Nothing Special   »   [go: up one dir, main page]

WO2002038153A1 - New use of 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine derivatives - Google Patents

New use of 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine derivatives Download PDF

Info

Publication number
WO2002038153A1
WO2002038153A1 PCT/SE2001/002523 SE0102523W WO0238153A1 WO 2002038153 A1 WO2002038153 A1 WO 2002038153A1 SE 0102523 W SE0102523 W SE 0102523W WO 0238153 A1 WO0238153 A1 WO 0238153A1
Authority
WO
WIPO (PCT)
Prior art keywords
imidazo
tetrahydro
rot
pyridine
mmol
Prior art date
Application number
PCT/SE2001/002523
Other languages
French (fr)
Inventor
Patrizia Caldirola
Olivier Besencon
Rolf Olsson
Johan ÖHMAN
Original Assignee
Biovitrum Ab
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 SE0004101A external-priority patent/SE0004101D0/en
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Priority to AU2002214505A priority Critical patent/AU2002214505A1/en
Publication of WO2002038153A1 publication Critical patent/WO2002038153A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to use of 4-alkyl-5-alkoxycarbonyl-4, 5, 6, 7- tetrahydroimidazo[4,5-c] pyridine derivatives for the manufacture of medicaments for, or treatment or prophylaxis of semicarbazide-sensitive amine oxidase (SSAO)-mediated complications.
  • SSAO semicarbazide-sensitive amine oxidase
  • SSAO Semicarbazide-sensitive amine oxidase
  • IDDM insulin dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • Heart attack, angina, strokes, amputations, blindness and renal failure are clinical events that represent the end point of the clinical study. Endothelial cells dysfunction may precede the diabetic state of complications.
  • the SSAO enzyme is located in the vascular smooth muscles, retina, kidney and the cartilage tissues, and in the circulating blood (Yu, P. H.
  • the general catalytic cycle is very similar to the one observed for other monoamine oxidases (Scheme 1).
  • the higher activity of SSAO as well as the higher concentration of its natural substrates, methylamine and aminoacetone, in diabetic patients, would lead to a higher production of formaldehyde, methylglyoxal and hydrogen peroxide.
  • These products are known to be highly cytotoxic for the endothelial cell layer and might lead to the observed microvascular complication in diabetic patients (Yu, P. H.
  • Scheme 1 SSAO's catalytic cycle.
  • the active site is represented schematically by the topaquinone residue as well as by a basic amino acid residue B " essential for the activity.
  • a method of treatment or prophylaxis of SSAO- mediated complications in mammals including humans comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (I):
  • R 5 is (a) H
  • C j .g alkyl denotes a saturated or unsaturated, straight, branched or cyclic alkyl group having from 1 to 8 carbon atoms.
  • Examples of said Cj.g alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, and straight- and branched-chain pentyl, hexyl, septyl and octyl, optionally substituted with 0-5 halogen atoms.
  • halogen shall mean fluorine, chlorine, or bromine.
  • Preferred compound of Formula (I) are: benzyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate; benzyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate; benzyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate;
  • the compounds of the Formula (I) can form acid addition salts with acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic .
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic .
  • Compounds of Formula (I) may also form solvates such as hydrates and the invention also extends to these forms. When referred to herein, it is understood that the term "compound of Formula (I)" also includes these forms.
  • Certain compounds of Formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods. Any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compounds of Formula (I) are used for treatment or prophylaxis of SSAO mediated vascular complications and for insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus.
  • R H: Benzyl (4S,6S)-6-(aminocarbonyl)-4-et yl-
  • the starting materials are commercially available or can be prepared following known procedures.
  • the compounds for treatment of SSAO mediated complications can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient.
  • Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15 th Ed., 1975).
  • the compounds and compositions can be administered orally, parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, or rectally.
  • Useful dosages of the compounds of Formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example, see U.S. Pat. No. 4,938,949.
  • the compound can be administered in unit dosage form; for example, containing about 0.05 mg to about 500 mg, conveniently about 0.1 mg to about 250 mg, most conveniently, about 1 mg to about 150 mg of active ingredient per unit dosage form.
  • the desired dose may be presented in a single dose or as divided doses administered at appropriate intervals.
  • the compositions can be administered orally, sublingually, transdermally, or parenterally at dose levels of about 0.01 to about 150 mg kg, preferably about 0.1 to about 50 mg/kg, and more preferably about 0.1 to about 30 mg/kg of mammal body weight.
  • RP-HPLCs were run on a Gilson system, using a 119 UV-detector (214 nm or 254 nm), a 805 manometric module, a 305- and a 306-pumps and a Vydac C ⁇ 8 -column (218TP1022); H 2 O+0.1%TFA/CH 3 CN were used as eluents. Mps were measured with a Gallenkamp apparatus and were uncorrected. NMR spectra were recorded on a Varian Inova 400 instrument.
  • EI-MS spectra were recorded on a JMS SX-102A mass spectrometer (Jeol, Tokyo, Jpn) at 70eV or on an Autospec-oaTOF Micromass Manchester instrument at 70 eV.
  • HRMS spectra were recorded on a LCT Micromass instrument with flow injection-electrospray positive mode; quaternary ammonium salts were used as references. Reactions were followed by MS, using a Platform I Micromass instrument, Manchester, with an electrospray positive and negative mode flow injection. Elemental analysis was run on an Elementar Vario EL instrument.
  • Benzyl chloroformate (0.845 mL, 5.64 mmol) was added dropwise over 1 min. The pH was maintained between 7 and 9 by adding from time to time aq. IM NaOH (total amount: about 5 mL). The mixture was stirred overnight while the temperature rose slowly to room temperature. The final pH was equal to 6.5 and an oily precipitate was lying in the bottom of the flask. This oily precipitate was decanted, dissolved in CHC1 3 and the solution dried over MgSO . After filtration, the filtrate was evaporated under reduced pressure. The residue was diluted in MeOH (20 mL) and aq. IM NaOH was added (10 mL).
  • Example 6 Methyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.38 mmol), K 2 CO 3 (690 mg, 5.00 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and methyl chloroformate (0.39 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer.
  • Example 7 Benzyl 4-ethyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5-carboxylate trifluoroacetate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (1.00 g, 4.48 mmol), K 2 CO 3 (1.24 g, 9.0 mmol), CHC1 3 (10 mL), H 2 O (8 mL) and benzyl chloroformate (1.36 mL, 9.0 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-8.5 with aq. IM HCl.
  • Benzyl 4-phenyI-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (800 mg, 2.54 mmol), K 2 CO 3 (737 mg, 5.33 mmol), CHC1 3 (6 mL), H 2 O (5 mL) and benzyl chloroformate (0.80 mL, 5.33 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl.
  • Example 9 Benzyl 4-benzyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate: According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- yridine dihydrochloride (500 mg, 1.74 mmol), K 2 CO 3 (507 mg, 3.67 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and benzyl chloroformate (0.55 mL, 3.67 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer.
  • Benzyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.52 mmol), K 2 CO 3 (720 mg, 5.2 mmol), CHC1 3 (6 mL), H 2 O (5 mL) and benzyl chloroformate (0.78 mL, 5.2 mmol). After basic treatment for lh the mixture was acidified to pH 8.5 with aq. IM HCl.
  • Methyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.68 mmol), K 2 CO 3 (778 mg, 5.63 mmol), CHC1 3 (6 mL), H 2 O (4 mL) and methyl chloroformate (0.436 mL, 5.63 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl.
  • Methyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.52 mmol), K 2 CO 3 (720 mg, 5.2 mmol), CHC1 3 (6 mL), H 2 O (4 mL) and methyl chloroformate (0.40 mL, 5.2 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Methyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c] pyridine dihydrochloride (800 mg, 2.54 mmol), K 2 CO 3 (737 mg, 5.33 mmol), CHC1 3 (8 mL), H 2 O (5 mL) and methyl chloroformate (0.412 mL, 5.33 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl.
  • Cyclopentyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridme-5- carboxylate trifluoroacetate According to GPII, starting from 4-ethyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.78 mmol), K 2 CO 3 (517 mg, 3.74 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and cyclopentyl chloroformate (511 mg, 3.74 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl.
  • Example 18 Cyclopentyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K 2 CO 3 (487 mg, 3.53 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and cyclopentyl chloroformate (482 mg, 3.53 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Cyclopentyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.59 mmol), K 2 CO 3 (461 mg, 3.34 mmol), CHC1 3 (5 mL), H 2 O (2.5 mL) and cyclopentyl chloroformate (456 mg, 3.34 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Example 21 4-Fluorophenyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K 2 CO 3 (487 mg, 3.53 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and 4-fluorophenyl chloroformate (0.47 mg, 3.6 mmol).
  • Methoxy-ethyI 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.78 mmol), K CO 3 (517 mg, 3.74 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and methoxyethyl chloroformate (518 mg, 3.74 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl.
  • Methoxyethyl 4-propyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K 2 CO 3 (487 mg, 3.53 mmol), CHC1 3 (4 mL), H 2 O (2 mL) and methoxyethyl chloroformate (490 mg, 3.53 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Methoxyethyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-phenyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.59 mmol), K 2 CO 3 (461 mg, 3.34 mmol), CHC1 3 (6 mL), H 2 O (4 mL) and methoxyethyl chloroformate (462 mg, 3.34 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl.
  • Benzyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.38 mmol), K 2 CO 3 (690 mg, 5.00 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and benzyl chloroformate (0.75 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Ste -stirrer.
  • Benzyl 4-benzyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5- carboxylate According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.74 mmol), K 2 CO 3 (507 mg, 3.67 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and benzyl chloroformate (0.55 mL, 3.67 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Ste ⁇ n-stirrer.
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed- vac.
  • the residue was purified by parallel FC with a gradient pump (MeOH/CHCl 3 0:100 -> 0:100 for 5 min, then -> 15:85 over 25 min).
  • 5-carboxylate According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.23 mmol), K 2 CO 3 (646 mg, 4.68 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.64 mL, 4.68 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL).
  • 2,2,2-Trichloroethyl -4-propy 1-1 ,4,6,7-tetrahy dro-5H-imidazo [4,5- c]pyridine-5-carboxylate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K 2 CO 3 (609 mg, 4.40 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.61 mL, 4.4 mmol).
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed-vac.
  • the residue was purified by parallel FC with a gradient pump (MeOH/CHCl 3 0:100 ⁇ 0:100 for 5 min, then ⁇ 15:85 over 25 min).
  • 2,2,2-Trichloroethyl -4-propyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5- c]pyridine-5-carboxylate According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K 2 CO 3 (609 mg, 4.40 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.61 mL, 4.4 mmol).
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed-vac.
  • the residue was purified by parallel FC with a gradient pump (MeOH/CHCl 3 0:100 ⁇ 0:100 for 5 min, then ⁇ 15:85 over 25 min).
  • the reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer.
  • the basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC1 3 and filtered several times. The combined org. phases were evaporated in a speed- vac.
  • Example 37 o 5-(4-Nitrob enzyl)-4-propyl-l ,4,6,7-tetrahy dro-5H-imidazo [4,5-c] py ridine-5- carboxylate: According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K 2 CO 3 (609 mg, 4.40 mmol), CHC1 3 (6 mL), H 2 O (3 mL) and old 4-nitrophenyl chloroformate (949 mg, 4.40 mmol).
  • This method is based on the horseradish peroxidase catalyzed hydrogen peroxide oxidation of 10-acetyl-3,7-dihydroxyphenoxazine (Molecular Probes A-6550), that yields a highly fluorescent product, resorufin.
  • 10 mM stock solution of substance in DMSO is serially diluted in 0.05 M sodium-potassium phosphate buffer.
  • SSAO substrate benzylamine
  • HRP horse radish peroxidase
  • the final concentrations in the assay volume are 104 ⁇ M benzylamine, 219 ⁇ M 10-acetyl-3,7-dihydroxyphenoxazine, 1.1 U/ml HRP and a dilution of the SSAO preparation of 1/600.
  • the fluorescence is measured at 560 ex / 590 em.
  • the inhibition is measured as % decrease of the signal compared to a control containing dilution of DMSO only (no substance).
  • Aldehyde detection SSAO activity is measured as increase of aldehyde formed from SSAO degradation of primary amines.
  • 14 C -labeled benzylamine is mixed with substance dilutions (from 10 mM stock solution in DMSO) in 0.05 M sodium-potassium phosphate buffer (pH 7.8). Enzyme, also diluted in phosphate buffer, is added and incubation is performed at room temperature for 60 minutes. The reaction is stopped with 1 M HCl. The formed ( 1 C -labeled) aldehyde is separated from the likewise 14 C -labeled benzylamine through extraction with toluene:ethyl acetate and then transferred to liquid scintillation vials for measurement of radioactivity in a beta counter.
  • the final concentrations in the assay volume are 150 ⁇ M benzylamine (0.037 MBq/ ⁇ mol), and a dilution of the SSAO preparation of l/150.
  • the inhibition is measured as % decrease of the signal compared to control containing dilution of DMSO only (no substance).
  • the compounds shown in Tables 2 and 3 were tested for biological activity, determined as per cent inhibition of SSAO at 12 ⁇ M concentration of the test compounds. The compounds were shown to inhibit SSAO to from 10 to 97 %.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Oncology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to the use of compounds of Formula (I), in which R?1, R2, R3 and R4¿ are as described in the specification, for the treatment or prophylaxis of SSAO-mediated complications, such as diabetes.

