Patent Application
20050256176
The present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising these, as well as their use.
The compounds of this invention are inhibitors of one or more metalloproteinase enzymes and are particularly effective as inhibitors of TNF-α (Tumour Necrosis Factor-α) production. Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N. M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMP) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF-α converting enzymes (ADAM10 and TACE); the ADAM-TS family (for example ADAM-TS1 and ADAM-TS4); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as the endothelin converting enzyme family and the angiotensin converting enzyme family.
Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biologically important cell mediators, such as tumour necrosis factor-α (TNF-α); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al., (1997) Biochem J. 321:265-279).
Metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these disease conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema and dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer's disease; and extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis.
A number of metalloproteinase inhibitors are known; different classes of compounds may have different degrees of potency and selectivity for inhibiting various metalloproteinases. We have discovered a class of compounds that are inhibitors of metalloproteinases and are of particular interest in inhibiting TACE. The compounds of this invention have beneficial potency and/or pharmacokinetic properties.
TACE (also known as ADAM17) which has been isolated and cloned [R. A. Black et al. (1997) Nature 385:729-733; M. L. Moss et al. (1997) Nature 385:733-736] is a member of the admalysin family of metalloproteins. TACE has been shown to be responsible for the cleavage of pro-TNF-α, a 26 kDa membrane bound protein to release 17 kDa biologically active soluble TNF-α. [Schlondorff et al. (2000) Biochem. J. 347: 131-138]. TACE mRNA is found in most tissues, however TNF-α is produced primarily by activated monocytes, macrophages and T lymphocytes. TNF-α has been implicated in a wide range of pro-inflammatory biological processes including induction of adhesion molecules and chemokines to promote cell trafficking, induction of matrix destroying enzymes, activation of fibroblasts to produce prostaglandins and activation of the immune system [Aggarwal et al (1996) Eur. Cytokine Netw. 7: 93-124]. Clinical use of the anti-TNF-α biologicals has shown TNF-α to play an important role in a range of inflammatory diseases including rheumatoid arthritis, Crohn's disease and psoriasis [Onrust et al (1998) Biodrugs 10: 397-422, Jarvis et al (1999) Drugs 57:945-964]. TACE activity has also been implicated in the shedding of other membrane bound proteins including TGFα, p75 & p55 TNF receptors, L-selectin and amyloid precursor protein [Black (2002) Int. J. Biochem. Cell Biol. 34: 1-5]. The biology of TACE inhibition has recently been reviewed and shows TACE to have a central role in TNF-α production and selective TACE inhibitors to have equal, and possibly greater, efficacy in the collagen induced arthritis model of RA than strategies that directly neutralise TNF-α [Newton et al (2001) Ann. Rheum. Dis. 60: iii25-iii32].
A TACE inhibitor might therefore be expected to show efficacy in all disease where TNF-α has been implicated including, but not limited to, inflammatory diseases including rheumatoid arthritis and psoriasis, autoimmune diseases, allergic/atopic diseases, transplant rejection and graft versus host disease, cardiovascular disease, reperfusion injury, malignancy and other proliferative diseases. A TACE inhibitor might also show efficacy in a respiratory disorder such as asthma or COPD.
Metalloproteinase inhibitors are known in the art. WO 02/096426 discloses hydantoin derivatives that are useful as inhibitors of metalloproteinases, TACE, aggrecanase or combinations thereof. The compounds disclosed therein comprises a hydantoin group and a phenyl group connected by a linking portion which differ from the present invention with regard to the linking portion. WO 02/074751 discloses compounds useful in the inhibition of metalloproteinases and in particular 1-(4-methyl-3,5-dioxoimidazolidin-4-yl)-N-[4-(4-chlorophenoxy)phenyl]methanesulphonamide which has been specifically disclaimed herein. The compounds of WO 02/074751 are particularly active against MMP12. WO 02/074750 also discloses metalloproteinase inhibitors.
We are able to provide compounds that have metalloproteinase inhibitory activity, and are in particular inhibitors of TACE (ADAM17).
According to the first aspect of the present invention there is provided a compound of formula (I), a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof:
wherein:
According to a second aspect of the invention there is provided a compound of formula (I), a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:
In particular the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof:
wherein:
In addition, the invention also provides a compound of formula (IB) or a pharmaceutically acceptable salt thereof:
wherein:
It is to be understood that, insofar as certain of the compounds of the invention defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon or sulphur atoms, the invention includes in its definition any such optically active or racemic form which possesses metalloproteinases inhibition activity and in particular TACE inhibition activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
Compounds of the invention are therefore provided as enantiomers, diastereomers, geometric isomers and atropisomers.
Within the present invention it is to be understood that a compound of the invention or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which has metalloproteinases inhibition activity and in particular TACE inhibition activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
It is also to be understood that certain compounds of the invention and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which have metalloproteinases inhibition activity and in particular TACE inhibition activity.
It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms which possess metalloproteinases inhibition activity and in particular TACE inhibition activity.
The present invention relates to compounds of the invention as defined herein as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of the invention and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of the invention as defined herein which are sufficiently basic to form such salts. Such acid addition salts include but are not limited to hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In addition where compounds of the invention are sufficiently acidic, salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salts for example triethylamine or tris-(2-hydroxyethyl)amine
The compounds of the invention may also be provided as in vivo hydrolysable esters. An in vivo hydrolysable ester of a compound of the invention containing a carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol. Such esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
Suitable pharmaceutically acceptable esters for carboxy include C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in compounds of this invention.
