US20170001962A1 - Processes for the Synthesis of Substituted Urea Compounds - Google Patents

Processes for the Synthesis of Substituted Urea Compounds Download PDF

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US20170001962A1
US20170001962A1 US15/113,619 US201515113619A US2017001962A1 US 20170001962 A1 US20170001962 A1 US 20170001962A1 US 201515113619 A US201515113619 A US 201515113619A US 2017001962 A1 US2017001962 A1 US 2017001962A1
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alkyl
heterocyclyl
heteroaryl
aryl
substituted
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Domenico Russo
Jorge Bruno Reis Wahnon
William Maton
Tibor Eszenyi
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Bial Portela and Cia SA
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Bial Portela and Cia SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C07C2101/08—
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to processes for the synthesis of substituted urea compounds and for intermediates useful in the production of such compounds.
  • it relates to processes for synthesising certain active pharmaceutical ingredients having a heteroaryl N-carboxamide core.
  • Molecules containing urea functional groups are of interest in medicinal chemistry.
  • a common method for their preparation is to convert a first amine component to an isocyanate or activated carbamate, followed by reaction with a second amine component.
  • this approach is not available when neither of the amine components is a primary amine.
  • secondary amines cannot be converted to isocyanates, and secondary carbamates are known to suffer from low reactivity in the required nucleophilic substitution reaction with the second amine component (see Lee et al. (2004) Tetrahedron 60, 3439).
  • Complex or harsh approaches have thus been used in these circumstances, e.g. the aluminium amide approach described by Lee et al. (above).
  • a number of molecules having fatty acid amide hydrolase (FAAH) inhibitory activity and containing urea groups are disclosed in WO 2010/074588.
  • a subgroup of the compounds disclosed in this document contain an imidazole-1-carboxamide motif.
  • These compounds are generally prepared using an approach comprising carbamoylation of 1H-imidazole derivatives with carbamoyl chlorides.
  • 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine-1-oxide is prepared by reaction of the imidazolylpyridine hydrochloride with potassium 2-methylpropan-2-olate in a mixed solvent of tetrahydrofuran (THF) and dimethylformamide (DMF), followed by addition of a catalytic amount of pyridine and N,N-dimethylpyridine-4-amine, this step being followed by addition of cyclohexyl(methyl)carbamic chloride.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • WO 2010/074588 The main limitation of the above procedure disclosed in WO 2010/074588 is the very low overall yield. This problem is addressed in WO 2012/015324, wherein the ureas of WO 2010/074588 are synthesised using an alternative approach based on the reaction of a phenylcarbamate derivative of an N-containing heteroaryl group with a primary or secondary amine. The yield using the phenylcarbamate approach is reported to be much improved, and WO 2012/015324 discourages the use of the carbamoyl chloride approach.
  • ⁇ -amino ketones For the preparation of 1H-imidazole derivatives, previous methods have involved the preparation of ⁇ -amino ketones as the key precursor in the ring formation reaction to produce the imidazole structure.
  • the synthesis of the ⁇ -amino ketones can be achieved, for example, by employing routes via ⁇ -halo ketones (Sorrell et al., J. Org. Chem., 1994, 59, 1589; WO 2006/047167) and/or ⁇ -azido ketones (Prakash et al., Molecules, 2006, 11, 523), or oxime sulfonates (Clemo et al. J. Chem. Soc., 1938, 753).
  • routes are complex multistep procedures employing particularly hazardous reagents.
  • R1R2NC( ⁇ O)Hal wherein Hal represents Cl, F, I or Br
  • the intermediate of Formula IIa′ is prepared by oxidation of the derivative of R5 and R6, R6-C( ⁇ O)CH 2 R5 to form a glyoxal intermediate R6-C( ⁇ O)(C ⁇ O)R5, which is subjected to treatment with ammonium hydroxide and an aldehyde R8CHO to provide the intermediate of Formula IIa′
  • R6 is NH 2 CONH-phenyl, or a nitrophenyl, aminophenyl or amino-protected aminophenyl precursor of this moiety which can be subjected to conversion to the NH 2 CONH-phenyl group after urea formation
  • R5 is H
  • R1 is methyl
  • R2 cyclopentyl
  • the process of the present invention provides a surprisingly beneficial approach to the production of such ureas and imidazoles.
