mixture using conventional methods. Many 2,4-dichloro-3-nitropyridines of the Formula II are known and can be readily prepared using known synthetic methods. (See, for example, Dellaria et al, U.S. Pat. No. 6,525,064 and the references cited therein.)
In step (2) of Reaction Scheme I a 2-chloro-3-nitropyridine of Formula III is reacted with an alkali metal azide to provide an 8-nitrotetrazolo[l,5- ]pyridin-7-amine of Formula IV. The reaction can be carried out by combining the compound of Formula III with an alkali metal azide, for example, sodium azide, in a suitable solvent such as N,N- dimethylformamide and heating, for example to about 50-60 °C, optionally in the presence of ammonium chloride. Alternatively, the reaction can be carried out by combining the compound of Formula III with an alkali metal azide, for example, sodium azide, in a suitable solvent such as acetonitrile/water, preferably 90/10 acetonitrile/water, in the presence of cerium III chloride, preferably cerium III chloride heptahydrate. Optionally, the reaction can be carried out with heating, for example, at the reflux temperature. The product can be isolated from the reaction mixture using conventional methods. In step (3) of Reaction Scheme I an 8-nitrotetrazolo[l,5-α]pyridin-7-amine of
Formula IV is reduced to provide a tetrazolo[l,5-α]pyridine-7,8-diamine of Formula V. The reduction can be carried out using a conventional heterogeneous hydrogenation catalyst, for example, platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethanol, isopropanol or toluene. Alternatively, Ni2B can be generated in situ from sodium borohydride and NiCl2 in the presence of methanol. The compound of Formula V is added to the reducing agent solution to effect reduction of the nitro group. When the compound of Formula V contains an alkenylene moiety, the Ni2B reducing agent can be used without reducing the alkenylene moiety. The product can be isolated from the reaction mixture using conventional methods.
In step (4) of Reaction Scheme I a tetrazolo[l,5-α]pyridine-7,8-diamine of Formula
V is reacted with a carboxylic acid of the formula R CO2H; an equivalent thereof selected from the corresponding acyl halide, R2C(O-alkyl)3, and R2C(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein R2 is as defined above and each alkyl contains 1 to 8 carbon atoms, to provide a 7H-imidazo[4,5-c]tetrazolo[l,5~α]pyridine of Formula VII. The reaction can be run in the absence of solvent or in an inert solvent such as, for example, toluene. The reaction may be run in the presence of cyclization conditions, which include sufficient heating (e.g., about 80-150 °C) to drive off any alcohol or water formed as a byproduct of the reaction, and optionally, in the presence of a catalyst such as pyridine hydrochloride. For example, an orthoester of the formula R2C(O-alkyl)3, (e.g., triethylorthoacetate) is combined with a tetrazolo[l,5- ]pyridine-7,8-diamine of Formula
V in toluene in the presence of pyridine hydrochloride and heated at the reflux temperature. The product or a pharmaceutically acceptable salt thereof can be isolated from the reaction mixture using conventional methods.
Alternatively, step 4 can include steps (4a) and (4b) of Reaction Scheme I. In step (4a) a tetrazolo[l,5- ]pyridine-7,8-diamine of Formula V is reacted with a carboxylic acid of the formula R CO2H, the corresponding acyl halide, or a mixture thereof, wherein R2 is as defined above, to provide an N-[tetrazolo[l,5-α]pyridin-8-yl]amide of Formula VI. The reaction can be run in an inert solvent such as toluene, dichloromethane, acetonitrile, or pyridine at a reduced temperature, such as about 0 °C. For example, an acyl halide can be added to a solution of the compound of Formula V in dichloromethane at about 0 °C in the presence of triethylamine. The product can be isolated from the reaction mixture using conventional methods.
In step (4b) of Reaction Scheme I anN-[tetrazolo[l,5-α]pyridin-8-yl]amide of Formula VI is cyclized to provide a 7H-imidazo[4,5-c]tetrazolo[l,5-α]pyridine of Formula VII. The reaction can be run at an elevated temperature, such as a reflux temperature, sufficient to drive off any water formed as a by-product of the reaction. Optionally, a catalyst such as pyridine hydrochloride can be included. The reaction can be run in the absence of a solvent or in an inert solvent, for example, a solvent have a boiling point of about 80 °C to about 150 °C, preferably at least about 100 °C, (e.g., toluene, pyridine). The product or a pharmaceutically acceptable salt thereof can be isolated from the reaction mixture using conventional methods.
In step (5) of Reaction Scheme I a 7H-imidazo[4,5-c]tetrazolo[l,5-a]pyridine of Formula VII is reacted with triphenylphosphine to form an N-triphenylphosphinyl intermediate of Formula VIII. The reaction with triphenylphosphine can be run in a suitable solvent such as toluene or 1,2-dichlorobenzene under an atmosphere of nitrogen with heating, for example at the reflux temperature.
In step (6) of Reaction Scheme I an N-triphenylphosphinyl intermediate of Formula VIII is hydrolyzed to provide a lH-imidazo[4,5-c]pyridin-4-amine of Formula I. The hydrolysis can be carried out by general methods well known to those skilled in the art, for example, by heating in a lower alkanol in the presence of an acid. The product can be isolated from the reaction mixture using conventional methods as the compound of
Formula I or as a pharmaceutically acceptable salt thereof. Reaction Scheme I
Figure imgf000008_0001
Reaction Scheme II also illustrates an embodiment of the invention where Rιa, R a,
R3 and R are as defined above.
In step (1) of Reaction Scheme II, the tetrazolo ring is reductively removed from a 7H-imidazo[4,5-c]tetrazolo[l,5-α]pyridine of the Formula Vila to provide a 1H- imidazo[4,5-c]pyridin-4-amine of the Formula la or a pharmaceutically acceptable salt thereof. The reaction can be carried out by reacting the 7H-imidazo[4,5-c]tetrazolo[l,5- jpyridine of Formula Vila with hydrogen in the presence of a catalyst and an acid. The reaction can be conveniently run in a Parr apparatus with a suitable catalyst, such as platinum TV oxide, and a suitable acid, such as trifluoroacetic acid or concentrated hydrochloric acid. The product can be isolated from the reaction mixture using conventional methods . Reaction Scheme II
Figure imgf000009_0001
When an alkenyl, alkenylene, or other readily reducible moiety is present and is to be kept from being reduced during the removal of the tetrazolo ring, steps (5) and (6) of Reaction Scheme I are preferred over Reaction Scheme II. For example, benzyl, phenylethyl, and -G=RZRZ moieties may be reduced or partially reduced in Reaction Scheme II.