Suitable pharmaceutically-acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include C1-10alkanoyl, for example formyl, acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, C1-10alkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(C1-4)alkylcarbamoyl and N-(di-(C1-4)alkylaminoethyl)-N-(C1-4)alkylcarbamoyl (to give carbamates); di-(C1-4)alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, (C1-4)alkylaminomethyl and di-((C1-4)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring. Other interesting in vivo hydrolysable esters include, for example, RAC(O)O(C1-6)alkyl-CO—, wherein RA is for example, benzyloxy-(C1-4)alkyl, or phenyl). Suitable substituents on a phenyl group in such esters include, for example, 4-(C1-4)piperazinyl-(C1-4)alkyl, piperazinyl-(C1-4)alkyl and morpholino-(C1-4)alkyl.
In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as tert-butyl are specific for the branched chain version only. For example, “C1-3alkyl” includes methyl, ethyl, propyl and isopropyl, “C1-4alkyl” additionally includes butyl and tert-butyl and examples of “C1-6alkyl” include the examples of “C1-4alkyl” and additionally pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl. An analogous convention applies to other generic terms, for example “C2-4alkenyl” includes vinyl, allyl and 1-propenyl and examples of “C2-6alkenyl” include the examples of “C2-4alkenyl” and additionally 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Examples of “C2-4alkynyl” includes ethynyl, 1-propynyl, 2-propynyl, 3-butynyl and examples of “C2-6alkynyl” include the examples of “C2-4alkynyl” and additionally 2-pentynyl, hexynyl and 1-methylpent-2-ynyl. Where examples are given for generic terms, it should be noted that these examples are not limiting.
“Cycloalkyl” is a monocyclic, saturated alkyl ring. The term “C3-4cycloalkyl” includes cyclopropyl and cyclobutyl. The term “C3-5cycloalkyl” includes “C3-4cycloalkyl and cyclopentyl. The term “C3-6cycloalkyl” includes “C3-5cycloalkyl”, and cyclohexyl. The term “C3-7cycloalkyl” includes “C3-6cycloalkyl” and additionally cycloheptyl. The term “C3-10cycloalkyl” includes “C3-7cycloalkyl” and additionally cyclooctyl, cyclononyl and cyclodecyl.
“Cycloalkenyl” is a monocyclic ring containing 1, 2, 3 or 4 double bonds. Examples of “C5-6cycloalkenyl” are cyclopentenyl, cyclohexenyl and cyclohexadiene, “C5-7cycloalkenyl” additionally includes cycloheptadiene and examples of “C5-10cycloalkenyl” include the examples of “C5-7cycloalkenyl” and cyclooctatriene.
Unless otherwise specified “aryl” is monocyclic or bicyclic. Examples of “aryl” therefore include phenyl (an example of monocyclic aryl) and naphthyl (an example of bicyclic aryl).
Examples of “arylC1-4alkyl” are benzyl, phenethyl, naphthylmethyl and naphthylethyl.
Unless otherwise specified “heteroaryl” is a monocyclic or bicyclic aryl ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised. Examples of heteroaryl are pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl and pyrazolopyridinyl. Preferably heteroaryl is pyridyl, imidazolyl, quinolinyl, pyrimidinyl, thienyl, pyrazolyl, thiazolyl, oxazolyl and isoxazolyl. More preferably heteroaryl is pyridyl, imidazolyl and pyrimidinyl. Examples of “monocyclic heteroaryl” are pyridyl, imidazolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl and pyrazinyl. Examples of “bicyclic heteroaryl” are quinolinyl, quinazolinyl, cinnolinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl and pyrazolopyridinyl. Preferred examples of B when B is heteroaryl are those examples of bicyclic heteroaryl.
Examples of “heteroarylC1-4alkyl” are pyridylmethyl, pyridylethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl.
“Heterocyclyl” is a saturated, unsaturated or partially saturated, monocyclic or bicyclic ring (unless otherwise stated) containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH2— group can optionally be replaced by a —C(O)—; and where unless stated to the contrary a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); a ring —NH is optionally substituted by acetyl, formyl, methyl or mesyl; and a ring is optionally substituted by one or more halo. Examples and suitable values of the term “heterocyclyl” are piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5-dioximidazolidinyl, 2,2-dimethyl-1,3-dioxolanyl and 3,4dimethylenedioxyphenyl. Preferred values are 3,4-dihydro-2H-pyran-5-yl, tetrahydrofuran-2-yl, 2,5-dioximidazolidinyl, 2,2-dimethyl-1,3-dioxolan-2-yl and 3,4-dimethylenedioxyphenyl. Other values are pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinoline, tetrahydroisoquinoline and isoindolinyl. Examples of monocyclic heterocyclyl are piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, pyranyl, tetrahydrofuranyl, 2,5-dioximidazolidinyl and 2,2-dimethyl-1,3-dioxolanyl. Examples of bicyclic heterocyclyl are pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, 2,3-methylenedioxyphenyl, and 3,4-methylenedioxyphenyl. Examples of saturated heterocyclyl are piperidinyl, pyrrolidinyl and morpholinyl.
The term “halo” refers to fluoro, chloro, bromo and iodo.
Examples of “C1-3alkoxy” and “C1-4alkoxy” include methoxy, ethoxy, propoxy and isopropoxy. Examples of “C1-6alkoxy” include the examples of “C1-4alkoxy” and additionally pentyloxy, 1-ethylpropoxy and hexyloxy.