  • the route is more direct than certain other processes, and produces a satisfactory yield.
  • a similar process for the production of substituted imidazoles is described by Cao et al. ( J. Chem. Res., 2011, 35, 600, see above). However, it was found that, for the compounds to be prepared according to the process of the invention, the method of Cao was not efficient.
  • the carbamoyl halide is a carbamoyl chloride.
  • the preparation of the carbamoyl chloride may be accomplished, for example, using a phosgene reagent.
  • the oxidation of the derivative of R5 and R6 may employ an inorganic acid, such as HX, where X is a halogen atom.
  • HX a halogen atom
  • HCl or HBr. HBr may be preferred.
  • solvent and oxidising reagent for this step DMSO may be used.
  • the processes of the present invention are useful for preparing compounds having FAAH inhibitory activity and containing urea groups, and in particular those compounds disclosed in WO 2010/074588.
  • the compounds of WO 2010/074588 may be used in a variety of diseases or conditions in which the endogenous endocannabinoid system is implicated.
  • C x-y alkyl refers to a linear or branched saturated hydrocarbon group containing from x to y carbon atoms.
  • C 1-6 alkyl refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • Examples of C 1-6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl and hexyl.
  • the hydrocarbon group is linear.
  • C 1-20 alkyl and C 1-10 alkyl are preferably C 1-6 alkyl.
  • C x-y alkyl is also used to mean a linear or branched saturated hydrocarbon group containing from x to y carbon atoms and in which a terminal methyl group is further substituted, i.e. so as to render a C x-y alkylene group.
  • C x-y haloalkyl refers to a C 1-6 alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl and trifluoroethyl.
  • C x-y alkynyl refers to a linear or branched hydrocarbon group containing from x to y carbon atoms and at least one carbon-carbon triple bond.
  • C 1-6 alkynyl refers to a linear or branched hydrocarbon group containing from 1 to 6 carbon atoms.
  • Examples of C 1-6 alkynyl groups include, ethynyl, methylbutynyl (e.g. 3-methyl-1-butynyl), 1,3-butadiynyl and 1,3,5-hexatriynyl.
  • aryl refers to a C 6-12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthalenyl and tetrahydronaphthalenyl.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
  • Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
  • bicyclic aromatic rings examples include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridyl, furopyridyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and imidazopyridyl.
  • heteroaryl substituted with one or more oxygen atoms refers to a heteroaryl ring which has one or more oxygen atoms bonded to the ring. It does not mean that the heteroaryl ring contains one or more oxygen atoms as ring atoms, although in some embodiments, this may be the case. Preferably, the one or more oxygen atoms is bonded to a nitrogen heteroatom in the heteroaryl ring.
  • a heteroaryl substituted with an oxygen atom may contain an N-oxide.
  • An example of a heteroaryl substituted with one or more oxygen atoms is 1-oxidopyridyl in which the pyridyl nitrogen is oxidised.
  • heterocyclyl refers to a 3-8 (preferably 4-8 and, more preferably, 4-7) membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen, silicon or sulphur.
  • Examples of such monocyclic rings include oxaziridinyl, oxiranyl, dioxiranyl, aziridinyl, pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,
  • bicyclic rings examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine, 4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl, and, tetrahydroisoquinolinyl.
  • heterocyclyl substituted with one or more oxygen atoms refers to a heterocyclyl ring which has one or more oxygen atoms bonded to the ring. It does not mean that the heterocyclyl ring contains one or more oxygen atoms as ring atoms, although in some embodiments, this may be the case. Preferably, the one or more oxygen atoms is bonded to a heteroatom, such as nitrogen or sulphur, in the heterocyclyl ring.
  • An example of a heterocyclyl substituted with one or more oxygen atoms is 1,1-dioxido-1,3-thiazolidinyl.
  • bicyclic ring and ‘fused’ in the context of a bicyclic ring refers in connection with this aspect to two rings which are joined together across a bond between two atoms (e.g. naphthalene), across a sequence of atoms to form a bridge (e.g. quinuclidine) or together at a single atom to form a spiro compound (e.g. 1,4-dioxa-8-aza-spiro[4.5]decane and N,3,3-dimethyl-1,5-dioxaspirol[5.5]undecan-9-yl).
  • two atoms e.g. naphthalene
  • a bridge e.g. quinuclidine
  • spiro compound e.g. 1,4-dioxa-8-aza-spiro[4.5]decane and N,3,3-dimethyl-1,5-dioxaspirol[5.5]undecan-9-yl
  • C x-y cycloalkyl refers to a saturated hydrocarbon ring of x to y carbon atoms which can be mono, bi or tricyclic.
  • C 3-10 cycloalkyl refers to a saturated mono, bi or tricyclic hydrocarbon ring of 3 to 10 carbon atoms.
  • Examples of C 3-10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl.
  • aryl C x-y alkyl refers to an aryl group as defined above attached to a C x-y alkyl as defined above.
  • aryl C 1-6 alkyl refers to an aryl group attached to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • Examples of aryl C 1-6 alkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexyl.
  • heteroaryl C x-y alkyl refers to a heteroaryl, heterocyclyl or C x-y cycloalkyl group as defined above attached to a C x-y alkyl as defined above.
  • C x-y alkoxy refers to an —O—C x-y alkyl group wherein C x-y alkyl is as defined above. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • aryl C x-y alkoxy refers to an aryl group as defined above attached to a C x-y alkoxy as defined above.
  • aryl C 1-6 alkoxy refers to an aryl group attached to an alkoxy group containing from 1 to 6 carbon atoms.
  • heteroaryl C x-y alkoxy refers to a heteroaryl group as defined above attached to a C x-y alkoxy as defined above.
  • heteroaryl C 1-6 alkoxy refers to a heteroaryl group attached to an alkoxy group containing from 1 to 6 carbon atoms.
  • heterocyclyl C x-y alkoxy refers to a heterocyclyl group as defined above attached to a C x-y alkoxy as defined above.
  • heterocyclyl C 1-6 alkoxy refers to a heterocyclyl group attached to an alkoxy group containing from 1 to 6 carbon atoms.
  • C x-y cycloalkyl C x-y alkoxy refers to a C x-y cycloalkyl group as defined above attached to a C x-y alkoxy as defined above.
  • C 1-6 cycloalkyl C 1-6 alkoxy refers to a cycloalkyl group containing from 1 to 6 carbon atoms attached to an alkoxy group containing from 1 to 6 carbon atoms.
  • aryloxy refers to an —O-aryl group. Examples of such groups include phenoxy.
  • heteroaryloxy and ‘heterocyclyloxy’ as used herein refer to an —O-heteroaryl and —O-heterocyclyl group respectively.
  • C x-y cycloalkyloxy refers to an —O—C x-y cycloalkyl group.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom, unless otherwise specified.
  • C x-y alkylamino refers to a secondary amine group (—NH(R)) of which the R group is selected from a linear or branched saturated hydrocarbon group containing from x to y carbon atoms.
  • R group is selected from a linear or branched saturated hydrocarbon group containing from x to y carbon atoms.
  • Examples of C x-y alkylamino groups include methylamino, ethylamino and propylamino.
  • C x-y dialkylamino refers to a tertiary amine group (—NR(R*)) of which the R and R* groups are each independently selected from a linear or branched saturated hydrocarbon group containing from x to y carbon atoms.
  • Examples of C x-y dialkylamino groups include dimethylamino, methylethylamino and diethylamino.
  • substituted C 1-6 alkyl used herein with reference to the identity of the various groups identified as R (for example, in the phrase ‘wherein R1e and R1f are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl’) means that the particular R group (e.g.
  • R1a, R2c, R5e, etc. can be substituted with one or more groups selected from R′, halogen, OH, OR′, SH, SR′, OCOR′, SCOR′, NH 2 , NO 2 , NHR′, NHSO 2 NH 2 , NHSO 2 R′, NR′COR′′, NHC(NH)NH 2 , NHCOR′, NR′R′′, COR′, CSR′, CN, COOH, COOR′, CONH 2 , CONHOH, CONHR′, CONR′R′′, CONHOR′, C(NOH)NH 2 , SO 2 R′, SO 3 H, SO 2 NH 2 , SO 2 NR′R′′, wherein R′ and R′′ are independently selected from C 1-6 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl, or R′ and R′′, together with the heteroatom to which they are joined, can form heterocyclyl.
  • acyl refers to a group selected from:
  • C x-y alkyl carbonyloxy refers to an alkyl group wherein C x-y alkyl is as defined herein and at least one methylene group (i.e. —CH 2 —) is replaced with an ester group (e.g. —CO 2 —).
  • Examples of C 1-6 alkyl carbonyloxy groups include ethanoate, propanoate, butanoate, pentanoate, and hexanoate.
  • C x-y alkyl carbonyl refers to an alkyl group wherein C x-y alkyl is as defined herein and at least one methylene group (i.e. —CH 2 —) is replaced with a carbonyl group (i.e. >C ⁇ O).
  • C 1-6 alkyl carbonyl groups include methylcarbonyl, ethyl-1-carbonyl, ethyl-2-carbonyl, propyl-1-carbonyl, propyl-2-carbonyl, propyl-3-carbonyl, isopropylcarbonyl, butyl-1-carbonyl, butyl-2-carbonyl, butyl-3-carbonyl, butyl-4-carbonyl, isobutylcarbonyl, tertiarybutylcarbonyl pentylcarbonyl, and hexylcarbonyl.
  • C x-y aryl carbonyl refers to an aryl group wherein C x-y aryl is as defined herein covalently linked to at least one carbonyl group (i.e. >C ⁇ O).
  • Examples of C 6-10 aryl carbonyl groups benzoyl, 1-naphthoyl, and 2-naphthoyl.
  • C x-y alkyl carbamoyl refers to an alkyl group wherein C x-y alkyl is as defined herein and at least one methylene group (i.e. —CH 2 —) is replaced with an amide group (e.g. —C(O)NR—, where R is a hydrogen atom, a 5- or 6-membered heterocyclyl group, a 5- or 6-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a C 1-6 alkyl group, or a C 6-14 aryl group, preferably a hydrogen atom).
  • amide group e.g. —C(O)NR—, where R is a hydrogen atom, a 5- or 6-membered heterocyclyl group, a 5- or 6-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a C 1-6 alkyl group, or a C 6-14 aryl group, preferably a
  • C 1-6 alkyl carbamoyl groups include ethyl carbamoyl, propyl carbamoyl, butyl carbamoyl, tert-butyl carbamoyl, pentyl carbamoyl, and hexyl carbamoyl.
  • C x-y alkoxy carbonyl refers to an alkyl group wherein C x-y alkyl is as defined herein and at least one methylene group (i.e. —CH 2 —) is replaced with an ester group (e.g. —OC(O)—).
  • Examples of C 1-6 alkyl carbonyl groups include ethyl oxycarbonyl, propyl oxycarbonyl, butyl oxycarbonyl, pentyl oxycarbonyl, and hexyl oxycarbonyl.
  • the acyl group is selected from:
  • (1) formyl i.e. —CHO
  • C 1-6 alkyl carbonyloxy optionally substituted with 1 to 3 groups selected from halogen, hydroxy, and aryl
  • C 1-6 alkyl carbonyl optionally substituted with 1 to 3 groups selected from halogen, hydroxy, and aryl
  • C 6-10 aryl carbonyl optionally substituted with 1 to 3 groups selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy
  • carboxyl i.e.
  • R1 is selected from H and C 1-4 alkyl. More preferably, R1 is selected from H, methyl and ethyl.
  • R2 is selected from aryl, heteroaryl, heterocyclyl, C 3-10 cycloalkyl, aryl C 1-6 alkyl, heteroaryl C 1-6 alkyl, heterocyclyl C 1-6 alkyl and C 3-10 cycloalkyl C 1-6 alkyl, each of which may be substituted or unsubstituted.
  • R2 is selected from aryl, heteroaryl, heterocyclyl, and C 3-10 cycloalkyl each of which may be substituted or unsubstituted.
  • R2 is selected from fully saturated heterocyclyl, and C 5-8 cycloalkyl each of which are monocyclic and may be substituted or unsubstituted.