In one embodiment, the present invention provides a process (i) for preparing 1H- imidazo[4,5-c]pyridin-4-amine compounds of the Formula I
Figure imgf000009_0002
and pharmaceutically acceptable salts thereof wherein R1; R , R3, and t are as defined above, which process comprises the steps of: providing a compound of the Formula VII
Figure imgf000009_0003
wherein Ri, R2, R and t are as defined above; reacting the compound of Formula VII with triphenylphosphine to provide an N-triphenylphosphinyl intermediate of Formula VIII
Figure imgf000010_0001
wherein Ri, R2, R3 and t are as defined above; and hydrolyzing the N-triphenylphosphinyl intermediate of Formula VIII to provide a compound of Formula I.
In another embodiment, the above process (i) further comprises the step of isolating the compound of Formula I or a pharmaceutically acceptable salt thereof.
In another embodiment, a process (ii) comprises the above process (i) further comprising the steps of: providing a compound of Formula V
Figure imgf000010_0002
wherein Rls R3 and t are as defined above; and reacting a compound of the Formula V with a carboxylic acid of the formula R2CO2H; an equivalent thereof selected from the corresponding acyl halide, R2C(O- alkyl)3, and R2C(O-alkyl) (O(O=)C-alkyl); or a mixture thereof, wherein R2 is as defined above, and each alkyl contains 1 to 8 carbon atoms, to provide a compound of the Formula VII.
In another embodiment, a process (iii) comprises the above process (ii) further comprising the steps of: providing a compound of Formula IV
Figure imgf000011_0001
rv wherein Rls R3 and Rt are as defined above; and reducing the compound of Formula TV to provide a compound of the Formula V.
In another embodiment, a process (iv) comprises the above process (iii) further comprising the steps of: providing a compound of Formula III
Figure imgf000011_0002
in wherein R1; R3 and t are as defined above; and reacting the compound of Fonnula III with an alkali metal azide to provide a compound of the Formula TV. In certain embodiments, the compound of Formula III is reacted with the alkali metal azide in the presence of cerium III chloride.
In another embodiment, a process (v) comprises the above process (iv) further comprising the steps of: providing a compound of Formula II
Figure imgf000011_0003
π wherein R and R4 are as defined above; and reacting the compound of Formula II with a compound of the formula RιNH2, wherein Ri is as defined above, to provide a compound of the Formula III.
In another embodiment, the above process (v) further comprises the step of isolating the compound of Formula I or a pharmaceutically acceptable salt thereof.
In one embodiment, a process (vi) comprises the above process (i) further comprising the steps of: providing a compound of Formula VI
Figure imgf000012_0001
VI wherein Rls R2, R3 and R4 are as defined above; and subjecting the compound of Formula VI to cyclization conditions, to provide a compound of the Formula VII.
In another embodiment, a process (vii) comprises the above process (vi) further comprising the steps of: providing a compound of Formula V
Figure imgf000012_0002
wherein Ri, R3 and R4 are as defined above; and reacting a compound of the Formula V with a carboxylic acid of the formula R2CO2H or the conesponding acyl halide, wherein R2 is as defined above, to form a compound of the Formula VI.
In another embodiment, a process (viii) comprises the above process (vii) further comprising the steps of: providing a compound of Formula TV
Figure imgf000013_0001
rv wherein Ri, R3 and Rt are as defined above; and reducing the compound of Formula IV to provide a compound of the Formula V.
In another embodiment, a process (ix) comprises the above process (viii) further comprising the steps of: providing a compound of Formula III
Figure imgf000013_0002
m wherein Rj, R3 and R4 are as defined above; and reacting the compound of Fonnula III with an alkali metal azide to provide a compound of the Formula TV. In one embodiment, the compound of Formula III is reacted with the alkali metal azide in the presence of cerium III chloride.
In another embodiment, a process (x) comprises the above process (ix) further comprising the steps of: providing a compound of Formula II
Figure imgf000013_0003
π wherein R3 and R4 are as defined above; and reacting the compound of Formula II with a compound of the formula R!NH , wherein Ri is as defined above, to provide a compound of the Formula III.
In another embodiment, the process (x) further comprises the step of isolating the compound of Formula I or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention provides a process (i-a) for preparing lH-imidazo[4,5-c]pyridin-4-amine compounds of the Formula la
Figure imgf000014_0001
la and pharmaceutically acceptable salts thereof, wherein Rla, R2a, R , and R4 are as defined above, which process comprises the steps of: providing a compound of Fonnula Vila
Figure imgf000014_0002
Vila wherein Rla, R2a, R3, and t are as defined above; and reductively removing the tetrazolo ring from the compound of Formula Vila to provide a compound of the Formula la. In one embodiment, the tetrazolo ring is reductively removed by reacting a compound of Fonnula Vila with hydrogen in the presence of a catalyst and an acid.
In another embodiment, the above process (i-a) further comprises the step of isolating the compound of Formula la or a pharmaceutically acceptable salt thereof.
In another embodiment, a process (ii-a) comprises the above process (i-a) further comprising the steps of: providing a compound of Formula Va
Figure imgf000015_0001
Va wherein Rla, R3 and Rt are as defined above; and reacting a compound of the Formula Va with a carboxylic acid of the formula R2aCO2H; an equivalent thereof selected from the conesponding acyl halide, R2aC(O- alkyl)3, and R aC(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein R2a is as defined above, and each alkyl contains 1 to 8 carbon atoms, to provide a compound of the Formula Vila.
In another embodiment, a process (iii-a) comprises the above process (ii-a) further comprising the steps of: providing a compound of Formula IVa
Figure imgf000015_0002
TVa wherein Rla, R3 and R4 are as defined above; and reducing the compound of Formula TVa to provide a compound of the Formula Va. In another embodiment, a process (iv-a) comprises the above process (iii-a) further comprising the steps of: providing a compound of Formula Ilia
Figure imgf000015_0003
TJIa wherein Rιa, R and t are as defined above; and reacting the compound of Formula Ilia with an alkali metal azide to provide a compound of the Formula IVa. In another embodiment, the compound of Formula Ilia is reacted with the alkali metal azide in the presence of cerium III chloride.
In another embodiment, a process (v-a) comprises the above process (iv-a) further comprising the steps of: providing a compound of Formula II
Figure imgf000016_0001
π wherein R and t are as defined above; and reacting the compound of Formula II with a compound of the formula RlaNH , wherein Rla is as defined above, to provide a compound of the Formula Ilia.