Description

NEW USE
TECHNICAL FIELD The present invention relates to use of 4-alkyl-5-alkoxycarbonyl-4, 5, 6, 7- tetrahydroimidazo[4,5-c] pyridine derivatives for the manufacture of medicaments for, or treatment or prophylaxis of semicarbazide-sensitive amine oxidase (SSAO)-mediated complications.
BACKGROUND ART Semicarbazide-sensitive amine oxidase, SSAO, is a monoamine oxidase that recently has been suggested to be responsible for microvascular complications in diabetic patients. Nephropathy, neuropathy and retinopathy represent the end results of microvascular complications in both insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM). Heart attack, angina, strokes, amputations, blindness and renal failure are clinical events that represent the end point of the clinical study. Endothelial cells dysfunction may precede the diabetic state of complications. The SSAO enzyme is located in the vascular smooth muscles, retina, kidney and the cartilage tissues, and in the circulating blood (Yu, P. H. Deamination of methylamine and angiopathy; toxicity of formaldehyde, oxidative stress and relevance to protein glycoxidation in diabetes. J. Neural. Transm. Suppl, 1998, 52, 201) and has been found to be overactive in diabetic patients (Ekblom, J. Potential therapeutic value of drugs inhibiting semicarbazide-sensitive amine oxidase: vascular cytoprotection in diabetes mellitus. Pharmacol. Res., 1998, 37, 87). SSAO oxidizes a primary amine into the corresponding aldehyde with the help of the non-proteogenic amino acid topaquinone (Scheme J). Oxidation of the aminophenol form of topaquinone into the quinone form, in order to close the catalytic cycle, is catalyzed by Cu(H), present in the active site of the enzyme. Hydrogen peroxide and ammonia are produced. The general catalytic cycle is very similar to the one observed for other monoamine oxidases (Scheme 1). The higher activity of SSAO as well as the higher concentration of its natural substrates, methylamine and aminoacetone, in diabetic patients, would lead to a higher production of formaldehyde, methylglyoxal and hydrogen peroxide. These products are known to be highly cytotoxic for the endothelial cell layer and might lead to the observed microvascular complication in diabetic patients (Yu, P. H. Deamination of methylamine and angiopathy; toxicity of formaldehyde, oxidative stress and relevance to protein glycoxidation in diabetes. J. Neural. Transm. Suppl, 1998, 52, 201). The inhibition of SSAO-mediated reactions is therefore a strategy that could be beneficial for a variety of pathological conditions.
Scheme 1: SSAO's catalytic cycle. The active site is represented schematically by the topaquinone residue as well as by a basic amino acid residue B" essential for the activity.
Figure imgf000003_0001
SUMMARY OF THE INVENTION According to the invention a method of treatment or prophylaxis of SSAO- mediated complications in mammals including humans is provided. The method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (I):
Figure imgf000003_0002
or a pharmaceutically acceptable salt thereof, wherein
R! is
(a) H, or
\ (b) CONH-R5;
R2 is
(a) COOR5,
(b) COR5,
(c) CONH-R5,
(d) CSNH-R5, or
(e) H;
R3 is
(a) H,
(b) Cj.8 alkyl, or
(c) (CH2)nAr;
R4 is
(a) H,
(b) Ar, or
(c) Cj.g alkyl; and
R5 is (a) H,
(b) (CH2)nAr,
(c) (CH2)nOAr,
(d) C g alkyl containing 0-2 oxygen atoms and optionally substituted with 0-5 halogen atoms, or (e) a polyether chain having the formula (CH2)xO(CH2)yO(CH2)zCH3; n is an integer 0 to 4; m is an integer 0 to 2; x and y are integers 2 to 4; z is an integer 0 to 3; Ar is phenyl, 1 -naphthyl or 2-naphthyl, unsubstituted optionally mono-or poly- substituted with electrodonating groups, halogen, Cι-6 alkyl, CF3, hydroxyl, Cι.6 alkoxyl, OCF3, CN, NO ,phenyloxyl, benzyloxyl, optionally substituted phenyl, alkylsulfonyl, Cι_6 alkenyl, -NH2, R7NH-, R7 R7N-, Cι.6 alkylcarboxyl, formyl, Cι_6 alkyl-CO-NH-, aminocarbonyl (R7 R7-N-CO-), SR7 wherein R7 is simultaneously or alternatively H or Cι_6 alkyl; cynnamoyl, unsubstituted or optionally substituted benzyl; 1,1-diphenyl ethyl, a monocyclic or bicyclic heterocyclic ring (furyl, pyrrolyl, triazolyl, diazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, benzoxadiazolyl which are unsubstituted or optionally mono or di-substituted with halogen, C^ alkyl); 2, or 3, or 4-pyridyl or a 5 to 7-membered unsaturated or partially or completely saturated heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur where nitrogen containing heterocycles may contain H or Cι.6 alkyl or CF3-CO- at the nitrogen atoms where such a substitution is allowed.
The term "Cj.g alkyl" denotes a saturated or unsaturated, straight, branched or cyclic alkyl group having from 1 to 8 carbon atoms. Examples of said Cj.g alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, and straight- and branched-chain pentyl, hexyl, septyl and octyl, optionally substituted with 0-5 halogen atoms.
The term "halogen" shall mean fluorine, chlorine, or bromine.
DETAILED DESCRIPTION OF THE INVENTION According to the present invention it has been found that 4-alkyl-5- alkoxycarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c] pyridine derivatives of Formula (I) are potent compounds for inhibiting SSAO-mediated reactions.
4-alkyl-5-alkoxycarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c] pyridine derivatives are known from GB 2 158 440 and U.S. 4,223,146. In the GB application the compounds are disclosed to have anti- viral activity. The compounds in the U.S. patent are useful as antiulcer agents and as inhibitors of gastric secretion. In Formula (I) preferred substituents are as follows: R1 is H, CO-NH2, R3 is d.3 alkyl or benzyl and R2 is COOR5 and R5 is
1) H or a linear, branched or cyclic Cι_8 alkyl which can be saturated or not, containing 0-2 oxygen atoms and optionally substituted with 0-5 halogen atoms;
2) (CH2)nAr, where n = 0-3 and Ar is a phenyl group or a phenyl group substituted with electrodonating groups and/or halogen atoms. Preferred compound of Formula (I) are: benzyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate; benzyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate; benzyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate;
2,2,2 -trichloroethyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate; and benzyl (4S,6S)-6-(aminocarbonyl)-4-ethyl-l ,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate.
The compounds of the Formula (I) can form acid addition salts with acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic . Compounds of Formula (I) may also form solvates such as hydrates and the invention also extends to these forms. When referred to herein, it is understood that the term "compound of Formula (I)" also includes these forms.
Certain compounds of Formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods. Any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
Preferably the compounds of Formula (I) are used for treatment or prophylaxis of SSAO mediated vascular complications and for insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus.
The compounds used in the invention are prepared according to known methods. The compounds can be prepared as follows: Scheme 2:
Figure imgf000007_0001
Figure imgf000007_0002
R = iBu: Benzyl (4S,6S)-4-et yl-
6-[(isobutylamino)-carbonyl]-
1,4,6,7-tetrahydro-
5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate
R = H: Benzyl (4S,6S)-6-(aminocarbonyl)-4-et yl-
1,4,6,7-tetrahydro-
5H-imidazo[4,5-c]pyridine-
5-carboxylate trifluoroacetate
Scheme 3:
Figure imgf000007_0003
X = H or COOH
Amide bond formation
Figure imgf000007_0004
Figure imgf000007_0005
The starting materials are commercially available or can be prepared following known procedures.
According to the present invention the compounds for treatment of SSAO mediated complications can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient. Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15th Ed., 1975). The compounds and compositions can be administered orally, parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, or rectally. Useful dosages of the compounds of Formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example, see U.S. Pat. No. 4,938,949.
The compound can be administered in unit dosage form; for example, containing about 0.05 mg to about 500 mg, conveniently about 0.1 mg to about 250 mg, most conveniently, about 1 mg to about 150 mg of active ingredient per unit dosage form. The desired dose may be presented in a single dose or as divided doses administered at appropriate intervals. The compositions can be administered orally, sublingually, transdermally, or parenterally at dose levels of about 0.01 to about 150 mg kg, preferably about 0.1 to about 50 mg/kg, and more preferably about 0.1 to about 30 mg/kg of mammal body weight.
The invention will now be illustrated with the following examples, which however, are not intended to limit the scope of the invention. The following abbreviations are used: aq: aqueous; br: broad; DIPEA: diisopropylethylamine; DMAP: 4-(NN- dimethylamino)pyridine; ECAO: Esterichia Coli amine oxidase; EDC'HCl: N-ethyl-N'- 3(dimethylamino)propylcarbodiimide hydrochloride; ET. electron impact; eq: equivalent; EtOAc: ethyl acetate; HOBt: hydroxybenzotriazol; HTS: high throughput screening;; Mp: melting point; HRMS: high resolution mass spectrum; org: organic; RP-HPLC: reversed-phase high pressure liquid chromatography; SAR: structure activity relationship; sat: saturated; TLC: thin layer chromatography.
Experimental: Solvents were purchased from Merck or Riedel-de Haen. Chemicals and reagents were purchased from Aldrich, Lancaster or Fluka. The buffer solution (pH 9) was bought from Merck (catalogue number 1.09461.1000, boric acid/KCl/ΝaOH). TLCs were run using SilicagelόO F2 4 plates purchased from Merck. TLCs were analyzed by UV or stained with a solution of KMnO4 in water. Flash chromatography was run using Silicagel 60 (230-400 mesh) from Merck. Parallel flash chromatography was run on a Foxy-200 system from Isco Inc. with 108-disposable columns for FC from Isco Inc. RP-HPLCs were run on a Gilson system, using a 119 UV-detector (214 nm or 254 nm), a 805 manometric module, a 305- and a 306-pumps and a Vydac Cι8-column (218TP1022); H2O+0.1%TFA/CH3CN were used as eluents. Mps were measured with a Gallenkamp apparatus and were uncorrected. NMR spectra were recorded on a Varian Inova 400 instrument. EI-MS spectra were recorded on a JMS SX-102A mass spectrometer (Jeol, Tokyo, Jpn) at 70eV or on an Autospec-oaTOF Micromass Manchester instrument at 70 eV. HRMS spectra were recorded on a LCT Micromass instrument with flow injection-electrospray positive mode; quaternary ammonium salts were used as references. Reactions were followed by MS, using a Platform I Micromass instrument, Manchester, with an electrospray positive and negative mode flow injection. Elemental analysis was run on an Elementar Vario EL instrument.
General Procedure I (GPI): A solution of histidine or histamine, NaOH and aldehyde was prepared in water and MeOH, and was heated under reflux for 24 h. After cooling the solution to room temperature, then to 0°C, aq. cone. HCl was added. See the specific examples for the work-up procedures.
General procedure II (GPII): A solution oftetrahydroimidazopyridine and K2CO3 in CHC13 and water was cooled to 0°C. The chloroformate, resp. the acyl chloride was added dropwise. The mixture was stirred for 24 h while warming up to room temperature. The phases were separated, the org. phase dried over Na2SO4 and the solvent removed under reduced pressure, the residue was dissolved or suspended in MeOH (3 mL/mmol of starting material) and aq. 1M NaOH (2 mL/mmol of starting material) was added. After 1 h, the mixture was worked-up and purified, see specific examples. Carboxylic acid Intermadiate (scheme 2)
(^S,6S)-4-Ethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid: According to GPI with histidine (15.5 g, 0.100 mol), NaOH (24 g, 0.60 mol), water (100 mL), MeOH (400 mL) and propionaldehyde (20 mL, 0.276 mol). The solution was then acidified to pH 7-8 with aq. cone. HCl (60 mL) and the solvent was removed under reduced pressure. After drying the residue thoroughly under high vacuum, the oil was triturated with hot EtOH and filtered (3x). The filtrate was evaporated under reduced pressure and the residue crystallised from EtOH/water. (4S,6S)-4-Ethyl-4,5,6,l- tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid was isolated as a white powder (6.44 g, 33%). 1H-NMR and NOE-measurement showed a cisltrans ratio of 9:1. Mp = 242-4 °C. 1H-NMR (400 MHz, D2O; only cis-stereoisαmer described): δ = 7.75 (s, 1H); 4.43 (m, br., 1H); 4.05 (dd, J; = 12.1 Hz, J2 = 5.2Hz, 1 H); 3.81 (dd, J, = 16.5 Hz, J2 = 5.3 Hz, 1H); 3.00 (ddd, J, = 16.5 Hz, J2 = 12.1 Hz, J3 = 2.4 Hz, 1H); 2.27 (m, 1H); 1.91 (m, 1H); 1.14 (t, J= 7.6 Hz, 3H). 13C-NMR (100 MHz, D2O): δ = 173.28 (s); 137.27 (d); 129.83 (s); 124.10 (s); 57.98 (d); 56.20 (d); 25.17 (t); 23.79 (t); 9.51 (q). MS (El): m/z = 194 (M+-H2, 2%); 166 (61%); 148 (9%); 120 (100%); 107 (10%); 93 (10%). HRMS: Calc. for C9H13N3O2: M+ = 195.1008; found: M+ = 195.0000. Intermediate 2 (Scheme 2) (4$, 6S)-5- [(Benzyloxy) carbonyl] -4-ethyl-4,5,6,7-tetr ahy dro-lH-imidazo [4,5- c]pyridine-6-carboxyIic acid: A solution of ( S,tfS)-4-Ethyl-4,5,6,7-tetrahydro-3H- imidazo[4,5-c]pyridine-6-carboxylic acid (500 mg, 2.56 mmol) in an aq. buffer solution at pH9 (5 mL) and dioxane (1 mL) was cooled to 0 °C. Benzyl chloroformate (0.845 mL, 5.64 mmol) was added dropwise over 1 min. The pH was maintained between 7 and 9 by adding from time to time aq. IM NaOH (total amount: about 5 mL). The mixture was stirred overnight while the temperature rose slowly to room temperature. The final pH was equal to 6.5 and an oily precipitate was lying in the bottom of the flask. This oily precipitate was decanted, dissolved in CHC13 and the solution dried over MgSO . After filtration, the filtrate was evaporated under reduced pressure. The residue was diluted in MeOH (20 mL) and aq. IM NaOH was added (10 mL). This solution was stirred at room temperature overnight and the pH was brought to 7 with aq. IM HCl. The solvent was removed under reduced pressure and the residue dried under high vacuum. The dried residue was purified by RP-HPLC (C18-column, 95% H2O → 15% H2O over 10 min → 0% H2O over lOmin). The acid was obtained as a foam (224 mg, 40%). 1H-NMR (400 MHz, CD3OD): δ = 8.15 (s, br., 1H); 7.40-7.23 (m, 5H); 5.46 (s, br., 1H); 5.21 (s, br., 3H); 2.83 (dd, J = 15.6 Hz, J2 = 6.1 Hz, 1H); 1.79 (s, br., 2H); 1.05 (s, br., 3H). MS (pos. ionization): m/z = 330 (MH+). Example 1 :
