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HK1161231B - Viral inhibitors - Google Patents

Viral inhibitors Download PDF

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Publication number
HK1161231B
HK1161231B HK11113246.2A HK11113246A HK1161231B HK 1161231 B HK1161231 B HK 1161231B HK 11113246 A HK11113246 A HK 11113246A HK 1161231 B HK1161231 B HK 1161231B
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HK
Hong Kong
Prior art keywords
phenyl
bromophenyl
imidazo
pyridine
substituted
Prior art date
Application number
HK11113246.2A
Other languages
German (de)
French (fr)
Chinese (zh)
Other versions
HK1161231A1 (en
Inventor
Gerhard PÜRSTINGER
Johan Neyts
Erik De Clercq
Original Assignee
鲁汶天主教大学研究开发部
吉尔利德科学股份有限公司
Purstinger, Gerhard
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
Priority claimed from GBGB0215293.2A external-priority patent/GB0215293D0/en
Priority claimed from GB0313251A external-priority patent/GB0313251D0/en
Application filed by 鲁汶天主教大学研究开发部, 吉尔利德科学股份有限公司, Purstinger, Gerhard filed Critical 鲁汶天主教大学研究开发部
Publication of HK1161231A1 publication Critical patent/HK1161231A1/en
Publication of HK1161231B publication Critical patent/HK1161231B/en

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Description

FIELD OF THE INVENTION
The present invention relates to a process for preparing a series of novel imidazo[4,5-c]pyridine derivatives, and pharmaceutically acceptable salts thereof, being useful to treat or prevent viral infections and to manufacture a medicine to treat or prevent viral infections, particularly infections with viruses belonging to the family of the Flaviviridae and Picomaviridae and more preferably infections with hepatitis-C-virus (HCV).
BACKGROUND OF THE INVENTION
The family of the Flaviviridae consists of 3 genera, the pestiviruses, the flaviviruses and the hepaciviruses and also contains the hepatitis G virus (HGV/GBV-C) that has not yet been assigned to a genus. Pestiviruses such as the Classical Swine Fever Virus (CSFV), the Bovine Viral Diarrhea Virus (BVDV) and the Border Disease Virus (BDV) cause infections of domestic livestock (respectively pigs, cattle and sheep) and are responsible for significant economic losses world-wide. BVDV, the prototypic representative of the pestivirus genus is ubiquitous and causes a range of clinical manifestations, including abortion, teratogenesis, respiratory problems, chronic wasting disease, immune system dysfunction, and predisposition to secondary viral and bacterial infections and may also cause acute fatal disease. Foetuses of cattle can be infected persistently with BVDV, these animals remain viremic throughout life and serve as a continuous sources for virus spread in herds.
Vaccines are used in some countries with varying degrees of success to control pestivirus disease. In other countries, animal culling and slaughter are used to contain pestivirus disease outbreaks.
The World Health Organization estimates that world-wide 170 million people (3% of the world's population) are chronically infected with HCV. These chronic carriers are at risk of developing cirrhosis and/or liver cancer. In studies with a 10 to 20 year follow-up, cirrhosis developed in 20 - 30 % of the patients, 1 to 5% of whom may develop liver cancer during the next then years. The only treatment option available today is the use of interferon α-2 (or its pegylated from) either alone or combined with ribavirin. However, sustained response is only observed in about 40% of the patients and treatment is associated with serious adverse effects. There is thus an urgent need for potent and selective inhibitors of the replication of the HCV in order to treat infections with HCV. Furthermore, the study of specific inhibitors of HCV replication has been hampered by the fact that it is not possible to propagate HCV (efficiently) in cell culture. Since HCV and pestiviruses belong to the same virus family and share many similarities (organisation of the genome, analogous gene products and replication cycle), pestiviruses have been adopted as a model and surrogate for HCV. For example BVDV is closely related to hepatitis C virus (HCV) and used as a surrogate virus in drug development for HCV infection.
The compound 3-[((2-dipropylamino)ethyl)thio]-5H-1,2,4-triazino[5,6-b]indole has been reported to selectively inhibit the replication of BVDV and other pestiviruses (Baginski SG et al., Proc. Natl. Acad. Sci. U.S.A. 2000 Jul 5;97(14):7981-6). Currently, there is no treatment strategy available for controlling infections caused by pestiviruses.
Coxsackie viruses belong to the group of the enteroviruses, family of the Picomaviridae. They cause a heterogeneous group of infections including herpangina, aseptic meningitis, a common-cold-like syndrome, a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot-mouth syndrome, pediatric and adult pancreatitis and serious myocarditis.
Currently only pleconaril (3-13,5-dimethyl-4-[[3-methyl-5-isoxazolyl)propyl]phenyl]-5-(trifluoromethyl-1,2,4-oxadiazole)) and enviroxime (2-amino-1-(isopropylsulfonyl)-6-benzimidazole phenyl ketone oxime) have been studied clinically for the treatment of infections with enteroviruses. Pleconaril is a so called "capsid function-inhibitor"; enviroxime prevents the formation of the RNA replicative intermediate. Enviroxime resulted in only modest clinical and virological benefit in some studies and no benefits in others. Clinical response with pleconaril has been observed in some studies, but the compound has not been approved by the Food and Drug Administration (hearing of March 18th, 2002).
US Patents 4,914,108 , 4,990,518 , 4,988,707 , 5,227,384 , 5,302,601 and 5,486,525 describe 5-substituted [4,5-c]imidazopyridine derivatives useful in the treatment of diseases or disorders mediated by platelet-activating factor. The compounds were found to inhibit 3H-PAF binding to human platelets.
EP 1132381 describes esters of 2,2-dimethylpropionic acid comprising a benzimidazole structure having an inhibitory activity of elastase.
WO 96/1192 describes compounds of the general formula Ar1-Q-Ar2-Y-R-Z, wherein Z is optionally a [4,5-c]imidazopyridine which are proposed as LTA4 hydrolase inhibitors useful for the treatment of inflammatory diseases mediated by LTB4 production.
WO 96/12703 describes heteroarylthioalkyl thiophenolic compounds having 5-lipoxygenase inhibitory activity which are suggested to be useful in the treatment of 5-lipoxygenase mediated conditions.
Chemical Abstracts acc no. 1987:18435 and Chemical Abstracts acc no. 1983:594812 describe the synthesis of two imidazo[4,5-b] and of imidazo[4,5c]pyridine derivatives substituted with piperazinyl and furanyl groups.
EP 1162196 describes fused ring compounds for the use as therapeutic agents for hepatitis C. The fused 5 and 6 membered ring is made up of optionally subsituted carbon atoms or nitrogen atoms and optionally one oxygen, sulfur atom or substituted nitrogen atom on the 5 membered ring. WO 95/02597 describes imidazo[4,5c]pyridine derivatives not substituted at the N5 with antiviral activity.
GB 2 158 440A discloses A 4,5,6,7-tetrahydroimidazol[4,5-c]pyridine derivative of general formula (I): wherein R1, which is bonded to the nitrogen atom in the 1- or 3- position, is a hydrogen atom; a linear or branched C1-C4 alkyl or C2-C4 alkenyl group; or a benzyl group optionally substituted by one or two substituents selected from a) C1-C4 alkoxy, b) C1-C4 alkylthio, c) fluorine, d) chlorine, e) bromine, f) trifluoromethyl, g) nitro, and h) methylendioxy; R2, R3 and R4 are independently hydrogen; a linear or branched C1-C4 alkyl or C2-C4 alkenyl group; a C3-C7 cycloalkyl group; a phenyl or benzyl group optionally substituted by one or two substituents selected from a) to h) as defined above; or R3 and R4, together with the carbon atom to which they are attached, form a C3-C7 ring; R8 and R7 are independently hydrogen; a linear or branched C1-C4 alkyl or C2-C4 alkenyl group; a C3-C7 cycloalkyl group; a phenyl or benzyl group optionally substituted by one or two substituents selected from a) to h) as defined above; an adamantyl or an adamantanemethyl group; or R6 and R7, together with the nitrogen atom to which they are attached, for a five-, six or seven membered heterocyclic ring which may contain one or more other heteroatom selected from 0 and NR2 wherein R2 is as defined above; and R5 represents a group of formula -C(=O)-R2, -C(=O)-OR2, R2 or -C(=Y)-NH-R6 wherein R2 is as defined above but is not a phenyl group when R5 is R2, and Y represents an oxygen or sulphur atom; and pharmaceutically acceptable acid addition salts thereof.
In view of their important pharmacological value, there is a need for processes for preparing drugs having antiviral activity, optionally selective activity against viruses belonging to the family of Flaviviridae including hepatitis C virus, and against viruses belonging to the family of Picomavidae.
SUMMARY OF THE INVENTION
In the present invention, processes for preparing new selective anti-viral compounds, or pharmaceutically acceptable salts thereof, are being provided. The compounds are imidazo[4,5-c]pyridine derivatives and it has been shown that they possess a broad anti-viral activity. Members of the Flaviviridae and of the Picomaviridae families are being inhibited. The present invention demonstrates that the compounds inhibit the replication of BVDV, HCV and Coxsackie virus. Furthermore, the anti-BVDV activity of the compounds is based on the inhibition of the viral polymerase enzyme of BVDV. Therefore, these imidazo[4,5-c]pyridine derivatives constitute a new potent class of anti-viral compounds that can be used in the treatment and prevention of viral infections in animals, mammals and humans, more specifically for the treatment and prevention of BVDV, HCV and Coxsackie virus infections.
The present invention relates to processes for preparing imidazo[4,5-c]pyridine derivatives or pharmaceutically acceptable salts thereof. The invention further relates to processes for preparing compounds having anti-viral activity, more specifically to processes for preparing imidazo[4,5-c]pyridine derivatives that inhibit the replication of viruses. Most particularly, the invention relates to processes for preparing imidazo[4,5-c]pyridine derivatives which inhibit the replication of viruses of the family of the Flaviviridae and the Picomaviridae and yet more specifically to compounds that inhibit the replication of BVDV (Bovine Viral Diarrhea Virus), HCV (Hepatitis C Virus) and Coxsackie virus.
The present invention relates to processes for preparing compounds of formula (II), and pharmaceutically acceptable salts thereof being useful in a treatment of viral infection or to manufacture a medicament to treat viral infections, wherein:
  • R1 is selected from phenyl substituted with 0-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R6; 1-naphthyl substituted with 0-3 R6; 2-naphthyl substituted with 0-3 R6; C3-7 cycloalkyl; C4-5-710 cycloalkenyl;
  • R2, R4 and R5 are independently selected from hydrogen; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR7R8; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
  • X is selected from the group -CH2-; -CH(CH3)-; -CH2-CH2-; -CH2-CH2-CH2-; -CH2-CH2-CH2-CH2; -OCH2-CH2-; -SCH2-CH2-; -NR10-CH2-CH2-; C3-7 cycloalkylidene; -C(CH3)2; -CH2-CH(CH3)-CH2-; -CH(CH3)-CH2-CH2-; -CH2-CH2-CH(CH3)-; -CH=CH-CH2-;
  • R3 is selected from phenyl substituted with 0-3 R17; (benzoannellated) 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R17; 1-naphthyl substituted with 0-3 R17; 2-naphthyl substituted with 0-3 R17; C3-7 cycloalkyl; C4-10 cycloalkenyl with the proviso that the double bond cannot be adjacent to a nitrogen;
  • R6 and R17 are independently selected from the group H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R18; phenyl; phenoxy; benzyl; hydroxymethyl;
  • R7 and R8 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12 or R7 and R8, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring;
  • R9 and R18 are independently selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
  • R10 is selected from the group H; C1-6 straight or branched alkyl; phenyl;
  • R12 is selected from the group H; C1-6 straight or branched alkyl; phenyl;
  • R13 and R14 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12 ; and
  • R15 and R16 are independently selected from the group H; C1-6 straight or branched alkyl; phenyl; said process comprising reacting an imidazo[4,5-c]pyridine represented by the structural formula (C) with an alkylating agent represented by the structural formula R3 - X - R' (D) wherein R' is chlorine or bromine, according to the scheme below:
in an appropriate solvent under addition of base at ambient temperature.
Another embodiment of the present invention relates to processes for preparing compounds of formula (II), and pharmaceutically acceptable salts thereof, being useful in a treatment of viral infection or to manufacture a medicament to treat viral infection, wherein:
  • R1 is selected from phenyl substituted with 0-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R6; 1-naphthyl substituted with 0-3 R6; 2-naphthyl substituted with 0-3 R6; C3-7 cycloalkyl; C45-7-10 cycloalkenyl;
  • R2, R4 and R5 are independently selected from hydrogen; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR7R8; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
  • X is selected from the group -CH2-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-CH2-;-CH=CH-CH2-;
  • R3 is selected from phenyl substituted with 0-3 R17; (benzoannellated) 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R17; 1-naphthyl substituted with 0-3 R17; 2-naphthyl substituted with 0-3 R17; C3-7 cycloalkyl; C4-7 cycloalkenyl with the proviso that the double bond cannot be adjacent to a nitrogen;
  • R6 and R17 are independently selected from the group H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R18; phenyl; phenoxy; benzyl; hydroxymethyl;
  • R7 and R8 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; alternatively, R7 and R8, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring;
  • R9 and R18 are independently selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
  • R12 is selected from the group H; C1-6 straight or branched alkyl; phenyl;
  • R13 and R14 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; and
  • R15 and R16 are independently selected from the group H; C1-6 straight or branched alkyl; phenyl;
Another embodiment of the present invention relates to processes for preparing compounds of formula (II), and pharmaceutically acceptable salts thereof being useful in a treatment of viral infection or to manufacture a medicament to treat viral infection, wherein:
  • R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or substituted with 1-3 R6; 2-naphthyl unsubstituted or substituted with 1-3 R6; C3-7 cycloalkyl; C5-7 cycloalkenyl;
  • R2, R4 and R5 are hydrogen;
  • X is selected from the group -CH2-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-CH2-;-CH=CH-CH2-;
  • R3 is selected from phenyl unsubstituted or substituted with 1-3 R17; (benzoannellated) 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R17; 1-naphthyl unsubstituted or substituted with 1-3 R17; 2-naphthyl substituted with 0-3 R17; C3-7 cycloalkyl; C5-7 cycloalkenyl with the proviso that the double bond cannot be adjacent to a nitrogen;
  • Each R6 and R17 is independently selected from the group H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
  • R9 is selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
  • Each R13 and R14 is independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; and
  • Each R15 and R16 is independendly selected from the group H; C1-6 straight or branched alkyl; phenyl;
Yet another embodiment of the present invention comprises processes for preparing the compounds of formula (II), and pharmaceutically acceptable salts thereof, being useful in a treatment of viral infection or to manufacture a medicament to treat viral infection, wherein:
  • R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or substituted with 1-3 R6 2-naphthyl unsubstituted or substituted with 1-3 R6;
  • R2, R4 and R5 are hydrogen;
  • X is selected from -CH2-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-CH2-; -CH=CH-CH2-;
  • R3 is selected from phenyl unsubstituted or substituted with 1-3 R17; 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-3 R17; 1-naphthyl unsubstituted or substituted with 1-3 R17; 2-naphthyl unsubstituted or substituted with 1-3 R17;
  • Each R6 and R17 is independently selected from the group H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
  • R9 is selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
  • Each R13 and R14 is independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12 ; and
  • Each R15 and R16 is independently selected from the group H; C1-6 straight or branched alkyl; phenyl.