“Heteroalkyl” is alkyl containing at least one carbon atom and having at least one carbon atom replaced by a hetero group independently selected from N, O, S, SO, SO2, (a hetero group being a hetero atom or group of atoms). Examples include —OCH2—, CH2O—, —CH2SO2CH2CH2— and —OCH(CH3)—.
“HaloC1-4alkyl” is a C1-4alkyl group substituted by one or more halo. Examples of “haloC1-4alkyl” include fluoromethyl, trifluoromethyl, 1-chloroethyl, 2-chloroethyl, 2-bromopropyl, 1-fluoroisopropyl and 4-chlorobutyl. Examples of “haloC1-6alkyl” include the examples of “haloC1-4alkyl” and 1-chloropentyl, 3-chloropentyl and 2-fluorohexyl.
Examples of “hydroxyC1-4alkyl” include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 1-hydroxyisopropyl and 4-hydroxybutyl.
Example of “C1-4alkoxyC1-4alkyl” include methoxymethyl, ethoxymethyl, methoxyethyl, methoxypropyl and propoxybutyl.
“HaloC1-4alkoxyC1-4alkyl” is a C1-4alkoxyC1-4alkyl group substituted by one or more halo. Examples of “haloC1-4alkoxyC1-4alkyl” include 1-(chloromethoxy)ethyl, 2-fluoroethoxymethyl, trifluoromethylmethoxy, 2-(4-bromobutoxy)ethyl and 2-(2-iodoethoxy)ethyl.
Examples of “carboxyC1-4alkyl” include carboxymethyl, 2-carboxyethyl and 2-carboxypropyl.
Heterocyclic rings are rings containing 1, 2 or 3 ring atoms selected from nitrogen, oxygen and sulphur. “Heterocyclic 5- to 7-membered” rings are pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, thiomorpholinyl, thiopyranyl and morpholinyl. “Heterocyclic 4- to 7-membered” rings include the examples of “heterocyclic 5 to 7-membered” and additionally azetidinyl. Similarly “heterocyclic 5- to 6-membered” rings includes pyrrolidinyl, pyrrolyl, pyrimidinyl, pyridinyl and piperidinyl, and “heterocyclic 4- to 6-membered” rings additionally includes azetidinyl.
Carbocyclic rings are saturated, partially saturated of unsaturated rings containing only carbon ring atoms. Examples are cyclopentanyl, cyclohexanyl, cyclohexenyl and phenyl. Such rings may be optionally substituted by halo, C1-4alkoxy, haloC1-4alkyl or C1-4alkoxyC1-4alkyl.
Saturated 5 to 7-membered rings include cyclopentane, cyclohexane and cycloheptane and saturated 3 to 7-membered rings additionally include cyclopropane and cyclobutane. Saturated 5 to 7-membered rings and 3 to 7-membered rings optionally containing 1 or 2 heteroatom groups selected from NH, O, S, SO and SO2 include pyrrolidine, piperidine, tetrahydrofuran and tetrahydropyran.
Where optional substituents are chosen from “one of more” groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. Preferably “one or more” means “1, 2 or 3” and this is particularly the case when the group or substituent is halo. “One or more” may also mean “1 or 2”.
Compounds of the present invention have been named with the aid of computer software (ACD/Name version 5.09).
Preferred values of Y1, Y2, z, n, t, R4, R5, R6, R7, R12 and R13 for a compound of formula (I), (IA) or (IB) are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined herein.
In one aspect of the invention Y1 and Y2 are both O.
In one aspect of the invention z is NR8.
In one aspect of the invention n is 1. In another aspect n is 0.
In one aspect of the invention t is 0. In another aspect t is 1.
In one aspect of the invention R4 is hydrogen or methyl. In another aspect R4 is hydrogen.
In one aspect of the invention R5 is hydrogen or methyl. In another aspect R5 is hydrogen.
In one aspect of the invention R6 is hydrogen or methyl. In another aspect R6 is hydrogen.
In one aspect of the invention R7 is hydrogen or a group selected from C1-6alkyl, C3-7cycloalkyl, aryl, heteroaryl or heterocyclyl where the group is optionally substituted by heterocyclyl, aryl and heteroaryl; and wherein the group from which R7 may be selected is optionally substituted on the group and/or on its optional substituent by one or more substituents independently selected from halo, cyano, C1-4alkyl, —OR21, —CO2R21, —NR21COR22, —NR21CO2R22 and —CONR21R22. In another aspect R7 is hydrogen or a group selected from C1-4alkyl, arylC1-4alkyl, heteroarylC1-4alkyl, heterocyclylC1-4alkyl, aryl, heteroaryl, heterocyclyl and C3-5cycloalkyl which group is optionally substituted by cyano, C1-4alkyl, —COC1-4alkyl, halo, —OR21, —NR21R22, —CO2R21 and —NR21CO2R22. In another aspect R7 is hydrogen or a group selected from C1-4alkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl optionally substituted by one or more C1-4alkoxy, fluoro, —COC1-3alkyl or —SO2C1-3alkyl. In a further aspect R7 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, tert-butyl, isobutyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, aminomethyl, 2-aminoethyl, 2-cyanoethyl, phenyl, pyridyl, benzyl, 3-methylbenzyl, phenylethyl, 4-chlorophenylethyl, 4-fluorophenylethyl, phenylpropyl, 4-chlorophenylpropyl, 4-fluorophenylpropyl, 4-methylpiperazin-1-ylethyl, morpholin-4-ylpropyl, pyrimidin-2-ylethyl, pyrimidin-2-ylpropyl, pyrimidin-2-ylbutyl, 5-fluoropyrimidin-2-ylpropyl, imidazol-1-ylpropyl, imidazol-1-ylbutyl, 1,3,4-triazolylpropyl, piperidinyl, carbamoylphenyl, tetrahydro-2H-pyranyl, tetrahydro-2H-pyranylmethyl, pyrid-2-ylmethyl, pyrid-4-ylmethyl, pyrid-3-ylmethyl, piperidin-4-ylmethyl, N-(tert-butoxycarbonyl)piperidin-4-yl, N-(methylcarbonyl)piperidin-4-yl, N-(tert-butoxycarbonyl)aminomethyl, benzyloxyethyl, N-(tert-butoxycarbonyl)piperidin-4-ylmethyl, (3,4,4-trimethyl-2,5-dioximidazolidin-1-yl)methyl, and N-benzoyl-N-phenylaminomethyl. In a further aspect R7 is hydrogen or C1-4alkyl optionally substituted by halo, hydroxy, C1-4alkoxy or amino. In another aspect R7 is hydrogen or C1-4alkyl. In a further aspect R7 is hydrogen, methyl or ethyl.