In another embodiment, the process (iv-a) further comprises the step of isolating the compound of Formula la or a pharmaceutically acceptable salt thereof.
In another embodiment, a process (vi-a) comprises the above process (i-a) further comprising the steps of: providing a compound of Formula Via
Figure imgf000016_0002
Via wherein Rla, R a, R3 and R- are as defined above; and subjecting the compound of Formula Via to cyclization conditions, to provide a compound of the Formula Vila.
In another embodiment, a process (vii-a) comprises the above process (vi-a) further comprising the steps of: providing, a compound of Formula Va
Figure imgf000017_0001
Va wherein Rla, R3 and Rt are as defined above; and reacting a compound of the Formula Va with a carboxylic acid of the formula R2aCO2H or the conesponding acyl halide, wherein R2a is as defined above, to form a compound of the Fonnula Via.
In another embodiment, a process (viii-a) comprises the above process (vii-a) further comprising the steps of: providing a compound of Formula IVa
Figure imgf000017_0002
wherein Rιa, R3 and t are as defined above; and reducing the compound of Formula IVa to provide a compound of the Formula Va. In another embodiment, a process (ix-a) comprises the above process (viii-a) further comprising the steps of: providing a compound of Formula Ilia
Figure imgf000017_0003
wherein Rla, R3 and Rt are as defined above; and reacting the compound of Formula Ilia with an alkali metal azide to provide a compound of the Formula IVa. In another embodiment the compound of Formula Ilia is reacted with the alkali metal azide in the presence of cerium III chloride.
In another embodiment, a process (x-a) comprises the above process (ix-a) further comprising the steps of: providing a compound of Formula II
Figure imgf000018_0001
π wherein R and t are as defined above; and reacting the compound of Formula II with a compound of the fonnula R aNH2, wherein Rja is as defined above, to provide a compound of the Formula Ilia.
In another embodiment, the above process (ix-a) further comprises the step of isolating the compound of Formula la or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention provides a process (xi) for preparing a chemical compound comprising the steps of: providing a compound of Formula III
Figure imgf000018_0002
rπ wherein Rl5 R3 and R^t are defined above; and reacting the compound of Formula III with an alkali metal azide to provide a compound of Formula IV
Figure imgf000019_0001
rv wherein Rj, R , and t are as defined above. In another embodiment, the compound of Formula III is reacted with the alkali metal azide in the presence of cerium III chloride.
In another embodiment, the process (xi) further comprises the steps of: providing a compound of Formula II
Figure imgf000019_0002
π wherein R3 and R4 are as defined above; and reacting the compound of Formula II with a compound of the fonnula RiM :, wherein Ri is as defined above, to provide a compound of Formula III. In another embodiment, a process (xii) comprises the above process (xi) further comprising the step of reducing the compound of Formula TV to provide a compound of Formula V
Figure imgf000019_0003
V wherein R^ R , and R4 are as defined above. In another embodiment, a process (xiii) comprises the above process (xii) further comprising the step of reacting a compound of Formula V with a carboxylic acid of the formula R2CO2H; an equivalent thereof selected from the conesponding acyl halide, R2C(O-alkyl)3, and R2C(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein each alkyl contains 1 to 8 carbon atoms; and R2 is as defined above; to provide a compound of the Formula VII
Figure imgf000020_0001
vπ wherein Rj, R2, R , and R4 are as defined above.
In another embodiment, a process (xiv) comprises the above process (xiii) further comprising the step of reacting the compound of Formula VII with triphenylphosphine to provide an N-triphenylphosphinyl intermediate of Formula VIII
Figure imgf000020_0002
viπ wherein Rls R2, R3, and t are as defined above. In another embodiment, a process (xv) comprises the above process (xii) further comprising the step of (a) reacting the compound of Formula V with a carboxylic acid of the formula R2CO H or the conesponding acyl halide to form a compound of the Formula VI
Figure imgf000020_0003
VI wherein Rl5 R2, R , and R4 are as defined above.
In another embodiment, a process (xvi) comprises the above process (xv) further comprising the step of (b) subjecting the compound of Fonnula VI to cyclization conditions, during step (a) or subsequent to the completion of step (a), to provide a compound of the Formula VII
Figure imgf000021_0001
vπ wherein Ri, R2, R3, and t are as defined above.
In another embodiment, a process (xvii) comprises the above process (xvi) further comprising the step of reacting the compound of Formula VII with triphenylphosphine to provide an N-triphenylphosphinyl intermediate of Formula VIII
Figure imgf000021_0002
vm wherein Rl9 R2, R3, and t are as defined above.
In some embodiments, Rl5 R , R3, and t in the above processes (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), (i-a), (ii-a), (iii-a), (iv-a), (v-a), (vi-a), (vii-a), (viii-a), (ix-a), and (x-a) are independently selected as follows:
RΪ is selected from alkyl of one to four carbon atoms, alkenyl of two to four carbon atoms, hydroxyalkyl of one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and phenylethyl; R2 and R2a are selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms; and R and R* are independently selected from hydrogen and alkyl of one to four carbon atoms. In certain embodiments, R1 is selected from rc -butyl, 2-methylpropyl, 2-methyl-l-propenyl, 2-hydroxy-2-methylpropyl, 2-ethoxyethyl, and 2-phenylethyl; R2 and R2a are selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl; R3 is methyl; and t is selected from hydrogen and methyl. In certain embodiments, is selected from 2-hydroxy-2-methylρropyl, 2-methylpropyl, and n-butyl. hi certain embodiments, R4 is methyl. In some embodiments, Rla in the above processes (i-a), (ii-a), (iii-a), (iv-a), (v-a), (vi-a), (vii-a), (viii-a), (ix-a), and (x-a) is independently selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms. In certain embodiments, Rla is selected from «-butyl, 2-methylpropyl, 2- hydroxy-2-methylpropyl, and 2-ethoxyethyl.
In other embodiments, the above processes (ii), (iii), (iv), (v), (xiii), and (xiv), wherein the compound of Formula V is reacted with a carboxylic acid of the formula R2CO H; an equivalent thereof selected from the conesponding acyl halide, R2C(O- alkyl)3, and R2C(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof; and wherein R2 is as defined above, are done in the presence of cyclization conditions to provide a compound of the Formula VII.