Particularly, an embodiment of the present invention comprises processes for preparing compounds of formula (II), and pharmaceutically acceptable salts thereof, being useful in a treatment of viral infection or to manufacture a medicament to treat viral infection, wherein:
  • R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or substituted with 1-3 R6; 2-naphthyl unsubstituted or substituted with 1-3 R6;
  • R2, R4 and R5 are hydrogen;
  • X is selected from -CH2-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-CH2-; -CH=CH-CH2-;
  • R3 is selected from phenyl unsubstituted or substituted with 1-3 R17; 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R17; 1-naphthyl substituted with 0-3 R17; 2-naphthyl unsubstituted or substituted with 1-3 R17;
  • Each R6 and R17 is independently selected from hydrogen; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
  • R9 is selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
  • Each R13 and R14 is independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12 ; and
  • Each R15 and R16 is independently selected from the group H; C1-6 straight or branched alkyl; phenyl.
According to a particular embodiment, the present invention relates to processes for preparing compounds selected from the following group of compounds, and pharmaceutically acceptable salts thereof, being useful in a treatment of viral infection or to manufacture a medicament to treat viral infections:
  • 2-((2,6-Difluorophenyl)-5-[(2,6-difluorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPRTI-8);
  • 5-Benzyl-2-(2,6-difluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-1);
  • 5-[((2,6-Difluorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-3);
  • 5-Benzyl-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-4);
  • 2-Phenyl-5-(3-phenylpropyl)-5H-imidazo[4,5-c]pyridine (GPJN-14);
  • 5-[((2-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-7);
  • 5-[((3-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-8);
  • 5-[((4-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-9);
  • 5-[((2-Methoxyphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-11);
  • 5-[((3-Methoxyphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-12);
  • 5-[((4-Methoxyphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-13);
  • 5-[((4-Methylphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-15);
  • 5-[((2-Fluorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-17);
  • 5-[((3-Fluorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-18);
  • 5-[((4-Fluorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-19);
  • 5-[((2-Methylphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-20);
  • 5-[((3-Methylphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-21);
  • 5-[((4-Bromophenyl)methyll-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-22)
  • 4-[((2-Phenyl-5H-imidazo[4,5-c]pyridin-5-yl)methyl]-benzonitrile (GPJN-23);
  • 2-Phenyl-5-[[4-(trifluoromethyl)phenyl]methyl]-5H-imidazo[4,5-c]pyridine (GPJN-24);
  • 5-[((4-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine hydrochloride (GPJN-9 x HCl);
  • 5-[((5-Chloro-2-thienyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-25);
  • 5-((2-Naphthalenylmethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-26);
  • 2-Phenyl-5-(4-phenylbutyl)-5H-imidazo[4,5-c]pyridine (GPJN-27);
  • 5-([1,1'-Biphenyl]-4-ylmethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine(GPJN-32);
  • 2-Phenyl-5-(1-phenylethyl)-5H-imidazo[4,5-c]pyridine (GPJN-33);
  • 5-((1-Naphthalenylmethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-36);
  • 2-((2,6-Difluorophenyl)-5-[(2,4-difluorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-40);
  • 5-[((4-Bromophenyl)methyl]-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-52);
  • 5-[((4-Bromophenyl)methyl]-2-(2-chlorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-54);
  • 5-[((4-Bromophenyl)methyl]-2-(3-chlorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-55);
  • 5-[((4-Bromophenyl)methyl]-2-(4-chlorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-56);
  • 5-[((4-Bromophenyl)methyl]-2-(2-pyridinyl)-5H-imidazo[4,5-c]pyridine (GPJN-58);
  • 5-[((4-Bromophenyl)methyl]-2-(2-thienyl)-5H-imidazo[4,5-c]pyridine (GPJN-53);
  • 5-[((4-Bromophenyl)methyl]-2-(1-naphthalenyl)-5H-imidazo[4,5-c]pyridine (GPJN-62);
  • 5-[((4-Bromophenyl)methyl]-2-(2-naphthalenyl)-5H-imidazo[4,5-c]pyridine (GPJN-63);
  • 5-[((4-Iodophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-68);
  • 5-[((4-Bromophenyl)methyl]-2-(3-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-50);
  • 5-[((4-Bromophenyl)methyl]-2-(3-methylphenyl)-5H-imidazo[4,5-c]pyridine (GPJN-60);
  • 5-[((4-Bromophenyl)methyl]-2-(3-methoxyphenyl)-5H-imidazo[4,5-c]pyridine (GPJN-64);
  • 5-[((4-Bromophenyl)methyl]-2-(3-bromophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-65);
  • 5-[((4-Chlorophenyl)methyl]-2-(3-bromophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-80);
  • 5-[((4-Chlorophenyl)methyl]-2-(3-chlorophenyl)-5H-imidazo[4,5-c]pyridine;
  • 5-((2-Phenoxy-ethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-73);
  • 5-((3-Phenyl-prop-2-en-1-yl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-75);
  • 2-((3-Bromophenyl)-5-[(4-iodophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-79);
  • 5-[((4-Bromophenyl)methyl]-2-[(phenylthio)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-83);
  • 5-[((4-Bromophenyl)methyl]-2-[3-(trifluoromethyl)phenyl]-5H-imidazo[4,5-c]pyridine (GPJN-87);
  • 5-([1,1'-Biphenyl]-4-ylmethyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-110);
  • 5-[((4-Chlorophenyl)methyl]-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-112);
  • 2-((2-Fluorophenyl)-5-[(4-iodophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-113); and
  • 5-[[4-(1,1-Dimethylethyl)phenyl]methyl]-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-114);
DETAILED DESCRIPTION
In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
The term "C1-18 alkyl" as used herein C1-C18 normal, secondary, or tertiary hydrocarbon.Examples are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu) 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term also includes C1-18 halo-alkyls, which is a C1-18 alkyl bearing at least one halogen.
As used herein and unless otherwise stated, the term "C3-10 cycloalkyl" means a monocyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or a C7-10 polycyclic saturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.
As used herein and unless otherwise stated, the term "C3-10 cycloalkylene" refers to a cyclic hydrocarbon radical of 3-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane; i.e. the divalent hydrocarbon radical corresponding to the above defined C3-10 cycloalkyl.
The terms "C2-18 alkenyl" and "C3-10 cycloalkenyl" as used herein is C2-C18 normal, secondary or tertiary and respectively C3-10 cyclic hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2 CH2CH2CH2CH=CH2). The double bond may be in the cis or trans configuration.
The term "heterocyclic ring" as used herein means pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl and isatinoyl.
By way of example, carbon bonded heterocyclic rings are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example, nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
As used herein and unless otherwise stated, the terms " C1-18 alkoxy " refers to substituents wherein a C1-18 alkyl is attached to an oxygen atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.
As used herein and unless otherwise stated, the term halogen means any atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.
As used herein and unless otherwise stated, the term " amino-acid" refers to a radical derived from a molecule having the chemical formula H2N-CHR28-COOH, wherein R28 is the side group of atoms characterizing the amino-acid type; said molecule may be one of the 20 naturally-occurring amino-acids or any non naturally-occurring amino-acid. Esters of amino acids included within this definition are substituted at one or more carboxyl groups with C1-6 alkyl. This is the case even when the amino acid is bonded through carboxyl because some amino acids contain more than one carboxyl groups, and in this case the unbonded carboxyl optionally is esterified.
R28 is C1-C6 alkyl or C1-C6 alkyl substituted with amino, carboxyl, amide, carboxyl (as well as esters, as noted above), hydroxyl, C6-C7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R28 also is taken together with the amino acid α nitrogen to form a proline residue (R27 is -(CH2)3-). However, R28 is generally the side group of a naturally-occurring amino acid such as H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2,-CHCH3-CH2-CH3, -CH2-C6H5, -CH2CH2-S-CH3, -CH2OH, -CH(OH)-CH3, -CH2-SH,-CH2-C6H4OH, -CH2-CO-NH2, -CH2-CH2-CO-NH2, -CH2-COOH, -CH2-CH2-COOH,-(CH2)4-NH2 and -(CH2)3-NH-C(NH2)-NH2. R28 also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
Optionally the amino acid residue is a hydrophobic residue such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. Optionally, the residue does not contain a sulfhydryl or guanidino substituent.
Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included.
Generally, only one of any site in the parental molecule is substituted with an amino acid, although it is within the scope of this invention to introduce amino acids at more than one permitted site. In general, the α-amino or α-carboxyl group of the amino acid are bonded to the remainder of the molecule, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates).
The amino acid esters optionally are hydrolyzable in vivo or in vitro under acidic (pH <3) or basic (pH >10) conditions. Optionally, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
The term "pharmaceutically acceptable salts" as used herein means the therapeutically active non-toxic salt forms which the compounds are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, Ca+2 and Mg+2. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained. Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic and the like.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids, especially the naturally-occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
The compounds of the invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4+ (wherein X is C1-C4 alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX4+ (wherein X typically is independently selected from H or a C1-C4 alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
The compounds of formula (II) can be prepared while using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.
General methods and materials for the preparation of the compounds of the invention:
The compounds according to the invention are conveniently prepared in two steps; known to to the skilled person. First, a (substituted) 3,4-diaminopyridine (A) is reacted with B to give imidazo[4,5-c]pyridines C (scheme 1). If Y is COOH, then the cyclization is carried out under acidic catalysis (preferably in polyphosphoric acid at a temperature between 90 and 200 °C); other methods include reaction in 4N hydrochloric acid at reflux temperature or neat at a temperature between 90 and 180 °C (for aliphatic carboxylic acids). In the case of acid-sensitive groups like alkoxy or thiophene, the reaction can be carried out in phosphorus oxychloride at a temperature between 70 and 120 °C. Alternatively, reaction with aldehydes (Y = CHO) or their bisulfite adducts under oxidative conditions (nitrobenzene, DDQ, copper(II)acetate, O2, sulfur etc.) gives imidazo[4,5-c]pyridines C. Other methods are the reaction of (substituted) 3,4-diaminopyridines (A) with orthoesters (Y = C(OR)3), anhydrides (Y = OCOOR) or acid halogenides (Y = COX), etc.
The imidazo[4,5-c]pyridines C can be formulated in three tautomeric forms (1H, 3H or 5H), as shown in scheme 2.
Substituents (R2, R4 and/or R5 ≠ H) can be introduced by two ways: i) either by cylization of an appropiately substituted 3,4-diaminopyridine A or ii) by introduction of the substituent(s) onto the imidazo[4,5-c]pyridine C. For example, halogens can be introduced in position 7 of the imidazo[4,5-c]pyridine C by direct halogenation (R5 = Br: with bromine in acetic acid or with NBS in acetic acid; R5 = Cl: with chlorine in acetic acid or with NCS in acetic acid). Another example is the direct nitration (R5 = NO2), followed by reduction to give the amino group (R5 = NH2). Substituents in position 4 of the imidazo[4,5-c]pyridine C can be introduced, for example, via the corresponding imidazo[4,5-c]pyridine N5-oxides.
Substituted 3,4-diaminopyridines can, for example, be prepared according to the following route (scheme 3): Nitration (HNO3/H2SO4) of a 2- or 3- substituted pyridine N-oxide gives the corresponding 4-nitro product. Double reduction of the N-oxide and the nitro group with iron in acetic acid gives the 2- or 3-substituted 4-aminopyridine. Subsequent nitration (HNO3/H2SO4) and reduction of the nitro group with iron in a mixture of concentrated hydrochloric acid and ethanol gives the desired substituted 3,4-diamino-pyridines.
In the case of the 3-substituted pyridines as starting materials 5-substituted 3,4-diaminopyridines are obtained. Nitration of 2-substituted 4-aminopyridines gives mixtures of 3- and 5-nitropyridines, with 3-nitration as the predominant reaction.
4-Amino-2-methoxy-3-nitropyridine can be prepared by reaction of 4-amino-2-chloro-3-nitropyridine with sodium methoxide. 3-Substituted 4-aminopyridines can also be prepared by electrophilic substitution of 4-aminopyridines (e.g. chlorination, bromination etc.). 4-Amino-3-bromo-5-nitropyridine can be obtained by bromination of 4-amino-3-nitropyridine.