4-Methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride: According to GPIwith histamine dihydrochloride (12.1 g, 0.109 mol), NaOH (10.9 g, 0.272 mol), water (100 mL), MeOH (450 mL) and acetaldehyde (15.5 mL, 0.276 mol). The solution was acidified to pH<l with aq. cone. HCl and the solvent was removed under reduced pressure. The residue was thoroughly dried under high vacuum. The resulting oil was triturated with MeOH (1x 150 mL, 2x 50 mL) and filtered. The filtrate was evaporated under reduced pressure and the residue dried under high vacuum. This residue was then suspended in "PrOH and this suspension refluxed for lh. After allowing it to cool to room temperature, the mixture was filtered and the precipitate dried under high vacuum. The product was obtained as a brown powder that was not purified further (21.2 g, 90%). 1H-NMR (400 MHz, D2O): δ = 8.70 (s, br., IH); 3.76 (m, br., IH); 3.53 (m, br., IH); 3.09 (s, br., 2H); 1.69 (s, br., 3H). Example 2:
4-Ethyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride: According to GPIwith histamine dihydrochloride (20.0 g, 0.109 mol), NaOH (19.6 g, 0.49 mol), water (100 mL), MeOH (450 mL) and propionaldehyde (20.0 mL, 0.276 mol). The reaction mixture was acidified to pH<l with aq. cone. HCl (200 mL) and the solvent was removed under reduced pressure. The residue was dried thoroughly under high vacuum and the resulting oil triturated with MeOH (1x150 mL and 2x50 mL). The filtrate was evaporated under reduced pressure and the residue dried under high vacuum. The resulting oil was triturated with EtOH (1x50 mL and 2x15 mL) and filtered. The precipitate was dried under high vacuum. 4-Ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride was obtained as a colorless powder (5.38 g, 22%). 1H-NMR (400 MHz, CD3OD): δ = 8.95 (s, IH); 4.69-4.61 (m, IH); 3.80-3.70 (m, IH); 3.55-3.46 (m, IH); 3.20-3.02 (m, 2H); 2.31-2.15 (m, IH); 2.05-1.92 (m, IH); 1.15 (t, J= 7.8 Hz, 3H). 13C-NMR (100 MHz, D2O): δ = 134.70 (d); 124.98 (s); 123.72 (s); 53.26 (d); 40.59 (t); 24.41 (t); 18.11 (t); 8.88 (q). MS (El): m/z = 151 (M+, 1%); 150 (2%); 122 (100%); 107 (5%); 95 (13%); 80 (3%). HRMS: calc. for C8H13N3: M = 151.1158; found: 151.1109. Example 3:
4-PropyI-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride: According to GPI with histamine dihydrochloride (20.0 g, 0.109 mol), NaOH (19.6 g, 0.49 mol), water (100 mL), MeOH (450 mL) and butyraldehyde (24.9 mL, 0.278 mol). The reaction mixture was acidified to pH<l with aq. cone. HCl (200 mL) and the solvent was removed under reduced pressure. The residue was dried thoroughly under high vacuum and the resulting oil triturated with MeOH (1x150 mL and 2x50 mL). The filtrate was evaporated under reduced pressure and the residue dried under high vacuum. The resulting oil was triturated with EtOH (1x50 mL and 2x15 mL) and filtered. The precipitate was dried under high vacuum. 4-Propyl-4,5,6,7-tetrahydro- lH-imidazo[4,5-c]pyridine dihydrochloride was obtained as a colorless powder (20.9g, 80%). 1H-NMR (400 MHz, CD3OD): δ = 8.99 (s, IH); 4.75 (dd, J7 = 9.0 Hz, J2 = 4.4 Hz, IH); 3.82-3.73 (m, IH); 3.59-3.50 (m, IH); 3.24-3.05 (m, 2H); 2.21-2.10 (m, IH); 2.04-1.90 (m, IH); 1.70-1.52 (m, 2H); 1.07 (t, J= 7.8 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 136.13 (d); 126.43 (s); 125.61 (s); 53.05 (d); 41.79 (t); 34.41 (t); 19.45 (t); 19.30 (t); 14.01 (q). MS (El): m/z = 165 (M+, 1%); 164 (2%); 135 (2%); 122 (100%); 95 (12%); 80 (2%); 68 (5%). Example 4: 4-Phenyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride:
According to GPIwith histamine (10.0 g, 90 mmol), NaOH (9.0 g, 225 mol), water (90 mL), MeOH (365 mL) and benzaldehyde (23.1 mL, 0.23 mol). The reaction mixture was acidified to pH<l with aq. cone. HCl (165 mL) and the solvent was removed under reduced pressure. The residue was dried thoroughly under high vacuum and the resulting oil triturated with hot 'PrOH (150 mL). The mixture was filtered and the precipitate washed with cold 'PrOH (2x30 mL). The filtrate was heated to reflux and hexane (210 mL) added slowly, whereas a precipitate formed. The mixture was cooled to room temperature, then to -18 °C. The precipitate was filtered and dried. 4-Phenyl- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride was obtained as a yellow powder that contained 0.7 eq of jPrOH (14.1 g, 12.2 g of product, 50%). 1H- NMR (400 MHz, CD3OD): δ = 8.96 (s, IH); 7.6-7.3 (m, 5H); 5.99 (s, IH); 3.75-3.60 (m, 2H); 3.38-3.30 (m, IH); 3.20 (dt, J7 = 16.6 Hz, J2 = 5.5 Hz, IH). 13C-NMR (100 MHz, D2O): δ = 135.25 (s); 131.33 (d); 129.84 (d); 129.45 (d); 126.47 (s); 122.81 (s); 55.45 (d); 40.18 (t); 18.17 (t). MS (El): m z = 199 (M*, 5%); 170 (100%); 122 (89%); 91 (3%). HRMS; Calc. for C12Hι3N3: M+ = 199.1107; found: 199.1109. Example 5:
4-Benzyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (3): According to GPIwith histamine dihydrochloride (20.0 g, 0.109 mol), NaOH (19.6 g, 0.49 mol), water (100 mL), MeOH (450 mL) and phenacetaldehyde (36 mL, 0.276 mol). The reaction mixture was acidified to pH<l with aq. cone. HCl (50 mL) and the solvent was removed under reduced pressure. The residue was dried thoroughly under high vacuum and the resulting oil triturated with MeOH (1x150 mL and 2x50 mL). The filtrate was evaporated under reduced pressure and the residue dried under high vacuum. The resulting oil was triturated with 'PrOH and filtered. The precipitate was dried under high vacuum. 4-Benzyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride was obtained as a colorless powder that still contained 1 eq. 'PrOH (31.9 g, 25 g of product, 96%). 1H-NMR (400 MHz, D2O): δ = 8.76 (s, IH); 7.52-7.43 (m, 3H); 7.40-7.35 (m, 2H); 5.07 (dd, J, = 9.1 Hz, J2 = 5.7 Hz, IH); 3.76 (dt, J, = 13.1 Hz, J2 = 5.2 Hz, IH); 3.63 (dd, J, = 14.4 Hz, J2 = 5.6 Hz, IH); 3.53 (ddd, J7 = 13.9 Hz, J2 = 7.6 Hz, Jj = 6.1 Hz, IH); 3.24 (dd, Jj = 14.2 Hz, J2 = 9.3 Hz, IH); 3.16 (dd, J7 = 12.9 Hz, J2 = 7.8 Hz, IH). Example 6: Methyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.38 mmol), K2CO3 (690 mg, 5.00 mmol), CHC13 (6 mL), H2O (3 mL) and methyl chloroformate (0.39 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0: 100 → 0: 100 for 5 min, then → 1 :3 over 25 min). Methyl 4- methyI-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (270 mg, 58%). Rf = 0.30 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.52 (s, IH); 4.99 (s, br., IH); 4.30 (s, br., IH); 3.71 (s, 3H); 3.15 (td, br., J; - 11.7 Hz, J2 = 3.7 Hz, IH); 2.67 (m, IH); 2.54 (dd, J/ = 15.6 Hz, J2 = 4.2 Hz, IH); 1.88 (d, J= 6.8 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 157.47 (s); 135.38 (d); 134.32 (s); 126.41 (s); 53.37 (q); 49.43 (d); 38.71 (t); 23.50 (t); 19.28 (q). MS (El): m/z = 195 (M+, 11%); 180 (100%); 136 (10%); 120 (16%); 107 (22%). HRMS: Calc. for C9Hι3N3O2: M+ = 195.1008; found: 195.1010. Example 7: Benzyl 4-ethyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5-carboxylate trifluoroacetate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (1.00 g, 4.48 mmol), K2CO3 (1.24 g, 9.0 mmol), CHC13 (10 mL), H2O (8 mL) and benzyl chloroformate (1.36 mL, 9.0 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-8.5 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure. Twice successively, the residue was treated with aq. IM HCl and the solvent removed under reduced pressure. The residue was then suspended in aq. IM HCl (15 mL) and washed with Et2O (2x). The aq. phase was evaporated under reduced pressure and the residue purified by RP-HPLC (95% H2O → 0% H2O over 20 min. Benzyl 4-ethyl-l, 4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (590 mg, 33%). 1H-NMR (400 MHz, CD3OD): δ = 8.75 (s, IH); 7.42-7.27 (m, 5H); 5.19 (s, br., 3H); 4.46 (m, br., IH); 3.25 (m, br., IH); 2.78 (m, br., IH); 2.69 (dd, J; = 15.4 Hz, J2 = 3.4 Hz, IH); 1.00 (s, br., 3H). 13C-NMR (100 MHz, CD3OD): δ = 134.09 (d); 129.46 (d); 129.19 (d); 68.90 (t); 52.60 (d); 38.25 (t); 28.04 (t); 10.86 (q). MS (El): m/z = 285 (M+, 0.4%); 256 (45%); 194 (34%); 150 (5%); 120 (9%); 107 (5%); 91 (100%). HRMS: Calc. for C16Hι9N3O2: M+ = 285.1477; found: 285.1471. Elemental analysis: Calc. for Cι6Hι9N3O2 C2HF3O2H2O: C 51.8%, H 5.3%, N 10.6%; found: C 52.0%, H 4.9%, N 9.8%. Example 8:
Benzyl 4-phenyI-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (800 mg, 2.54 mmol), K2CO3 (737 mg, 5.33 mmol), CHC13 (6 mL), H2O (5 mL) and benzyl chloroformate (0.80 mL, 5.33 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO . The solvent was removed under reduced pressure and the residue purified by RP-HPLC (95% H2O → 0% H2O over 20 min). Benzyl 4~phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (291 mg, 25%) that contained 0.65 eq. H2O according to the elemental analysis. tR = 11.26 min. 1H-NMR (400 MHz, CD3OD): δ = 8.83 (s, IH); 7.48-7.27 (m, 10H); 6.48 (s, br., IH); 5.26 (d, br., J= 10.8 Hz, IH); 5.18 (d, J- 12.0 Hz, IH); 4.38 (d, br., J- 12.2 Hz, IH); 3.20 (ddd, J; = 15.9 Hz, J2 = 11.2 Hz, Jj = 4.6 Hz, IH); 2.96-2.78 (m, 2H). 13C-NMR (100 MHz, CD3OD): δ = 139.04 (s); 137.49 (s); 134.91 (d); 129.89-128.98 (several peaks, d and s); 127.85 (s); 69.11 (t); 54.16 (d); 38.12 (t); 22.24 (t). MS (El): m/z = 333 (M+, 9%); 242 (89%); 212 (4%); 198 (61%); 169 (27%); 91 (100%). Elemental analysis: Calc. for
C20Hι9N3O2 C2HF3O2-2/3H2O: C 57.5%, H 4.7%, 9.1%; found: C 57.5%, H 4.4%, N 9.1%.
Example 9: Benzyl 4-benzyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate: According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- yridine dihydrochloride (500 mg, 1.74 mmol), K2CO3 (507 mg, 3.67 mmol), CHC13 (6 mL), H2O (3 mL) and benzyl chloroformate (0.55 mL, 3.67 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC1 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 → 0:100 for 5 min, then → 1:3 over 25 min). Benzyl 4-benzyl- l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (225 mg, 42%). Rf = 0.31 (MeOH/CHCl3 1:9). 1H-NMR (400MHz, CD3OD): δ = 7.57 (s, IH); 7.23, 7.15 and 7.03 (m, 10H, rot.); 5.33, 5.25, 5.08 and 4.95 (m, 2H, rot.); 4.84 and 4.60 (d, J= 12.2 Hz, IH, rot); 4.81 and 4.17 (dd, Jt = 13.2 Hz and 13.7 Hz, J2 = 5.4 Hz and 4.6 Hz, IH, rot.); 3.24-2.90 (m, 3H, rot.); 2.83-2.33 ( , 2H, rot.). 13C-NMR
(100 MHz, CD3OD): δ = 157.24 and 156.95 (s, rot); 139.24 and 138.79 (s, rot); 137.46 (s); 135.51 and 135.46 (d, rot); 130.44 (d); 129.39, 129.24, 129.13, 129.01, 128.93, 128.83 and 128.72 (3xd, rot.); 127.36 (d); 68.31 and 68.17 (t, rot.); 55.24 and 54.53 (d, rot.); 40.96 and 40.20 (t, rot); 39.73 and 38.97 (t, rot.); 23.39 and 22.88 (t, rot.). MS (El): m/z = 256 (M+-C7H7, 26%); 212 (22%); 91 (100%). HRMS: Calc. for C21H21N3O2: M+ = 347.1634; found: 347.1603. Example 10:
Benzyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.52 mmol), K2CO3 (720 mg, 5.2 mmol), CHC13 (6 mL), H2O (5 mL) and benzyl chloroformate (0.78 mL, 5.2 mmol). After basic treatment for lh the mixture was acidified to pH 8.5 with aq. IM HCl. The reaction mixture was extracted with CHC1 (3x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by RP-HPLC (85% H2O → 0% H2O over 20 min). Benzyl 4-propyl- l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam that was crystallised from Et2O (276 mg, 27%). Mp = 166-7 °C. tR = 8.46 min. 1H-NMR (400 MHz, CD3OD): δ = 8.74 (s); 7.42-7.27 (m, 5H); 5.31 (m, br., IH); 5.18 (s, br., 2H); 4.44 (m, br., IH); 3.25 (m, br., IH); 2.78 (m, br., IH); 2.68 (dd, J7 = 15.6 Hz, J2 = 3.4 Hz, IH); 1.76 (m, 2H); 1.44 (m, br., 2H); 0.98 (m, br., 3H). 13C- NMR (100 MHz, CD3OD); δ = 156.92 (s); 134.08 (d); 130-128 (several peaks, s and d); 68.93 (t); 51.13 (d); 38.15 (t); 36.74 (t); 22.16 (t); 20.27 (t); 14.07 (q). MS (El): m z - 300 (M+H+, 20%); 256 (51%); 212 (60%); 208 (28%); 192 (3%); 164 (16%); 120 (12%); 91 (100%). Elemental analysis: Calc. for Cι7H2ιN3O2 C2HF3O2: C 55.2%, H 5.4%, N 10.2%; found C 55.1%, H 5.1%, N 10.0%. Example 11:
Methyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.68 mmol), K2CO3 (778 mg, 5.63 mmol), CHC13 (6 mL), H2O (4 mL) and methyl chloroformate (0.436 mL, 5.63 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by RP-HPLC (95% H2O over 5 min then -» 40% H2O over 10 min). Methyl 4- ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (71 mg, 8%). 1H-NMR (400 MHz, CD3OD): δ = 8.78 (s, IH); 4.19 (s, br., IH); 4.43 (s, br., IH); 3.75 (s, 3H); 3.22 (m, br., IH); 2.79 (m, IH); 2.69 (m, IH); 1.86 (m, 2H); 1.03 (t, J= 7.6 Hz, 3H). 13C-NMR (100 MHz, d6-DMSO, at 70 °C): δ = 157.77 (s); 134.06 (d); 129.55 (s); 127.63 (s); 53.74 (q); 52.52 (d); 38.09 (t); 27.92 (t); 22.00 (t); 10.81 (q). MS (El): m/z = 209 (M÷, 4%); 180 (100%); 150 (4%); 120 (54%); 107 (11%); 94 (15%); 93 (20%); 59 (76%). HRMS: Calc. for C10H15N3O2: M+ = 209.1164; found: 209.1171. Example 12:
Methyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.52 mmol), K2CO3 (720 mg, 5.2 mmol), CHC13 (6 mL), H2O (4 mL) and methyl chloroformate (0.40 mL, 5.2 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO . The solvent was removed under reduced pressure and the residue purified by RP-HPLC (95% H2O → 40% H2O over 15 min). Methyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (134 mg, 16%). 1H-NMR (400 MHz, CD3OD): δ = 8.78 (s); 5.29 (s, br., IH); 4.39 (s, br., IH); 3.73 (s, 3H); 3.25 (s, br., IH); 2.80 (m, IH); 2.70 (dd, J, = 15.9 Hz, J2 = 3.9 Hz, IH); 1.79 (m, IH); 1.46 (m, IH); 1.00 (t, J= 7.3Hz, 3H). 13C-NMR (100 MHz, d6-DMSO, at 70 °C); δ = 155.23 (s); 132.46 (d);
127.74 (s); 125.32 (s); 52.35 (q); 49.05 (d); 36.45 (t); 34.90 (t); 20.49 (t); 18.23 (t); 13.12 (q). MS (El): m z = 223 (M+, 2%); 194 (0.5%); 192 (1%); 180 (100%); 164 (1%); 148 (1%); 121 (6%); 120 (13%); 107 (4%). HRMS: Calc. for CπH17N3O2: M+ - 223.1321; found: 223.1323. Example 13:
Methyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c] pyridine dihydrochloride (800 mg, 2.54 mmol), K2CO3 (737 mg, 5.33 mmol), CHC13 (8 mL), H2O (5 mL) and methyl chloroformate (0.412 mL, 5.33 mmol). After basic treatment for 1 h the mixture was acidified to pH 8 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO . The solvent was removed under reduced pressure and the residue purified by RP-HPLC (95% H2O → 40% H2O over 15 min). Methyl 4-phenyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5-carboxyIate trifluoroacetate was obtained as foam (506 mg, 54%) that contained 1 eq water according to the elemental analysis. 1H-NMR (400 MHz, CD3OD): δ = 8.84 (s); 7.47- 7.24 (m, 5H); 6.46 (s, br., IH); 4.34 (d, br., J= 11.2 Hz, IH); 3.79 (s, 3H); 3.18 (ddd, Jι = 15.9 Hz, J2 = 11.2 Hz, J3 = 4.6 Hz, IH); 2.96-2.86 (m, IH); 2.82 (dd, J; = 15.6 Hz, J2 = 3.7 Hz, IH). 13C-NMR (100 MHz, d6-DMSO, at 70 °C): δ = 154.83 (s); 138.18 (s);
133.75 (d); 128.33 (d); 127.99 (d); 127.26 (d); 127.15 (s); 125.44 (s); 52.56 (q); 52.26 (d); 36.58 (t); 20.64 (t). MS (El): m/z = 257 (M+, 100%); 242 (27%); 226 (7%); 198 (22%); 180 (67%); 121 (6%); 120 (11%). HRMS: Calc. for Cι4Hι5N3O2: M+ = 257.1164; found: 257.1164. Elemental analysis: Calc. for Cι4H15N3O2C2HF3O2Η2O: C 49.4%, H 4.7%, N 10.8%; found: C 49.8%, H 4.8%, N 10.4%. Example 14:
4-Ethyl-5-(phenoxyacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine trifluoroacetate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.68 mmol), K2CO3 (778 mg, 5.63 mmol), CHC13 (6 mL), H2O (4 mL) and phenoxyacetyl chloride (0.78 mL, 5.6 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (3x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by RP-HPLC (85% H2O → 0% H2O over 20 min). 4-Ethyl-5-(phenoxyacetyl)- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine trifluoroacetate was obtained as foam (490 mg, 46%o) that contained 1.5 eq. H2O according to the elemental analysis. tR = 5.95 min. 1H-NMR (400 MHz, CD3OD): δ = 8.72 (s, IH); 7.25 (t, J= 7.3Hz, 2H); 7.08-6.82 (m, 3H); 5.61 (dd, J; = 9.3 Hz, J2 = 4.6 Hz, 0.9H, 1st rot.); 4.90-4.70 (m, 2 and 0.2H, 2nd rot.); 4.25 (dd, J = 14.4 Hz, J2 = 5.2 Hz, 0.9H, 1st rot); 3.52 (ddd, J = 14.9 Hz, J2 = 12.0 Hz, Jj = 4.4 Hz, 0.9H, 1st rot.); 3.17 (m, 0.1H, 2nd rot); 2.93 (m, IH); 2.76 (m, IH); 1.10 and 0.97 (t, J= 7.3 Hz, 3H, 2 rot.). 13C-NMR (100 MHz, CD3OD): δ = 170.08 (s); 159.18 (s); 134.29 (d); 130.48 (d); 129.34 (s); 127.20 (s); 122.60 (d); 115.62 (d); 68.03 (t); 50.38 (d); 39.47 (t); 27.75 (t); 22.86 (t); 10.80 (q). MS (El): m/z = 285 (M+, 15%); 256 (60%); 192 (43%); 178 (4%); 150 (13%); 135 (20%); 107 (45%); 77 (100%). HRMS: Calc. for C16H19N3O2: M1" = 285.1477; found: 285.1472. Elemental analysis: Calc. for C16H19N3O2 C2HF3O23/2H2O: C 50.7%, H 5.4%, N 9.8%; found: C 50.6%, H 5.6%, N 9.4%. Example 15:
4-Propyl-5-(phenoxyacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (600 mg, 2.52 mmol), K2CO3 (720 mg, 5.2 mmol), CHC13 (6 mL), H2O (4 mL) and phenoxyacetyl chloride (0.72 mL, 5.2 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by RP-HPLC (80% H2O → 0% H2O over 20 min. 4-Propyl-5- (phenoxyacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine trifluoroacetate was obtained as foam (307 mg, 30%) that contained 1.5 eq. H2O according to elemental analysis. tR = 6.36 min. 1H-NMR (400 MHz, CD3OD): δ = 8.74 (s, IH); 7.30-7.10 (m, 2H); 6.99-6.85 (m, 3H); 5.70 (t, J= 7.1 Hz, 0.9H, 1st rot.); 4.97-4.71 (m, 2H and 0.2H, 2nd rot.); 4.27 (dd, J/ = 14.6 Hz, J2 = 5.4 Hz, 0.9H, 1st rot); 3.54 (ddd, J; = 15.3 Hz, J2 = 11.7 Hz, Jj = 4.2 Hz, 0.9H, 1st rot.); 3.19 (m, 0.1H, 2nd rot.); 2.94 (ddd, J, = 16.9 Hz, J2 = 11.7 Hz, J = 5.4 Hz, 0.9H, 1st rot); 2.78 (dd, J} = 16.1 Hz, J2 = 3.7 Hz, 0.9H, 1st rot.); 2.70 (m, 0.2H, 2nd rot.); 1.88 (m, 0.1H, 2nd rot.); 1.80 (m, 0.9H, 1st rot.); 1.52 (m, 0.1H, 2nd rot.); 1.39. (m, 0.9H, 1st rot.); 1.00 and 0.95 (t, J= 7.5 Hz, 3H). 13C-NMR (100MHz, CD3OD); δ = 170.04 (s); 134.29 (d); 130.49 (d); 129.57 (s); 127.16 (s); 122.63 (d); 115.65 (d); 68.08 (t); 48.86 (d); 39,39 (t); 36.71 (t); 22.89 (t); 20.19 (t); 14.18 (q). MS (El): m/z = 299 (M1", 21%); 256 (100%); 206 (64%); 192 (4%); 135 (23%); 120 (40%); 107 (39%); 93 (15%). HRMS: Calc. for Cι7H2ιN3O2: M+ = 299.1634; found: 299.1630. Elemental analysis: Calc. for C17H2ιN3O2 C2HF3O2-3/2H2O: C 51.8%, H 5.7%, N 9.5%; found: C 51.9%, H 5.6%, N 9.2%. Example 16:
4-Phenyl-5-(phenoxyacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine trifluoroacetate: According to GPII, starting from 4-phenyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (800 mg, 2.54 mmol), K2CO3 (737 mg, 5.33 mmol), CHC13 (8 L), H2O (6 mL) and phenoxyacetyl chloride (0.74 mL, 5.33 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO . The solvent was removed under reduced pressure and the residue purified by RP-HPLC (85% H2O → 0% H2O over 20 min). 4-Phenyl-5- (phenoxyacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine trifluoroacetate was obtained as foam (400 mg, 35%). tR = 6.93 min. 1H-NMR (400 MHz, CD3OD): δ = 8.85 (s, IH); 7.46-7.23 (m, 7H); 7.00-6.86 (m, 3H); 4.96-4.76 (m, 3H); 4.20 (dd, // = 14.4 Hz, J2 = 4.9 Hz, IH); 3.45 (m, IH); 3.06 (m, IH); 2.91 (d, J= 15.6Hz, IH). 13C-NMR (100 MHz, d6-DMSO): δ = 166.72 (s); 157.72 (s); 138.00 (s); 134.10 (d); 129.27 (d); 128.62 (d); 128.32 (d); 127.77 (d); 127.42 (s); 124.84 (s); 120.89 (d); 114.52 (d); 65.93 (t); 49.70 (d); 37.73 (t); 21.59 (t). MS (El): m/z = 333 (M+, 77%); 256 (4%); 240 (100%); 226 (13%); 198 (56%); 169 (48%); 135 (3%); 122 (8%); 120 (12%); 94 (19%); 77 (73%). HRMS: Calc. for C20Hι9N3O2: M+ = 333.1477; found: 333.1475. Example 17:
Cyclopentyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridme-5- carboxylate trifluoroacetate: According to GPII, starting from 4-ethyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.78 mmol), K2CO3 (517 mg, 3.74 mmol), CHC13 (4 mL), H2O (2 mL) and cyclopentyl chloroformate (511 mg, 3.74 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (3x) and the combined org. phases were dried over Na2SO . The solvent was removed under reduced pressure and the residue purified by RP-HPLC (95% H2O → 65%» H2O over 10 min -» 0% H2O over 10 min). Cyclopentyl 4-ethyl-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (174 mg, 26%). tR = 10.14 min. 1H-NMR (400 MHz, CD3OD): δ = 8.75 (s); 5.17 (s, br., IH); 5.12 (t, J= 5.4 Hz, IH); 3.21 (s, br., IH); 2.76 (m, IH); 2.68 (dd, J7 = 14.9 Hz, J2 = 3.4 Hz, IH); 1.95-1.58 (m, 10H); 1.02 (t, J= 7.3 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 157.00 (s); 134.08 (d); 129.71 (s); 127.70 (s); 80.44 (d); 52.48 (d); 37.72 (t); 33.78 (t); 27.86 (t); 24.61 (t); 22.00 (t); 10.95 (q). MS (El): m z = 263 (M+, 4%); 234 (48%); 194 (12%); 178 (12%); 166 (100%); 122 (33%); 120 (14%); 107 (5%), 93 (5%). HRMS: Calc. for C14H2]N3O2: M+ = 263.1634; found: 263.1595. Example 18: Cyclopentyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K2CO3 (487 mg, 3.53 mmol), CHC13 (4 mL), H2O (2 mL) and cyclopentyl chloroformate (482 mg, 3.53 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by RP- HPLC (95% H2O - 65% H2O over 10 min -» 0% H2O over 10 min). Cyclopentyl 4-propyl-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (106 mg, 27%). tR = 10.97 min. 1H-NMR (400 MHz, CD3OD): δ = 8.75 (s, IH); 5.25 (m, br., IH); 5.11 (s, br., IH); 4.38 (m, br., IH); 3.22 (m, br., IH); 2.77 (m, br., IH); 2.68 (dd, /; = 15.9 Hz, J2 = 4.4 Hz, IH); 1.95-1.58 (m, 10H); 1.46 (m, 12H); 1.00 (t, /= 7.3 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 134.05 (d); 129.87 (s); 127.67 (s); 80.47 (d); 51.03 (d); 38.10 (t); 36.99 (t); 33.79 (t); 24.59 (t); 21.91 (t); 20.34 (t); 14.12 (q). MS (El): m/z = 277 (M+, 1%); 234 (32%); 208 (9%); 192 (10%); 166 (74%); 164 (7%); 150 (4%); 135 (5%); 122 (36%); 120 (49%); 95 (15%); 69 (100%). HRMS: Calc. for C15H23N3O2: M+ = 277.1790; found: 277.1780. Example 19:
Cyclopentyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-phenyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.59 mmol), K2CO3 (461 mg, 3.34 mmol), CHC13 (5 mL), H2O (2.5 mL) and cyclopentyl chloroformate (456 mg, 3.34 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by RP-HPLC (95% H2O -» 65% H2O over 10 min → 0% H2O over 10 min). Cyclopentyl 4-phenyl-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (162 mg, 24%) that contained leq. H2O according to the elemental analysis. tR= 10.35 min. 1H-NMR (400 MHz, CD3OD): δ = 8.83 (s, IH); 7.43-7.35 (m, 3H); 7.32-7.27 (m, 2H); 6.44 (s, br., IH); 5.16 (s, br., IH); 4.34 (s, br., IH); 3.18 (m, IH); 2.91 (dd, /; = 16.1Hz, J2 = 5.9Hz, IH); 2.83 (dd, J/ = 16.4 Hz, J2 = 4.9 Hz, IH); 1.97-1.56 (m, 8H). 13C-NMR (100 MHz, CD3OD): δ = 139.24 (s); 134.90 (d); 129.90 (d); 129.84 (d); 129.43 (s); 128.89 (d); 127.38 (s); 80.75 (d); 54.01 (d); 38.01 (t); 33.84 (t); 33.71 (t); 24.58 (t); 22.18 (t). MS (El): m z = 311 (M+, 56%); 242 (100%); 226 (24%); 198 (91%); 169 (72%); 166 (39%); 122 (13%). HRMS: Calc. for d8H21N3O2: M+ = 311.1634; found: 311.1625. Elemental analysis: Calc. for Cι8H2ιN3O2C2HF3O2Η2O: C 54.2%, H 5.5%, N 9.5%; found: C 54.1%, H 5.4%, N 9.4%. Example 20:
4-Fluorophenyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-ethyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.78 mmol), K2CO3 (517 mg, 3.74 mmol), CHC13 (4 mL), H2O (2 mL) and 4-fluorophenyl chloroformate (0.49 mL, 3.7 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (3x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure, the residue taken in aq. IM HCl and washed with Et2O (lx). The aq. phase was evaporated under reduced pressure and the residue was purified by RP-HPLC (90% H2O → 65% H2O over 10 min → 5% H2O over 10 min). 4-Fluorophenyl 4-ethyI- 1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate was obtained as foam (64 mg, 9%). tR = 9.21 min. 1H-NMR (400 MHz, CD3OD): δ = 8.80 (s, IH); 7.12 (m, 4H); 5.81 (m, br., IH); 4.55 (m, br., IH); 3.44 (m, br., IH); 2.97 (m, br., IH); 2.81 (m, br., IH); 1.96 (m, br., 2H); 1.12 (m, br., 3H). 13C-NMR (100 MHz, CD3OD): δ = 161.44 (sd, JF = 182 Hz); 155.77 (s); 148.38 (s); 134.25 (d); 129.36 (s); 127.63 (s); 124.33 (d); 116.76 (sd, JF = 17 Hz); 53.01 (d); 38.31 (t); 27.62 (t); 22.39 (t); 10.84 (q). MS (El): m/z = 289 (M+, 6%); 260 (100%); 178 (77%); 122 (12%); 120 (12%); 112 (7%); 95 (15%). HRMS: Calc. for Cι5H16FN3O2: M1" = 289.1227; found: 289. 1228. Example 21: 4-Fluorophenyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K2CO3 (487 mg, 3.53 mmol), CHC13 (4 mL), H2O (2 mL) and 4-fluorophenyl chloroformate (0.47 mg, 3.6 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by FC (MeOH/CHCl3 2:98 → 5:95 → 10:90 → 1 :1). 4-Fluorophenyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate was obtained as foam (92 mg, 18%). Rf = 0.20 (MeOH/CHCl3 1 :9). 1H-NMR (400 MHz, CDC13): δ = 7.80 (s, br., IH); 7.03 (m, br., 4H); 7.23 and 4.93 (m, IH, rot.); 4.45 and 4.36 (m, IH, rot.); 3.43-3.09 (m, IH); 2.88- 2.76, 2.69-2.46 and 2.32-2.18 (m, 2H, rot); 1.93-1.33 (m, 2H, rot); 0.98-0.87 (m, 3H, rot.). 13C-NMR (100 MHz, CDC13): δ = 159.93 (sd, JF= 182 Hz); 154.43 (s); 147.15 (s); 134.15 (d); 123.09 (d); 115.88 (dd, JF = 18 Hz); 53.16 and 52.58 (d, rot.); 38.96 and 38.74 (t, rot.); 37.01 and 36.64 (t, rot.); 23.36 and 22.27 (t, rot.); 19.67 and 19.34 (t, rot.); 14.34 and 14.18 (q, rot.). MS (El): m/z = 303 (M+, 2%); 260 (100%); 224 (5%); 208 (7%); 150 (19%); 122 (17%); 112 (10%). HRMS: Calc. for C16Hι8FN3O2: M+ = 303.1383; found: 303.1392. Example 22:
Methoxy-ethyI 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.78 mmol), K CO3 (517 mg, 3.74 mmol), CHC13 (4 mL), H2O (2 mL) and methoxyethyl chloroformate (518 mg, 3.74 mmol). After basic treatment for 1 h the mixture was acidified to pH 9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (3x) and the combined org. phases were dried over Na2SO4. The residue was purified by FC (MeOH/CHCl3 2:98 -» 5:95 -» 10:90). Methoxy-ethyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate was obtained as foam (98 mg, 22%) that contained 0.5 eq. H2O according to the elemental analysis. Rf = 0.05 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.55 (s, IH); 5.00 (s, br., IH); 4.35 (m, br., IH); 4.24 (s, br., 2H); 3.60 (s, br., 2H); 3.35 (s, br., 3H); 3.18 (s, br., IH); 2.71 (ddd, /, = 16.4 Hz, J2 = 12.0 Hz, J = 5.6 Hz, IH); 2.53 (dd, /} = 15.4 Hz, J2 = 3.4 Hz, IH); 1.89 (m, IH); 1.71 (m, IH); 1.00 (t, /= 7.3 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 157.50 (s); 135.22 (d); 133.67 (s);
126.64 (s); 71.86 (t); 65.80 (t); 59.06 (q); 54.81 (d); 39.18 and 38.88 (t, rot); 28.49 and 28.27 (t, rot.); 23.59 and 23.07 (t, rot.); 11.14 (q). MS (El): m/z = 253 (M1", 6%); 224 (100%); 194 (4%); 166 (7%); 150 (3%); 122 (38%). HRMS: Calc. for Cι2Hι9N3O3: M*" = 253.1426; found: 253.1421. Elemental analysis: Calc. for Ci2Hι9N3O3 l/2H2O: C 54.95%, H 7.68%, N 16.07%; found: C 55.07%, H 7.81%, N 15.78%. Example 23:
Methoxyethyl 4-propyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (400 mg, 1.68 mmol), K2CO3 (487 mg, 3.53 mmol), CHC13 (4 mL), H2O (2 mL) and methoxyethyl chloroformate (490 mg, 3.53 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by FC (MeOH/CHCl3 2:98 - 5:95 → 10:90). Methoxyethyl 4-propyl- l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (87 mg, 20%) that contained 0.25 eq. H2O according to the elemental analysis. Rf = 0.25 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.51 (s, IH); 5.08 (s, br., IH); 4.32 (m, br., IH); 4.23 (m, br., 2H); 3.59 (s, br., 2H); 3.36 and 3.34 (s, 3H, rot); 3.17 (m, br., 1H); 2.70 (ddd, J, = 16.1 Hz, J2 = 12.0 Hz, Jj = 5.6 Hz, IH); 2.53 (dd, Jy = 15.4 Hz, J2 = 3.2 Hz, IH); 1.79 (m, IH); 1.70 (m, IH); 1.45 (m, 2H); 0.97 (t, /= 7.6 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 157.44 (s); 135.22 (d); 133.93 (s); 126.82 (s); 71.84 (t); 65.79 (t); 59.05 (q); 53.30 (d); 39.10 and 38.80 (t, rot); 37.71 and 37.46 (t, rot); 23.59 and 23.06 (t, rot.); 20.49 (t); 14.41 (q). MS (El): m/z = 267 (M , 7%); 224 (100%); 208 (6%); 192 (7%); 180 (12%); 166 (11%); 122 (62%). HRMS: Calc. for Cι3H2ιN3O3: M+ = 267.1581; found: 267.1582. Elemental analysis: Calc. for Cι3H2ιN3O3T/4H2O: C 57.44%, H 7.97%, N 15.52%; found: C 57.28%, H 8.11%, N 15.22%. Example 24:
Methoxyethyl 4-phenyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-phenyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.59 mmol), K2CO3 (461 mg, 3.34 mmol), CHC13 (6 mL), H2O (4 mL) and methoxyethyl chloroformate (462 mg, 3.34 mmol). After basic treatment for 1 h the mixture was acidified to pH 8-9 with aq. IM HCl. The reaction mixture was extracted with CHC13 (4x) and the combined org. phases were dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified by FC (MeOH/CHCl3 2:98 → 5:95 → 10:90). Methoxyethyl 4-phenyI- l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (267 mg, 56%). Rf = 0.26 (MeOH/CHCl3 1 :9). 1H-NMR (400 MHz, CD3OD): δ = 7.62 (s, IH); 7.30 (m, 5H); 6.30 (s, br., IH); 4.29 (m, br., 2H); 3.65 (m, br., 2H); 3.38 (s, 3H); 3.09 (m, IH); 2.82 (m, br., IH); 2.65 (m, br., IH). 13C-NMR (100 MHz, CD3OD): δ = 157.09 (s); 141.43 (s); 135.89 (d); 131.30 (s); 129.25 (d); 129.03 (d); 128.77 (d); 128.34 (s); 77.81 (t); 65.99 (t); 59.08 (q); 56.09 (d); 38.95 and 38.81 (t, rot.); 23.51 and 23.07 (t, rot.). MS (El): m/z = 301 (M+, 24%); 242 (26%); 198 (41%); 115 (10%); 88 (11%). HRMS: Calc. for Cι6Hι9N3O3: M+ = 301.1426; found: 301.1419. Example 25:
Benzyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.38 mmol), K2CO3 (690 mg, 5.00 mmol), CHC13 (6 mL), H2O (3 mL) and benzyl chloroformate (0.75 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Ste -stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 → 0:100 for 5 min, then -> 1 :3 over 25 min). Benzyl 4- methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (193 mg, 30%). Rf = 0.25 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.51 (s, IH); 7.38-7.52 (m, 5H); 5.13 (m, br., 3H); 4.33 (d, br., /= 10 Hz, IH); 3.16 (t, br., /= 11.2 Hz, IH); 2.66 (m, br., IH); 2.54 (d, br., /= 12.9 Hz, IH); 1.38 (d, /= 6.8 Hz, 3H). 13C-NMR (100 MHz, CDC13): δ = 155.43 and 155.12 (s, rot); 136.49 (s); 134.00 (d); 132.85 (s); 128.45 (d); 127.98 (d); 127.67 (d); 125.94 and 124.83 (s, rot); 67.30 (t); 48.36 (d); 37.81 (t); 23.19 and 22.51 (t, rot); 19.56 and 19.14 (q, rot.). MS (El): m/z = 271 (M+, 0.5%); 256 (6%); 180 (82%); 136 (16%); 108 (14%); 91 (100%). HRMS: Calc. for C15H17N3O2: M+ = 271.1321; found: 271.1308. Example 26:
Benzyl 4-benzyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.74 mmol), K2CO3 (507 mg, 3.67 mmol), CHC13 (6 mL), H2O (3 mL) and benzyl chloroformate (0.55 mL, 3.67 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Steτn-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 → 0:100 for 5 min, then → 1:3 over 25 min). Benzyl 4- benzyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (225 mg, 42%). Rf = 0.31 (MeOH/CHCl3 1:9). 1H-NMR (400MHz, CD3OD): δ = 7.57 (s, IH); 7.23, 7.15 and 7.03 (m, 10H, rot.); 5.33, 5.25, 5.08 and 4.95 (m, 2H, rot); 4.84 and 4.60 (d, /= 12.2 Hz, IH, rot); 4.81 and 4.17 (dd, /; = 13.2 Hz and 13.7 Hz, J2 = 5.4 Hz and 4.6 Hz, IH, rot.); 3.24-2.90 (m, 3H, rot.); 2.83-2.33 (m, 2H, rot). 13C- NMR (100 MHz, CD3OD): δ = 157.24 and 156.95 (s, rot); 139.24 and 138.79 (s, rot); 137.46 (s); 135.51 and 135.46 (d, rot.); 130.44 (d); 129.39, 129.24, 129.13, 129.01, 128.93, 128.83 and 128.72 (3xd, rot); 127.36 (d); 68.31 and 68.17 (t, rot); 55.24 and 54.53 (d, rot.); 40.96 and 40.20 (t, rot.); 39.73 and 38.97 (t, rot.); 23.39 and 22.88 (t, rot). MS (El): m/z = 256 (M+-C7H7, 26%); 212 (22%); 91 (100%). HRMS: Calc. for C2ιH2ιN3O2: M+ = 347.1634; found: 347.1603. Example 27:
4-Methy l-5-(phenoxy acetyl)-4,5,6,7-tetrahydro-l H-imidazo [4,5-c] pyridine : According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-l H-imidazo [4,5- c]pyridine dihydrochloride (500 mg, 2.38 mmol), K2CO3 (690 mg, 5.00 mmol), CHC13 (6 mL), H2O (3 mL) and phenoxyacetyl chloride (0.69 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Ste -stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump
(MeOH/CHCl3 0:100 → 0:100 for 5 min, then → 1:3 over 25 min). 4-Methyl-5- (phenoxyacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine was obtained as foam (28 mg, 5%). Rf = 0.12 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.55 and 7.53 (s, IH, rot.); 7.26 (t, /= 7.1 Hz, 2H); 6.99-6.90 (m, 3H); 5.45 and 5.05 (q, /= 6.6 Hz, IH, rot.); 4.95-4.77 (m, 3H); 4.73 and 4.14 (dd, J, = 13.4 Hz and 14.2 Hz, J2 = 5.4 Hz and 5.1 Hz, IH, rot); 3.46 and 3.12 (ddd, J; = 12.0 Hz and 12.9 Hz, J2 = 12.0 Hz and 12.9 Hz, J3 = 4.2 Hz and 4.9 Hz, IH, rot.); 2.88-2.54 (m, 2H, rot.); 1.54 and 1.41 (d, /= 6.6 Hz and 6.8 Hz, 3H, rot.). 13C-NMR (100 MHz, CDC13): δ = 166.41 and 166.91 (s); 157.83 (s); 134.29 (d); 129.74 (d); 121.86 (d); 114.74 and 114.63 (d, rot); 68.18 and 67.47 (t, rot.); 50.15 and 46.78 (d, rot.); 39.81 and 35.94 (t, rot.); 24.03 and 22.04 (t, rot); 20.52 and 18.91 (q, rot). MS (El): m/z = 271 (M+, 20%); 194 (1%); 178 (100%); 164 (10%); 135 (15%); 107 (44%); 94 (15%). Example 28:
Allyl 4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate: According to GPII, starting from 4-methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine dihydrochloride (500 mg, 2.38 mmol), K2CO3 (690 mg, 5.00 mmol), CHC13 (6 mL), H2O (3 mL) and allyl chloroformate (0.53 mL, 5.0 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Sterø-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed- vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0: 100 → 0:100 for 5 min, then → 1:3 over 25 min). Allyl 4-methyl-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (284 mg, 54%). Rf = 0.30 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.53 (s, IH); 6.00-5.85 (m, IH); 5.29 (ddd, // = 17.2 Hz, J2 = 3.2 Hz, J3 = 1.7 Hz, IH); 5.19 (ddd, Jj = 10.5 Hz, J2 = 2.8 Hz, Jj = 1.3 Hz, IH); 5.11 (d, br., J = 6.4Hz, IH); 4.60 (dd, /, = 3.9Hz, J2 = 1.2Hz, 2H); 4.33 (dd, Ji = 13.4Hz, J2 = 4.9 Hz, IH); 3.16 (m, br., IH); 2.68 (m, IH); 2.55 (ddd, J = 15.4 Hz, J2 = 4.2 Hz, Jj = 1.0 Hz, IH); 1.39 (d, /= 6.8 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 156.58 (s); 135.40 (d); 134.31 (s); 134.09 (d); 126.31 (s); 117.73 (t); 67.25 (t); 49.39 (d); 38.71 (t); 23.57 and 23.24 (t, rot.); 19.54 and 19.16 (q, rot.). MS (El): m/z = 221 (M+, 2%); 206 (27%); 180 (100%); 136 (30%); 120 (30%); 107 (38%). HRMS: Calc. for CnH15N3O2: M+ = 221.1164; found: 221.1160. Example 29:
Allyl 4-ethyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate: According to GPII, starting from benzyl-4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5- c]pyridine-5-carboxylate trifluoroacetate (500 mg, 2.23 mmol), K2CO3 (646 mg, 4.68 mmol), CHC13 (6 mL), H2O (3 mL) and allyl chloroformate (0.50 mL, 4.7 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed- vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 -> 0:100 for 5 min, then -> 15:85 over 25 min). Allyl 4-ethyl- 3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (2.2 mg, 0.4%>). The low yield is probably due to a leak during the FC. Rf = 0.15
(MeOH/CHCl3 1 :9). 1H-NMR (400 MHz, CD3OD): δ = 7.52 (s, IH); 5.95 (m, IH); 5.29 (dd, // = 17.3 Hz, J2 = 1.2 Hz, IH); 5.20 (dd, J, = 10.5 Hz, J2 = 1.2 Hz, IH); 4.99 (m, br., IH); 4.60 (d, /= 5.1 Hz, 2H); 4.34 (dd, /; = 13.4 Hz, J2 = 4.6 Hz, IH); 3.19 (m, br., IH); 2.70 (dddd, /; = 15.6 Hz, J2 = 12.0 Hz, Jj = 5.6 Hz, J4 = 1.2 Hz, IH); 2.53 (ddd, /; = 15.4 Hz, J2 = 4.2 Hz, Jj = 1.0 Hz, IH); 1.88 (dddd, J/ = 15.1 Hz, J2 = 15.1 Hz, Jj = 7.6 Hz, J4 = 4.6 Hz, IH); 1.71 (m, IH); 0.99 (t, J= 7.6 Hz, 3H). MS (El): m/z = 235 (M*, 2%); 206 (100%); 194 (16%); 178 (5%); 162 (38%); 150 (4%). HRMS: Calc. for C12H17N3O2: M+ = 235.1321; found: 235.1330. Example 30:
Allyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate: According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- yridine dihydrochloride (500 mg, 2.10 mmol), K2CO3 (609 mg, 4.40 mmol), CHC13 (6 mL), H2O (3 mL) and allyl chloroformate (0.47 mL, 4.4 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Sterø-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed- vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl 0:100 - 0:100 for 5 min, then - 1:3 over 25 min). Allyl 4-propyl-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (68 mg, 13%). Rf = 0.20 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.51 (s, IH); 5.96 (m, IH); 5.29 (d, br., /= 17.3 Hz, IH); 5.19 (dd, J/ = 10.5 Hz, J2 = 1.2 Hz, IH); 5.09 (s, br., IH); 4.60 (m, 2H); 4.32 (d, br., J= 13.4 Hz, IH); 3.19 (d, br., /= 11.5 Hz, IH); 2.70 (m, IH); 2.55 (dd, /; = 15.4 Hz, J2 = 4.2 Hz, IH); 1.79 (m, IH); 1.70 (m, IH); 1.45 (m, 2H); 0.96 (t, /= 7.3 Hz, 3H). 13C-NMR (100 MHz, CD3OD): δ = 157.43 (s); 135.38 (d); 134.26(s); 134.14 (d); 126.51 (s); 118.02 and 117.75 (t, rot); 67.36 (t); 53.46 and 53.30 (d, rot.); 39.10 and 38.81 (t, rot.); 37.71 and 37.45 (t, rot.); 23.62 and 22.97 (t, rot.); 20.51 (t); 14.34 (q). MS (El): m/z = 249 (M+, 1%); 206 (44%); 192 (2%); 162 (13%); 135 (4%); 120 (34%); 107 (7%). HRMS: Calc. for Cι3H19N3O2: M+ = 249.1477; found: 249.1468. Example 31: 2,2,2-Trichloroethyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-
5-carboxylate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.23 mmol), K2CO3 (646 mg, 4.68 mmol), CHC13 (6 mL), H2O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.64 mL, 4.68 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 → 0:100 for 5 min, then → 1:3 over 25 min). 2,2,2- Trichloroethyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (168 mg, 23%). Rf = 0.16 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.53 (s, IH); 5.05 (m, IH); 4.97-4.72 (m, 2H); 4.39 (m, IH); 3.25 (m, IH); 2.76 (m, IH); 2.58 (dd, J = 15.4 Hz, J2 = 3.9 Hz, IH); 1.93 (m, IH); 1.75 (m, IH); 1.03 (m, 3H, rot). 13C-NMR (100 MHz, CD3OD): δ = 155.57 (s); 135.38 (d); 76.22 and 76.02 (t, rot.); 55.53 (d); 39.47 (t); 28.57 and 28.23 (t, rot); 23.70 and 22.89 (t, rot); 11.40 and 11.11 (q, rot.). MS (El): m/z = 325, 327, 329 v , 2%); 296, 298, 300 (100%); 262 (3%); 178 (19%); 166 (14%); 133 (17%); 122 (38%); 120 (38%); 107 (9%). HRMS: Calc. for CπH14Cl3N3O2: M+ = 325.0152; found: 325.0148. Example 32:
Allyl 4-benzyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5-c] pyridine-5-carboxylate: According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine dihydrochloride (500 mg, 1.74 mmol), K2CO3 (507 mg, 3.67 mmol),
CHC13 (6 mL), H2O (3 mL) and allyl chloroformate (0.39 mL, 3.67 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Ste/w-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 → 0:100 for 5 min, then -» 1:3 over 25 min). Allyl 4-benzyl- l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (63 mg, 12%). Rf = 0.31 (MeOH/CHCl3 1 :9). 1H-NMR (400 MHz, CD3OD): δ = 7.59 (s, IH); 7.29-6.94 (m, 5H); 5.86 and 5.69 (m, IH, rot.); 5.32 and 5.23 (m, IH, rot.); 5.23-5.12 (m, IH); 5.04 (d, br., J= 12.7 Hz, IH); 4.49 and 4.29 (m, 2H, rot); 4.18 and 4.03 (dd, J, = 13.4 Hz and 12.7 Hz, J2 = 4.9 Hz and 4.4 Hz, IH, rot.); 3.24-2.38 (m, 5H, rot). 13C-NMR (100 MHz, CD3OD): δ = 157.06 and 156.80 (s, rot); 139.33 and 138.83 (s, rot); 135.52 (d); 134.08, 133.78 and 133.49 (2x s, rot); 130.47 (d); 129.21 and 129.12 (d, rot); 127.54 and 127.32 (d, rot); 117.67 and 117.55 (t, rot); 67.17 (t); 55.19 and 54.45 (d, rot.); 40.99 and 40.24 (t, rot.); 39.65 and 38.85 (t, rot.); 23.36 and 22.92 (t, rot.). MS (El): m/z = 297 (M+, 0.05%); 240 (3%); 22 (14%); 206 (100%); 162 (21%); 120 (21%); 91 (50%). HRMS: Calc. for Cι7H19N3O2: M+ = 297.1477; found: 297.1448. Example 33:
2,2,2-Trichloroethyl -4-propy 1-1 ,4,6,7-tetrahy dro-5H-imidazo [4,5- c]pyridine-5-carboxylate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K2CO3 (609 mg, 4.40 mmol), CHC13 (6 mL), H2O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.61 mL, 4.4 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 → 0:100 for 5 min, then → 15:85 over 25 min). 2,2,2-Trichloroethyl 4-propyl-l ,4,6,7-tetrahy dro-5H- imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam that still contained 0.2 eq. H2O according to the elemental analysis (196 mg, 27%). Rf = 0.25 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 7.53 (s, IH); 5.15 (m, br., IH); 4.85 (m, 2H); 4.36 (m, IH); 3.26 (m, IH); 2.76 (m, IH); 2.58 (d, J= 15.4 Hz, IH); 2.30 (d, /= 15.1 Hz, IH); 1.83 (m, IH); 1.73 (m, IH); 1.47 (m, 2H); 0.98 (t, /= 7.3 Hz, IH). 13C-NMR (100 MHz, CD3OD): δ = 155.53 (s); 135.38 (d); 76.23 and 76.02 (t, rot); 54.15 and 53.90 (s, rot); 51.78 and 51.61 (d, rot.); 39.42 and 39.04 (t, rot); 37.84, 37.37, 37.11 and 36.64 (t, rot.); 23.70, 22.86, 22.27 and 21.56 (t, rot.); 20.74, 20.60, 20.49 and 20.34 (t, rot.); 14.51, 14.45, 14.22 and 14.27 (q, rot). MS (El): m/z = 296, 298 and 300 (100%); 262 (4%); 208 (10%); 192 (16%); 166 (24%); 137 (17%); 122 (38%); 95 (25%). HRMS: Calc. for Cι2Hι6Cl3N3O2: M+ = 339.0308; found: 339.0318. Elemental analysis: Calc. for Cι2H16Cl3N3O2T/5H2O: C 41.87%, H 4.80%, N 12.21%; found: C 41.87%, H 4.84%, N 11.81%. Example 34:
2,2,2-Trichloroethyl -4-propyl-l ,4,6,7-tetrahydro-5H-imidazo [4,5- c]pyridine-5-carboxylate: According to GPII, starting from 4-propyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K2CO3 (609 mg, 4.40 mmol), CHC13 (6 mL), H2O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.61 mL, 4.4 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 → 0:100 for 5 min, then → 15:85 over 25 min). 2,2,2-trichloroethyl 4-propyI-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam that still contained 0.2 eq. H2O according to the elemental analysis (196 mg, 27%). Rf = 0.25 (MeOH/CHCl3 1 :9). 1H-NMR (400 MHz, CD3OD): δ - 7.53 (s, IH); 5.15 (m, br., IH); 4.85 (m, 2H); 4.36 (m, IH); 3.26 (m, IH); 2.76 (m, IH); 2.58 (d, /= 15.4 Hz, IH); 2.30 (d, /= 15.1 Hz, IH); 1.83 (m, IH); 1.73 (m, IH); 1.47 (m, 2H); 0.98 (t, /= 7.3 Hz, IH). 13C-NMR (100 MHz, CD3OD): δ = 155.53 (s); 135.38 (d); 76.23 and 76.02 (t, rot); 54.15 and 53.90 (s, rot); 51.78 and 51.61 (d, rot); 39.42 and 39.04 (t, rot); 37.84, 37.37, 37.11 and 36.64 (t, rot.); 23.70, 22.86, 22.27 and 21.56 (t, rot); 20.74, 20.60, 20.49 and 20.34 (t, rot); 14.51, 14.45, 14.22 and 14.27 (q, rot). MS (El): m/z = 296, 298 and 300 (100%); 262 (4%); 208 (10%); 192 (16%); 166 (24%); 137 (17%); 122 (38%); 95 (25%). HRMS: Calc. for Cι2Hι6Cl3N3O2: M1" = 339.0308; found: 339.0318. Elemental analysis: Calc. for C12Hι6Cl3N3O2 l/5H2O: C 41.87%, H 4.80%, N 12.21%; found: C 41.87%, H 4.84%, N 11.81%. Example 35:
2,2,2-Trichloroethyl 4-benzyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine- 5-carboxylate: According to GPII, starting from 4-benzyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 1.74 mmol), K2CO3 (507 mg, 3.67 mmol), CHC13 (6 mL), H2O (3 mL) and 2,2,2-trichloroethyl chloroformate (0.51 L, 3.7 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stem-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed- vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 -> 0:100 for 5 min, then → 15:85 over 25 min 2,2,2- trichloroethyl 4-benzyI-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate was obtained as foam (211 mg, 31%). Rf = 0.22 (MeOH/CHCl3 1:9). 1H- NMR (400 MHz, CD3OD): δ = 7.61 (s, IH); 7.27-7.07 (m, 5H); 5.86 and 5.12 (m, IH, rot.); 4.79-4.63 (m, 1.5H, rot.); 4.83-4.16 (m, 1.5H, rot.); 3.28-3.22 (m, IH, rot.); 3.20- 2.85 (m, 2H, rot.); 2.73-2.63 (m, IH, rot.); 2.49 and 2.20 (dd, /; = 15.4 Hz and 15.6 Hz, J2 = 3.2 Hz and 3.9 Hz, IH, rot). 13C-NMR (100 MHz, CD3OD): δ = 155.32, 155.13 and 154.98 (s, rot); 138.94, 138.66, 138.25 and 138.07 (s, rot); 135.69 and 135.60 (d, rot); 130.62 and 130.51 (d, rot); 129.34, 129.21 and 129.06 (d, rot); 127.69, 127.58 127.45 and 127.39 (d, rot); 75.97 and 75.88 (t, rot); 55.41 and 55.13 (s, rot); 52.84 and 52.70 (d, rot.); 40.89, 40.26 and 40.18 (t, rot.); 39.88, 39.70, 39.50 and 39.29 (t, rot.); 23.42, 22.74, 22.06 and 21.53 (t, rot.). MS (El): m/z = 387 (ft , 0.3%); 296, 298 and 300 (100%); 262 (4%); 226 (2%); 166 (22%); 122 (35%). HRMS: Calc. for Cι6H16Cl3N3O2: M+ = 387.0308; found: 387.0318. Elemental analysis: Calc. for C16H16Cl3N3O2: C 49.44%, H 4.15%, N 10.81%; found: C 49.53%, H 4.29%, N 10.36%.
Example 36:
4-Ethyl-5-(4-nitrobenzyl)-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate: According to GPII, starting from 4-ethyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.23 mmol), K2CO3 (646 mg, 4.68 mmol), CHC13 (6 mL), H2O (3 mL) and old 4-nitrophenyl chloroformate (1.01 g, 4.68 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a screwed tap and stirred in a Stew-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed- vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed- vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 -» 0:100 for 5 min, then → 1:3 over 25 min). 4-Ethyl-5-(4- nitrobenzyl)-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate as obtained as foam (23 mg, 4%). Rf = 0.11 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 8.17 (d, /= 8.8 Hz, 2H); 7.62 (d, /= 8.8 Hz, 2H); 7.51 (s, IH); 3.88 (d, / = 14.4 Hz, IH); 3.74 (d, /= 14.4 Hz, IH); 3.43 (t, /= 6.1 Hz, IH); 3.11 (m, IH); 2.77 (m, 2H); 2.46 (dt, J} = 15.4 Hz, J2 = 4.5 Hz, IH); 1.78 (m, 2H); 0.89 (t, J= 7.3 Hz, 3H). 5 13C-NMR (100 MHz, CD3OD): δ = 149.30 (s); 148.35 (s); 134.81 (d); 130.54 (d);
124.23 (d); 60.23 (d); 57.61 (t); 46.45 (t); 27.43 (t); 20.98 (t); 10.72 (q). MS (El): m/z = 286 (M+, 0.4%); 257 (100%); 241 (1%); 227 (1%); 211 (8%); 136 (4%); 122 (7%); 120 (11%). HRMS: Calc. for Cι5H20N4O2: M1" = 286.1430; found: 286.1436. Example 37: o 5-(4-Nitrob enzyl)-4-propyl-l ,4,6,7-tetrahy dro-5H-imidazo [4,5-c] py ridine-5- carboxylate: According to GPII, starting from 4-propyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine dihydrochloride (500 mg, 2.10 mmol), K2CO3 (609 mg, 4.40 mmol), CHC13 (6 mL), H2O (3 mL) and old 4-nitrophenyl chloroformate (949 mg, 4.40 mmol). The reaction was carried out in a parallel fashion in a test-tube closed with a 5 screwed tap and stirred in a Stem-stirrer. The basic treatment was carried out in MeOH (6 mL) and aq. IM NaOH (4 mL). After 1 h the mixture was acidified with aq. IM HCl (3 mL). The reaction mixture was evaporated in a speed-vac overnight. The residue was triturated with CHC13 and filtered several times. The combined org. phases were evaporated in a speed-vac. The residue was purified by parallel FC with a gradient pump (MeOH/CHCl3 0:100 - 0:100 for 5 min, then -> 1 :3 over 25 min). 5-(4-
Nitrobenzyl)-4-proρyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate was obtained as foam (88 mg, 14%). Rf = 0.24 (MeOH/CHCl3 1:9). 1H-NMR (400 MHz, CD3OD): δ = 8.14 (d, J= 8.8 Hz, 2H); 7.58 (d, J= 8.8 Hz, 2H); 7.50 (s, IH); 3.83 (d, J= 14.4 Hz, IH); 3.74 (d, J= 14.4 Hz, IH); 3.49 (t, J= 5.9 Hz, IH); 3.12 (m, IH); 2.85-2.70 (m, 2H); 2.44 (ddd, J = 15.9 Hz, J2 = 5.1 Hz, J = 3.9 Hz, IH); 1.69 (m, 2H); 1.39 (m, 2H); 0.82 (t, J= 7.3 Hz, 3H). 13C-NMR (100 MHz, CDC13): δ = 148.03 (s); 147.07 (s); 133.47 (d); 132.38 (s); 129.28 (d); 126.14 (s); 123.53 (d); 57.83 (d); 56.83 (t); 45.02 (t); 36.37 (t); 20.00 (t); 19.40 (t); 14.31 (q). MS (El): m z = 299 (M - H+, 0.5%); 257 (100%); 241 (1%); 211 (9%); 136 (4%); 122 (3%); 120 (9%); 106 (3%); 90 (8%). Elemental analysis: Calc. for Cι6H22N4O2: C 63.56%, H 7.33%, N 17.06%; found: C 63.00%, H 7.32%, N 17.17%. Example 38:
Benzyl ( S,6'S)-4-ethyl-6-[(isobύtylamino)-carbonyl]-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxyIate trifluoroacetate: (^S,6'S)-5- [(Benzyloxy)carbonyl]-4-ethyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxyhc acid (99 mg, 0.30 mmol) was dissolved in DMF (2 mL). EDCHCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), DMAP (cat. amount) and isobutylamine (70 μL, 0.70 mmol) were added. The solution was stirred for 24 h. After removing the solvent under reduced pressure, the residue was purified by RP-HPLC (95% H2O → 65% H2O over 10 min → 0% H2O over 10 min). Benzyl (4S,6S)-4-et yl-6- [(isobutylamino)-carbonyl]-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate was obtained as foam (38.8 mg, 34%). ^-NMR (400 MHz, CDC13): δ = 8.46 (s, IH); 7.43-7.31 (m, 5H); 6.50 (s, br., IH); 5.36 (s, br., IH); 5.24 (s, br., 3H); 3.35 (d, /= 16.4 Hz, IH); 3.05 (dt, // = 19.8 Hz, J2 = 6.7 Hz, IH); 2.90 (s, br., IH); 2.82 (dd, / = 16.4 Hz, J2 = 6.8 Hz, IH); 1.87-1.74 (m, br., IH); 1.69 (s, br., IH); 1.61 (m, IH); 0.86 (s, br., 9H). 13C-NMR (100 MHz, CDC13): δ = 170.82 (s); 157.60 (s); 135.30 (s); 133.16 (d);.128.70 (d); 126.47 (s); 124.79 (s); 69.03 (t); 51.88 (d); 50.73 (d); 47.32 (t); 28.16 (d and t); 20.33 (t); 20.21 (q); 10.97 (q). MS (El): m/z = 384 (M+, 11%); 355 (20%); 311 (15%); 284 (6%); 249 (7%); 194 (3%); 150 (8%); 122 (9%); 91 (100%). HRMS: Calc. for C21H28N4O3: M+ = 384.2161; found: 384.2172. Example 39:
Benzyl (4S,6S)-6-(aminocarbonyl)-4-ethyl-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate: To a solution of (^S,5S)-5- [(Benzyloxy)carbonyl]-4-ethyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxyhc acid (80 mg, 0.24 mmol) in DMF (2 mL) were added NH3/dioxane (0.5M, 1.5 mL, 0.75 mmol), EDCHCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol) and DMAP (cat. amount). The solution was stirred overnight and the solvent removed under reduced pressure. The residue was dried under high vacuum and purified by RP-HPLC (95% H2O → 65% H2O over 10 min → 0% H2O over 10 min). Benzyl (4S,6S)-6- (aminocarbonyl)-4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate trifluoroacetate was obtained as foam (32.6 mg, 40%). Η-NMR (400 MHz, CD3OD): δ = 8.76 (s, IH); 7.47-7.21 (m, 5H); 5.48 (s, br., IH); 5.33-5.10 (m, br., 3H); 3.24 (dd, J = 16.1 Hz, J2 = 0.7 Hz, IH); 2.83 (ddd, /, = 16.4 Hz, J2 = 6.8 Hz, Jj = 1.7 Hz); 1.90-1.73 (m, 2H); 1.06 (s, br,, 3H). MS (El): m/z = 328 (M+, 4%); 284 (2%); 210 (6%); 193 (14%); 176 (3%); 107 (6%); 91 (100%). HRMS: Calc. for C17H20N4O3: M+ = 328.1535; found: 328.1523.
SSAO activity assays
All assays were performed at room temperature with SSAO purified from human umbilical cord arteries. The enzyme activity was measured with two different methods, based on the detection of either hydrogen peroxide or the aldehyde that is formed from SSAO catalysis of its main substrates, primary amines. Hydrogen peroxide detection
This method is based on the horseradish peroxidase catalyzed hydrogen peroxide oxidation of 10-acetyl-3,7-dihydroxyphenoxazine (Molecular Probes A-6550), that yields a highly fluorescent product, resorufin. Briefly, 10 mM stock solution of substance in DMSO is serially diluted in 0.05 M sodium-potassium phosphate buffer. These dilutions are mixed with benzylamine (SSAO substrate) and a reagent solution consisting of SSAO enzyme, horse radish peroxidase (HRP) and 10- acetyl-3,7-dihydroxyphenoxazine. The final concentrations in the assay volume are 104 μM benzylamine, 219 μM 10-acetyl-3,7-dihydroxyphenoxazine, 1.1 U/ml HRP and a dilution of the SSAO preparation of 1/600. After two hours of incubation in flat- bottomed polystyrene microtiter plates, the fluorescence is measured at 560 ex / 590 em. The inhibition is measured as % decrease of the signal compared to a control containing dilution of DMSO only (no substance). Aldehyde detection SSAO activity is measured as increase of aldehyde formed from SSAO degradation of primary amines. Briefly, in conical glass centrifuge tubes, 14C -labeled benzylamine is mixed with substance dilutions (from 10 mM stock solution in DMSO) in 0.05 M sodium-potassium phosphate buffer (pH 7.8). Enzyme, also diluted in phosphate buffer, is added and incubation is performed at room temperature for 60 minutes. The reaction is stopped with 1 M HCl. The formed (1 C -labeled) aldehyde is separated from the likewise 14C -labeled benzylamine through extraction with toluene:ethyl acetate and then transferred to liquid scintillation vials for measurement of radioactivity in a beta counter. The final concentrations in the assay volume are 150 μM benzylamine (0.037 MBq/μmol), and a dilution of the SSAO preparation of l/150.The inhibition is measured as % decrease of the signal compared to control containing dilution of DMSO only (no substance).
Biological activity
The compounds shown in Tables 2 and 3 were tested for biological activity, determined as per cent inhibition of SSAO at 12 μM concentration of the test compounds. The compounds were shown to inhibit SSAO to from 10 to 97 %.
Figure imgf000036_0001
Table 2
Figure imgf000036_0002
Figure imgf000037_0001
Figure imgf000038_0002
Table 3
Figure imgf000038_0001
Figure imgf000038_0003