In one aspect of the invention R8 is hydrogen or methyl. In another aspect R8 is hydrogen.
In one aspect of the invention R9 is hydrogen or methyl.
In one aspect of the invention R10 is hydrogen or methyl.
In one aspect of the invention R11 is methyl.
In one aspect of the invention R12 is hydrogen or methyl. In another aspect R12 is hydrogen.
In one aspect of the invention R13 is hydrogen or methyl. In another aspect R13 is hydrogen.
In one aspect of the invention R16 is hydrogen or methyl.
In one aspect of the invention R17 is selected from fluoro, chloro, methyl or methoxy.
In one aspect of the invention R18 is hydrogen or a group selected from C1-6alkyl, aryl and arylC1-4alkyl where the group is optionally substituted by halo. In another aspect R18 is hydrogen or a group selected from methyl, phenyl and benzyl where the group is optionally substituted by chloro.
In one aspect of the invention R19 is a group selected from C1-6alkyl, aryl and arylC1-4alkyl where the group is optionally substituted by halo. In another aspect R19 is a group selected from methyl, phenyl and benzyl where the group is optionally substituted by chloro. In one aspect R19 is methyl.
In one aspect of the invention R20 is hydrogen or methyl.
In one aspect of the invention R21 is hydrogen, methyl, ethyl, phenyl and benzyl.
In one aspect of the invention R22 is hydrogen, methyl, ethyl, tert-butyl, phenyl and benzyl. In another aspect R22 is hydrogen or methyl.
In one aspect of the invention R25 is a group selected from C1-6alkyl, aryl and arylC1-4alkyl where the group is optionally substituted by halo. In another aspect R25 is a group selected from methyl, phenyl and benzyl where the group is optionally substituted by chloro. In one aspect R25 is methyl.
Preferred values of W, V, B, R3, R4, R5, R6 and R7 for a compound of formula (I) are as follows:
In one aspect of the invention W is NR1. In another aspect W is CR1R2. In a further aspect W is a bond.
In one aspect of the invention V is C═O. In another aspect V is SO2. In a further aspect V is NR15C═O.
In one aspect of the invention V and W together form C═O. In another aspect V and W together form NR15C═ONR1.
In one aspect of the invention, when V is C(═O), NR15C(═O) or NR15SO2; or when V is SO2 and n is 1 and W is NR1, CR1R2 or a bond; or when V is SO2 and n is 0 and W is CR1R2; then B is a group selected from aryl, heteroaryl and heterocyclyl where each group is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, C1-4alkyl (optionally substituted by one or more halo), C2-4alkynyl, heteroaryl, —OR9, cyano, —NR9R10, —CONR9R10 and —NR9COR10; or B is C2-4alkenyl or C2-4alkynyl optionally substituted by C1-4alkyl, C3-6cycloalkyl or heterocyclyl. In one aspect of the invention B is a group selected from aryl and heteroaryl where each group is optionally substituted by one or more groups independently selected from halo, C1-4alkyl (optionally substituted by one or more halo), C2-4alkenyl (optionally substituted by halo) and C2-4alkynyl (optionally substituted by halo); or B is C2-4alkenyl or C2-4alkynyl, each being optionally substituted by a group selected from C1-4alkyl, C3-6cycloalkyl, aryl, heteroaryl, heterocyclyl whereby this group is optionally substituted by one or more halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, —CONHR9, —CONR9R10, —SO2R11, —SO2NR9R10, —NR9SO2R11, C1-4alkyl and C1-4alkoxy; provided that when t is 0 and B is monocyclic aryl or monocyclic heteroaryl then the monocyclic group that is B is substituted on the carbon or nitrogen adjacent to the atom to which the oxygen is attached, by a substituent group described above. In one aspect of the invention, when V is SO2 and n is 0 and W is NR1 or a bond; B is a group selected from bicyclic aryl, bicyclic heteroaryl and bicyclic heterocyclyl, where each group is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, C1-4alkyl (optionally substituted by one or more halo), C2-4alkynyl, heteroaryl, —OR9, cyano, —NR9R10, —CONR9R10 and —NR9COR10; or B is C2-4alkenyl or C2-4alkynyl optionally substituted by C1-4alkyl, C3-6cycloalkyl or heterocyclyl. In a further aspect of the invention B is 2-methylquinolin-4-yl, 2,5-dimethylphenyl or 2,5-dimethylpyrid-4-yl.