The second and final step is the reaction of the imidazo[4,5-c]pyridines C with an alkylating agent D (R6 = Cl, Br, etc.) in an appropiate solvent (preferably DMF) under addition of a base (preferably aqueous sodium hydroxide) at ambient temperature (scheme 4).
This reaction gives mixtures of three products (alkylation at the N1, N3 or N5 of the imidazo[4,5-c]pyridine C, respectively). For example, reaction of imidazo[4,5-c]pyridine C (R1 = 2,6-difluorophenyl, R2 = R4 = R5 = H) with 2,6-difluorobenzyl bromide gave the following mixture (scheme 5):
This mixture can be separated by column chromatography (silica gel, eluent: mixture of dichloromethane and methanol). The structures of the isolated components can then be assigned by NMR spectroscopy (for example by one-dimensional NOE-techniques: irradiation at the CH2 resonance frequency; applying this to GPRTI-8 gives signal enhancements of the protons in positions 4 and 6 of the imidazo[4,5-c]pyridine ringsystem) or by single crystal x-ray analysis.
Alternatively, the crude reaction mixture can be recrystallized from an appropiate solvent (mixture), e.g. from a mixture of diisopropyl ether and ethyl acetate, to give the pure N5 alkylated products.
(Hetero)aromatic substituents on (hetero)aromatic rings (R2, R4, R5, R6, R17 R19) can be introduced by crosscoupling reactions, e.g. Suzuki coupling.
In the case of hydroxy, mercapto or amino substituents in position 4 or 6 of the imidazopyridine I (Z = O, S or NR), tautomers can be formulated:
Analogous compounds are synthesized in the same fashion as in the foregoing schemes by varying the starting materials, intermediates, solvents and conditions as will be known by those skilled in the art.
EXAMPLES
The following examples illustrate the present invention without being limited thereto. Part A represent the preparation of the compounds. Table 8 : Structures of examples and their respective codes
 Table 8 : Structures of examples and their respective codes
1 GPRTI-8 - 2,6-difluorophenyl H 2,6-difluorophenyl H H
2 GPJN-1 - 2,6-difluorophenyl H phenyl H H
3 GPJN-2 - 2,6-difluorophenyl H phenyl H H
4 GPJN-3 - phenyl H 2,6-difluorophenyl H H
5 GPJN-4 - phenyl H phenyl H H
6 GPJN-7 - phenyl H 2-chorophenyl H H
7 GPJN-8 - phenyl H 3-chorophenyl H H
8 GPJN-9 - phenyl H 4-chorophenyl H H
9 GPJN-11 - phenyl H 2-methoxyphenyl H H
10 GPJN-12 - phenyl H 3-methoxyphenyl H H
11 GPJN-13 - phenyl H 4-methoxyphenyl H H
12 GPJN-14 - phenyl H phenyl H H
13 GPJN-15 - phenyl H 4-methylphenyl H H
14 GPJN-16 - phenyl H 4-(1,1-dimethylethyl)phenyl H H
15 GPJN-17 - phenyl H 2-fluorophenyl H H
16 GPJN-18 - phenyl H 3-fluorophenyl H H
17 GPJN-19 - phenyl H 4-fluorophenyl H H
18 GPJN-20 - phenyl H 2-methylphenyl H H
19 GPJN-21 - phenyl H 3-methylphenyl H H
20 GPJN-22 - phenyl H 4-bromophenyl H H
21 GPJN-23 - phenyl H 4-cyanophenyl H H
22 GPJN-24 - phenyl H 4-(trifluoromethyl)phenyl H H
23 GPJN-25 - phenyl H 5-chloro-2-thienyl H H
24 GPJN-26 - phenyl H 2-naphthalenyl H H
25 GPJN-27 - phenyl H phenyl H H
26 GPJN-31 - phenyl H 4-pyridinyl H H
27 GPJN-32 - phenyl H 4-phenyl-phenyl H H
28 GPJN-33 - phenyl H phenyl H H
29 GPJN-34 - phenyl H 2-pyridinyl H H
30 GPJN-35 - phenyl H 3-pyridinyl H H
31 GPJN-36 - phenyl H 1-naphthalenyl H H
32 GPJN-37 - phenyl H cyclohexyl H H
33 GPJN-39 - 2,6-difluorophenyl H 4-fluorophenyl H H
34 GPJN-40 - 2,6-difluorophenyl H 2,4-difluorophenyl H H
35 GPJN-41 - 2,6-difluorophenyl H 2,4,6-trifluorophenyl H H
36 GPJN-42 - phenyl H 2-bromophenyl H H
37 GPJN-43 - phenyl H 3-bromophenyl H H
38 GPJN-44 - phenyl H 2-cyanophenyl H H
39 GPJN-45 - phenyl H 3-cyanophenyl H H
40 GPJN-46 - phenyl H 2-(trifluoromethyl)phenyl H H
41 GPJN-47 - phenyl H 3-(trifluoromethyl)phenyl H H
42 GPJN-48 H H 4-bromophenyl H H
43 GPJN-49 - 4-pyridyl H 4-bromophenyl H H
44 GPJN-50 - 3-fluorophenyl H 4-bromophenyl H H
45 GPJN-51 - 4-fluorophenyl H 4-bromophenyl H H
46 GPJN-52 - 2-fluorophenyl H 4-bromophenyl H H
47 GPJN-53 - 2-thienyl H 4-bromophenyl H H
48 GPJN-54 - 2-chlorophenyl H 4-bromophenyl H H
49 GPJN-55 - 3-chlorophenyl H 4-bromophenyl H H
50 GPJN-56 - 4-chlorophenyl H 4-bromophenyl H H
51 GPJN-57 - 3-pyridyl H 4-bromophenyl H H
52 GPJN-58 - 2-pyridyl H 4-bromophenyl H H
53 GPJN-59 - 2-methylphenyl H 4-bromophenyl H H
54 GPJN-60 - 3-methylphenyl H 4-bromophenyl H H
55 GPJN-61 - 4-methylphenyl H 4-bromophenyl H H
56 GPJN-62 - 1-naphtalenyl H 4-bromophenyl H H
57 GPJN-63 - 2-naphtalenyl H 4-bromophenyl H H
58 GPJN-64 - 3-methoxyphenyl H 4-bromophenyl H H
59 GPJN-65 - 3-bromophenyl H 4-bromophenyl H H
60 GPJN-66 - 3-(dimethylamino)phenyl H 4-bromophenyl H H
61 GPJN-67 phenyl H 4-bromophenyl H H
62 GPJN-68 - phenyl H 4-iodophenyl H H
63 GPJN-69 - 3-iodophenyl H 4-bromophenyl H H
64 GPJN-70 - 2-bromophenyl H 4-bromophenyl H H
65 GPJN-73 - phenyl H phenyl H H
66 GPJN-74 - phenyl H 3,4-dichlorophenyl H H
67 GPJN-75 - phenyl H phenyl H H
68 GPJN-76 phenyl H 4-bromophenyl H H
69 GPJN-77 phenyl H 4-bromophenyl H H
70 GPJN-78 - 3,5-dibromophenyl H 4-bromophenyl H H
71 GPJN-79 - 3-bromophenyl H 4-iodophenyl H H
72 GPJN-80 - 3-bromophenyl H 4-chlorophenyl H H
73 GPJN-81 CH=CH phenyl H 4-bromophenyl H H
74 GPJN-82 phenyl H 4-bromophenyl H H
75 GPJN-83 phenyl H 4-bromophenyl H H
76 GPJN-84 - 3-bromophenyl H 3,4-dichlorophenyl H H
77 GPJN-85 phenyl H 4-bromophenyl H H
78 GPJN-86 - 5-bromo-2-thienyl H 4-bromophenyl H H
79 GPJN-87 - 3-(trifluoromethyl)phenyl H 4-bromophenyl H H
80 GPJN-88 - phenyl H 4-(trifluoromethoxy)phenyl H H
81 GPJN-89 - 2,3,6-trifluorophenyl H 4-bromophenyl H H
82 GPJN-90 - 2,5-difluorophenyl H 4-bromophenyl H H
83 GPJN-91 - phenyl H 4-bromophenyl H Br
84 GPJN-94 - phenyl H 4-carboxyphenyl H H
85 GPJN-95 - phenyl OH 4-bromophenyl H H
86 GPJN-96 - phenyl Cl 4-bromophenyl H H
87 GPJN-98 phenyl H phenyl H H
88 GPJN-99 - 3-bromophenyl H phenyl H H
89 GPJN-100 - 3-bromophenyl H phenyl H H
90 GPJN-103 - phenyl H 4-bromophenyl H Cl
91 GPJN-104 - phenyl H 4-bromophenyl H
92 GPJN-105 - 2-fluorophenyl H phenyl H H
93 GPJN-106 - 2-fluorophenyl H 2-methylphenyl H H
94 GPJN-107 - 2-fluorophenyl H 3-methylphenyl H H
95 GPJN-108 - 2-fluorophenyl H 4-methylphenyl H H
96 GPJN-109 - phenyl 4-bromophenyl H H
97 GPJN-110 - 2-fluorophenyl H 4-phenyl-phenyl H H
98 GPJN-111 phenyl H 4-phenyl-phenyl H H
99 GPJN-112 - 2-fluorophenyl H 4-chlorophenyl H H
100 GPJN-113 - 2-fluorophenyl H 4-iodophenyl H H
101 GPJN-114 - 2-fluorophenyl H 4-(1,1-dimethylethyl)phenyl H H
102 GPJN-115 - 1-naphtalenyl H 4-phenyl-phenyl H H
103 GPC-10 - 2,6-difluorophenyl H 3,4-dichlorophenyl H H
104 GPC-11 - 3-fluorophenyl H 2,4-difluorophenyl H H
105 GPC-12 - 2,3,6-trifluorophenyl H 2,4-difluorophenyl H H
106 GPC-13 - 2,5-difluorophenyl H 2,4-difluorophenyl H H
PART A EXAMPLE 1 - preparation of 2-(2,6-Difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine
A mixture of 3,4-diaminopyridine (2.00 g), 2,6-difluorobenzoic acid (1 equivalent) and polyphosphoric acid (50 g) was heated at 180°C for 4 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of solid Na2CO3. The crude product was collected by filtration, washed with water and dried. It was used in the next step without further purification.
Recrystallized from water; brownish crystals; mp: 189-190°C; yield: 60%; 1H NMR (200 MHz, DMSO-d6) δ 13.20 (br s, 1H, NH), 9.04 (br s, 1H, H4), 8.37 (br d, 1H, H6, J=5.4 Hz), 7.76-7.61 (m, 2H, H7/4'), 7.42-7.30 (m, 2H, H3'/5').
EXAMPLE 2 - preparation of 2-Phenyl-1(3)H-imidazo[4,5-c]pyridine (GPJN-10)
A mixture of 3,4-diaminopyridine (2.00 g), benzoic acid (1 equivalent) and polyphosphoric acid (50 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of solid Na2CO3. The crude product was collected by filtration, washed with water and dried. It was used in the next step without further purification.
Recrystallized from water; off-white crystals; mp: 229-230°C; yield: 96%; 1H NMR (200 MHz, DMSO-d6) δ 8.95 (d, 1H, H4, J=1.0 Hz), 8.31 (d, 1H, H6, J=5.4 Hz), 8.28-8.17 (m, 2H, arom. H), 7.64-7.50 (m, 4H, arom. H).
EXAMPLE 3 - preparation of 2-(2,6-Difluorophenyl)-5-[(2,6-difluorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPRTI-8)
2-(2,6-Difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.500 g) was dissolved in dry DMF (5 mL) and the resulting solution was cooled to 0°C. Aqueous 50% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 2,6-difluorobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (50 mL) was added, the precipitate was collected by filtration and dried to give the crude product mixture.
Recrystallized from ethyl acetate; colorless crystals; mp: 195-197°C; yield: 65%; 1H NMR (200 MHz, DMSO-d6) δ 9.08 (br s, 1H, H4), 8.09 (dd, 1H, H6, J=6.6, 1.7 Hz), 7.82 (d, 1H, H7, J=6.6 Hz), 7.63-7.46 (m, 2H, H4'/4"), 7.29-7.13 (m, 4H, H3'/5'/3"/5"), 5.87 (s, 2H, CH2); MS (EI, 70 eV) m/z 357 (M+, 77%), 338 (4%), 230 (11%), 127 (100%); Anal. (C19H11F4N3) calcd.: C 63.87%, H 3.10%, N 11.76%, found: C 63.83%, H 3.15%, N 11.63%.
EXAMPLE 4 - preparation of 5-Benzyl-2-(2,6-difluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-1)
Prepared as described in example 3 from 2-(2,6-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.500 g) and benzyl bromide (0.444 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether and ethyl acetate; off-white crystals; mp: 180-181°C (degr.); yield: 30%; 1H NMR (200 MHz, DMSO-d6) δ 9.24 (br d, 1H, H4, J=1.5 Hz), 8.25 (dd, 1H, H6, J=6.9, 1.5 Hz), 7.81 (d, 1H, H7, J=6.9 Hz), 7.60-7.33 (m, 6H, H4'/2"/3"/4"/5"/6"), 7.26-7.13 (m, 2H, H3'/5'), 5.71 (s, 2H, CH2).
EXAMPLE 5 - preparation of 5-[(2,6-Difluorophenyl)methyl]phenyl-5H-imidazo[4,5-c]pyridine (GPJN-3)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.500 g) and 2,6-difluorobenzyl bromide (0.636 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (25 mL) and ethyl acetate (60 mL); colorless crystals; mp: 214-216°C; yield: 64%; 1H NMR (200 MHz, DMSO-d6) δ 8.91 (br s, 1H, H4), 8.39-8.32 (m, 2H, arom. H), 8.01 (dd, 1H, H6, J=6.9, 1.5 Hz), 7.72 (d, 1H, H7, J=6.9 Hz), 7.63-7.37 (m, 4H, arom. H), 7.30-7.16 (m, 2H, H3'/5'), 5.81 (s, 2H, CH2).