Claims

1. Use of a compound of Formula (I)
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof, wherein
R] is
(a) H, or
(b) CONH-R5;
R2 is
(a) COOR5,
(b) COR5,
(c) CONH-R5,
(d) CSNH-R5, or
(e) H;
R3 is
(a) H,
(b) Ci_g alkyl, or
(c) (CH2)nAr;
R4 is
(a) H,
(b) Ar, or
(c) Cj.8 alkyl; and
R5 is (a) H,
(b) (CH2)nAr,
(c) (CH2)nOAr,
(d) C^ alkyl containing 0-2 oxygen atoms and optionally substituted with 0-5 halogen atoms, or (e) a polyether chain having the formula (CH2)xO(CH2)yO(CH2)zCH3 ; n is an integer 0 to 4; m is an integer 0 to 2; x and y are integers 2 to 4; z is an integer 0 to 3; Ar is phenyl, 1-naphthyl or 2-naphthyl, unsubstituted optionally mono-or poly- substituted with electrodonating groups, halogen, C β alkyl, CF , hydroxyl, -6 alkoxyl, OCF3, CN, NO2, phenyloxyl, benzyloxyl, optionally substituted phenyl, alkylsulfonyl, Cι_6 alkenyl, -NH2, R7NH-, R7 R7N-, Cι_6 alkylcarboxyl, formyl, Ci-β alkyl-CO-NH-, aminocarbonyl (R7 R7-N-CO-), SR7 wherein R7 is simultaneously or alternatively H or Cι_6 alkyl; cynnamoyl, unsubstituted or optionally substituted benzyl; 1,1-diphenylethyl, a monocyclic or bicyclic heterocyclic ring (furyl, pyrrolyl, triazolyl, diazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, indolyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, benzoxadiazolyl which are unsubstituted or optionally mono or di-substituted with halogen, Cι-6 alkyl); 2, or 3, or 4-pyridyl or a 5 to 7-membered unsaturated or partially or completely saturated heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur where nitrogen containing heterocycles may contain H or Cι-6 alkyl or CF3-CO- at the nitrogen atoms where such a substitution is allowed; in the manufacture of a medicament for the treatment or prophylaxis of SSAO- mediated complications.
The use according to claim 1 wherein R is H.
3. The use according to claim 1 or 2 wherein R is COOR .
4. The use according to any one of claims 1 to 3 wherein R is Cι-3 alkyl or benzyl.
5. The use according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of: benzyl 4-methyl- 1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate; benzyl 4-ethyl- 1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate; benzyl 4-propyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate trifluoroacetate;
2,2,2-Trichloroethyl 4-ethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate; and benzyl (4S,6S)-6-(aminocarbonyl)-4-ethyl- 1 ,4,6,7-tetrahydro-5H-imidazo[4,5- c]pyridine-5 -carboxylate trifluoroacetate.
6. The use according to any one of claims 1 to 5, wherein the said SSAO-mediated complication is diabetes.
7. The use according to any one of claims 1 to 5, wherein the said SSAO-mediated complication is a vascular complication.
8. A pharmaceutical formulation for use in the treatment or prophylaxis of an SSAO-mediated complication, comprising as active ingredient a compound as defined in any one of claims 1 to 5, together with a pharmaceutically acceptable carrier.
9. The pharmaceutical formulation according to claim 8, wherein the said SSAO- mediated complication is diabetes.
10. The pharmaceutical formulation according to claim 8, wherein the said SSAO- mediated complication is a vascular complication.
PCT/SE2001/002523 2000-11-09 2001-11-09 New use of 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine derivatives WO2002038153A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002214505A AU2002214505A1 (en) 2000-11-09 2001-11-09 New use of 4, 5, 6, 7-tetrahydroimidazo-(4,5-c)pyridine derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE0004101A SE0004101D0 (en) 2000-11-09 2000-11-09 New use
SE0004101-2 2000-11-09
US25215600P 2000-11-20 2000-11-20
US60/252,156 2000-11-20

Publications (1)

Publication Number Publication Date
WO2002038153A1 true WO2002038153A1 (en) 2002-05-16

Family

ID=26655299

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2001/002523 WO2002038153A1 (en) 2000-11-09 2001-11-09 New use of 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine derivatives

Country Status (2)

Country Link
AU (1) AU2002214505A1 (en)
WO (1) WO2002038153A1 (en)

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051842A2 (en) * 2001-12-14 2003-06-26 Novo Nordisk A/S Compositions decreasing activity of hormone-sensitive lipase
WO2005063261A1 (en) * 2003-12-31 2005-07-14 Faron Pharmaceuticals Oy Aminoglycoside antibiotics for use as vap-1/ssao inhibitors
WO2005072738A1 (en) * 2004-01-30 2005-08-11 Faron Pharmaceuticals Oy Compositions useful especially for treatment or prevention of metabolic syndrome
US7071355B2 (en) 2002-12-23 2006-07-04 4 Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7125901B2 (en) 2003-01-27 2006-10-24 Astellas Pharma Inc. Thiazole derivatives
US7247736B2 (en) 2002-12-23 2007-07-24 4Sc Ag Method of identifying inhibitors of DHODH
JP2008508188A (en) * 2004-07-27 2008-03-21 アステラス製薬株式会社 Thiazole derivatives having VAP-1 inhibitor activity
US7365094B2 (en) 2002-12-23 2008-04-29 4Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2010031789A1 (en) * 2008-09-16 2010-03-25 Biovitrum Ab (Publ) New compounds i
WO2010031791A1 (en) * 2008-09-16 2010-03-25 Biovitrum Ab (Publ) New compounds ii
WO2010064020A1 (en) 2008-12-04 2010-06-10 Proximagen Ltd. Imidazopyridine compounds
EP2283833A2 (en) 2004-02-25 2011-02-16 La Jolla Pharmaceutical Co. Amines and amides for the treatment of diseases
KR20110022574A (en) 2008-05-30 2011-03-07 가부시키가이샤 아루떼꾸 우에노 Benzene or thiophene derivative and use thereof as vap-1 inhibitor
WO2011029996A1 (en) 2009-09-08 2011-03-17 Biotie Therapies Corp. Use of vap-1 inhibitors for treating fibrotic conditions
WO2011034078A1 (en) 2009-09-16 2011-03-24 アステラス製薬株式会社 Glycine compound
WO2011113798A2 (en) 2010-03-15 2011-09-22 Proximagen Limited New enzyme inhibitor compounds
US8119651B2 (en) 2004-01-30 2012-02-21 Biotie Therapies Corp. Compositions useful especially for treatment or prevention of metabolic syndrome
WO2012120195A1 (en) 2011-03-08 2012-09-13 Biotie Therapies Corporation New pyridazinone and pyridone compounds
WO2012124696A1 (en) 2011-03-15 2012-09-20 アステラス製薬株式会社 Guanidine compound
WO2013037411A1 (en) 2011-09-14 2013-03-21 Proximagen Limited New enzyme inhibitor compounds
WO2013038189A1 (en) 2011-09-14 2013-03-21 Proximagen Ltd. New enzyme inhibitor compounds
US8507690B2 (en) 2008-01-31 2013-08-13 R-Tech Ueno, Ltd. Thiazole derivative and use thereof as VAP-1 inhibitor
US20140275013A1 (en) * 2013-03-15 2014-09-18 University Of Washington Through Its Center For Commercialization Compounds and compositions for the treatment of parasitic diseases
WO2014199171A1 (en) 2013-06-12 2014-12-18 Proximagen Limited New therapeutic uses of enzyme inhibitors
WO2015159112A1 (en) 2014-04-15 2015-10-22 Pécsi Tudományegyetem Semicarbazide-sensitive amine oxidase inhibitors for use as analgesics in traumatic neuropathy and neurogenic inflammation
US9186361B2 (en) 2013-03-15 2015-11-17 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
WO2015189534A1 (en) 2014-06-12 2015-12-17 Proximagen Limited Vap-1 inhibitors for treating muscular dystrophy
WO2016042332A1 (en) * 2014-09-17 2016-03-24 Proximagen Limited Imidazo[4,5-c]pyridine derived ssao inhibitors
WO2016042331A1 (en) * 2014-09-17 2016-03-24 Proximagen Limited Imidazo[4,5-c]pyridine derived ssao inhibitors
US9296754B2 (en) 2013-03-15 2016-03-29 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9303034B2 (en) 2013-12-19 2016-04-05 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9428498B2 (en) 2013-03-13 2016-08-30 Proximagen Limited Substituted imidazo[4,5-c]pyridine compounds and compositions thereof
WO2016194390A1 (en) 2015-06-05 2016-12-08 R-Tech Ueno, Ltd. Pharmaceutical composition for use in the treatment of cancer
US9580415B2 (en) 2013-03-13 2017-02-28 Proximagen Limited Compounds
US9765092B2 (en) 2013-11-19 2017-09-19 Actelion Pharmaceuticals Ltd Tricyclic piperidine compounds
CN107915719A (en) * 2017-12-29 2018-04-17 佛山汉方中医医院有限公司 SSAO inhibitor of a kind of methyl adamantane and pyridine structure and application thereof
CN107935990A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 Containing adamantane and alcoxyl pyridine structure compound, preparation method and the usage
CN107935993A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 Methyl adamantane and nitropyridine structural derivative, Its Preparation Method And Use
CN107935989A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 Adamantane and itrile group pyridine structure compound, preparation method and the usage
CN107935992A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 One kind contains adamantane and haloperidid structural compounds and purposes
CN108033945A (en) * 2017-12-29 2018-05-15 佛山汉方中医医院有限公司 A kind of adamantane and nitropyridine structural compounds and purposes
CN108033946A (en) * 2017-12-29 2018-05-15 佛山汉方中医医院有限公司 A kind of SSAO inhibitor, preparation method and its usage containing adamantane structure
JP2018513189A (en) * 2015-04-24 2018-05-24 プロキシマジェン リミティド Pharmaceutical salt forms of inhibitors of semicarbazide sensitive amine oxidase (SSAO)
CN108084155A (en) * 2017-12-29 2018-05-29 佛山汉方中医医院有限公司 SSAO inhibitor of methyl adamantane and alcoxyl pyridine structure and application thereof
CN108084154A (en) * 2017-12-29 2018-05-29 佛山汉方中医医院有限公司 A kind of adamantane and amido pyridine structure derivative, preparation method and the usage
CN108129458A (en) * 2017-12-29 2018-06-08 佛山汉方中医医院有限公司 A kind of adamantane and dimethylaminopyridine structural derivative, preparation method and the usage
CN108191823A (en) * 2017-12-29 2018-06-22 佛山汉方中医医院有限公司 A kind of alkyl substitution adamantane SSAO inhibitor, preparation method and its usage
CN108191825A (en) * 2017-12-29 2018-06-22 佛山汉方中医医院有限公司 A kind of methyl adamantane and nitropyridine structural derivative and application thereof
CN108191824A (en) * 2017-12-29 2018-06-22 佛山汉方中医医院有限公司 A kind of methyl adamantane and dimethylaminopyridine structural derivative, Its Preparation Method And Use
JP2018517683A (en) * 2015-05-04 2018-07-05 アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ Tricyclic piperidine compounds
JP2018524392A (en) * 2015-07-24 2018-08-30 ベネボレンタイ ケンブリッジ リミティド Novel therapeutic compounds and their use in therapy
US10189839B2 (en) 2013-11-19 2019-01-29 Actelion Pharmaceuticals Ltd Tricyclic imidazole compounds as inhibitors of tryptophan hydroxylase
CN109988147A (en) * 2017-12-29 2019-07-09 佛山汉方中医医院有限公司 SSAO inhibitor, preparation method and its usage containing adamantane structure
US10369139B2 (en) 2015-04-24 2019-08-06 Benevolentai Cambridge Limited Crystalline compound as semicarbazide-sensitive amine oxidase (SSAO) enzyme inhibitor
EP3777846A1 (en) 2015-12-07 2021-02-17 BenevolentAI Cambridge Limited Vap-1 inhibitors for treating pain

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4141899A (en) * 1976-01-07 1979-02-27 Societa' Farmaceutici Italia S.P.A. 4,5,6,7-Tetrahydroimidazo-[4,5-c]-pyridine derivatives
GB2158440A (en) * 1985-01-22 1985-11-13 Erba Farmitalia 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine derivatives
WO1993023023A1 (en) * 1992-05-15 1993-11-25 University Of Saskatchewan Method for preventing endothelium damage in mammals and for alleviating pain associated with gout and arthritis
WO2000063208A1 (en) * 1999-04-16 2000-10-26 Novo Nordisk A/S Substituted imidazoles, their preparation and use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4141899A (en) * 1976-01-07 1979-02-27 Societa' Farmaceutici Italia S.P.A. 4,5,6,7-Tetrahydroimidazo-[4,5-c]-pyridine derivatives
GB2158440A (en) * 1985-01-22 1985-11-13 Erba Farmitalia 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine derivatives
WO1993023023A1 (en) * 1992-05-15 1993-11-25 University Of Saskatchewan Method for preventing endothelium damage in mammals and for alleviating pain associated with gout and arthritis
WO2000063208A1 (en) * 1999-04-16 2000-10-26 Novo Nordisk A/S Substituted imidazoles, their preparation and use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANIM., PLANT MICROB. TOXINS, PROC. INT. SYMP., 4TH (1976) MEETING DATE 1974, vol. 1, 1976, pages 273 - 286 *
DATABASE CAPLUS [online] PREUSSER H.J. ET AL.: "Antimicrobial activity of alkaloids from amphibian venoms and effects on the ultrastructure of yeast cells", XP002908095, accession no. STN Database accession no. 1977:479326 *