In other embodiments, the above processes (ii-a), (iii-a), (iv-a), and (v-a), wherein the compound of Formula Va is reacted with a carboxylic acid of the formula R aCO2H; an equivalent thereof selected from the conesponding acyl halide, R aC(O-alkyl)3, and
R aC(O-alkyl) (O(O=)C-alkyl); or a mixture thereof; and wherein R2a is as defined above, are done in the presence of cyclization conditions to provide a compound of the Fonnula Vila.
In other embodiments, the alkali metal azide in the above processes (iv), (v), (ix), (x), (iv-a), (v-a), (ix-a), (x-a), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), and (xviii) is sodium azide.
In other embodiments, the compound of Formula IV or TVa is reduced with a heterogeneous hydrogenation catalyst in the above processes (iii), (iv), (v), (viii), (ix), (x), (iii-a), (iv-a), (v-a), (viii-a), (ix-a), (x-a), (xii), (xiii), (xiv), (xv), (xvi), (xvii), and (xviii). In other embodiments, in the above processes (vii), (viii), (ix), (x), (vii-a), (viii-a),
(ix-a), (x-a), (xvi), and (xvii) the compound of Formula V is reacted with the conesponding acyl halide to form the compound of Formula VI, and the compound of Formula VI is subjected to cyclization conditions which include an elevated temperature and the presence of pyridine hydrochloride. In certain embodiments, the acyl halide is ethoxyacetyl chloride.
In some embodiments, in the above processes (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (i-a), (ii-a), (iii-a), (iv-a), (v-a), (vi-a), (vii-a), (viii-a), (ix-a), and (x-a) the compound of Formula I or la is 2-(ethoxymethyl)-l-(2-methylpropyl)-6-methyl-lH- imidazo[4,5-c]pyridin-4-amine.
In another aspect, the invention provides novel compounds useful as intermediates in the preparation of the compounds of Formulas I and la. These intermediates have the structural Formulas IV- VII.
One class of intermediate compounds has the Fonnula TV:
Figure imgf000023_0001
TV
wherein
RΪ is selected from the group consisting of hydrogen; CΗRxRy wherein Rx is hydrogen and Ry is selected from the group consisting of alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRZRZ wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms; and
R3 and R4 are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms.
In some embodiments, R\ is selected from alkyl of one to four carbon atoms, alkenyl of two to four carbon atoms, hydroxyalkyl of one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and phenylethyl; and R3 and R4 are independently selected from hydrogen and alkyl of one to four carbon atoms.
In some embodiments, Rl5 R3, and are independently selected as follows: Rt is selected from n-butyl, 2-methylpropyl, 2-methyl-l-propenyl, 2-hydroxy-2-methylpropyl, 2-ethoxyethyl, and 2-phenylethyl; R3 is methyl, and Rt is selected from hydrogen and methyl. In some prefened embodiments, R and t are methyl.
Another class of intermediate compounds has the Formula V
Figure imgf000024_0001
V wherein R1; R3 and t are selected as described above for intermediate compounds of the Fonnula IV.
Another class of intermediate compounds has the Formula VI
Figure imgf000024_0002
VI wherein Rls R3 and R4 are selected as described above for intennediate compounds of the
Fonnula TV, and
R2 is selected from the group consisting of hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms. In some embodiments, R2 is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
In some embodiments, R2 is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl. Another class of intermediate compounds has the Formula VII
Figure imgf000025_0001
wherein Rl5 R2, R3, and R4 are selected as described above for the intermediate compound of the Fonnula VI, and wherein when R\ is hydrogen, at least one of R2, R3, or Rt is other than hydrogen. The processes of the invention are useful for making compounds and salts of
Formulas I and la, or for making intennediates which are useful for making such compounds and salts. Compounds and salts of Formulas I and la are disclosed in U.S. Pat. No. 5,446,153 as having immunomodulating activity, including, for example, inducing the biosynthesis of interferon, and exhibiting antiviral and antituor activity. Various aspects and embodiments of the invention are further described by the
Examples, which are provided for illustration purposes only and are not intended to be limiting in any way.
EXAMPLES
Example 1 N-(2-Methylpropyl)-5-methyl-8-nitrotetraazolo[l,5-Ω]pyridin-7-amine
Figure imgf000025_0002
Part A Under a nitrogen atmosphere, a solution of 2,4-dichloro-6-methyl-3-nitropyridine
(125 g, 0.604 mol) in anhydrous N,N-dimethylformamide (625 mL) was cooled to 0 °C. Triethylamine (84.2 mL, 0.604 mol) was added. 2-Methylpropylamine (66 mL, 0.664 mol) was added dropwise to the resulting solution over a period of one hour; the reaction reached a temperature of 17 °C and became yellow. The reaction was allowed to warm to room temperature and stir overnight. The reaction mixture was filtered to remove salts, and then the N,N-dimethylformamide was removed under reduced pressure. The crude product was dissolved in ethyl acetate (750 mL), and the solution was washed with water (3 x IL), dried over magnesium sulfate, and then concentrated under reduced pressure. Hexane (300 mL) was added to the resulting yellow oil; the mixture was heated until the oil dissolved and then placed in a freezer. After ten minutes, the recrystallization mixture was seeded with crystals made in a previous run and then left undisturbed for four hours. The resulting precipitate was filtered, washed with cold hexane, and dried in a vacuum oven at room temperature to provide 98 g of 2-chloro-N-(2-methylpropyl)-6-methyl-3- nitropyridin-4-amine.
Part B
Under a nitrogen atmosphere, a mixture of 2-chloro-N-(2-methylpropyl)-6-methyl- 3-nitropyridin-4-amine (10.0 g, 41.0 mmol), sodium azide (2.67 g, 41.0 mmol), and anhydrous N,N-dimethylformamide (200 mL) was heated at 60 °C. After 5 hours, the dark green solution was allowed to cool to room temperature, poured slowly into water (2 L), and stined for fifteen minutes. A green precipitate formed, which was filtered and washed with water to yield 9.37 g ofN-(2-methylpropyl)-5-methyl-8-nitrotetraazolo[l,5-Ω]pyridin- 7-amine as a light green solid, m.p. 185-187 °C.