EXAMPLE 6 - preparation of 5-Benzyl-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-4)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.500 g) and benzyl bromide (0.526 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (25 mL), ethyl acetate (50 mL) and methanol (4 mL); colorless crystals; mp: 214-216°C; yield: 33%; 1H NMR (200 MHz, DMSO-d6) δ 9.09 (d, 1H, H4, J=1.4 Hz), 8.40-8.33 (m, 2H, arom. H), 8.18 (dd, 1H, H6, J=6.9, 1.4 Hz), 7.73 (d, 1H, H7, J=6.9 Hz), 7.52-7.32 (m, 8H, arom. H), 5.66 (s, 2H, CH2).
EXAMPLE 7 - preparation of 2-(2,6-Difluorophenyl)-5-(2-phenylethyl)-5H-imidazo[4,5-c]pyridine (GPJN-2)
Prepared as described in example 3 from 2-(2,6-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.500 g) and 2-phenylethyl bromide (0.480 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (50 mL) and ethyl acetate (40 mL); off-white crystals; mp: 184-186°C (degr.); yield: 14%; 1H NMR (200 MHz, DMSO-d6) δ 9.02 (br d, 1H, H4, J=1.4 Hz), 8.09 (dd, 1H, H6, J=6.7, 1.4 Hz), 7.74 (d, 1H, H7, J=6.7 Hz), 7.60-7.45 (m, 1H, H4'), 7.34-7.12 (m, 7H, H3'/5'/2"/3"/4"/5"/6"), 4.74 (t, 2H, N-CH2, J=7.4 Hz), 3.26 (t, 2H, CH2, J=7.4 Hz).
EXAMPLE 8 - preparation of 2-Phenyl-5-(3-phenylpropyl)-5H-imidazo[4,5-c]pyridine (GPJN-14)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 1-bromo-3-phenylpropane (0.367 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (7 mL); off-white crystals; mp: 44-46°C; yield: 44%; 1H NMR (200 MHz, DMSO-d6) δ 8.95 (d, 1H, H4, J=1.4 Hz), 8.40-8.33 (m, 2H, arom. H), 8.09 (dd, 1H, H6, J=6.8, 1.4 Hz), 7.71 (d, 1H, H7, J=6.8 Hz), 7.52-7.13 (m, 8H, arom. H), 4. 84 (t, 2H, N-CH2, J=7.2 Hz), 2.65-2.57 (m, 2H, CH2), 2.31-2.16 (m, 2H, CH2).
EXAMPLE 9 - preparation of 5-[(2-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-7)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 2-chlorobenzyl chloride (0.297 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (25 mL) and ethyl acetate (65 mL); colorless crystals; mp: 224-225°C; yield: 52%; 1H NMR (200 MHz, DMSO-d6) δ 8.99 (d, 1H, H4, J=1.6 Hz), 8.40-8.33 (m, 2H, arom. H), 8.10 (dd, 1H, H6, J=6.7, 1.6 Hz), 7.75 (d, 1H, H7, J=6.7 Hz), 7.59-7.34 (m, 6H, arom. H), 7.18-7.12 (m, 1H, arom. H), 5.80 (s, 2H, CH2).
EXAMPLE 10 - preparation of 5-[(3-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-8)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 3-chlorobenzyl bromide (0.379 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (27 mL); colorless crystals; mp: 210-212°C; yield: 54%; 1H NMR (200 MHz, DMSO-d6) δ 9.12 (d, 1H, H4, J=1.5 Hz), 8.39-8.32 (m, 2H, arom. H), 8.20 (dd, 1H, H6, J=6.7, 1.5 Hz), 7.74 (d, 1H, H7, J=6.7 Hz), 7.61-7.38 (m, 7H, arom. H), 5.66 (s, 2H, CH2).
EXAMPLE 11 - preparation of 5-[(4-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-9)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-chlorobenzyl chloride (0.297 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (24 mL); colorless crystals; mp: 211-212°C; yield: 55%; 1H NMR (200 MHz, DMSO-d6) δ 9.09 (d, 1H, H4, J=1.5 Hz), 8.40-8.33 (m, 2H, arom. H), 8.17 (dd, 1H, H6, J=6.9, 1.5 Hz), 7.73 (d, 1H, H7, J=6.9 Hz), 7.52-7.40 (m, 7H, arom. H), 5.66 (s, 2H, CH2).
EXAMPLE 12 - preparation of 5-[(2-Methoxyphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-11)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 2-methoxybenzyl chloride (0.288 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (30 mL); colorless crystals; mp: 182-184°C; yield: 60%; 1H NMR (200 MHz, DMSO-d6) δ 8.94 (d, 1H, H4, J=1.6 Hz), 8.39-8.32 (m, 2H, arom. H), 8.08 (dd, 1H, H6, J=6.7, 1.6 Hz), 7.69 (d, 1H, H7, J=6.7 Hz), 7.51-7.29 (m, 5H, arom. H), 7.10-6.94 (m, 2H, arom. H), 5.61 (s, 2H, CH2), 3.84 (s, 3H, OCH3).
EXAMPLE 13 - preparation of 5-[(3-Methoxyphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-12)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 3-methoxybenzyl chloride (0.288 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (23 mL); colorless crystals; mp: 157-158°C; yield: 62%; 1H NMR (200 MHz, DMSO-d6) δ 9.10 (d, 1H, H4, J=1.7 Hz), 8.40-8.33 (m, 2H, arom. H), 8.18 (dd, 1H, H6, J=6.7, 1.7 Hz), 7.72 (d, 1H, H7, J=6.7 Hz), 7.52-7.27 (m, 4H, arom. H), 7.10-6.89 (m, 3H, arom. H), 5.61 (s, 2H, CH2), 3.75 (s, 3H, OCH3).
EXAMPLE 14 - preparation of 5-[(4-Methoxyphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-13)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-methoxybenzyl chloride (0.288 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (31 mL); colorless crystals; mp: 211-212°C; yield: 52%; 1H NMR (200 MHz, DMSO-d6) δ 9.07 (d, 1H, H4, J=1.5 Hz), 8.39-8.32 (m, 2H, arom. H), 8.16 (dd, 1H, H6, J=6.9, 1.5 Hz), 7.70 (d, 1H, H7, J=6.9 Hz), 7.51-7.37 (m, 5H, arom. H), 6.99-6.92 (AA'BB', 2H, arom. H), 5.57 (s, 2H, CH2), 3.73 (s, 3H, OCH3).
EXAMPLE 15 - preparation of 5-[(2-Methylphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-20)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 2-methylbenzyl chloride (0.259 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (44 mL); colorless crystals; mp: 223-224°C; yield: 60%; 1H NMR (200 MHz, DMSO-d6) δ 8.93 (d, 1H, H4, J=1.6 Hz), 8.41-8.33 (m, 2H, arom. H), 8.04 (dd, 1H, H6, J=6.7, 1.6 Hz), 7.75 (d, 1H, H7, J=6.7 Hz), 7.53-7.15 (m, 5H, arom. H), 6.92 (br d, 1H, arom. H, J=7.0 Hz), 5.73 (s, 2H, CH2), 2.32 (s, 3H, CH3).
EXAMPLE 16 - preparation of 5-[(3-Methylphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-21)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 3-methylbenzyl chloride (0.259 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (15 mL); colorless crystals; mp: 183-185°C; yield: 46%; 1H NMR (200 MHz, DMSO-d6) δ 9.08 (d, 1H, H4, J=1.5 Hz), 8.40-8.33 (m, 2H, arom. H), 8.16 (dd, 1H, H6, J=6.7, 1.5 Hz), 7.72 (d, 1H, H7, J=6.7 Hz), 7.52-7.14 (m, 7H, arom. H), 5.61 (s, 2H, CH2), 2.29 (s, 3H, CH3).
EXAMPLE 17 - preparation of 5-[(4-Methylphenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-15)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-methylbenzyl chloride (0.259 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (32 mL); colorless crystals; mp: 206-208°C; yield: 57%; 1H NMR (200 MHz, DMSO-d6) δ 9.07 (d, 1H, H4, J=1.5 Hz), 8.39-8.32 (m, 2H, arom. H), 8.15 (dd, 1H, H6, J=6.7, 1.5 Hz), 7.71 (d, 1H, H7, J=6.7 Hz), 7.52-7.17 (m, 7H, arom. H), 5.60 (s, 2H, CH2), 2.28 (s, 3H, CH3).
EXAMPLE 18 - preparation of 5-[(2-Fluorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-17)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 2-fluorobenzyl bromide (0.349 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (37 mL); colorless crystals; mp: 209-211°C; yield: 67%; 1H NMR (200 MHz, DMSO-d6) δ 9.01 (br s, 1H, H4), 8.41-8.33 (m, 2H, arom. H), 8.06 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.74 (d, 1H, H7, J=6.8 Hz), 7.52-7.21 (m, 7H, arom. H), 5.76 (s, 2H, CH2).
EXAMPLE 19 - preparation of 5-[(3-Fluorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-18)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 3-fluorobenzyl bromide (0.349 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (34 mL); colorless crystals; mp: 228-230°C; yield: 55%; 1H NMR (200 MHz, DMSO-d6) δ 9.12 (d, 1H, H4, J=1.5 Hz), 8.41-8.33 (m, 2H, arom. H), 8.20 (dd, 1H, H6, J=6.7, 1.5 Hz), 7.74 (d, 1H, H7, J=6.7 Hz), 7.52-7.15 (m, 7H, arom. H), 5.67 (s, 2H, CH2).
EXAMPLE 20 - preparation of 5-[(4-Fluorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c] pyridine (GPJN-19)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-fluorobenzyl chloride (0.267 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (19 mL); colorless crystals; mp: 205-206°C; yield: 56%; 1H NMR (200 MHz, DMSO-d6) δ 9.11 (d, 1H, H4, J=1.7 Hz), 8.40-8.33 (m, 2H, arom. H), 8.18 (dd, 1H, H6, J=6.8, 1.7 Hz), 7.73 (d, 1H, H7, J=6.8 Hz), 7.61-7.37 (m, 5H, arom. H), 7.30-7.18 (m, 2H, arom. H), 5.64 (s, 2H, CH2).
EXAMPLE 21 - preparation of 5-[[4-(1,1-Dimethylethyl)phenyl]methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-16)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-tert-butylbenzyl bromide (0.419 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (23 mL); colorless crystals; mp: 213-215°C; yield: 49%; 1H NMR (200 MHz, DMSO-d6) δ 9.07 (d, 1H, H4, J=1.6 Hz), 8.39-8.33 (m, 2H, arom. H), 8.17 (dd, 1H, H6, J=6.7, 1.6 Hz), 7.71 (d, 1H, H7, J=6.7 Hz), 7.53-7.35 (m, 7H, arom. H), 5.61 (s, 2H, CH2), 1.24 (s, 9H, (CH3)3).
EXAMPLE 22 - preparation of 5-[(4-Bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-22)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-bromobenzyl bromide (0.461 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (26 mL); colorless crystals; mp: 212-214°C; yield: 45%; 1H NMR (200 MHz, DMSO-d6) δ 9.09 (br s, 1H, H4), 8.40-8.33 (m, 2H, arom. H), 8.17 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.73 (d, 1H, H7, J=6.8 Hz), 7.64-7.58 (AA'BB', 2H, arom. H), 7.52-7.37 (m, 5H, arom. H), 5.64 (s, 2H, CH2).
EXAMPLE 23 - preparation of 4-[(2-Phenyl-5H-imidazo[4,5-c]pyridin-5-yl)methyl]-benzonitrile (GPJN-23)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-bromomethyl-benzonitrile (0.362 g, 1.2 equivalents).
Recrystallized twice from a mixture of diisopropyl ether (10 mL) and ethyl acetate (25 mL); pale orange crystals; mp: 93°C (degr.); yield: 34%; 1H NMR (200 MHz, DMSO-d6) δ 9.10 (d, 1H, H4, J=1.5 Hz), 8.40-8.33 (m, 2H, arom. H), 8.18 (dd, 1H, H6, J=6.9, 1.5 Hz), 7.91-7.85 (AA'BB', 2H, arom. H), 7.75 (d, 1H, H7, J=6.9 Hz), 7.61-7.55 (AA'BB', 2H, arom. H), 7.52-7.37 (m, 3H, arom. H), 5.77 (s, 2H, CH2).
EXAMPLE 24 - preparation of 2-Phenyl-5-[[4-(trifluoromethyl)phenyl]methyl]-5H-imidazo [4,5-c]pyridine (GPJN-24)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-(trifluoromethyl)benzyl bromide (0.441 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (20 mL); colorless crystals; mp: 230-232°C; yield: 50%; 1H NMR (200 MHz, DMSO-d6) δ 9.12 (d, 1H, H4, J=1.6 Hz), 8.40-8.33 (m, 2H, arom. H), 8.19 (dd, 1H, H6, J=6.9, 1.6 Hz), 7.81-7.73 (m, 3H, arom. H), 7.65-7.59 (AA'BB', 2H, arom. H), 7.53-7.38 (m, 3H, arom. H), 5.78 (s, 2H, CH2).
EXAMPLE 25 - preparation of 5-[(4-Chlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine hydrochloride (GPJN-9 x HCl)
98 mg of 5-(4-chloro-benzyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-9) were dissolved in dry dichloromethane (18 mL) and to this solution was added one equivalent of HCl (1M in diethyl ether). After 2 hours the precipitate was collected by filtration and dried to give 70 % of the hydrochloride; colorless crystals; mp:147-148°C (degr.).