In one aspect of the invention R1 is hydrogen or methyl.
In one aspect of the invention R2 is hydrogen or methyl.
In one aspect of the invention R3 is hydrogen or methyl.
In one aspect of the invention R1 and R3 together with the nitrogen or carbon and carbon to which they are respectively attached form a 2,2-dimethylthiomorpholine, piperidine, pyrrolidine, piperazine, morpholine, cyclopentane or cyclohexane ring.
In one aspect of the invention R3 and R4 together form a pyrrolidine ring or a tetrahydro-2H-pyran ring.
In one aspect of the invention R3 and R5 together with the carbon atoms to which they are attached form a piperidine ring substituted by methyl.
In one aspect of the invention R3 and R7 together with the carbon atoms to which they are each attached and (CR5R6)n form a piperidinyl, pyrrolidinyl, piperazine or morpholine ring.
In one aspect R15 is hydrogen or methyl.
In addition to the preferred values of Y1, Y2, z, n, t, R4, R5, R6, R7, R12 and R13 mentioned above in relation to a compound of formula (I), (IA) or (IB), other preferred values of W, V, B, R3, R4, R5 and R7 for a compound of formula (IA) are as follows. These values may also be used where appropriate with any of the definitions, claims or embodiments defined herein.
In one aspect of the invention W is a bond or CR1R2. In another aspect W is NR1. In another aspect W is CR1R2. In a further aspect W is a bond.
In this aspect of the invention V is NR15SO2.
In one aspect of the invention, B is a group selected from aryl, heteroaryl and heterocyclyl where each group is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, C1-4alkyl (optionally substituted by one or more halo), C2-4alkynyl, heteroaryl, —OR9, cyano, —NR9R10, —CONR9R10 and —NR9COR10; or B is C2-4alkenyl or C2-4alkynyl optionally substituted by C1-4alkyl, C3-6cycloalkyl or heterocyclyl. In another aspect, B is phenyl, naphthyl, pyridyl, imidazolyl, quinolinyl, cinnolyl, isoquinolinyl, thienopyridyl, naphthyridinyl, 2,5-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, thienopyrimidinyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridoimidazolyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, indolizinyl, isobenzofuranyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and isoindolinyl, where each is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, C1-4alkyl (optionally substituted by one or more fluoro), C2-4alkynyl, heteroaryl, —OR9, cyano, —NR9R10, —CONR9R10 and —NR9COR10; or B is vinyl or ethynyl optionally substituted by C1-4alkyl. In a preferred aspect B is bicyclic aryl, bicyclic heteroaryl or bicyclic heterocyclyl optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, cyano, C1-4alkyl (optionally substituted by R9 or C1-4alkoxy, or one or more halo), C2-4alkenyl (optionally substituted by halo or R9), C2-4alkynyl (optionally substituted by halo or R9), C3-6cycloalkyl (optionally substituted by R9 or one or more halo), C5-6cycloalkenyl (optionally substituted by halo or R9), aryl (optionally substituted by halo or C1-4alkyl), heteroaryl (optionally substituted by halo or C1-4alkyl), heterocyclyl (optionally substituted by C1-4alkyl), —SR11, —SOR11, —SO2R11, —SO2NR9R10, —NR9SO2R11, —NHCONR9R10, —OR9, —NR9R10, —CONR9R10 and —NR9COR10; or B is phenyl, pyridyl or pyrimidinyl substituted at the 2- and 5 positions (whereby the 1-position is the atom by which B is bonded to (CR12CR13)t) by groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, cyano, C1-4alkyl (optionally substituted by R9 or C1-4alkoxy, or one or more halo), C2-4alkenyl (optionally substituted by halo or R9), C2-4alkynyl (optionally substituted by halo or R9), C3-6cycloalkyl (optionally substituted by R9 or one or more halo), C5-6cycloalkenyl (optionally substituted by halo or R9), aryl (optionally substituted by halo or C1-4alkyl), heteroaryl (optionally substituted by halo or C1-4alkyl), heterocyclyl (optionally substituted by C1-4alkyl), —SR11, —SOR11, —SO2R11, —SO2NR9R10, —NR9SO2R11, —NHCONR9R10, —OR9, —NR9R10, —CONR9R10 and —NR9COR10. In a preferred aspect B is bicyclic aryl, bicyclic heteroaryl or bicyclic heterocyclyl optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, cyano, C1-4alkyl (optionally substituted by R9 or C1-4alkoxy, or one or more halo), C2-4alkenyl (optionally substituted by halo or R9), C2-4alkynyl (optionally substituted by halo or R9), C3-6cycloalkyl (optionally substituted by R9 or one or more halo), C5-6cycloalkenyl (optionally substituted by halo or R9), aryl (optionally substituted by halo or C1-4alkyl), heteroaryl (optionally substituted by halo or C1-4alkyl), heterocyclyl (optionally substituted by C1-4alkyl), —SR11, —SOR11, —SO2R11, —SO2NR9R10, —NR9SO2R11, —NHCONR9R10, —OR9, —NR9R10, —CONR9R10 and —NR9COR10. In a further aspect B is quinolin-4-yl, naphth-1-yl, 2-methylquinolin-4-yl, 3-methylnaphthyl, 7-methylquinolin-5-yl, 6-methylquinolin-8-yl, 7-methylisoquinolin-5-yl, 6-methylthieno[2,3-b]pyridyl, 5-methylthieno[3,2-b]pyridyl, 2-methyl-1,8-naphthyridinyl, 2-trifluoromethylquinolin-4-yl, 2-ethynylquinolin-4-yl, 7-chloroquinolin-5-yl, 7-fluoro-2-methylquinolin-4-yl, 2-methyl-N-oxoquinolin-4-yl, 3-methylisoquinolin-1-yl, 5-fluoro-2-methylquinolin-4-yl, 2,5-dimethylpyridin-4-yl, 2,5-dimethylphenyl, 2,5-difluorophenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 5-fluoro-2-methylpyridinyl, 1-methylquinolinyl, 7-chloroquinolin-4-yl, 8-chloroquinolin-4-yl, 6-chloroquinolin-4-yl, 5-methylthieno[2,3-d]pyrimidin-4-yl, 7-methylthieno[3,2-d]pyrimidin-4-yl, 8-fluoroquinolin-4-yl, 6-fluoroquinolin-4-yl, 2-methylquinolin-4-yl, 6-chloro-2-methylquinolin-4-yl, 1,6-naphthyridin-4-yl, thieno[3,2-b]pyrid-7-yl, 5-fluoro-2-(isoxazol-5-yl)phenyl, 2-chloro-5-fluorophenyl, vinyl, ethynyl, prop-1-enyl, prop-1-ynyl or but-1-ynyl. In another aspect of the invention B is a group selected from aryl and heteroaryl where each group is optionally substituted by one or more groups independently selected from halo, C1-4alkyl (optionally substituted by one or more halo), C2-4alkenyl (optionally substituted by halo) and C2-4alkynyl (optionally substituted by halo); or B is C2-4alkenyl or C2-4alkynyl, each being optionally substituted by a group selected from C1-4alkyl, C3-6cycloalkyl, aryl, heteroaryl, heterocyclyl which group is optionally substituted by one or more halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, —CONHR9, —CONR9R10, —SO2R11, —SO2NR9R10, —NR9SO2R11, C1-4alkyl and C1-4alkoxy; provided that when t is 0 and B is monocyclic aryl or monocyclic heteroaryl then the monocyclic group that is B is substituted on the carbon or nitrogen adjacent to the atom to which the oxygen is attached, by a substituent group described above. In another aspect of the invention B is a group selected from quinolinyl, pyridyl and phenyl where each group is optionally substituted by one or more methyl, trifluoromethyl, trifluoromethoxy, or halo. In another aspect B is C2-4alkenyl or C2-4alkynyl optionally substituted by C1-4alkyl, C3-6cycloalkyl or heterocyclyl. In a further aspect of the invention B is 2-methylquinolin-4-yl, 2,5-dimethylphenyl or 2,5-dimethylpyrid-4-yl. In yet another aspect B is 2-methylquinolin-4-yl or 2,5-dimethylphenyl. In a further aspect B is 2-methylquinolin-4-yl.
In one aspect of the invention R1 is hydrogen or C1-4alkyl optionally substituted by halo, hydroxy or C1-4alkoxy. In another aspect R1 is hydrogen or methyl.
In one aspect of the invention R2 is hydrogen or methyl.
In one aspect of the invention R3 is hydrogen, methyl, ethyl, propyl or phenyl. In another aspect R3 is hydrogen.
In one aspect of the invention R1 and R3 together with the nitrogen or carbon atoms and carbon atom to which they are respectively attached form a 2,2-dimethylthiomorpholine, piperidine, pyrrolidine, piperazine, morpholine, cyclopentane or cyclohexane ring.
In one aspect of the invention R3 and R4 together with the carbon atom to which they are attached form a piperidine, pyrrolidine, tetrahydrofuran or tetrahydropyran ring. In one aspect of the invention R3 and R4 together form a pyrrolidine ring or a tetrahydro-2H-pyran ring.
In one aspect of the invention R3 and R5 together with the carbon atoms to which they are attached form a piperidine or pyrrolidine ring optionally substituted by methyl. In another aspect R3 and R5 together with the carbon atoms to which they are attached form a piperidine ring substituted by methyl
In one aspect of the invention R3 and R7 together with the carbon atoms to which they are each attached and (CR5R6)n form a piperidine, pyrrolidine, piperazine, morpholine, tetrahydrofuran, tetrahydrpyran, cyclohexane or cyclopentane ring. In another aspect R3 and R7 together with the carbon atoms to which they are each attached and (CR5R6)n form a piperidinyl, pyrrolidinyl, piperazine or morpholine ring. In a further aspect R3 and R7 together with the carbon atoms to which they are each attached and (CR5R6)n form a tetrahydrofuran, cylohexane or cyclopentane ring.
In one aspect R15 is hydrogen or methyl.
In addition to the preferred values of Y1, Y2, z, n, t, R4, R5, R6, R7, R12 and R13 mentioned above in relation to a compound of formula (I), (IA) or (IB), other preferred values of W, V, B, R3, R4, R5 and R7 for a compound of formula (IB) are as follows. These values may also be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
In one aspect of the invention W is NR1.
In one aspect of the invention V is SO2. In another aspect V is CO.