Example 2 N7-(2-Methylpropyl)-5-methyltetraazolo[l,5- ]pyridine-7,8-diamine
Figure imgf000026_0001
N-(2-Methylpropyl)-5-methyl-8-nitrotetraazolo[l,5-α]pyridin-7-amine (9.60 g, 43.6 mmol) was dissolved in warm anhydrous toluene (900 mL) and methanol (100 mL) and then added to a 2 L stainless steel Pan vessel. The vessel was flushed several times with nitrogen, and 5% platinum on carbon (2.0 g) was added to the solution. The vessel was flushed multiple times with hydrogen, and then placed under hydrogen pressure (50 psi, 3.4 x 105 Pa). After two hours, no frrrther hydrogen was consumed. The reaction mixture was filtered through a layer of filter agent (available from Aldrich, Milwaukee, WI under the trade name CELITE), and the filter cake was washed with hot toluene (1 L). The filtrate was concentrated under reduced pressure to yield 8.5 g N7-(2-methylpropyl)-5- methyltetraazolo[l,5-α]pyridine-7,8-diamine as a light orange solid, m. p. 159-162 °C.
Example 3 2-Ethoxy-N-{7-[(2-methylpropyl)amino]-5-methyltetraazolo[l,5- ]pyridin-8-yl}acetamide
Figure imgf000027_0001
A mixture of N7-(2-methylpropyl)-5-methyltetraazolo[ 1 ,5-a]pyridine-7,8-diamine
(8.4 g, 38.1 mmol) in anhydrous dichloromethane (300 mL) was cooled to 0 °C under a nitrogen atmosphere, and triethylamine (5.3 mL, 38.1 mmol) was added. A solution of ethoxyacetyl chloride (4.7 g, 38.1 mmol) in dichloromethane (100 mL) was added dropwise over a period of five minutes, and a homogeneous solution resulted. After the solution was stined for one hour, it was allowed to warm to room temperature, washed with water (2 x 200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.2 g of 2-ethoxy-N-{7-[(2-methylpropyl)amino]-5- methyltetraazolo[l,5-α]pyridin-8-yl}acetamide as a light tan solid, m. p. 182-185 °C.
Example 4
8-(Ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5-c]tetraazolo[l,5- βjpyridine
Figure imgf000027_0002
A solution of 2-ethoxy-N-{7-[(2-methylpropyl)amino]-5-methyltetraazolo[l,5- α]pyridin-8-yl}acetamide (10.9 g, 35.6 mmol) and pyridine hydrochloride (10 g) in pyridine (100 mL) was heated at reflux under a nitrogen atmosphere for five days. An analysis by high-performance liquid chromatography indicated the presence of 16% starting material, and an additional 10 g of pyridine hydrochloride was added. After a total of seven days, the reaction was complete, and the solvent was removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate (500 mL), and the solution was washed with water (3 x 200 mL), dried over magnesium sulfate, filtered, and concentrated to 200 mL. Needles began to form in the solution, which was placed in a freezer for two hours. The crystals were then filtered and washed with cold ethyl acetate to yield 6.85 g of 8-(ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5- c]tetraazolo[l,5-β]pyridine as light brown needles, m. p. 158-160 °C.
Example 5 2-(Ethoxymethyl)- 1 -(2-methylpropyl)-6-methyl- lH-imidazo[4,5-c]pyridin-4-amine hydrochloride
Figure imgf000028_0001
A mixture of 8-(ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5- c]tetraazolo[l,5-α]pyridine (6.5 g, 22.5 mmol), triphenylphosphine (6.5 g, 24.8 mmol), and toluene (130 mL) was stined and heated at reflux under nitrogen for 24 hours.
Additional triphenylphosphine (3.0 g, 11.4 mmol) was added to the cloudy mixture, and the reaction was continued for three days. The solvent was removed under reduced pressure, and the resulting brown oil was dissolved in methanol (lOOmL). Following the addition of a 1.0 M solution of hydrochloric acid in diethyl ether (45mL) to the methanol solution, the reaction was heated at reflux overnight. The solvents were removed under reduced pressure, and water (200 mL) was added to the resulting brown oil, forming a white precipitate that was removed by filtration. Solid sodium carbonate (6.5 g) was added to the aqueous solution, followed by extraction with dichloromethane (2 x 200 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil, which was dissolved in 2-propanol (45 mL). A 1.0 M solution of hydrochloric acid in diethyl ether (22.5 mL) was added to the solution of crude product, and a white solid formed. After one hour the solid was isolated by filtration, washed with cold 2-propanol and diethyl ether, and dried in a vacuum oven at 90 °C for two days to yield 4.3 g of 2-(ethoxymethyl)-l-(2-methylpropyl)-6-methyl-lH- imidazo[4,5-c]pyridin-4-amine hydrochloride as a white solid, m. p. 181-183 °C. Analysis: Calculated for Cι4Η22N4O- HC1: %C, 56.27; %H, 7.76; %N, 18.75. Found: %C, 56.33; %H, 7.67; %N, 18.90.
Example 6 2-(Ethoxymethyl)-l-(2-methylpropyl)-6-methyl-lH-imidazo[4,5-c]pyridin-4-amine
Figure imgf000029_0001
8-(Ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5-c]tetraazolo[l,5- jpyridine (6.5 g, 22.5 mmol), trifluoroacetic acid (67 mL), and platinum (IV) oxide (0.47 g) are added to a stainless steel Parr vessel, which is then placed under hydrogen pressure (50 psi, 3.4 x 105 Pa). For the first eight hours, the vessel is flushed with hydrogen every two hours and then maintained under hydrogen pressure (50 psi, 3.4 x 105 Pa) overnight. The reaction mixture is filtered through a layer of CELITE filter aid, and the filter cake is washed with additional trifluoroacetic acid. The filtrate is concentrated under reduced pressure to yield a light brown oil, which is dissolved in 37% aqueous hydrochloric acid (25 mL). Sodium carbonate is added to this solution until it exhibits pΗ 12. The resulting solution is extracted with chloroform. The chloroform solution is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide about 4 g of 2- (ethoxymethyl)-l-(2-methylpropyl)-6-methyl-lH-imidazo[4,5-c]pyridin-4-amine as a white solid. The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.

Claims

What is Claimed is:
1. A process for preparing lH-imidazo[4,5-c]pyridin-4-amine compounds of the Formula I
Figure imgf000031_0001
and pharmaceutically acceptable salts thereof wherein
Ri is selected from the group consisting of hydrogen; CΗRxRy wherein Rx is hydrogen and Ry is selected from the group consisting of alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRzRz wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms;
R2 is selected from the group consisting of hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; and R3 and are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms, which process comprises the steps of: providing a compound of the Formula VII
Figure imgf000032_0001
vπ wherein R\, R2, R and R4 are as defined above; reacting the compound of Formula VII with triphenylphosphine to provide an N-triphenylphosphinyl intermediate of Fonnula VIII
Figure imgf000032_0002
Vm wherein R1} R2, R3 and Rt are as defined above; and hydrolyzing the N-triphenylphosphinyl intermediate of Fonnula VIII to provide a compound of Formula I.