EXAMPLE 26 - preparation of 5-[(5-Chloro-2-thienyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-25)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 2-chloro-5-chloromethyl-thiophene (0.308 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (50 mL); off-white crystals; mp: 215-216°C; yield: 39%; 1H NMR (200 MHz, DMSO-d6) δ 9.07 (d, 1H, H4, J=1.5 Hz), 8.40-8.33 (m, 2H, arom. H), 8.19 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.74 (d, 1H, H7, J=6.8 Hz), 7.55-7.37 (m, 3H, arom. H), 7.28 (d, 1H, thiophene-H, J=3.8 Hz), 7.08 (d, 1H, thiophene-H, J=3.8 Hz), 5.81 (s, 2H, CH2).
EXAMPLE 27 - preparation of 5-(2-Naphthalenylmethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-26)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 2-bromomethyl-naphthalene (0.408 g, 1.2 equivalents).
Recrystallized from a mixture of ethyl acetate (20 mL) and ethanol (8 mL); colorless crystals; mp: 267°C; yield: 36%; 1H NMR (200 MHz, DMSO-d6) δ 9.17 (d, 1H, H4, J=1.7 Hz), 8.40-8.33 (m, 2H, arom. H), 8.23 (dd, 1H, H6, J=6.7, 1.7 Hz), 7.99-7.87 (m, 4H, arom. H), 7.74 (d, 1H, H7, J=6.7 Hz), 7.60-7.37 (m, 6H, arom. H), 5.84 (s, 2H, CH2).
EXAMPLE 28 - preparation of 2-Phenyl-5-(4-phenylbutyl)-5H-imidazo[4,5-c]pyridine (GPJN-27)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 1-chloro-4-phenylbutane (0.311 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (11 mL); colorless crystals; mp: 119-120°C; yield: 53%; 1H NMR (200 MHz, DMSO-d6) δ 8.95 (d, 1H, H4, J=1.4 Hz), 8.40-8.33 (m, 2H, arom. H), 8.07 (dd, 1H, H6, J=6.8, 1.4 Hz), 7.70 (d, 1H, H7, J=6.8 Hz), 7.52-7.37 (m, 3H, arom. H), 7.31-7.10 (m, 5H, arom. H), 4.46 (t, 2H, CH2, J=7.1 Hz), 2.62 (t, 2H, CH2, J=7.6 Hz), 2.00-1.85 (m, 2H, CH2), 1.63-1.46 (m, 2H, CH2).
EXAMPLE 29 - preparation of 5-(3-Methyl-2-butenyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-28)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-bromo-2-methylbut-2-ene (0.275 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (11 mL); off-white crystals; mp: 162-163°C; yield: 58%; 1H NMR (200 MHz, DMSO-d6) δ 8.86 (d, 1H, H4, J=1.7 Hz), 8.40-8.33 (m, 2H, arom. H), 7.99 (dd, 1H, H6, J=6.8, 1.7 Hz), 7.71 (d, 1H, H7, J=6.8 Hz), 7.52-7.37 (m, 3H, arom. H), 5.57-5.47 (m, 1H, =CH), 5.06 (br d, 2H, CH2, J=7.4 Hz), 1.86 (br s, 3H, CH3), 1.77 (br s, 3H, CH3).
EXAMPLE 30 - preparation of 5-Ethyl-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-29)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and ethyl iodide (0.288 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (5 mL) and ethyl acetate (12 mL); colorless crystals; mp: 188°C; yield: 22%; 1H NMR (200 MHz, DMSO-d6) δ 8.96 (d, 1H, H4, J=1.6 Hz), 8.40-8.33 (m, 2H, arom. H), 8.09 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.71 (d, 1H, H7, J=6.8 Hz), 7.52-7.36 (m, 3H, arom. H), 4.47 (q, 2H, CH2, J=7.3 Hz), 1.52 (t, 3H, CH3, J=7.3 Hz).
EXAMPLE 31 - preparation of 5-[2-[bis(1-Methylethyl)amino]ethyl]-2-phenyl-5H-imidazo [4,5-c]pyridine (GPJN-30)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g), and 2-(diisopropylamino)ethyl chloride hydrochloride (0.369 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (10 mL); colorless crystals; mp: 151-152°C; yield: 57%; 1H NMR (200 MHz, DMSO-d6) δ 8.80 (d, 1H, H4, J=1.5 Hz), 8.39-8.33 (m, 2H, arom. H), 7.99 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.67 (d, 1H, H7, J=6.8 Hz), 7.51-7.36 (m, 3H, arom. H), 4.36 (t, 2H, CH2, J=5.4 Hz), 3.04-2.84 (m, 4H, 2 x CH and CH2), 0.78 (d, 12H, 4 x CH3, J=6.6 Hz).
EXAMPLE 32 - preparation of 2-Phenyl-5-(4-pyridinylmethyl)-5H-imidazo[4,5-c]pyridine (GPJN-31)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g), and 4-chloromethyl-pyridine hydrochloride (0.303 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (15 mL); colorless crystals (hygroscopic); yield: 25%; 1H NMR (200 MHz, DMSO-d6) δ 9.09 (d, 1H, H4, J=1.6 Hz), 8.60-8.57 (m, 2H, pyridine-H2/6), 8.40-8.33 (m, 2H, arom. H), 8.17 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.67 (d, 1H, H7, J=6.8 Hz), 7.52-7.37 (m, 3H, arom. H), 7.31-7.28 (m, 2H, pyridine-H3/5), 5.74 (s, 2H, CH2).
EXAMPLE 33 - preparation of 2-Phenyl-5-(2-pyridinylmethyl)-5H-imidazo[4,5-c]pyridine (GPJN-34)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g), and 2-chloromethyl-pyridine hydrochloride (0.303 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (17 mL); colorless crystals; mp: 102-103°C; yield: 44%; 1H NMR (200 MHz, DMSO-d6) δ 9.02 (d, 1H, H4, J=1.4 Hz), 8.53 (ddd, 1H, pyridine-H6, J=4.7, 1.7, 0.8 Hz), 8.40-8.33 (m, 2H, arom. H), 8.13 (dd, 1H, H6, J=6.8, 1.4 Hz), 7.90-7.82 (m, 1H, pyridine-H4), 7.72 (d, 1H, H7, J=6.8 Hz), 7.52-7.33 (m, 5H, arom. H), 5.79 (s, 2H, CH2).
EXAMPLE 34 - preparation of 2-Phenyl-5-(3-pyridinylmethyl)-5H-imidazo[4,5-c]pyridine (GPJN-35)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g), and 3-chloromethyl-pyridine hydrochloride (0.303 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (41 mL); off-white crystals; mp: 53°C (degr.); yield: 46%; 1H NMR (200 MHz, DMSO-d6) δ 9.14 (d, 1H, H4, J=1.6 Hz), 8.76 (br d, 1H, pyridine-H2), 8.57 (dd, 1H, pyridine-H6, J=4.8, 1.6 Hz), 8.40-8.33 (m, 2H, arom. H), 8.22 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.90-7.84 (m, 1H, pyridine-H4), 7.74 (d, 1H, H7, J=6.8 Hz), 7.52-7.38 (m, 45H, arom. H), 5.71 (s, 2H, CH2).
EXAMPLE 35 - preparation of 5-([1,1'-Biphenyl]-4-ylmethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-32)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-chloromethyl-biphenyl (0.374 g, 1.2 equivalents).
Recrystallized from a mixture of ethyl acetate (50 mL) and ethanol (1.5 mL); colorless crystals; mp: 247-248°C; yield: 65%; 1H NMR (200 MHz, DMSO-d6) δ 9.14 (d, 1H, H4, J=1.4 Hz), 8.40-8.33 (m, 2H, arom. H), 8.22 (dd, 1H, H6, J=6.8, 1.4 Hz), 7.75 (d, 1H, H7, J=6.8 Hz), 7.72-7.30 (m, 12H, arom. H), 5.71 (s, 2H, CH2).
EXAMPLE 36 - preparation of 2-Phenyl-5-(1-phenylethyl)-5H-imidazo[4,5-c]pyridine (GPJN-33)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 1-phenylethyl bromide (0.341 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (40 mL); colorless crystals; mp: 190-192°C; yield: 57%; 1H NMR (200 MHz, DMSO-d6) δ 9.13 (d, 1H, H4, J=1.6 Hz), 8.39-8.33 (m, 2H, arom. H), 8.19 (dd, 1H, H6, J=6.7, 1.6 Hz), 7.70 (d, 1H, H7, J=6.7 Hz), 7.53-7.31 (m, 8H, arom. H), 6.01 (q, 1H, CH, J=7.0 Hz), 2.04 (d, 3H, CH3, J=7.0 Hz).
EXAMPLE 37 - preparation of 5-(1-Naphthalenylmethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-36)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 1-chloromethyl-naphthalene (0.326 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (45 mL); colorless crystals; mp: 191°C; yield: 73%; 1H NMR (200 MHz, DMSO-d6) δ 9.08 (d, 1H, H4, J=1.5 Hz), 8.39-8.33 (m, 2H, arom. H), 8.23-8.15 (m, 2H, arom. H), 7.75 (d, 1H, H7, J=6.8 Hz), 7.68-7.37 (m, 6H, arom. H), 7.25 (br d, 1H, arom. H, J=6.6 Hz), 6.22 (s, 2H, CH2).
EXAMPLE 38 - preparation of 5-(Cyclohexylmethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-37)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and cyclohexylmethyl bromide (0.327 g, 1.2 equivalents) with heating at 80°C.
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (14 mL); colorless crystals; mp: 188-189°C; yield: 36%; 1H NMR (200 MHz, DMSO-d6) δ 8.89 (d, 1H, H4, J=1.5 Hz), 8.39-8.33 (m, 2H, arom. H), 8.03 (dd, 1H, H6, J=6.6, 1.5 Hz), 7.69 (d, 1H, H7, J=6.6 Hz), 7.52-7.37 (m, 3H, arom. H), 4.28 (d, 2H, CH2, J=7.4 Hz), 2.02-0.92 (m, 11H, cyclohexyl H).
EXAMPLE 39 - preparation of 5-(3-Methylbutyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-38)
Prepared as described in example 3 from 2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 1-bromo-3-methylbutane (0.279 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (17 mL); colorless crystals; mp: 207°C; yield: 37%; 1H NMR (200 MHz, DMSO-d6) δ 8.96 (d, 1H, H4, J=1.5 Hz), 8.40-8.34 (m, 2H, arom. H), 8.09 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.70 (d, 1H, H7, J=6.8 Hz), 7.52-7.37 (m, 3H, arom. H), 4.45 (t, 2H, CH2, J=7.4 Hz), 1.87-1.75 (m, 2H, CH2), 1.53 (hept, 1H, CH, J=6.6 Hz), 0.94 (d, 6H, (CH3)2).
EXAMPLE 40 - preparation of 2-(2,6-Difluorophenyl)-5-[(4-fluorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-39)
Prepared as described in example 3 from 2-(2,6-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-fluorobenzyl chloride (0.225 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (10 mL); off-white crystals; mp: 104-105°C; yield: 48%; 1H NMR (200 MHz, DMSO-d6) δ 9.26 (d, 1H, H4, J=1.4 Hz), 8.26 (dd, 1H, H6, J=6.8, 1.4 Hz), 7.81 (d, 1H, H7, J=6.8 Hz), 7.61-7.45 (m, 3H, arom. H), 7.30-7.13 (m, 4H, arom. H), 5.69 (s, 2H, CH2).
EXAMPLE 41 - preparation of 2-(2,6-Difluorophenyl)-5-[(2,4-difluorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-40)
Prepared as described in example 3 from 2-(2,6-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 2,4-difluorobenzyl bromide (0.322 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (8 mL); off-white crystals; mp: 186-188°C; yield: 29%; 1H NMR (200 MHz, DMSO-d6) δ 9.16 (br s, 1H, H4), 8.18 (dd, 1H, H6, J=6.8, 1.3 Hz), 7.82 (d, 1H, H7, J=6.8 Hz), 7.64-7.11 (m, 6H, arom. H), 5.78 (s, 2H, CH2).
EXAMPLE 42 - preparation of 2-(2,6-Difluorophenyl)-5-[(2,4,6-trifluorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-41)
Prepared as described in example 3 from 2-(2,6-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.200 g) and 2,4,6-trifluorobenzyl bromide (0.234 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (8 mL); off-white crystals; mp: 186-187°C; yield: 26%; 1H NMR (200 MHz, DMSO-d6) δ 9.06 (br s, 1H, H4), 8.08 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.81 (d, 1H, H7, J=6.8 Hz), 7.61-7.46 (m, 1H, H4'), 7.42-7.13 (m, 4H, H3'/5'/3"/5"), 5.82 (s, 2H, CH2).
EXAMPLE 43 - preparation of 5-[(4-Bromophenyl)methyl]-2-ethyl-5H-imidazo[4,5-c]pyridine (GPJN-48)
A mixture of 3,4-diaminopyridine (1.00 g), propionic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 150°C for 1 h and then at 190°C for 2 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of 2N NaOH and extracted with ethyl acetate (100 mL) six times. The combined organic phases were dried (Na2SO4) and evaporated to give the crude product, which was recrystallized from ethyl acetate (100 mL) to give 56% of 2-ethyl-1(3)H-imidazo[4,5-c]pyridine as a white powder.
2-Ethyl-1(3)H-imidazo[4,5-c]pyridine (0.245 g) was dissolved in dry DMF (6 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (50 mL) was added, the precipitate was collected by filtration and dried to give the crude product mixture.
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (6 mL); off-white crystals; mp: 149-151°C (degr.); yield: 47%; 1H NMR (200 MHz, DMSO-d6) δ 8.89 (d, 1H, H4, J=1.5 Hz), 8.09 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.62-7.54 (m, 3H, arom. H), 7.39-7.32 (AA'BB', 2H, arom. H), 5.60 (s, 2H, CH2), 2.84 (q, 2H, CH2, J=7.5 Hz), 1.30 (t, 3H, CH3, J=7.5 Hz).