  • R2 may be an unsubstituted cyclopentyl or unsubstituted cyclohexyl, or a fully saturated heterocyclyl, wherein the heterocyclyl ring contains a single heteroatom, such as nitrogen or oxygen.
  • R2 is heterocyclyl, it is preferably six membered heterocyclyl and the heteroatom in the said heterocyclyl group is at the 4-position relative to the position of attachment of the heterocyclyl group R2 to the urea nitrogen.
  • the heteroatom is preferably a nitrogen heteroatom which is substituted with a group selected from CN, CONH 2 , C(NOH)NH 2 , SO 2 —C 1-4 alkyl, SO 2 -aryl, CO-heteroaryl, CO—C 1-4 alkyl, COO—C 1-4 alkyl, C 1-4 alkyl, aryl C 1-3 alkyl, heteroaryl C 1-3 alkyl, heterocyclyl C 1-3 alkyl, aryl, heteroaryl, and heterocyclyl, wherein the C 1-4 alkyl may optionally be substituted with OH, CN, COOH, the SO 2 -aryl may optionally be substituted with a C 1-4 alkyl or C 1-4 haloalkyl, the CO— heteroaryl may optionally be substituted with a heteroaryl or halogen, the heteroaryl C 1-3 alkyl may optionally be substituted with COO—C 1-3 alkyl, and the heteroaryl may optionally
  • R6 is selected from monocyclic aryl, monocyclic heteroaryl, and heterocyclyl, each of which may be substituted or unsubstituted.
  • R6 is a substituted aryl
  • said aryl is preferably substituted with one or more groups selected from halogen, R6a, OH, OR6a, NH 2 , NO 2 , NHC(NH)NH 2 , NHR6a, NR6aR6b, C(NOH)NH 2 , COR6a, COOH, COOR6a, CONH 2 , CONHOH, SO 2 R6a, SO 2 NR6aR6b, wherein R6a and R6b are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl, wherein R6a and R6b are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, heteroaryl, C 3
  • each of these moieties may optionally be substituted with one or more groups selected from OR6c, OH, and CONH 2 , wherein R6c and R6d are independently selected from C 1-6 alkyl, substituted C 1-6 alkyl, aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl, and wherein, when the substituent of R6 is heteroaryl or heterocyclyl, each of these moieties may optionally be substituted with one or more oxygen atoms.
  • R6 is a substituted aryl which is substituted with one or more groups selected from halogen, OH, C 1-4 alkoxy, CONH 2 , C(NOH)NH 2 , CONHOH, SO 2 —C 1-4 alkyl, heterocyclyl, and aryl, wherein the heterocyclyl may optionally be substituted with an oxygen atom and the aryl may optionally be substituted with CONH 2 .
  • R6 is a heterocyclyl which is substituted with an oxygen atom.
  • R6 is a monocyclic heteroaryl which is substituted with an oxygen atom.
  • R5 is hydrogen
  • R8 is hydrogen or a group selected from:
  • C 1-6 alkyl optionally substituted with one or more groups selected from halogen, hydroxy, and C 1-6 alkoxy optionally substituted with 1 to 3 groups selected from hydroxy, C 1-6 alkyl, C 1-6 alkylamino, and C 1-6 dialkylamino; aryl optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, acyl, and aryl optionally substituted with 1 to 3 groups selected from halogen, C 1-6 haloalkyl, and acyl; heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkoxy, acyl, and C 1-6 alkyl optionally substituted with 1 to 3 groups selected from heterocyclyl and heteroaryl each of which is optionally further substituted with 1 to 3 groups selected from C 1-6 alkyl, and heteroaryl C 1-6 haloalkyl; heterocyclyl optional
  • R8 is hydrogen, i.e. the aldehyde R8CHO employed is formaldehyde.
  • the process of the second aspect is useful for obtaining the intermediates of Formula IIa′.
  • a process for obtaining an intermediate of this type is described by Cao et al. (see above).
  • DCM is not an efficient solvent.
  • a solvent comprising butanol, preferably 1-butanol is a useful extraction solvent.
  • the aqueous media in the reaction mixture can be evaporated, and the remaining material can be dissolved in a suitable solvent for further processing.