2. The process of claim 1, further comprising the step of isolating the compound of
Formula I or a pharmaceutically acceptable salt thereof.
3. The process according to claim 1, wherein R\ is selected from alkyl of one to four carbon atoms, alkenyl of two to four carbon atoms, hydroxyalkyl of one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and phenylethyl.
4. The process according to claim 3, wherein R is selected from 2-hydroxy-2- methylpropyl, 2-methylpropyl, and n-butyl.
5. The process according to claim 1, wherein R2 is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
6. The process according to claim 5, wherein R2 is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl.
7. The process according to claim 1, wherein R3 is methyl, and R4 is hydrogen or methyl.
8. The process of claim 1, further comprising the steps of: providing a compound of Formula V
Figure imgf000033_0001
wherein R1} R3 and R4 are as defined in claim 1; and reacting a compound of the Formula V with a carboxylic acid of the formula R2CO2H; an equivalent thereof selected from the conesponding acyl halide, R2C(O- alkyl)3, and R2C(O-alkyι)2(O(O-)C-alkyl); or a mixture thereof, wherein R2 is as defined in claim 1, and each alkyl contains 1 to 8 carbon atoms, to provide a compound of the Formula VII.
9. The process of claim 8, further comprising the steps of: providing a compound of Formula TV
Figure imgf000033_0002
TV wherein Rls R3 and t are as described in claim 8; and reducing the compound of Formula IV to provide a compound of the Formula V.
10. The process of claim 9, further comprising the steps of: providing a compound of Formula III
Figure imgf000034_0001
wherein Rl5 R3 and Rt are as described in claim 9; and reacting the compound of Formula III with an alkali metal azide to provide a compound of the Formula IV.
11. The process according to claim 10, wherein the compound of Formula III is reacted with the alkali metal azide in the presence of cerium III chloride.
12. The process of claim 10, further comprising the steps of: providing a compound of Formula II
Figure imgf000034_0002
π wherein R3 and R4 are as described in claim 10; and reacting the compound of Formula II with a compound of the formula R1NH2, wherein Ri is as defined in claim 10, to provide a compound of the Formula III.
13. The process of claim 10, further comprising the step of isolating the compound of Fonnula I or a pharmaceutically acceptable salt thereof.
14. The process according to claim 10, wherein Rl5 R2, R3, and t are independently selected as follows:
R\ is selected from alkyl of one to four carbon atoms, alkenyl of two to four carbon atoms, hydroxyalkyl of one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and phenylethyl;
R2 is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms;
R3 is selected from hydrogen and alkyl of one to four carbon atoms; and 1^4 is selected from hydrogen and alkyl of one to four carbon atoms.
15. The process according to claim 14, wherein Ri, R2, R3, and R4 are independently selected as follows:
Ri is selected from 2-hydroxy-2-methylpropyl, 2-methylpropyl, and «-butyl; R2 is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl;
R3 is methyl; and R4 is selected from hydrogen and methyl.
16. The process of claim 1, further comprising the steps of: providing a compound of Fonnula VI
Figure imgf000035_0001
VI wherein Ri, R2, R3 and Rt are as defined in claim 1 ; and subjecting the compound of Formula VI to cyclization conditions, to provide a compound of the Formula VII.
17. The process of claim 16, further comprising the steps of: providing a compound of Formula V
Figure imgf000036_0001
V wherein Rls R3 and t are as defined in claim 16; and reacting a compound of the Formula V with a carboxylic acid of the formula R2CO2H or the conesponding acyl halide, wherein R2 is as defined in claim 16, to form a compound of the Fonnula VI.
18. The process of claim 17, further comprising the steps of: providing a compound of Formula IV
Figure imgf000036_0002
TV wherein Rl5 R3 and R are as described in claim 17; and reducing the compound of Formula IV to provide a compound of the Formula V.
19. The process of claim 18, further comprising the steps of: providing a compound of Formula III
Figure imgf000037_0001
m wherein R1} R3 and Rt are as described in claim 18; and reacting the compound of Formula III with an alkali metal azide to provide a compound of the Formula TV.
20. The process according to claim 19, wherein the compound of Formula III is reacted with the alkali metal azide in the presence of cerium III chloride.
21. The process of claim 19, further comprising the steps of: providing a compound of Formula II
Figure imgf000037_0002
wherein R3 and R4 are as described in claim 19; and reacting the compound of Formula II with a compound of the fonnula RιNH , wherein R is as defined in claim 19, to provide a compound of the Formula III.
22. The process of claim 19, further comprising the step of isolating the compound of Formula I or a pharmaceutically acceptable salt thereof.
23. The process according to claim 19, wherein R\, R2, R3, and t are independently selected as follows:
R\ is selected from alkyl of one to four carbon atoms, alkenyl of two to four carbon atoms, hydroxyalkyl of one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and phenylethyl;
R2 is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms;
R3 is selected from hydrogen and alkyl of one to four carbon atoms; and 1^ is selected from hydrogen and alkyl of one to four carbon atoms.
24. The process according to claim 23, wherein Ri, R2, R3, and R4 are independently selected as follows:
Ri is selected from 2-hydroxy-2-methylpropyl, 2-methylpropyl, and n-butyl; R2 is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl;
R3 is methyl; and R is selected from hydrogen and methyl.
25. A process for preparing lH-imidazo[4,5-c]pyridin-4-amine compounds of the Formula la
Figure imgf000038_0001
la and pharmaceutically acceptable salts thereof, wherein Rla is selected from hydrogen and
CΗRxRy wherein Rx is hydrogen and Ry is selected from alkyl or cyclic alkyl containing one to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon; R2a is selected from hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; and
R3 and R4 are independently selected from hydrogen and alkyl of one to five carbon atoms; which process comprises the steps of: providing a compound of Formula Vila
Figure imgf000039_0001
wherein Rla, R2a, R3, and R4 are as defined above; and reductively removing the tetrazolo ring from the compound of Formula Vila to provide a compound of the Formula la.
26. The process according to claim 25, wherein the tetrazolo ring is reductively removed by reacting a compound of Formula Vila with hydrogen in the presence of a catalyst and an acid.
27. The process of claim 25, further comprising the step of isolating the compound of Formula la or a pharmaceutically acceptable salt thereof.