EXAMPLE 44 - preparation of 5-[(4-Bromophenyl)methyl]-2-(2-chlorophenyl)-5H-imidazo [4,5-c]pyridine (GPJN-54)
A mixture of 3,4-diaminopyridine (1.00 g), 2-chlorobenzoic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of 2N NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (100 mL) and ethanol (17 mL) to give 67% of 2-(2-chlorophenyl)-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-(2-Chlorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.383 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (25 mL); pale orange powder; mp: 190-192°C; yield: 33%; 1H NMR (200 MHz, DMSO-d6) δ 9.21 (d, 1H, H4, J=1.6 Hz), 8.22 (dd, 1H, H6, J=6.8, 1.6 Hz), 8.09-8.02 (m, 1H, arom. H), 7.80 (d, 1H, H7, J=6.8 Hz), 7.65-7.51 (m, 3H, arom. H), 7.46-7.38 (m, 4H, arom. H), 5.67 (s, 2H, CH2).
EXAMPLE 45 - preparation of 5-[(4-Bromophenyl)methyl]-2-(3-chlorophenyl)-5H-imidazo [4,5-c]pyridine (GPJN-55)
A mixture of 3,4-diaminopyridine (1.00 g), 3-chlorobenzoic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of 2N NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (100 mL) and ethanol (180 mL) to give 63% of 2-(3-chlorophenyl)-1(3)H-imidazo[4,5-c]pyridine as a white powder.
2-(3-Chlorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.383 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (45 mL); colorless powder; mp: 155-157°C; yield: 42%; 1H NMR (200 MHz, DMSO-d6) δ 9.16 (d, 1H, H4, J=1.5 Hz), 8.35-8.28 (m, 2H, arom. H), 8.20 (dd, 1H, H6, J=6.9, 1.5 Hz), 7.80 (d, 1H, H7, J=6.9 Hz), 7.64-7.38 (m, 6H, arom. H), 5.66 (s, 2H, CH2).
EXAMPLE 46 - preparation of 5-[(4-Bromophenyl)methyl]-2-(4-chlorophenyl)-5H-imidazo [4,5-c]pyridine (GPJN-56)
A mixture of 3,4-diaminopyridine (1.00 g), 4-chlorobenzoic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of 2N NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (100 mL) and ethanol (110 mL) to give 47% of 2-(4-chlorophenyl)-1(3)H-imidazo[4,5-c]pyridine as a colorless powder.
2-(4-Chlorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.383 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (25 mL); off-white powder; mp: 214-215°C; yield: 67%; 1H NMR (200 MHz, DMSO-d6) δ 9.13 (d, 1H, H4, J=1.6 Hz), 8.39-8.32 (AA'BB', 2H, arom. H), 8.18 (dd, 1H, H6, J=6.9, 1.6 Hz), 7.64-7.58 (AA'BB', 2H, arom. H), 7.56-7.49 (AA'BB', 2H, arom. H), 7.44-7.38 (AA'BB', 2H, arom. H), 5.65 (s, 2H, CH2).
EXAMPLE 47 - preparation of 5-[(4-Bromophenyl)methyl]-2-(2-pyridinyl)-5H-imidazo[4,5-c]pyridine (GPJN-58)
A mixture of 3,4-diaminopyridine (1.00 g), picolinic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of solid NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (50 mL) and ethanol (7 mL) to give 55% of 2-(2-pyridyl)-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-(2-Pyridyl)-1(3)H-imidazo[4,5-c]pyridine (0.327 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of ethyl acetate (75 mL) and ethanol (10 mL); pale brown crystals; mp: 256-258°C; yield: 43%; 1H NMR (200 MHz, DMSO-d6) δ 9.21 (d, 1H, H4, J=1.4 Hz), 8.68 (ddd, 1H, pyridine-H6), 8.40 (ddd, 1H, pyridine-H), 8.20 (dd, 1H, H6, J=6.8, 1.4 Hz), 7.89 (ddd, H, pyridine-H), 7.79 (d, 1H, H7, J=6.8 Hz), 7.65-7.58 (AA'BB', 2H, arom. H), 7.45-7.37 (m, 3H, arom. H), 5.68 (s, 2H, CH2).
EXAMPLE 48 - preparation of 5-[(4-Bromophenyl)methyl]-2-(3-pyridinyl)-5H-imidazo[4,5-c]pyridine (GPJN-57)
A mixture of 3,4-diaminopyridine (1.00 g), nicotinic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of solid NaOH and the resulting solution was evaporated. The residue was extracted twice with ethyl acetate (2 x 200 mL) and the combined organic phases were dried (Na2SO4) and evaporated. The crude product, thus obtained, was recrystallized from a mixture of ethyl acetate (50 mL) and ethanol (13 mL) to give 34% of 2-(3-pyridyl)-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-(3-Pyridyl)-1(3)H-imidazo[4,5-c]pyridine (0.327 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (10 mL), ethyl acetate (75 mL) and ethanol (20 mL); pale yellow powder; mp: 270-272°C; yield: 40%; 1H NMR (200 MHz, DMSO-d6) δ 9.49 (m, 1H, pyridine-H2), 9.18 (d, 1H, H4, J=1.5 Hz), 8.65-8.60 (m, 2H, arom. H), 8.21 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.79 (d, 1H, H7, J=6.8 Hz), 7.65-7.58 (AA'BB', 2H, arom. H), 7.54-7.38 (m, 3H, arom. H), 5.66 (s, 2H, CH2).
EXAMPLE 49 - preparation of 5-[(4-Bromophenyl)methyl]-2-(4-pyridinyl)-5H-imidazo[4,5-c]pyridine (GPJN-49)
A mixture of 3,4-diaminopyridine (1.00 g), isonicotinic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of solid NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from water (55 mL) to give 84% of 2-(4-pyridyl)-1(3)H-imidazo[4,5-c]pyridine as a pale orange powder.
2-(4-Pyridyl)-1(3)H-imidazo[4,5-c]pyridine (0.327 g) was dissolved in dry DMF (11 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (75 mL); pale brown powder; mp: 190-194°C (degr.); yield: 40%; 1H NMR (200 MHz, DMSO-d6) δ 9.25 (d, 1H, H4, J=1.4 Hz), 8.70-8.67 (m, 2H, pyridine-H2/6), 8.25-8.20 (m, 3H, arom. H), 7.83 (d, 1H, H7, J=6.8 Hz), 7.64-7.58 (AA'BB', 2H, arom. H), 7.45-7.39 (AA'BB', 2H, arom. H), 5.68 (s, 2H, CH2).
EXAMPLE 50 - preparation of 5-[(4-Bromophenyl)methyl]-2-(2-thienyl)-5H-imidazo[4,5-c] pyridine (GPJN-53)
A mixture of 3,4-diaminopyridine (1.00 g), thiophene-2-carboxylic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of solid NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (50 mL) and ethanol (25 ml) to give 30% of 2-(2-thienyl)-1(3)H-imidazo[4,5-c]pyridine as pale yellow crystals.
2-(2-Thienyl)-1(3)H-imidazo[4,5-c]pyridine (0.335 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from ethyl acetate (70 mL); pale yellow powder; mp: 230-231°C; yield: 24%; 1H NMR (200 MHz, DMSO-d6) δ 9.01 (d, 1H, H4, J=1.5 Hz), 8.16 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.81 (dd, 1H, thiophene-H, J=3.6, 1.4 Hz), 7.67 (d, 1H, H7, J=6.8 Hz), 7.64-7.57 (m, 3H, arom. H), 7.43-7.37 (AA'BB', 2H, arom. H), 5.63 (s, 2H, CH2).
EXAMPLE 51 - preparation of 2-Benzyl-5-[(4-bromophenyl)methyl]-5H-imidazo[4,5-c] pyridine (GPJN-67)
A mixture of 3,4-diaminopyridine (1.00 g), phenylacetic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 120°C for 1 h and then at 150°C for 12 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of solid NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (76 mL) to give 57% of 2-benzyl-1(3)H-imidazo[4,5-c]pyridine as a colorless powder.
2-Benzyl-1(3)H-imidazo[4,5-c]pyridine (0.500 g) was dissolved in dry DMF (5 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of ethyl acetate (50 mL) and ethanol (6.5 mL); pale yellow powder; mp: 232-233°C; yield: 46%; 1H NMR (200 MHz, DMSO-d6) δ 8.94 (d, 1H, H4, J=1.4 Hz), 8.10 (dd, 1H, H6, J=6.8, 1.4 Hz), 7.61-7.39 (m, 3H, arom. H), 7.38-7.10 (m, 7H, arom. H), 5.65 (s, 2H, 5-CH2), 4.17 (s, 2H, 2-CH2).
EXAMPLE 52 - preparation of 5-[(4-Bromophenyl)methyl]-2-(1-naphthalenyl)-5H-imidazo [4,5-c]pyridine (GPJN-62)
A mixture of 3,4-diaminopyridine (1.00 g), 1-naphthoic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 hours with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of solid NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (100 mL) and ethanol (130 mL) to give 47% of 2-(1-naphthalenyl)-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-(1-Naphthalenyl)-1(3)H-imidazo[4,5-c]pyridine (0.409 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (10 mL), ethyl acetate (50 mL) and ethanol (5 mL); pale yellow powder; mp: 210-213°C (degr.); yield: 22%; 1H NMR (200 MHz, DMSO-d6) δ 9.73 (m, 1H, arom. H), 9.22 (d, 1H, H4, J=1.6 Hz), 8.52 (dd, 1H, arom. H, J=7.2, 1.4 Hz), 8.23 (dd, 1H, H6, J=6.8, 1.6 Hz), 8.03-7.95 (m, 2H, arom. H), 7.83 (d, 1H, H7, J=6.8 Hz), 7.65-7.41 (m, 7H, arom. H), 5.68 (s, 2H, CH2).
EXAMPLE 53 - preparation of 5-[(4-Bromophenyl)methyl]-2-(2-naphthalenyl)-5H-imidazo [4,5-c]pyridine (GPJN-63)
A mixture of 3,4-diaminopyridine (1.00 g), 2-naphthoic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 hours with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of solid NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (100 mL) and ethanol (400 mL) to give 28% of 2-(2-naphthalenyl)-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-(2-Naphthalenyl)-1(3)H-imidazo[4,5-c]pyridine (0.409 g) was dissolved in dry DMF (10 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (20 mL) and ethyl acetate (60 mL); pale orange powder; mp: 133-138°C (degr.); yield: 52%; 1H NMR (200 MHz, DMSO-d6) δ 9.13 (d, 1H, H4, J=1.4 Hz), 8.93 (br s, 1H, arom. H), 8.51 (dd, 1H, arom. H, J=8.6, 1.6 Hz), 8.19 (dd, 1H, H6, J=6.7, 1.4 Hz), 8.10-7.90 (m, 3H, arom. H), 7.76 (d, 1H, H7, J=6.7 Hz), 7.65-7.50 (m, 4H, arom. H), 7.52-7.39 (AA'BB', 2H, arom. H), 5.67 (s, 2H, CH2).
EXAMPLE 54 - preparation of 5-[(4-Bromophenyl)methyl]-2-(2-fluorophenyl)-5H-imidazo [4,5-c]pyridine (GPJN-52)
A mixture of 3,4-diaminopyridine (1.00 g), 2-fluorobenzoic acid (1 equivalent) and polyphosphoric acid (25 g) was heated at 190°C for 3 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was made alkaline by addition of 2N NaOH and the resulting precipitate was collected by filtration and dried. The crude product was recrystallized from a mixture of water (100 mL) and ethanol (20 mL) to give 87% of 2-(2-fluorophenyl)-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-(2-Fluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.355 g) was dissolved in dry DMF (7 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (80 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (25 mL); off-white powder; mp: 156°C; yield: 53%; 1H NMR (200 MHz, DMSO-d6) δ 9.18 (d, 1H, H4, J=1.6 Hz), 8.35-8.26 (m, 1H, arom. H), 8.20 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.78 (d, 1H, H7, J=6.8 Hz), 7.64-7.58 (AA'BB', 2H, arom. H), 7.52-7.24 (m, 5H, arom. H), 5.66 (s, 2H, CH2).
EXAMPLE 55 - preparation of 5-[(4-Bromophenyl)methyl]-2-[(1E)-2-phenylethenyl]-5H-imidazo[4,5-c]pyridine (GPJN-81)
A mixture of 3,4-diaminopyridine (0.500 g) and cinnamic acid (2.036 g, 3 equivalents) was heated at 160°C for 24 h with stirring. The resulting mixture was cooled to ambient temperature and washed with diisopropyl ether. The remaining solid was dissolved in ethyl acetate and the resulting solution was extracted with 2N aqueous sodium hydroxide solution. The organic phase was dried and evaporated to give 0.580 g of a pale brown solid. Recrystallization from a mixture of diisopropyl ether (20 mL) and ethyl acetate (31 mL) gave 30% of 2-[(1E)-2-phenylethenyl]-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-[(1E)-2-Phenylethenyl]-1(3)H-imidazo[4,5-c]pyridine (0.250 g) was dissolved in dry DMF (3 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (30 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (35 mL); pale brown powder; mp: 212-214°C (degr.); yield: 27%; 1H NMR (200 MHz, DMSO-d6) δ 9.02 (d, 1H, H4, J=1.6 Hz), 8.15 (dd, 1H, H6, J=6.6, 1.6 Hz), 7.83 (d, 1H, =CH, J=16.2 Hz), 7.72-7.59 (m, 5H, arom. H), 7.48-7.30 (m, 6H), 5.63 (s, 2H, CH2).