  • R6 is NH 2 CONH-phenyl, or the nitrophenyl, aminophenyl or amino-protected aminophenyl precursor of this moiety which is subjected to conversion to the NH 2 CONH-phenyl group after urea formation, and R5 is H, R1 is methyl and R2 is cyclopentyl.
  • R5 is preferably hydrogen
  • R6 is preferably selected from monocyclic aryl, monocyclic heteroaryl, and heterocyclyl, each of which may be substituted with one or more of the substituents defined for R6 above in connection with the first aspect or with NH 2 CONH—.
  • R8 is preferably hydrogen.
  • the resulting intermediate of Formula IIa′ is reacted with a carbamoyl halide R1R2NC( ⁇ O)Hal to form a urea of Formula IIa or Formula A, as described in the first aspect.
  • R5 may be hydrogen
  • R6 may be selected from monocyclic aryl, monocyclic heteroaryl, and heterocyclyl, each of which may be substituted with one or more of the substituents defined for R6 above in connection with the first aspect or with NH 2 CONH—.
  • a process for preparing a substituted urea compound of Formula A as described above, or a pharmaceutically acceptable salt or derivative thereof comprising the reaction of an intermediate of Formula IIa′ as defined above, with a carbamoyl halide of the formula: R1R2NC( ⁇ O)Hal, in a solvent consisting essentially of pyridine, wherein R6 is NH 2 CONH-phenyl, or a nitrophenyl, aminophenyl or amino-protected aminophenyl precursor of this moiety which can be subjected to conversion to the NH 2 CONH-phenyl group after urea formation, and R5 is H, R1 is methyl and R2 is cyclopentyl, and wherein Hal represents Cl, F, I or Br.
  • the solvent used for the reaction of the intermediate of Formula IIa′ with the carbamoyl halide consists essentially of pyridine.
  • ‘consists essentially of pyridine’ means that the solvent used for the reaction comprises at least 10% v/v pyridine together with other, preferably miscible, solvents.
  • Such other solvents may comprise, for example, dichloromethane or dimethylformamide.
  • the solvent comprises at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% v/v pyridine. Allowing the reaction solvent to contain other solvents means that one or both of the reacting species can be introduced in a solvent other than pyridine, provided that the solvent used for the reaction contains enough pyridine to produce an improvement in yield, as demonstrated by the process described herein. The higher the content of pyridine in the solvent, however, the greater the improvement in yield. The purity of the urea produced may also be enhanced by the pyridine solvent.
  • the product mixture after urea formation may be further treated with water.
  • the isolation procedure of the product may be simplified, since the addition of water has been found to promote precipitation of the product from the crude product mixture.
  • the product mixture after urea formation may be further treated with a C 5-10 alkane or mixtures thereof, preferably a C 5-8 alkane or mixtures thereof.
  • the C 5-10 alkane or mixtures thereof may be employed as a solvent in an extraction procedure to purify and isolate the compound of Formula A.
  • an anti-solvent comprising heptane is especially advantageous in such a treatment and leads to an improved yield of the desired product.
  • C 5-10 alkane refers to linear or branched alkanes having 5 to 10 carbon atoms.
  • heptane includes n-heptane and any structural isomers thereof, such as isoheptane (2-methylhexane), 3-methylhexane, 2,2-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, etc.
  • the urea product is subjected to conversion of R6, where necessary, to the NH 2 CONH-phenyl group of the compound of Formula A.
  • ‘Pharmaceutically acceptable salts’ of compounds prepared by the present invention include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids. Salts with acids may, in particular, be employed in some instances.
  • Exemplary salts include hydrochloride salt, acetate salt, trifluoroacetate salt, methanesulfonate salt, 2-hydroxypropane-1,2,3-tricarboxylate salt, (2R,3R)-2,3-dihydroxysuccinate salt, phosphate salt, sulphate salt, benzoate salt, 2-hydroxy-benzoate salt, S-(+)-mandelate salt, S-( ⁇ )-malate salt, S-( ⁇ ) pyroglutamate salt, pyruvate salt, p-toluenesulfonate salt, 1-R-( ⁇ )-camphorsulfonate salt, fumarate salt and oxalate salt.
  • the compound prepared by the present invention may be in either solvate (e.g. hydrate) or non-solvate (e.g. non-hydrate) form. When in a solvate form, additional solvents may be alcohols such as propan-2-ol.
  • ‘Pharmaceutically acceptable esters’ of compounds of the invention are derivatives in which one or more carboxyl (i.e. —C(O)OH) groups of the said compounds are modified by reaction with an alcoholic moiety U—OH so as to yield —C(O)OU groups, wherein U may be C 1-18 alkyl (e.g. C 1-6 alkyl), aryl, heteroaryl, C 3-8 cycloalkyl or combinations thereof.
  • U may be C 1-18 alkyl (e.g. C 1-6 alkyl), aryl, heteroaryl, C 3-8 cycloalkyl or combinations thereof.
  • ‘Pharmaceutically acceptable derivatives’ of the compound of Formula A prepared by the invention are derivatives in which one or more groups of the compound is modified by reaction with another molecule.
  • derivatives of the compound of Formula A include the modification of the NH 2 group as shown in the following Scheme.
  • derivatives include the products of reaction of the NH 2 group of 4-(3-aminophenyl)-N-cyclopentyl-N-methyl-1H-imidazole-1-carboxamide with R—N ⁇ C ⁇ O isocyanate (see R. G. Arnold, J. A. Nelson, J. J. Verbanc: Recent Advances in Isocyanate Chemistry Chemical Reviews, 57(1), 47-76, 1957 and the references therein) to form NH—(C ⁇ O)—NHR derivative, or with Cl—(C ⁇ O)—Cl and NHR 2 (see H. Babad, A. G.
  • R may be C 1-18 alkyl (e.g. C 1-6 alkyl), aryl, heteroaryl, C 3-8 cycloalkyl or combinations thereof.
  • Pharmaceutically acceptable derivatives can be produced in any suitable way and methods for their production would be apparent to one skilled in the art based on well known principles in organic and medicinal chemistry (for example, suitable methods are disclosed in Vogel's Textbook of Practical Organic Chemistry, 5 th edition, Longman, 1989).
  • compounds prepared by the invention may exist as alternative tautomeric forms (e.g. keto/enol, amide/imidic acid), the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions.
  • a process for the synthesis of N-methylcyclopentylamine hydrochloride comprising the reaction of cyclopentylamine with a chloroformate, carried out in 2-methyltetrahydrofuran as the solvent, so as to form a cyclopentylcarbamate, followed by reduction of the cyclopentylcarbamate and acidification with HCl to N-methylcyclopentylamine hydrochloride.
  • This process can be used to efficiently produce N-methylcyclopentylamine hydrochloride, a key intermediate in the preparation of the compound of Formula A.
  • an intermediate may be prepared by other means (for example, reductive amination)
  • the present process provides high yield and good quality product.
  • 2-methyltetrahydrofuran as the solvent in the cyclopentylcarbamate formation step leads to an improved yield.
  • the use of 2-methyltetrahydrofuran also avoids the need to use methyl tert-butyl ether in the work-up procedure.
  • the cyclopentylcarbamate formation is conducted in basic conditions, for example, NaOH (e.g. 3M).
  • the chloroformate used for this step may, for example, be C 1-4 , such as ethyl, chloroformate.
  • the reduction step may be conducted using lithium aluminium hydride (LAH), in a solvent such as tetrahydrofuran or 2-methyltetrahydrofuran.
  • LAH lithium aluminium hydride
  • the two step process can be advantageously telescoped into a single procedure, without requiring purification of the cyclopentylcarbamate product.
  • this procedure is effective even when a reduced amount of lithium aluminium hydride is used.
  • HCl e.g. concentrated
  • solvent system employed for isolation is preferably dichloromethane/methyl tert-butyl ether.
  • N-methylcyclopentylamine hydrochloride produced according to this process may subsequently be used for the preparation of a compound of Formula A, using any of the processes for preparation of that compound described herein.
  • Room temperature in the following schemes means the temperature ranging from 20° C. to 25° C.
  • Potassium cyanate (0.445 g, 5.49 mmol) was added portionwise to a stirred solution of 4-(3-aminophenyl)-N-cyclopentyl-N-methyl-1H-imidazole-1-carboxamide (1.3 g, 4.57 mmol) in a mixture of 2N hydrogen chloride (2.286 mL, 4.57 mmol) in Water (4 mL) at 0° C. The mixture was allowed to stir at room temperature for 24 h. Potassium cyanate (0.220 g, 2.74 mmol) was added and the mixture was allowed to stir at room temperature for another night. Water was added and the organic layer was diluted with a mixture of DCM/isop 7:3.