28. The process according to claim 25, wherein Rla is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
29. The process according to claim 28, wherein Rιa is selected from 2-hydroxy-2- methylpropyl, 2-methylpropyl, and n-butyl.
30. The process according to claim 25, wherein R2a is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
31. The process according to claim 30, wherein R2a is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl.
32. The process according to claim 25, wherein R3 is methyl, and R^ is hydrogen or methyl.
33. The process of claim 25, further comprising the steps of: providing a compound of Formula Va
Figure imgf000040_0001
Va wherein Rιa, R3 and R4 are as defined in claim 25; and reacting a compound of the Formula Va with a carboxylic acid of the formula .
R aCO H; an equivalent thereof selected from the conesponding acyl halide, R2aC(O- alkyl)3, and R2aC(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein R2a is as defined in claim 25, and each alkyl contains 1 to 8 carbon atoms, to provide a compound of the Formula Vila.
34. The process of claim 33, further comprising the steps of: providing a compound of Formula IVa
Figure imgf000041_0001
wherein Rla, R3 and t are as described in claim 33; and reducing the compound of Formula IVa to provide a compound of the Formula Va.
35. The process of claim 34, further comprising the steps of: providing a compound of Formula Ilia
Figure imgf000041_0002
ma wherein Rla, R3 and t are as described in claim 34; and reacting the compound of Formula Ilia with an alkali metal azide to provide a compound of the Formula IVa.
36. The process according to claim 35, wherein the compound of Formula Ilia is reacted with the alkali metal azide in the presence of cerium III chloride.
37. The process of claim 35, further comprising the steps of: providing a compound of Formula II
Figure imgf000041_0003
π wherein R3 and t are as described in claim 35; and reacting the compound of Formula II with a compound of the formula RlaNH , wherein Rla is as defined in claim 35, to provide a compound of the Formula Ilia.
38. The process of claim 35, further comprising the step of isolating the compound of
Formula la or a pharmaceutically acceptable salt thereof.
39. The process according to claim 35, wherein Rιa, R2a, R3, and R are independently selected as follows: Rla is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms;
R2a is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms;
R3 is selected from hydrogen and alkyl of one to four carbon atoms; and R4 is selected from hydrogen and alkyl of one to four carbon atoms.
40. The process according to claim 39, wherein Rla, R2a, R , and R4 are independently selected as follows:
Rla is selected from 2-hydroxy-2-methylpropyl, 2-methylpropyl, and n -butyl; R2a is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl;
R3 is methyl; and t is selected from hydrogen and methyl.
41. The process of claim 25, further comprising the steps of: providing a compound of Formula Via
Figure imgf000043_0001
Via wherein Rla, R a, R3 and Rt are as defined in claim 25; and subjecting the compound of Formula Via to cyclization conditions, to provide a compound of the Formula Vila.
42. The process of claim 41, further comprising the steps of: providing a compound of Formula Va
Figure imgf000043_0002
Va wherein Rla, R3 and R4 are as defined in claim 41 ; and reacting a compound of the Formula Va with a carboxylic acid of the formula R2aCO2H or the conesponding acyl halide, wherein R2a is as defined in claim 41, to form a compound of the Fonnula Via.
43. The process of claim 42, further comprising the steps of: providing a compound of Formula IVa
Figure imgf000043_0003
TVa wherein Rla, R3 and are as described in claim 42; and reducing the compound of Formula TVa to provide a compound of the Formula Va.
44. The process of claim 43, further comprising the steps of: providing a compound of Formula Ilia
Figure imgf000044_0001
ma wherein Rla, R and R4 are as described in claim 43; and reacting the compound of Formula Ilia with an alkali metal azide to provide a compound of the Formula TVa.
45. The process according to claim 44, wherein the compound of Formula Ilia is reacted with the alkali metal azide in the presence of cerium III chloride.
46. The process of claim 44, further comprising the steps of: providing a compound of Formula II
Figure imgf000044_0002
π wherein R3 and R4 are as described in claim 44; and reacting the compound of Formula II with a compound of the formula RιaNH2, wherein Rιa is as defined in claim 44, to provide a compound of the Formula Ilia.
47. The process of claim 44, further comprising the step of isolating the compound of Formula la or a pharmaceutically acceptable salt thereof.
48. The process according to claim 44, wherein Rla, R2a, R , and t are independently selected as follows:
Ria is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms;
R2a is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, and alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms;
R3 is selected from hydrogen and alkyl of one to four carbon atoms; and , R4 is selected from hydrogen and alkyl of one to four carbon atoms.
49. The process according to claim 48, wherein Rla, R2a, R3, and t are independently selected as follows:
Ri is selected from 2-hydroxy-2-methylpropyl, 2-methylpropyl, and «-butyl; R2 is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, 2-methoxyethyl, and ethoxymethyl;
R3 is methyl; and
R4 is selected from hydrogen and methyl.
50. A process for preparing a chemical compound comprising the steps of: providing a compound of Formula III
Figure imgf000045_0001
wherein
R3 and are independently selected from hydrogen and alkyl of one to five carbon atoms, and
Ri is selected from hydrogen; CHRxRy wherein Rx is hydrogen and Ry is selected from alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRZRZ wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms; and reacting the compound of Formula III with an alkali metal azide to provide a compound of Formula IV
TV wherein R1} R3, and R4 are as defined above.
51. The process according to claim 50, wherein the compound of Fonnula III is reacted with the alkali metal azide in the presence of cerium III chloride.
52. The process according to claim 50, wherein R1} R , and ^ are independently selected as follows:
Ri is selected from alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and phenylethyl;
R3 is selected from hydrogen and alkyl of one to four carbon atoms; and Rt is selected from hydrogen and alkyl of one to four carbon atoms.
53. The process according to claim 52, wherein R\, R3, and t are independently selected as follows:
Ri is selected from 2-hydroxy-2-methylpropyl, 2-methylpropyl, and 7z-butyl;
R3 is methyl; and
Rt is selected from hydrogen and methyl.
54. The process of claim 50, further comprising the steps of: providing a compound of Formula II
Figure imgf000047_0001
wherein R3 and R are as defined in claim 50; and reacting the compound of Formula II with a compound of the fonnula RιNH , wherein R\ is as defined in claim 50, to provide a compound of Formula III.
55. The process of claim 50, further comprising the step of reducing the compound of Formula TV to provide a compound of Formula V
Figure imgf000047_0002
V wherein Ri, R3, and R are as defined in claim 50.