EXAMPLE 56 - preparation of 5-[(4-Bromophenyl)methyl]-2-[(phenylthio)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-83)
A mixture of 3,4-diaminopyridine (0.500 g) and phenylthioacetic acid (2.312 g, 3 equivalents) was heated at 160°C for 6 h with stirring. The resulting mixture was cooled to ambient temperature and washed with diisopropyl ether. The remaining solid was dissolved in ethyl acetate and the resulting solution was extracted with 2N aqueous sodium hydroxide solution. The organic phase was dried and evaporated to give 0.520 g of a pale brown solid. Recrystallization from a mixture of diisopropyl ether (20 mL) and ethyl acetate (16 mL) gave 32% of 2-[(phenylthio)methyl]-1(3)H-imidazo[4,5-c]pyridine as an off-white powder.
2-[(Phenylthio)methyl]-1(3)H-imidazo[4,5-c]pyridine (0.300 g) was dissolved in dry DMF (5 mL) and the resulting solution was cooled to 0°C. Aqueous 33% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 4-bromobenzyl bromide (1.2 equivalents) was added portionwise and the resulting mixture was stirred for 24 h at room temperature. Finally, water (50 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (30 mL); pale brown powder; mp: 168-170°C (degr.); yield: 32%; 1H NMR (200 MHz, DMSO-d6) δ 9.05 (d, 1H, H4, J=1.6 Hz), 8.16 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.67 (d, 1H, H7, J=6.8 Hz), 7.63-7.56 (AA'BB', 2H, arom. H), 7.48-7.14 (m, 6H, arom. H), 7.18-7.09 (m, 1H, arom. H), 5.63 (s, 2H, N-CH2), 4.41 (s, 2H, S-CH2).
EXAMPLE 57 - preparation of 5-([1,1'-Biphenyl]-4-ylmethyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-110)
Prepared as described in example 3 from 2-(2-fluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.263 g) and 4-chloromethyl-biphenyl (0.300 g, 1.2 equivalents).
Recrystallized from ethyl acetate (55 mL); colorless needles; mp: 216°C; yield: 35%; 1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.6 Hz), 8.36-8.23 (m, 2H, arom. H), 7.80 (d, 1H, H7, J=6.6 Hz), 7.73-7.24 (m, 12H, arom. H), 5.73 (s, 2H, CH2).
EXAMPLE 58 - preparation of 5-[(4-Chlorophenyl)methyl]-2-(2-fluorophenyl)-5H-imidazo [4,5-c]pyridine (GPJN-112)
Prepared as described in example 3 from 2-(2-fluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.300 g) and 4-chlorobenzyl chloride (0.272 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (25 mL); off-white crystals; mp: 167°C; yield: 53%; 1H NMR (200 MHz, DMSO-d6) δ 9.18 (d, 1H, H4, J=1.4 Hz), 8.35-8.26 (m, 1H, arom. H), 8.21 (dd, 1H, H6, J=6.6, 1.4 Hz), 7.78 (d, 1H, H7, J=6.6 Hz), 7.53-7.24 (m, 7H, arom. H), 5.68 (s, 2H, CH2).
EXAMPLE 59 - preparation of 2-(2-Fluorophenyl)-5-[(4-iodophenyl)methyl]-5H-imidazo [4,5-c]pyridine (GPJN-113)
Prepared as described in example 3 from 2-(2-fluorophenyl)-1(3)H-imidazo[4,5-c] pyridine (0.300 g) and 4-iodobenzyl bromide (0.501 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (25 mL); off-white crystals; mp: 181°C; yield: 75%; 1H NMR (200 MHz, DMSO-d6) δ 9.17 (d, 1H, H4, J=1.6 Hz), 8.35-8.26 (m, 1H, arom. H), 8.19 (dd, 1H, H6, J=6.6, 1.6 Hz), 7.81-7.74 (m, 3H, arom. H), 7.52-7.23 (m, 5H, arom. H), 5.64 (s, 2H, CH2).
EXAMPLE 60 - preparation of 5-[[4-(1,1-Dimethylethyl)phenyl]methyl]-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-114)
Prepared as described in example 3 from 2-(2-fluorophenyl)-1(3)H-imidazo[4,5-c] pyridine (0.300 g) and 4-tert-butylbenzyl bromide (0.384 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (58 mL); colorless crystals; mp: 235°C; yield: 59%; 1H NMR (200 MHz, DMSO-d6) δ 9.17 (d, 1H, H4, J=1.6 Hz), 8.35-8.26 (m, 1H, arom. H), 8.21 (dd, 1H, H6, J=6.8, 1.6 Hz), 7.77 (d, 1H, H7, J=6.8 Hz), 7.52-7.24 (m, 7H, arom. H), 5.64 (s, 2H, CH2), 1.25 (s, 9H, (CH3)3).
EXAMPLE 61 - preparation of 5-([1,1'-Biphenyl]-4-ylmethyl)-2-(1-naphthalenyl)-5H-imidazo[4,5-c]pyridine (GPJN-115)
Prepared as described in example 3 from 2-(1-naphthalenyl)-1(3)H-imidazo[4,5-c]pyridine (0.303 g) and 4-chloromethyl-biphenyl (0.300 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (5 mL) and ethyl acetate (43 mL); off-white powder; mp: 216°C; yield: 23%; 1H NMR (200 MHz, DMSO-d6) δ 9.77-9.71 (m, 1H, arom. H), 9.28 (d, 1H, H4, J=1.6 Hz), 8.53 (dd, 1H, arom. H, J=7.2, 1.2 Hz), 8.29 (dd, 1H, H6, J=6.6, 1.6 Hz), 8.02-7.32 (m, 15H, arom. H), 5.75 (s, 2H, CH2).
EXAMPLE 62 - preparation of 5-[(4-Bromophenyl)methyl]-2-(phenoxymethyl)-5H-imidazo [4,5-c]pyridine (GPJN-82)
Prepared in analogy to example 56 by using phenoxyacetic acid instead of phenylthioacetic acid.
Recrystallized from a mixture of diisopropyl ether (10 mL) and ethyl acetate (30 mL); off-white powder; mp: 168-169°C; yield: 31%; 1H NMR (200 MHz, DMSO-d6) δ 9.13 (d, 1H, H4, J=1.5 Hz), 8.19 (dd, 1H, H6, J=6.8, 1.5 Hz), 7.72 (d, 1H, H7, J=6.8 Hz), 7.63-7.56 (AA'BB', 2H, arom. H), 7.42-7.35 (AA'BB', 2H, arom. H), 7.31-6.86 (m, 5H, arom. H), 5.65 (s, 2H, N-CH2), 5.28 (s, 2H, O-CH2).
EXAMPLE 63 - preparation of 5-[(4-Bromophenyl)methyl]-4-chloro-2-phenyl-5H-imidazo [4,5-c]pyridine (GPJN-96)
Prepared as described in example 3 from 4-chloro-2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.425 g) and 4-bromobenzyl bromide (0.270 g, 1.2 equivalents).
Purified by column chromatography (dichloromethane: methanol = 20:1); colorless crystals; mp: 245-250°C; yield: 11%; 1H NMR (200 MHz, DMSO-d6) δ 8.44 (d, 1H, H6, J=6.7 Hz), 8.40-8.33 (m, 2H, arom. H), 7.83 (d, 1H, H7, J=6.7 Hz), 7.63-7.57 (AA'BB', 2H, arom. H), 7.55-7.43 (m, 3H, arom. H), 7.21-7.15 (AA'BB', 2H, arom. H), 5.88 (s, 2H, CH2).
EXAMPLE 64 - preparation of 5-[(4-Bromophenyl)methyl]-4-hydroxy-2-phenyl-5H-imidazo [4,5-c]pyridine (GPJN-95) (= 5-[(4-Bromophenyl)methyl]-1,4-dihydro-4-oxo-2-phenyl-5H-imidazo[4,5-c]pyridine)
5-[(4-Bromophenyl)methyl]-4-chloro-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-96) (see example 63) (0.200 g) was dissolved in DMF (5 mL) and 2N aqueous sodium hydroxide solution (10 mL) was added. The resulting mixture was heated at 60°C for 24 h. Then water (50 mL) was added and the resulting mixture was neutralized by addition of 2N HCl. The precipitate was collected by filtration to give the crude product.
Recrystallized from a mixture of diisopropyl ether (25 mL) and ethyl acetate (23 mL); colorless powder; mp: 268-270°C; yield: 81%; 1H NMR (200 MHz, DMSO-d6) δ 8.17-8.13 (m, 2H, arom. H), 7.59-7.44 (m, 6H, arom. H), 7.28-7.23 (AA'BB', 2H, arom. H), 6.67 (br d, 2H, H7, J=6.8 Hz), 5.21 (s, 2H, CH2).
EXAMPLE 65 - preparation of 5-[(4-Bromophenyl)methyl]-7-chloro-2-phenyl-5H-imidazo [4,5-c]pyridine (GPJN-103)
Prepared as described in example 3 from 7-chloro-2-phenyl-1(3)H-imidazo[4,5-c]pyridine (0.300 g) (prepared as described in example 2 from 5-chloro-3,4-diaminopyridine and benzoic acid) and 4-bromobenzyl bromide (0.240 g, 1.2 equivalents).
Recrystallized from a mixture of diisopropyl ether (10 mL), ethyl acetate (35 mL) and ethanol (2mL); off-white crystals; mp: 215-217°C; yield: 48%; 1H NMR (200 MHz, DMSO-d6) δ 9.17 (d, 1H, H4, J=1.2 Hz), 8.56 (d, 1H, H6, J=1.2 Hz), 8.40-8.33 (m, 2H, arom. H), 7.65-7.59 (AA'BB', 2H, arom. H), 7.54-7.44 (m, 5H, arom. H), 5.65 (s, 2H, CH2).
In analogy to the above examples, the following additional compounds were prepared:
  • 5-[((2-Bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-42)
  • 5-[((3-Bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-43)
  • 2-[((2-Phenyl-5H-imidazo[4,5-c]pyridin-5-yl)methyl]-benzonitrile (GPJN-44)
  • 3-[((2-Phenyl-5H-imidazo[4,5-c]pyridin-5-yl)methyl]-benzonitrile (GPJN-45)
  • 2-Phenyl-5-[[2-(trifluoromethyl)phenyl]methyl]-5H-imidazo[4,5-c]pyridine (GPJN-46)
  • 2-Phenyl-5-[[3-(trifluoromethyl)phenyl]methyl]-5H-imidazo[4,5-c]pyridine (GPJN-47)
  • 5-[((4-Bromophenyl)methyl]-2-(3-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-50)
  • 5-[((4-Bromophenyl)methyl]-2-(3-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-51)
  • 5-[((4-Bromophenyl)methyl]-2-(2-methylphenyl)-5H-imidazo[4,5-c]pyridine (GPJN-59)
  • 5-[((4-Bromophenyl)methyl]-2-(3-methylphenyl)-5H-imidazo[4,5-c]pyridine (GPJN-60)
  • 5-[((4-Bromophenyl)methyl]-2-(4-methylphenyl)-5H-imidazo[4,5-c]pyridine (GPJN-61)
  • 5-[((4-Bromophenyl)methyl]-2-(3-methoxyphenyl)-5H-imidazo[4,5-c]pyridine (GPJN-64)
  • 2-((3-Bromophenyl)-5-[(4-bromophenyl)methyl]- 5H-imidazo[4,5-c]pyridine (GPJN-65)
  • N,N-Dimethyl-3-[5-[(4-Bromophenyl)methyl]-5H-imidazo[4,5-c]pyridin-2-yl]-benzenamine (GPJN-66)
  • 5-[((4-Iodophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-68)
  • 5-[((4-Bromophenyl)methyl]-2-(3-iodophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-69)
  • 5-[((4-Bromophenyl)methyl]-2-(2-bromophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-70)
  • 5-((2-Ethylbutyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-72)
  • 5-((2-Phenoxyethyl)-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-73)
  • 5-[((3,4-Dichlorophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-74)
  • 2-Phenyl-5-(3-phenyl-2-propenyl)- 5H-imidazo[4,5-c]pyridine (GPJN-75)
  • 5-[((4-Bromophenyl)methyl]-2-(2-phenylethyl)-5H-imidazo[4,5-c]pyridine (GPJN-76)
  • 5-[((4-Bromophenyl)methyl]-2-(3-phenylpropyl)-5H-imidazo[4,5-c]pyridine (GPJN-77)
  • 5-[((4-Bromophenyl)methyl]-2-(3,5-dibromophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-78)
  • 2-((3-Bromophenyl)-5-[(4-iodophenyl)methyl]- 5H-imidazo[4,5-c]pyridine (GPJN-79)
  • 2-((3-Bromophenyl)-5-[(4-chlorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-80)
  • 2-((3-Bromophenyl)-5-[(3,4-dichlorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-84)
  • 5-[((4-Bromophenyl)methyl]-2-(4-phenylbutyl)-5H-imidazo[4,5-c]pyridine (GPJN-85)
  • 5-[((4-Bromophenyl)methyl]-2-(5-bromo-2-thienyl)-5H-imidazo[4,5-c]pyridine (GPJN-86)
  • 5-[((4-Bromophenyl)methyl]-2-[3-(trifluoromethyl)phenyl]-5H-imidazo[4,5-c]pyridine (GPJN-87)
  • 2-Phenyl-5-[[4-(trifluoromethoxy)phenyl]methyl]-5H-imidazo[4,5-c]pyridine (GPJN-88)
  • 5-[((4-Bromophenyl)methyl]-2-(2,3,6-trifluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-89)
  • 5-[((4-Bromophenyl)methyl]-2-(2,5-difluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-90)
  • 7-Bromo-5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-91)
  • 4-[2-Phenyl-5H-imidazo[4,5-c]pyridin-5-yl]-benzoic acid (GPJN-94)
  • 2-Benzyl-5-(2-phenylethyl)-5H-imidazo[4,5-c]pyridine (GPJN-98)
  • 2-((3-Bromophenyl)-5-(3-phenylpropyl)-5H-imidazo[4,5-c]pyridine (GPJN-99)
  • 2-((3-Bromophenyl)-5-(2-phenoxyethyl)-5H-imidazo[4,5-c]pyridine (GPJN-100)
  • 5-[((4-Bromophenyl)methyl]-7-methyl-2-phenyl-5H-imidazo[4,5-c]pyridine (GPJN-104)
  • 5-Benzyl-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPJN-105)
  • 2-((2-Fluorophenyl)-5-[(2-methylphenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-106)
  • 2-((2-Fluorophenyl)-5-[(3-methylphenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-107)
  • 2-((2-Fluorophenyl)-5-[(4-methylphenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-108)
  • 5-([1,1'-Biphenyl]-4-ylmethyl)-2-[(phenylthio)methyl]-5H-imidazo[4,5-c]pyridine (GPJN-111)
  • 5-[((3,4-Dichlorophenyl)methyl]-2-(2,6-difluorophenyl)-5H-imidazo[4,5-c]pyridine (GPC-10)
  • 5-[((2,4-Difluorophenyl)methyl]-2-(3-fluorophenyl)-5H-imidazo[4,5-c]pyridine (GPC-11)
  • 5-[((2,4-Difluorophenyl)methyl]-2-(2,3,6-trifluorophenyl)-5H-imidazo[4,5-c]pyridine (GPC-12)
  • 2-((2,5-Difluorophenyl)-5-[(2,4-difluorophenyl)methyl]-5H-imidazo[4,5-c]pyridine (GPC-13)

Claims (11)

  1. A process for preparing an imidazo[4,5-c]pyridine compound of formula (II): wherein:
    - R1 is selected from phenyl substituted with 0-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R6; 1-naphthyl substituted with 0-3 R6; 2-naphthyl substituted with 0-3 R6; C3-7 cycloalkyl; C5-7 cycloalkenyl;
    - R2, R4 and R5 are independently selected from hydrogen; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR7R8; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
    - X is selected from the group -CH2-; -CH(CH3)-; -CH2-CH2-; -CH2-CH2-CH2-; -CH2-CH2-CH2-CH2; -OCH2-CH2-; -SCH2-CH2-; -NR10-CH2-CH2-; C3-7 cycloalkylidene; -C(CH3)2; -CH2-CH(CH3)-CH2-; -CH(CH3)-CH2-CH2-; -CH2-CH2-CH(CH3)-; -CH=CH-CH2-;
    - R3 is selected from phenyl substituted with 0-3 R17; 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R17; 1-naphthyl substituted with 0-3 R17; 2-naphthyl substituted with 0-3 R17; C3-7 cycloalkyl; C4-10 cycloalkenyl with the proviso that the double bond cannot be adjacent to a nitrogen;
    - R6 and R17 are independently selected from H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R18; phenyl; phenoxy; benzyl; hydroxymethyl;
    - R7 and R8 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12 or R7 and R8, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring;
    - R9 and R18 are independently selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
    - R10 is selected from the group H; C1-6 straight or branched alkyl; phenyl;
    - R12 is selected from the group H; C1-6 straight or branched alkyl; phenyl;
    - R13 and R14 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; and
    - R15 and R16 are independently selected from the group H; C1-6 straight or branched alkyl; phenyl; or a pharmaceutically acceptable salt thereof, said process comprising reacting an imidazo[4,5-c]pyridine represented by the structural formula (C) with an alkylating agent represented by the structural formula R3 - X - R' (D) wherein R' is chlorine or bromine, according to the scheme below: in an appropriate solvent under addition of base at ambient temperature.
  2. A process for preparing an imidazo[4,5-c]pyridine compound according to claim 1, wherein:
    - R1 is selected from phenyl substituted with 0-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R6; 1-naphthyl substituted with 0-3 R6; 2-naphthyl substituted with 0-3 R6; C3-7 cycloalkyl; C5-7 cycloalkenyl;
    - R2, R4 and R5 are independently selected from hydrogen; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR7R8; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
    - X is selected from the group -CH2-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-CH2-; - CH=CH-CH2-;
    - R3 is selected from phenyl substituted with 0-3 R17; 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R17; 1-naphthyl substituted with 0-3 R17; 2-naphthyl substituted with 0-3 R17; C3-7 cycloalkyl; C4-7 cycloalkenyl with the proviso that the double bond cannot be adjacent to a nitrogen;
    - R6 and R17 are independently selected from H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R18; phenyl; phenoxy; benzyl; hydroxymethyl;
    - R7 and R8 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; alternatively, R7 and R8, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring;
    - R9 and R18 are independently selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
    - R12 is selected from the group H; C1-6 straight or branched alkyl; phenyl;
    - R13 and R14 are independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; and
    - R15 and R16 are independently selected from H; C1-6 straight or branched alkyl; phenyl. or a pharmaceutically acceptable salt thereof.
  3. A process for preparing an imidazo[4,5-c]pyridine compound according to claim 1, wherein:
    - R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or substituted with 1-3 R6; 2-naphthyl unsubstituted or substituted with 1-3 R6; C3-7 cycloalkyl; C5-7 cycloalkenyl;
    - R2, R4 and R5 are hydrogen;
    - X is selected from the group -CH2-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-CH2-; - CH=CH-CH2-;
    - R3 is selected from phenyl unsubstituted or substituted with 1-3 R17 ; 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R17; 1-naphthyl unsubstituted or substituted with 1-3 R17; 2-naphthyl substituted with 0-3 R17; C3-7 cycloalkyl; C5-7 cycloalkenyl with the proviso that the double bond cannot be adjacent to a nitrogen;
    - each R6 and R17 is independently selected from H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
    - R9 is selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
    - each R13 and R14 is independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; and
    - each R15 and R16 is independently selected from the group H; C1-6 straight or branched alkyl; phenyl; or a pharmaceutically acceptable salt thereof.
  4. A process for preparing an imidazo[4,5-c]pyridine compound according to claim 1, wherein:
    - R1 is selected from phenyl unsubstituted or substituted with 1-3 R6; 5 or 6 membered heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-2 R6; 1-naphthyl unsubstituted or substituted with 1-3 R6; 2-naphthyl unsubstituted or substituted with 1-3 R6;
    - R2, R4 and R5 are hydrogen;
    - X is selected from -CH2-; -CH(CH3)-; -CH2-CH2-CH2-; -OCH2-CH2-; -CH=CH-CH2-;
    - R3 is selected from phenyl unsubstituted or substituted with 1-3 R17 ; 5 or 6 membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group O, N, and S, unsubstituted or substituted with 1-3 R17; 1-naphthyl unsubstituted or substituted with 1-3 R17; 2-naphthyl unsubstituted or substituted with 1-3 R17;
    - each R6 and R17 is independently selected from H; straight or branched C1-6 alkoxy; straight or branched C1-6 alkyl; F; Cl; Br; I; OH; CN; NO2; NR13R14; OCF3; CF3; C(=O)R9; phenyl; phenoxy; benzyl; hydroxymethyl;
    - R9 is selected from H; OH; straight or branched C1-6 alkyl; straight or branched C1-6 alkoxy; NR15R16; phenyl;
    - each R13 and R14 is independently selected from H; straight or branched C1-6 alkyl; phenyl; C(=O)R12; and
    - each R15 and R16 is independently selected from the group H; C1-6 straight or branched alkyl; phenyl; or a pharmaceutically acceptable salt thereof.
  5. A process for preparing an imidazo[4,5-c]pyridine compound according to any one of claims 1 to 4, wherein the aromatic heterocyclic ring is selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thiofuranyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl and isothiazolyl.
  6. A process for preparing an imidazo[4,5-c]pyridine compound according to claim 1, wherein R2, R4 and R5 are hydrogen, and being selected from the group identified in the following table: Entry X 1 2,6-difluorophenyl 2,6-difluorophenyl 2 2,6-difluorophenyl phenyl 3 2,6-difluorophenyl phenyl 4 phenyl 2,6-difluorophenyl 5 phenyl phenyl 6 phenyl 2-chorophenyl 7 phenyl 3-chorophenyl 8 phenyl 4-chorophenyl 9 phenyl 2-methoxyphenyl 10 phenyl 3-methoxyphenyl 11 phenyl 4-methoxyphenyl 12 phenyl phenyl 13 phenyl 4-methylphenyl 14 phenyl 4-(1,1-dimethylethyl)phenyl 15 phenyl 2-fluorophenyl 16 phenyl 3-fluorophenyl 17 phenyl 4-fluorophenyl 18 phenyl 2-methylphenyl 19 phenyl 3-methylphenyl 20 phenyl 4-bromophenyl 21 phenyl 4-cyanophenyl 22 phenyl 4-(trifluoromethyl)phenyl 23 phenyl 5-chloro-2-thienyl 24 phenyl 2-naphthyl 25 phenyl phenyl 26 phenyl 4-pyridinyl 27 phenyl 4-phenyl-phenyl 28 phenyl phenyl 29 phenyl 2-pyridinyl 30 phenyl 3-pyridinyl 31 phenyl 1-naphthyl 32 phenyl cyclohexyl 33 2,6-difluorophenyl 4-fluorophenyl 34 2,6-difluorophenyl 2,4-difluorophenyl 35 2,6-difluorophenyl 2,4,6-trifluorophenyl 36 phenyl 2-bromophenyl 37 phenyl 3-bromophenyl 38 phenyl 2-cyanophenyl 39 phenyl 3-cyanophenyl 40 phenyl 2-(trifluoromethyl)phenyl 41 phenyl 3-(trifluoromethyl)phenyl 43 4-pyridyl 4-bromophenyl 44 3-fluorophenyl 4-bromophenyl 45 4-fluorophenyl 4-bromophenyl 46 2-fluorophenyl 4-bromophenyl 47 2-thienyl 4-bromophenyl 48 2-chlorophenyl 4-bromophenyl 49 3-chlorophenyl 4-bromophenyl 50 4-chlorophenyl 4-bromophenyl 51 3-pyridyl 4-bromophenyl 52 2-pyridyl 4-bromophenyl 53 2-methylphenyl 4-bromophenyl 54 3-methylphenyl 4-bromophenyl 55 4-methylphenyl 4-bromophenyl 56 1-naphthyl 4-bromophenyl 57 2-naphthyl 4-bromophenyl 58 3-methoxyphenyl 4-bromophenyl 59 3-bromophenyl 4-bromophenyl 60 3-(dimethylamino)phenyl 4-bromophenyl 62 phenyl 4-iodophenyl 63 3-iodophenyl 4-bromophenyl 64 2-bromophenyl 4-bromophenyl 65 phenyl phenyl 66 phenyl 3,4-dichlorophenyl 67 phenyl phenyl 70 3,5-dibromophenyl 4-bromophenyl 71 3-bromophenyl 4-iodophenyl 72 3-bromophenyl 4-chlorophenyl 76 3-bromophenyl 3,4-dichlorophenyl 78 5-bromo-2-thienyl 4-bromophenyl 79 3-(trifluoromethyl)phenyl 4-bromophenyl 80 phenyl 4-(trifluoromethoxy)phenyl 81 2,3,6-trifluorophenyl 4-bromophenyl 82 2,5-difluorophenyl 4-bromophenyl 84 phenyl 4-carboxyphenyl 88 3-bromophenyl phenyl 89 3-bromophenyl phenyl 92 2-fluorophenyl phenyl 93 2-fluorophenyl 2-methylphenyl 94 2-fluorophenyl 3-methylphenyl 95 2-fluorophenyl 4-methylphenyl 97 2-fluorophenyl 4-phenyl-phenyl 99 2-fluorophenyl 4-chlorophenyl 100 2-fluorophenyl 4-iodophenyl 101 2-fluorophenyl 4-(1,1-dimethylethyl)phenyl 102 1-naphthyl 4-phenyl-phenyl 103 2,6-difluorophenyl 3,4-dichlorophenyl 104 3-fluorophenyl 2,4-difluorophenyl 105 2,3,6-trifluorophenyl 2,4-difluorophenyl 106 2,5-difluorophenyl 2,4-difluorophenyl
  7. A process for preparing a pharmaceutically acceptable salt of an imidazo[4,5-c]pyridine compound according to any one of claims 1 to 6, wherein said compound is combined with a cation selected from the group consisting of alkali and alkaline earth metal ions and ammonium and quaternary amino ions.
  8. A process for preparing a pharmaceutically acceptable salt of an imidazo[4,5-c]pyridine compound according to claim 7, wherein said cation is an alkali or alkaline earth metal ion and wherein said process comprises the step of reacting said imidazo[4,5-c]pyridine compound with the metal hydroxide.
  9. A process for preparing a pharmaceutically acceptable salt of an imidazo[4,5-c]pyridine compound according to claim 7 or claim 8, wherein said cation is selected from the group consisting of Li+ , Na+ and K+ .
  10. A process for preparing a pharmaceutically acceptable salt of an imidazo[4,5-c]pyridine compound according to any one of claims 1 to 6, comprising reacting said imidazo[4,5-c]pyridine compound with an organic or inorganic acid.
  11. A process for preparing a pharmaceutically acceptable salt of an imidazo[4,5-c]pyridine compound according to claim 10, wherein said organic or inorganic acid is selected from the group consisting of hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic and p-aminosalicylic acids.
HK11113246.2A 2002-07-03 2011-12-07 Viral inhibitors HK1161231B (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0215293 2002-07-03
GBGB0215293.2A GB0215293D0 (en) 2002-07-03 2002-07-03 Viral inhibitors
GB0313251A GB0313251D0 (en) 2003-06-10 2003-06-10 Viral inhibitors
GB0313251 2003-06-10

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HK1161231A1 HK1161231A1 (en) 2012-08-24
HK1161231B true HK1161231B (en) 2015-03-27

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