  • the compounds of the invention above were characterised by melting point and NMR as detailed below.
  • NMR spectra were recorded on a Bruker Avance DPX400 spectrometer with solvent used as internal standard. 13C spectra were recorded at 100 MHz and 1H spectra were recorded at 400 MHz. Data are reported in the following order: approximate chemical shift (ppm), number of protons, multiplicity (br, broad; d, doublet; m, multiplet; s, singlet, t; triplet) and coupling constant (Hz).
  • ammonium hydroxide (337 ml, 2422 mmol) was cooled to 5° C. (ice bath) and the formaldehyde (37%, 54.1 ml, 727 mmol) was added dropwise over 20 minutes keeping internal temperature below 10° C.
  • the resulting clear solution was charged into a 1 L jacketed laboratory reactor. The solution was cooled to 5° C. Sol 1 was then added dropwise over 1 h30 keeping the internal temperature below 8° C.
  • the resulting material can then be used for urea formation, followed by conversion of the nitro group, as described above, to yield the compound of Formula A.
  • Example 2 THF is used as solvent for the urea formation reaction between the imidazole and the cyclopentyl(methyl)carbamic chloride. It has been found that an improved yield may be obtained by using a solvent consisting essentially of pyridine.
  • the wet material is dissolved in refluxing IPA (28.5 vol) and decolorizing charcoal is charged (0.33 wt). After stirring for not more than 30 min at reflux, charcoal is filtered off and the mixture concentrated until a final volume of 5 vol. After overnight stirring at r.t. filter the suspension and wash the cake with IPA (1 vol). The light beige solid is dried under vacuum at not more than 45° C. until loss on drying ⁇ 1.0%.
  • the yield was approaching 90%, and the purity around 98%.
  • the resulting nitro compound can be converted to the compound of Formula A, for example as described above.
  • a second minor batch of material was isolated from the formamide mother liquors after dilution with water (4 vol), 2M HCl (1.3 vol) then filtered. The resulting mother liquors were then basified with NaOH (until pH-14). The solids were filtered and washed with water (1 vol). The product was then dried under vacuum at temperature NMT 45° C. until LOD ⁇ 1.0%. The lower temperature and lower amount of formamide compared to a previous process did not comprise the overall yield, and there was a subsequent reduction in the overall solvent volumes required during the work-up procedure. A second batch of product was also isolated from the mother liquors of formamide.
  • the aniline is dissolved in AcOH (7 vol) at room temperature. After all solids have dissolved add water (4 vol). Cool the reaction mixture to 0° C. prior to addition of a solution of potassium cyanate (0.71 wt, 2.5 eq) in water (4 vol). Check conversion by HPLC. The resulting solution is stirred at 0° C. until completion (SM ⁇ 0.1%). Warm mixture to rt slowly. Within 1 h, the precipitation of the product occurred. To the resulting slurry is added water (11 vol). The beige suspension is then aged for 1 h at room temperature then filtered. The beige solid is washed with water (7 vol), dried under vacuum oven until LOD ⁇ 1.5%. The relatively swift addition rate of potassium cyanate and/or the low reaction temperature seemed to favour urea formation, and limited the amount of impurities in the crude reaction mixture.
  • the present invention therefore provides, in an embodiment, a process for preparing the compound of Formula A in which the compound is recrystallised from acetic acid, preferably with subsequent treatment of the solid using ethanol to remove residual acetic acid.
  • the resulting grey suspension was then cooled to 0° C., diluted with MTBE (225 mL, around 4.5 vol).
  • To the grey slurry was added drop wise water (31 mL) over 2 h (Note: strong gas evolution and exothermic event), followed by 10% NaOH (46 mL).
  • To the off-white suspension was added dropwise water (93 mL), the mixture was stirred for 1 h at 20° C. then MgSO4 (104 g, 2 wt) was added. The resulting thick slurry was stirred for 1 h at 20° C., then filtered.

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