Cited By (115)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051841A2 (en) * 2001-12-14 2003-06-26 Novo Nordisk A/S Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
WO2003051842A3 (en) * 2001-12-14 2004-06-03 Novo Nordisk As Compositions decreasing activity of hormone-sensitive lipase
WO2003051841A3 (en) * 2001-12-14 2004-06-24 Novo Nordisk As Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
WO2003051842A2 (en) * 2001-12-14 2003-06-26 Novo Nordisk A/S Compositions decreasing activity of hormone-sensitive lipase
US7067517B2 (en) 2001-12-14 2006-06-27 Nero Nordisk A/S Use of compounds for decreasing activity of hormone-sensitive lipase
US7279470B2 (en) 2001-12-14 2007-10-09 Novo Nordisk A/S Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
US7247736B2 (en) 2002-12-23 2007-07-24 4Sc Ag Method of identifying inhibitors of DHODH
US7365094B2 (en) 2002-12-23 2008-04-29 4Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7071355B2 (en) 2002-12-23 2006-07-04 4 Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7125901B2 (en) 2003-01-27 2006-10-24 Astellas Pharma Inc. Thiazole derivatives
US7442715B2 (en) 2003-01-27 2008-10-28 Astellas Pharma Inc. Thiazole derivatives
WO2005063261A1 (en) * 2003-12-31 2005-07-14 Faron Pharmaceuticals Oy Aminoglycoside antibiotics for use as vap-1/ssao inhibitors
WO2005072738A1 (en) * 2004-01-30 2005-08-11 Faron Pharmaceuticals Oy Compositions useful especially for treatment or prevention of metabolic syndrome
US8119651B2 (en) 2004-01-30 2012-02-21 Biotie Therapies Corp. Compositions useful especially for treatment or prevention of metabolic syndrome
EP2283833A2 (en) 2004-02-25 2011-02-16 La Jolla Pharmaceutical Co. Amines and amides for the treatment of diseases
JP2008508188A (en) * 2004-07-27 2008-03-21 アステラス製薬株式会社 Thiazole derivatives having VAP-1 inhibitor activity
EP2676955A1 (en) 2008-01-31 2013-12-25 R-Tech Ueno, Ltd. Thiazole Derivative and use thereof as VAP-1 Inhibitor
US8507690B2 (en) 2008-01-31 2013-08-13 R-Tech Ueno, Ltd. Thiazole derivative and use thereof as VAP-1 inhibitor
KR20110022574A (en) 2008-05-30 2011-03-07 가부시키가이샤 아루떼꾸 우에노 Benzene or thiophene derivative and use thereof as vap-1 inhibitor
EP2886534A1 (en) 2008-05-30 2015-06-24 R-Tech Ueno, Ltd. Benzene or thiophene derivative and use thereof as VAP-1 inhibitor
US8999989B2 (en) 2008-05-30 2015-04-07 R-Tech Ueno, Ltd. Benzene or thiophene derivative and use thereof as VAP-1 inhibitor
US9603833B2 (en) 2008-05-30 2017-03-28 R-Tech Ueno, Ltd. Benzene or thiophene derivative and use thereof as VAP-1 inhibitor
US8569338B2 (en) 2008-09-16 2013-10-29 Proximagen Ltd. Methods of using 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine compounds
WO2010031789A1 (en) * 2008-09-16 2010-03-25 Biovitrum Ab (Publ) New compounds i
JP2012506368A (en) * 2008-09-16 2012-03-15 プロキシマジェン エルティーディー New Compound I
US8263616B2 (en) 2008-09-16 2012-09-11 Proximagen Ltd 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine compounds
US11040969B2 (en) 2008-09-16 2021-06-22 Benevolentai Cambridge Limited Compounds I
US9035066B2 (en) 2008-09-16 2015-05-19 Proximagen Limited Method of using 4,5,6,7-tetrahydroimidazo[4,5-C]pyridine compounds
US10399973B2 (en) 2008-09-16 2019-09-03 Benevolentai Cambridge Limited Compounds I
WO2010031791A1 (en) * 2008-09-16 2010-03-25 Biovitrum Ab (Publ) New compounds ii
US9493457B2 (en) 2008-09-16 2016-11-15 Proximagen Limited 4,5,6,7-tetrahyroimidazo[4,5-c]pyridine compounds
US20110195992A1 (en) * 2008-09-16 2011-08-11 Proximagen Limited New compounds ii
AU2009294660B2 (en) * 2008-09-16 2013-11-14 Benevolentai Cambridge Limited New compounds I
US9890160B2 (en) 2008-09-16 2018-02-13 Proximagen Limited Compounds I
US8633318B2 (en) 2008-09-16 2014-01-21 Proximagen Ltd Compounds for treatment or prevention of inflammation, an inflammatory disease, or an immune or an autoimmune disorder
EA019167B1 (en) * 2008-09-16 2014-01-30 Проксимаген Лимитед Compounds inhibiting ssao activity
WO2010064020A1 (en) 2008-12-04 2010-06-10 Proximagen Ltd. Imidazopyridine compounds
RU2580626C2 (en) * 2009-09-08 2016-04-10 Байотай Терапис Корп. Use of vap-1 inhibitors for fibrotic sickness treatment
US10576148B2 (en) 2009-09-08 2020-03-03 Biotie Therapies Corp. Use of VAP-1 inhibitors for treating fibrotic conditions
US9795671B2 (en) 2009-09-08 2017-10-24 Biotie Therapies Corp. Use of VAP-1 inhibitors for treating fibrotic conditions
WO2011029996A1 (en) 2009-09-08 2011-03-17 Biotie Therapies Corp. Use of vap-1 inhibitors for treating fibrotic conditions
US8802679B2 (en) 2009-09-16 2014-08-12 Astellas Pharma Inc. Glycine compound
WO2011034078A1 (en) 2009-09-16 2011-03-24 アステラス製薬株式会社 Glycine compound
EP2927233A1 (en) 2010-03-15 2015-10-07 Proximagen Limited Inhibitors of semicarbazide-sensitive amine oxidase
WO2011113798A2 (en) 2010-03-15 2011-09-22 Proximagen Limited New enzyme inhibitor compounds
US9227967B2 (en) 2010-03-15 2016-01-05 Proximagen Limited Inhibitor compounds of semicarbazide-sensitive amine oxidases
WO2012120195A1 (en) 2011-03-08 2012-09-13 Biotie Therapies Corporation New pyridazinone and pyridone compounds
KR20140014153A (en) 2011-03-15 2014-02-05 아스테라스 세이야쿠 가부시키가이샤 Guanidine compound
EP3002278A1 (en) 2011-03-15 2016-04-06 Astellas Pharma Inc. Guanidine compound
WO2012124696A1 (en) 2011-03-15 2012-09-20 アステラス製薬株式会社 Guanidine compound
US9051283B2 (en) 2011-03-15 2015-06-09 Astellas Pharma Inc. Guanidine compound
US8716470B2 (en) 2011-03-15 2014-05-06 Astellas Pharma Inc. Guanidine compound
US9556160B2 (en) 2011-03-15 2017-01-31 Astellas Pharma Inc. Guanidine compound
CN103889983B (en) * 2011-09-14 2015-12-09 普罗克西梅根有限公司 Inhibitor compound
US9150574B2 (en) 2011-09-14 2015-10-06 Proximagen Limited Enzyme inhibitor compounds
WO2013037411A1 (en) 2011-09-14 2013-03-21 Proximagen Limited New enzyme inhibitor compounds
WO2013038189A1 (en) 2011-09-14 2013-03-21 Proximagen Ltd. New enzyme inhibitor compounds
CN103889983A (en) * 2011-09-14 2014-06-25 普罗克西梅根有限公司 New enzyme inhibitor compounds
US9428498B2 (en) 2013-03-13 2016-08-30 Proximagen Limited Substituted imidazo[4,5-c]pyridine compounds and compositions thereof
US10766897B2 (en) 2013-03-13 2020-09-08 Proximagen, Llc Imidazo[4,5-c]pyridine and pyrrolo[2,3-c]pyridine derivatives as SSAO inhibitors
US11512082B2 (en) 2013-03-13 2022-11-29 Proximagen, Llc Substituted imidazo[4,5-c]pyridine compounds and compositions thereof
US9951068B2 (en) 2013-03-13 2018-04-24 Proximagen Limited Imidazo[4,5-C]pyridine and pyrrolo[2,3-C]pyridine derivatives as SSAO inhibitors
US10590125B2 (en) 2013-03-13 2020-03-17 Proximagen, Llc Compounds
US10428066B2 (en) 2013-03-13 2019-10-01 Proximagen, Llc Imidazo[4,5-C]pyridine and pyrrolo[2,3-C]pyridine derivatives as SSAO inhibitors
US9580415B2 (en) 2013-03-13 2017-02-28 Proximagen Limited Compounds
US10968223B2 (en) 2013-03-13 2021-04-06 Proximagen, Llc Imidazo[4,5-c]pyridine and pyrrolo[2,3-c]pyridine derivatives as SSAO inhibitors
US9676769B2 (en) 2013-03-13 2017-06-13 Proximagen Limited Imidazo[4,5-C]pyridine and pyrrolo[2,3-C]pyridine derivatives as SSAO inhibitors
US20140275013A1 (en) * 2013-03-15 2014-09-18 University Of Washington Through Its Center For Commercialization Compounds and compositions for the treatment of parasitic diseases
US9296754B2 (en) 2013-03-15 2016-03-29 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9233961B2 (en) 2013-03-15 2016-01-12 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9186361B2 (en) 2013-03-15 2015-11-17 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
WO2014199171A1 (en) 2013-06-12 2014-12-18 Proximagen Limited New therapeutic uses of enzyme inhibitors
US9765092B2 (en) 2013-11-19 2017-09-19 Actelion Pharmaceuticals Ltd Tricyclic piperidine compounds
US10189839B2 (en) 2013-11-19 2019-01-29 Actelion Pharmaceuticals Ltd Tricyclic imidazole compounds as inhibitors of tryptophan hydroxylase
US9303034B2 (en) 2013-12-19 2016-04-05 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US10596175B2 (en) 2013-12-19 2020-03-24 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US10085989B2 (en) 2013-12-19 2018-10-02 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US11123348B2 (en) 2013-12-19 2021-09-21 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9700559B2 (en) 2013-12-19 2017-07-11 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
WO2015159112A1 (en) 2014-04-15 2015-10-22 Pécsi Tudományegyetem Semicarbazide-sensitive amine oxidase inhibitors for use as analgesics in traumatic neuropathy and neurogenic inflammation
WO2015189534A1 (en) 2014-06-12 2015-12-17 Proximagen Limited Vap-1 inhibitors for treating muscular dystrophy
JP2017532315A (en) * 2014-09-17 2017-11-02 プロクシマゲン リミテッド SSAO inhibitor derived from imidazo [4,5-C] pyridine
US11530208B2 (en) 2014-09-17 2022-12-20 Proximagen, Llc Imidazo[4,5-C]pyridine derived SSAO inhibitors
AU2015316611B2 (en) * 2014-09-17 2019-05-30 Proximagen, Llc Imidazo[4,5-c]pyridine derived SSAO inhibitors
WO2016042332A1 (en) * 2014-09-17 2016-03-24 Proximagen Limited Imidazo[4,5-c]pyridine derived ssao inhibitors
WO2016042331A1 (en) * 2014-09-17 2016-03-24 Proximagen Limited Imidazo[4,5-c]pyridine derived ssao inhibitors
CN107074854A (en) * 2014-09-17 2017-08-18 普罗克斯马根有限公司 The pyridine derived SSAO inhibitor of imidazo [4,5 c]
CN107074853A (en) * 2014-09-17 2017-08-18 普罗克斯马根有限公司 The pyridine derived SSAO inhibitor of imidazo [4,5 c]
AU2015316610B2 (en) * 2014-09-17 2019-05-30 Proximagen, Llc Imidazo[4,5-c]pyridine derived SSAO inhibitors
CN107074853B (en) * 2014-09-17 2019-07-23 普罗克斯马根有限责任公司 The pyridine derived SSAO inhibitor of imidazo [4,5-c]
JP2017528493A (en) * 2014-09-17 2017-09-28 プロクシマゲン リミテッド SSAO inhibitor derived from imidazo [4,5-C] pyridine
CN107074854B (en) * 2014-09-17 2019-07-19 普罗克斯马根有限责任公司 The pyridine derived SSAO inhibitor of imidazo [4,5-c]
US10065954B2 (en) 2014-09-17 2018-09-04 Proximagen Limited Substituted imidazo[4,5-c]pyridines as SSAO inhibitors
US10316034B2 (en) 2015-04-24 2019-06-11 Benevolentai Cambridge Limited Pharmaceutical salt forms of an inhibitor of semicarbazide-sensitive amine oxidase (SSAO)
US10369139B2 (en) 2015-04-24 2019-08-06 Benevolentai Cambridge Limited Crystalline compound as semicarbazide-sensitive amine oxidase (SSAO) enzyme inhibitor
JP2018513189A (en) * 2015-04-24 2018-05-24 プロキシマジェン リミティド Pharmaceutical salt forms of inhibitors of semicarbazide sensitive amine oxidase (SSAO)
JP2018517683A (en) * 2015-05-04 2018-07-05 アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ Tricyclic piperidine compounds
WO2016194390A1 (en) 2015-06-05 2016-12-08 R-Tech Ueno, Ltd. Pharmaceutical composition for use in the treatment of cancer
JP2018524392A (en) * 2015-07-24 2018-08-30 ベネボレンタイ ケンブリッジ リミティド Novel therapeutic compounds and their use in therapy
JP2021035977A (en) * 2015-07-24 2021-03-04 プロキシマジェン，リミティド ライアビリティ カンパニー New therapeutic compound and use in therapy
EP3777846A1 (en) 2015-12-07 2021-02-17 BenevolentAI Cambridge Limited Vap-1 inhibitors for treating pain
CN108084155A (en) * 2017-12-29 2018-05-29 佛山汉方中医医院有限公司 SSAO inhibitor of methyl adamantane and alcoxyl pyridine structure and application thereof
CN108191825A (en) * 2017-12-29 2018-06-22 佛山汉方中医医院有限公司 A kind of methyl adamantane and nitropyridine structural derivative and application thereof
CN108129458A (en) * 2017-12-29 2018-06-08 佛山汉方中医医院有限公司 A kind of adamantane and dimethylaminopyridine structural derivative, preparation method and the usage
CN108084154A (en) * 2017-12-29 2018-05-29 佛山汉方中医医院有限公司 A kind of adamantane and amido pyridine structure derivative, preparation method and the usage
CN107915719A (en) * 2017-12-29 2018-04-17 佛山汉方中医医院有限公司 SSAO inhibitor of a kind of methyl adamantane and pyridine structure and application thereof
CN109988147A (en) * 2017-12-29 2019-07-09 佛山汉方中医医院有限公司 SSAO inhibitor, preparation method and its usage containing adamantane structure
CN108033946A (en) * 2017-12-29 2018-05-15 佛山汉方中医医院有限公司 A kind of SSAO inhibitor, preparation method and its usage containing adamantane structure
CN108191823A (en) * 2017-12-29 2018-06-22 佛山汉方中医医院有限公司 A kind of alkyl substitution adamantane SSAO inhibitor, preparation method and its usage
CN108191824A (en) * 2017-12-29 2018-06-22 佛山汉方中医医院有限公司 A kind of methyl adamantane and dimethylaminopyridine structural derivative, Its Preparation Method And Use
CN108033945A (en) * 2017-12-29 2018-05-15 佛山汉方中医医院有限公司 A kind of adamantane and nitropyridine structural compounds and purposes
CN107935992A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 One kind contains adamantane and haloperidid structural compounds and purposes
CN107935989A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 Adamantane and itrile group pyridine structure compound, preparation method and the usage
CN107935993A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 Methyl adamantane and nitropyridine structural derivative, Its Preparation Method And Use
CN107935990A (en) * 2017-12-29 2018-04-20 佛山汉方中医医院有限公司 Containing adamantane and alcoxyl pyridine structure compound, preparation method and the usage

Also Published As

Publication number Publication date
AU2002214505A1 (en) 2002-05-21

Similar Documents

Publication Publication Date Title
WO2002038153A1 (en) New use of 4, 5, 6, 7-tetrahydroimidazo-[4,5-c]pyridine derivatives
US11345714B2 (en) Compounds targeting proteins, compositions, methods, and uses thereof
US11459312B2 (en) Sulphur substituted 3-oxo-2,3-dihydropyridazine-4-carboxamides
US6043252A (en) Carboline derivatives
ES2585262T3 (en) Hexahydropyran [3,4-d] [1,3] thiazin-2-amine heterocyclic compounds substituted as inhibitors of PPA, BACE1 and BACE2
AU2013340726B2 (en) Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
JP5700837B2 (en) Pyrazolopyridine derivatives as NADPH oxidase inhibitors
KR101126383B1 (en) Tricyclic compounds
US11524944B2 (en) 2-phenylpyrimidine-4-carboxamides as AHR inhibitors
JP2002528533A (en) Novel inhibitors of the enzyme IMPDH
CA3022044A1 (en) Isoquinolin-3-yl carboxamides and preparation and use thereof
ZA200604528B (en) Polycyclic agents for the treatment of respiratory syncytial virus infections
EA035592B1 (en) Histone deacetylase inhibitors and compositions and methods of use thereof
JP5897566B2 (en) Cyclic N, N&#39;-diarylthiourea and N, N&#39;-diarylurea-androgen receptor antagonists, anticancer agents, methods for their preparation and uses
EA016575B1 (en) Carboline derivatives useful in the inhibition of angiogenesis
WO2005047286A1 (en) Heterocyclic spiro compound
JP2000513717A (en) Carboline derivative
SK20182000A3 (en) Retinoid-associated receptor regulators
JP2017537948A (en) Amidothiadiazole derivatives as NADPH oxidase inhibitors
US20220144845A1 (en) SUBSTITUTED PYRROLO[1,2-a]QUINOXALIN-4(5H)-ONES AS CX3CR1 ANTAGONISTS
TWI771303B (en) Compounds and their use for reducing uric acid levels
JP2012126737A (en) Tricyclic compound and use thereof
AU2013364038B2 (en) Diazole amides
US20020198189A1 (en) New use
JP2022544199A (en) Thienopyrimidine derivatives and their use as ACC inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP