EP2321280A2 - Synthese von 3,4-dyaryl-4,5-dihydro-(1h)-pyrazol-1-carboxamidin-derivaten - Google Patents

Synthese von 3,4-dyaryl-4,5-dihydro-(1h)-pyrazol-1-carboxamidin-derivaten

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Publication number
EP2321280A2
EP2321280A2 EP09781267A EP09781267A EP2321280A2 EP 2321280 A2 EP2321280 A2 EP 2321280A2 EP 09781267 A EP09781267 A EP 09781267A EP 09781267 A EP09781267 A EP 09781267A EP 2321280 A2 EP2321280 A2 EP 2321280A2
Authority
EP
European Patent Office
Prior art keywords
formula
compound
alkyl
chosen
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09781267A
Other languages
English (en)
French (fr)
Inventor
Josephus H. M. Lange
Hans J. Sanders
Jeroen Van Rheenen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Healthcare Products BV
Original Assignee
Abbott Healthcare Products BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Healthcare Products BV filed Critical Abbott Healthcare Products BV
Priority to EP09781267A priority Critical patent/EP2321280A2/de
Publication of EP2321280A2 publication Critical patent/EP2321280A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • 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
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to organic chemistry, in particular to processes for the preparation of 3,4- diaryl-4,5-dihydro-(1 H)-pyrazole-1-carboxamidine derivatives, known as potent cannabinoid-CB-i receptor antagonists.
  • the invention also relates to novel intermediates of these compounds.
  • Compounds A and B are 3,4-diaryl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine derivatives representative for the cannabinoid-CBi receptor antagonists disclosed in WO 01/70700 and WO 03/026648.
  • the objective of the present invention was to develop a novel synthetic route to 3,4-diaryl-4,5- dihydro-(1 H)-pyrazole-1-carboxamidine derivatives, with higher yields than the known routes, and avoiding the use of corrosive reagents.
  • R 1 and R 2 independently are chosen from (d- 3 )-alkyl or (Ci. 3 )-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy and cyano, - m and n independently are 0, 1 or 2,
  • R 3 is branched or linear (Ci -8 )-alkyl or (C 3-8 )-cycloalkyl
  • R 4 is chosen from phenyl, thienyl or pyridyl, which groups are unsubstituted or substituted with 1 or 2 substituents, which can be the same or different, chosen from (Ci -3 )-alkyl or (Ci -3 ) -alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy and cyano, or R 4 represents a monocyclic or bicyclic (C 5 .i 0 )-alkyl or (C 5- i 0 )-alkenyl group, or a monocyclic or bicyclic hetero-(C 5 -io)-alkyl or hetero-(C 5- io)-alkenyl group containing one or two ring heteroatoms or ring heteroatom-containing moieties chosen from N, O, S or SO 2 , and which R 4 group is unsubstituted or substituted with a substituent chosen from hydroxy or (Ci -3 )- alkyl
  • the invention also relates to a process for the preparation of a compound of formula (I) wherein Ri and R 2 independently are chosen from (Ci. 3 )-alkyl, trifluoromethyl or halogen; m and n independently are 0 or 1 ; R 3 is branched or linear (Ci_ 3 )-alkyl; R 4 represents phenyl, unsubstituted or substituted with 1 substituent chosen from (Ci.
  • R 4 represents a monocyclic hetero-(C 5 -io)-alkyl group, which contains one or two ring heteroatoms chosen from N, O and S or R 4 represents a 4,4-difluoropiperidin-1-yl, 4- fluoropiperidin-1-yl or 4-(trifluoromethyl)piperidin-1 -yl group.
  • Another embodiment relates to a process for the preparation of a compound of formula (I) wherein Ri and R 2 are halogen; m and n independently are 0 or 1 ; R 3 is methyl; R 4 represents phenyl, unsubstituted or substituted with 1 halogen atom, or R 4 represents a piperidin-1 -yl or 4,4-difluoropiperidin-1 -yl group.
  • a further embodiment provides a process for the preparation of a compound of formula (I) wherein R 1 is 4-CI; m is 1 and n is 0; R 3 is methyl, and R 4 is chosen from 4-chlorophenyl, piperidin-1 -yl and 4,4-difluoropiperidin-1-yl.
  • R 3 is branched or linear (Ci_ 8 )-alkyl, and the other symbols have the meanings given above, as well as tautomers, stereoisomers, N-oxides, and salts of any of the foregoing.
  • Such compounds are useful in the synthesis of compounds of formula (I).
  • Further embodiments provide one or more compounds of formula (IV)
  • R x represents a linear (Ci_ 8 )alkyl group, and the symbols have the meanings given above, as well as tautomers, stereoisomers, N-oxides, and salts of any of the foregoing.
  • Such compounds are useful in the synthesis of compounds of formula (I).
  • Isolation and purification of the compounds and intermediates described herein can be affected, if desired, by any suitable separation or purification procedure, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be taken from the preparations and examples. However, other equivalent separation or isolation procedures could, of course, also be used.
  • the compounds of the present invention may contain one or more chiral centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All compounds of the present invention contain a chiral center at the C 4 atom of their 4,5-dihydro-1 H-pyrazole moiety. Depending on the nature of the various substituents, the molecule can have additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers. All of the possible optical isomers, enantiomers and diastereomers, in mixtures and as pure or partially purified compounds, belong to this invention. The present invention comprehends all such isomeric forms of these compounds.
  • Formulae (III), (Ilia) and (IV) show the structure of the class of compounds without preferred stereochemistry.
  • the independent syntheses of these optical isomers, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed therein.
  • Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing a chiral center of known absolute configuration.
  • Racemic mixtures of the compounds can be separated into the individual enantiomers by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling often consists of the formation of salts using an enantiomerically pure acid or base, for example (-)-di-p-toluoyl-D- tartaric acid or (+ )-d i-p-tol uoy l-L-tarta ric acid.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, well-known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well-known in the art.
  • Cis and trans isomers of compounds of formulae (III), (Ilia) and (IV), or salts thereof, also belong to the invention, and this applies to their tautomers, too.
  • the synthetic strategy in this novel route is essentially different from the known routes since in those the R 3 -NH moiety in the compound of general formula (I) was introduced by a nucleophilic displacement of a leaving group - such as a chloro atom or a methylsulfanyl group - in the last step of the reaction sequence.
  • a leaving group - such as a chloro atom or a methylsulfanyl group - in the last step of the reaction sequence.
  • the R 3 NH group is introduced at a much earlier stage in the process as an electrophile (R 3 -isothiocyanate) via reaction with the nucleophilic pyrazoline building block (II).
  • R 4 SO 2 N moiety in the compound of general formula (I) is introduced in the last step of the reaction sequence, whereas in all prior art routes this particular moiety was introduced at an earlier stage in the process.
  • alkyl denotes a univalent saturated, branched or linear, hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, fert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc.
  • the same carbon content applies to the parent term 'alkane', and to derivative terms like 'alkoxy'.
  • the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms, i.e., the prefix (C x - y )- defines the number of carbon atoms present from the integer "x" to the integer "y” inclusive.
  • '(Ci. 3 )-alkyl' for example, includes methyl, ethyl, n-propyl or isopropyl, and '(Ci.
  • alkyl' includes 'methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl'.
  • alkenyl' denotes linear or branched hydrocarbon radicals having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, etc., and for example represents (C 2-4 )alkenyl.
  • 'Halo' or 'Halogen' refers to chloro, fluoro, bromo or iodo; 'hetero' as in 'heteroalkyl, heteroaromatic', etc. includes containing one or more N, O or S atoms, 'heteroalkyl' includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.
  • substituted means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents can be provided, the substituents are independently selected, and need not to be the same.
  • unsubstituted means that the specified group bears no substituents.
  • 'Cs- ⁇ -cycloalkyl' includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopheptyl or cyclooctyl;
  • 'C 5 .i 0 bicycloalkyl group' refers to carbo-bicyclic ring systems including bicyclo[2.2.1 ]heptanyl, bicyclo[3.3.0]octanyl or the bicyclo[3.1.1] heptanyl group;
  • amino refers to a nitrogen atom being either terminal, or a linker between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively) amine.
  • sulfinyl and sulfonyl as used herein as part of another group respectively refer to an -SO- or an - SO 2 - group.
  • the terms 'compound' or 'compounds' include tautomers, stereoisomers, N-oxides, isotopically-labelled analogues, or pharmacologically acceptable salts, also when not explicitly mentioned.
  • the term "leaving group” shall mean a charged or uncharged atom or group leaving during a substitution or displacement reaction.
  • the term refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile.
  • Such leaving groups are well known in the art. Examples include, but are not limited to, N- hydroxysuccinimide, N-hydroxybenzotriazole, halides (Br, Cl, I), triflates, mesylates, tosylates, and the like. (For more information on the leaving group concept, see: Michael B. Smith and
  • Sepacore chromatographic separations were carried out using Supelco equipment, VersaFLASHTM columns, VersaPakTM silica cartridges, B ⁇ chi UV monitor C-630, B ⁇ chi Pump module C-605, B ⁇ chi fraction collector C-660 and B ⁇ chi pump manager C-615. Melting points were recorded on a B ⁇ chi B-545 melting point apparatus or determined by DSC (differential scanning calorimetry) methods.
  • 3,4-diaryl-4,5-dihydro-1 H-pyrazole-1 -carboxamidine derivatives of formula (II) can be obtained via known methods, as described in WO01/70700, WO 03/026648, Lange, J. H. M. et al., J. Med. Chem. 2004, 47, 627.
  • the novel synthetic route is given in the scheme below:
  • (I) 3,4-Diaryl-4,5-dihydro-(1 H)-pyrazoles of formula (II) can be prepared as described by Grosscurt, et al. (J. Agric. Food Chem. 1979, 27, 406), and can be reacted with an alkylisothiocyanate, or a cycloalkylisothiocyanate, in a (d ⁇ -alcohol such as absolute ethanol, to give a 3,4-diaryl-N- alkyl-4,5-dihydro-(1 H)-pyrazole-1-carbothioamide or 3,4-diaryl-N-cycloalkyl-4,5-dihydro-(1 H)- pyrazole-1 -carbothioamide of formula (III).
  • Salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid such as hydrochloric acid, or with an organic acid such as fumaric acid.
  • a suitable acid for instance an inorganic acid such as hydrochloric acid, or with an organic acid such as fumaric acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP09781267A 2008-08-01 2009-07-30 Synthese von 3,4-dyaryl-4,5-dihydro-(1h)-pyrazol-1-carboxamidin-derivaten Withdrawn EP2321280A2 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09781267A EP2321280A2 (de) 2008-08-01 2009-07-30 Synthese von 3,4-dyaryl-4,5-dihydro-(1h)-pyrazol-1-carboxamidin-derivaten

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US8547508P 2008-08-01 2008-08-01
EP08161619 2008-08-01
EP09781267A EP2321280A2 (de) 2008-08-01 2009-07-30 Synthese von 3,4-dyaryl-4,5-dihydro-(1h)-pyrazol-1-carboxamidin-derivaten
PCT/EP2009/059844 WO2010012797A2 (en) 2008-08-01 2009-07-30 Synthesis of 3,4-diaryl-4,5-dihydro-(1h)-pyrazole-1- carboxamidine derivatives

Publications (1)

Publication Number Publication Date
EP2321280A2 true EP2321280A2 (de) 2011-05-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP09781267A Withdrawn EP2321280A2 (de) 2008-08-01 2009-07-30 Synthese von 3,4-dyaryl-4,5-dihydro-(1h)-pyrazol-1-carboxamidin-derivaten

Country Status (12)

Country Link
EP (1) EP2321280A2 (de)
JP (1) JP2011529868A (de)
KR (1) KR20110042095A (de)
CN (1) CN102089284A (de)
AR (1) AR072539A1 (de)
AU (1) AU2009275838A1 (de)
BR (1) BRPI0916692A2 (de)
CA (1) CA2729969A1 (de)
EA (1) EA201170284A1 (de)
MX (1) MX2011001211A (de)
TW (1) TW201010981A (de)
WO (1) WO2010012797A2 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR079935A1 (es) * 2010-01-29 2012-02-29 Abbott Healthcare Products Bv Sintesis de derivados de pirazolin carboxamidina sustituida
WO2020236411A1 (en) * 2019-05-17 2020-11-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A scalable synthesis of dual-target inhibitor of cannabinoid-1 receptor and inducible nitric oxide synthase
CN111686806B (zh) * 2020-05-29 2022-09-30 黑龙江大学 一种聚[2-(3-噻吩基)乙醇]/石墨相氮化碳复合可见光催化剂的制备方法及应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2074179A1 (en) * 1990-01-31 1991-08-01 Charles R. Harrison Arthropodicidal pyrazolines, pyrazolidines and hyrazines
DE4005114A1 (de) * 1990-02-17 1991-08-22 Bayer Ag Substituierte pyrazolinderivate
UA74367C2 (uk) * 2000-03-23 2005-12-15 Сольве Фармас'Ютікалз Б.В. ПОХІДНІ 4,5-ДИГІДРО-1Н-ПІРАЗОЛУ, ЩО ВИЯВЛЯЮТЬ АНТАГОНІСТИЧНУ АКТИВНІСТЬ ЩОДО СВ<sub>1</sub>, СПОСІБ ЇХ ОДЕРЖАННЯ, ФАРМАЦЕВТИЧНА КОМПОЗИЦІЯ ТА СПОСІБ ЇЇ ВИГОТОВЛЕННЯ, СПОСІБ ЛІКУВАННЯ ЗАХВОРЮВАНЬ (ВАРІАНТИ)
HRP20030913A2 (en) * 2001-09-21 2004-06-30 Solvay Pharm Bv 4,5-dihydro-1h-pyrazole derivatives having potent cb1-antagonistic activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010012797A2 *

Also Published As

Publication number Publication date
JP2011529868A (ja) 2011-12-15
CN102089284A (zh) 2011-06-08
MX2011001211A (es) 2011-03-29
EA201170284A1 (ru) 2011-06-30
AR072539A1 (es) 2010-09-01
BRPI0916692A2 (pt) 2016-05-17
CA2729969A1 (en) 2010-02-04
AU2009275838A1 (en) 2010-02-04
KR20110042095A (ko) 2011-04-22
TW201010981A (en) 2010-03-16
WO2010012797A2 (en) 2010-02-04
WO2010012797A3 (en) 2010-04-22

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