56. The process of claim 55, further comprising the step of reacting a compound of Formula V with a carboxylic acid of the fonnula R2CO2H; an equivalent thereof selected from the conesponding acyl halide, R C(O-alkyl)3, and R2C(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein each alkyl contains 1 to 8 carbon atoms; and
R2 is selected from hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and moφholinoalkyl wherein the alkyl moiety contains one to four carbon atoms, to provide a compound of the Formula VII
Figure imgf000048_0001
vπ wherein R2 is as defined above, and Rl3 R3, and t are as defined in claim 55.
57. The process of claim 56, further comprising the step of reacting the compound of Formula VII with triphenylphosphine to provide an N-triphenylphosphinyl intermediate of Formula VIII
Figure imgf000048_0002
vm wherein Ri, R2, R , and Rt are as defined in claim 56.
58. The process of claim 55, further comprising the step of (a) reacting the compound of Formula V with a carboxylic acid of the formula R2CO2H or the conesponding acyl halide to form a compound of the Fonnula VI
Figure imgf000048_0003
VI wherein R1} R3, and Rt are as defined in claim 55; and R is selected from the group consisting of hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms.
59. The process of claim 58, further comprising the step of (b) subjecting the compound of Formula VI to cyclization conditions, during step (a) or subsequent to the completion of step (a), to provide a compound of the Formula VII
Figure imgf000049_0001
VE wherein Ri, R2, R , and R4 are as defined in claim 58.
60. The process of claim 59, further comprising the step of reacting the compound of
Formula VII with triphenylphosphine to provide an N-triphenylphosphinyl intennediate of Fonnula VIII
Figure imgf000049_0002
vm wherein R1} R2, R , and are as defined in claim 59.
61. The process according to claim 8, wherein the reacting of the compound of Formula V with a carboxylic acid of the fonnula R2CO2H; an equivalent thereof selected from the conesponding acyl halide, R2C(O-alkyT)3, and R2C(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein R is as defined in claim 8, is done in the presence of cyclization conditions to provide a compound of the Formula VII.
62. The process according to claim 33, wherein the reacting of the compound of Formula Va with a carboxylic acid of the formula R2aCO H; an equivalent thereof selected from the conesponding acyl halide, R2aC(O-alkyl)3, and R2aC(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein R a is as defined in claim 33, is done in the presence of cyclization conditions to provide a compound of the Formula Vila.
63. The process according to claim 56, wherein the reacting of the compound of Formula V with a carboxylic acid of the formula R2CO2H; an equivalent thereof selected from the conesponding acyl halide, R C(O-alkyl)3, and R2C(O-alkyl)2(O(O=)C-alkyl); or a mixture thereof, wherein R is as defined in claim 56, is done in the presence of cyclization conditions to provide a compound of the Formula VII.
64. The process according to claim 10, wherein the alkali metal azide is sodium azide.
65. The process according to claim 19, wherein the alkali metal azide is sodium azide.
66. The process according to claim 35, wherein the alkali metal azide is sodium azide.
67. The process according to claim 44, wherein the alkali metal azide is sodium azide.
68. The process according to claim 50, wherein the alkali metal azide is sodium azide.
69. The process according to claim 9, wherein the compound of Formula TV is reduced with a heterogeneous hydrogenation catalyst.
70. The process according to claim 18, wherein the compound of Formula TV is reduced with a heterogeneous hydrogenation catalyst.
71. The process according to claim 34, wherein the compound of Formula TVa is reduced with a heterogeneous hydrogenation catalyst.
72. The process according to claim 43, wherein the compound of Formula IVa is reduced with a heterogeneous hydrogenation catalyst.
73. The process according to claim 55, wherein the compound of Formula TV is reduced with a heterogeneous hydrogenation catalyst.
74. The process according to claim 17, wherein in the compound of Formula V is reacted with the conesponding acyl halide to form the compound of Fonnula VI, and the compound of Fonnula VI is subjected to cyclization conditions which include an elevated temperature and the presence of pyridine hydrochloride.
75. The process according to claim 74, wherein the acyl halide is ethoxyacetyl chloride.
76. The process according to claim 42, wherein in the compound of Formula Va is reacted with the conesponding acyl halide to form the compound of Formula Via, and the compound of Fonnula Via is subjected to cyclization conditions which include an elevated temperature and the presence of pyridine hydrochloride.
77. The process according to claim 76, wherein the acyl halide is ethoxyacetyl chloride.
78. The process according to claim 59, wherein in the compound of Formula V is reacted with the conesponding acyl halide to form the compound of Formula VI, and the compound of Fonnula VI is subjected to cyclization conditions which include an elevated temperature and the presence of pyridine hydrochloride.
79. The process according to claim 78, wherein the acyl halide is ethoxyacetyl chloride.
80. The process according to claim 1 wherein the compound of Formula I is 2-(ethoxymethyl)-l-(2-methylpropyl)-6-methyl-lH-imidazo[4,5-c]pyridin-4-amine.
81. The process according to claim 25 wherein the compound of Formula la is 2-(ethoxymethyl)-l-(2-methylpropyl)-6-methyl-lH-imidazo[4,5-c]pyridin-4-amine.
82. A compound of the Formula TV
Figure imgf000052_0001
TV wherein Ri is selected from the group consisting of hydrogen; CHRxRy wherein Rx is hydrogen and Ry is selected from the group consisting of alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRZRZ wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms; and
R and R4 are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms.
83. A compound of the Formula V
Figure imgf000052_0002
wherein
Ri is selected from the group consisting of hydrogen; CHRxRy wherein Rx is hydrogen and Ry is selected from the group consisting of alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRZRZ wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms; and
R3 and R are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms.
84. A compound of the Formula VI
Figure imgf000053_0001
VI wherein
Ri is selected from the group consisting of hydrogen; CHRxRy wherein Rx is hydrogen and Ry is selected from the group consisting of alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRZRZ wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms;
R2 is selected from the group consisting of hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; and
R3 and t are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms.
85. A compound of the Fonnula VII
Figure imgf000054_0001
wherein
Ri is selected from the group consisting of hydrogen; CHRxRy wherein Rx is hydrogen and Ry is selected from the group consisting of alkyl or cyclic alkyl containing one to ten carbon atoms, alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and -C=CRZRZ wherein each Rz is independently alkyl or cyclic alkyl of one to six carbon atoms; R2 is selected from the group consisting of hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; and
R3 and Rt are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms with the proviso that when Ri is hydrogen then at least one of R2, R3 or R4 is other than hydrogen.
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