In one aspect of the invention, B is a group selected from aryl, heteroaryl and heterocyclyl where each group is optionally substituted by one or more groups independently selected from nitro, trifluoromethyl, trifluoromethoxy, halo, C1-4alkyl (optionally substituted by one or more halo), C2-4alkynyl, heteroaryl, —OR9, cyano, —NR9R10, —CONR9R10 and —NR9COR10; or B is C2-4alkenyl or C2-4alkynyl optionally substituted by C1-4alkyl, C3-6cycloalkyl or heterocyclyl; provided that when t is 0 such that B is directly attached to the oxygen atom shown in formula (IB) and B is monocyclic aryl or monocyclic heteroaryl and n is 0 then the monocyclic group that is B is substituted on one of the atoms adjacent to the atom to which the oxygen is attached, by a group selected from those listed in the definition of B which optionally substitute B. In one aspect of the invention B is a group selected from aryl and heteroaryl where each group is optionally substituted by one or more groups independently selected from halo, C1-4alkyl (optionally substituted by one or more halo), C2-4alkenyl (optionally substituted by halo) and C2-4alkynyl (optionally substituted by halo); or B is C2-4alkenyl or C2-4alkynyl, each being optionally substituted by a group selected from C1-4alkyl, C3-6cycloalkyl, aryl, heteroaryl, heterocyclyl whereby this group is optionally substituted by one or more halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, —CONHR9, —CONR9R10, —SO2R11, —SO2NR9R10,
In one aspect of the invention R1 and R3 together with the nitrogen and carbon atoms to which they are respectively attached form a saturated 4- to 6-membered ring optionally containing a further heteroatom group selected from NH, O, S or SO2. In another aspect R1 and R3 together with the nitrogen and carbon atoms to which they are respectively attached form a saturated 5- to 6-membered ring optionally substituted on carbon by C1-4alkyl, fluoro or C1-4alkoxy. In another aspect R1 and R3 together with the nitrogen and carbon atoms to which they are respectively attached form a saturated 5- to 6-membered ring i.e pyrrolidinyl or piperidinyl.
A preferred class of compound is of formula (IA) wherein:
Another preferred class of compound is of formula (A) wherein:
Another preferred class of compound is of formula (IA) wherein:
Another preferred class of compound is of formula (IA) wherein:
A preferred class of compound is of the formula (IB) wherein:
Another preferred class of compound is of the formula (IB) wherein:
Another preferred class of compound is of the formula (IB) wherein:
In another aspect of the invention, preferred compounds of the invention are any one of:
Preferred compounds of formula (IA) are:
Preferred compounds of formula (IB) are:
In another aspect the present invention provides a process for the preparation of a compound of formula (IA) or (IB) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein Y1 and Y2 are both O, z is NR8 and R8 is hydrogen, which comprises converting a ketone or aldehyde of formula (IIA) or (IIB) into a compound of formula (IA) or (IB);
and thereafter if necessary:
A ketone or aldehyde of formula (IIB) may be prepared by a process comprising converting a compound of formula (IIIB) (where R is C1-10alkyl and X is O or XR is NHOMe) into an aldehyde or ketone of formula (IIB);
Suitable reagents for such a transformation are Grignard reagents of formula R7MgX (where X is halo) to prepare ketones or diisobutylaluminium hydride in dichloromethane at −78° C. under an argon atmosphere to prepare aldehydes.
A compound of formula (IIIB) can be prepared by reaction of a compound of formula (IVB) with a compound of formula (VB) or its salt under standard sulphonamide formation conditions (e.g. triethylamine in dichloromethane at temperatures from 0° C. to 50° C.);
Many compounds of formula (VB) are commercially available or can be easily prepared by the skilled person. The sulphonyl chloride of formula (IVB) can be prepared as outlined in Scheme 4 which comprises;
In another aspect the present invention provides a process for the preparation of a compound of formula (IB) or a pharmaceutically acceptable salt or in vivo hydrolysable ester, which process comprises coupling a sulphonyl chloride of formula (IVB) with an amine of formula (VIIIB) under standard sulphonamide formation conditions and followed by deprotection.
Also provided is a process for the preparation of an amine of formula (VIIIB) as shown in Scheme 6 which comprises the steps of:
There is also provided a process for the preparation of a compound of formula (IA), which process comprises:
Further aspects of the invention include a process for preparing a compound of formula (IA) which when W is NR1 comprises:
reaction of an amine of formula (VIIIA) with a suitable chlorosulphonamide intermediate under standard sulphonamide formation conditions (as described above in c)); or when W is a bond or CR1R2, comprises
reaction of a hydantoin sulphonyl chloride of formula (XVA) with a suitable chlorosulphonamide intermediate under standard sulphonamide formation conditions (as described above in d));
and thereafter if necessary:
An amine of formula (VIIIA) may be obtained by processes that are analogous to those shown in schemes 6 and 6a for the preparation of an amine of formula (VIIIB) or its deprotected analogue.
A sulphonyl chloride of formula (XVA) can be formed as follows:
The process of Scheme 8 comprises the steps of:
A compound of formula (IA) or (IB) can be prepared by removal of protecting groups on the hydantoin directly. The protecting group can be tert-butyloxycarbonyl (BOC), benzyl (Bn) or benzyloxycarbonyl (cbz). These can be removed by treatment with trifluoroacetic acid or HCl in dioxane for the former or by treatment with palladium/hydrogen for the latter two.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
As stated hereinbefore the compounds defined in the present invention possesses metalloproteinases inhibitory activity, and in particular TACE inhibitory activity. This property may be assessed, for example, using the procedure set out below.
Isolated Enzyme Assays
Matrix Metalloproteinase Family Including for Example MMP13.
Recombinant human proMMP13 may be expressed and purified as described by Knauper et al. [V. Knauper et al., (1996) The Biochemical Journal 271:1544-1550 (1996)]. The purified enzyme can be used to monitor inhibitors of activity as follows: purified proMMP13 is activated using 1 mM amino phenyl mercuric acid (APMA), 20 hours at 21° C.; the activated MMP13 (11.25 ng per assay) is incubated for 4-5 hours at 35° C. in assay buffer (0.1M Tris-HCl, pH 7.5 containing 0.1M NaCl, 20 mM CaCl2, 0.02 mM ZnCl and 0.05% (w/v) Brij 35 using the synthetic substrate 7-methoxycoumarin-4-yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl.Ala.Arg.NH2 in the presence or absence of inhibitors. Activity is determined by measuring the fluorescence at λex 328 nm and λem 393 nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescenceplus inhibitor−Fluorescencebackground] divided by the [Fluorescenceminus inhibitor−Fluorescencebackground].
A similar protocol can be used for other expressed and purified pro MMPs using substrates and buffers conditions optimal for the particular MMP, for instance as described in C. Graham Knight et al., (1992) FEBS Lett. 296(3):263-266.
Adamalysin Family Including for Example TNF Convertase
The ability of the compounds to inhibit proTNF-α convertase enzyme (TACE) may be assessed using a partially purified, isolated enzyme assay, the enzyme being obtained from the membranes of THP-1 as described by K. M. Mohler et al., (1994) Nature 370:218-220. The purified enzyme activity and inhibition thereof is determined by incubating the partially purified enzyme in the presence or absence of test compounds using the substrate 4′,5′-Dimethoxy-fluoresceinyl Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-succinimid-1-yl)-fluorescein)-NH2 in assay buffer (50 mM Tris HCl, pH 7.4 containing 0.1% (w/v) Triton X-100 and 2 mM CaCl2), at 26° C. for 4 hours. The amount of inhibition is determined as for MMP13 except λex 485 nm and λem 538 nm were used. The substrate was synthesised as follows. The peptidic part of the substrate was assembled on Fmoc-NH-Rink-MBHA-polystyrene resin either manually or on an automated peptide synthesiser by standard methods involving the use of Fmoc-amino acids and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) as coupling agent with at least a 4- or 5-fold excess of Fmoc-amino acid and HBTU. Ser1 and Pro2 were double-coupled. The following side chain protection strategy was employed; Ser1(But), Gln5(Trityl), Arg8,12(Pmc or Pbf), Ser9,10,11(Trityl), Cys13(Trityl). Following assembly, the N-terminal Fmoc-protecting group was removed by treating the Fmoc-peptidyl-resin with in DMF. The amino-peptidyl-resin so obtained was acylated by treatment for 1.5-2 hr at 70° C. with 1.5-2 equivalents of 4′,5′-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna & Ullman, (1980) Anal Biochem. 108:156-161) which had been preactivated with diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF]. The dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane. The dimethoxyfluoresceinyl-peptide was isolated by evaporation, trituration with diethyl ether and filtration. The isolated peptide was reacted with 4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid. The product was characterised by MALDI-TOF MS and amino acid analysis.
The compounds of this invention are active against TACE (causing at least 50% inhibition) at less than 10 μM. In particular compound 1A gave 50% inhibition at 71 nM and compound 2A gave 50% inhibition at 37 nM.
Natural Substrates
The activity of the compounds of the invention as inhibitors of aggrecan degradation may be assayed using methods for example based on the disclosures of E. C. Arner et al., (1998) Osteoarthritis and Cartilage 6:214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601 and the antibodies described therein. The potency of compounds to act as inhibitors against collagenases can be determined as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99:340-345.
Inhibition of Metalloproteinase Activity in Cell/Tissue Based Activity
Test as an Agent to Inhibit Membrane Sheddases such as TNF Convertase
The ability of the compounds of this invention to inhibit the cellular processing of TNP-α production may be assessed in THP-1 cells using an ELISA to detect released TNF essentially as described K. M. Mohler et al., (1994) Nature 370:218-220. In a similar fashion the processing or shedding of other membrane molecules such as those described in N. M. Hooper et al., (1997) Biochem. J. 321:265-279 may be tested using appropriate cell lines and with suitable antibodies to detect the shed protein.
Test as an Agent to Inhibit Cell Based Invasion
The ability of the compound of this invention to inhibit the migration of cells in an invasion assay may be determined as described in A. Albini et al., (1987) Cancer Research 47:3239-3245.
Test as an Agent to Inhibit Whole Blood TNF Sheddase Activity
The ability of the compounds of this invention to inhibit TNF-α production is assessed in a human whole blood assay where LPS is used to stimulate the release of TNF-α. 160 μl of heparinized (10 Units/ml) human blood obtained from volunteers, was added to the plate and incubated with 20 μl of test compound (duplicates), in RPMI1640+bicarbonate, penicillin, streptomycin, glutamine and 1% DMSO, for 30 min at 37° C. in a humidified (5% CO2/95% air) incubator, prior to addition of 20 μL LPS (E. coli. 0111:B4; final concentration 10 μg/ml). Each assay includes controls of neat blood incubated with medium alone or LPS (6 wells/plate of each). The plates are then incubated for 6 hours at 37° C. (humidified incubator), centrifuged (2000 rpm for 10 min; 4° C.), plasma harvested (50-100 μl) and stored in 96 well plates at −70° C. before subsequent analysis for TNF-α concentration by ELISA.
Test as an Agent to Inhibit In Vitro Cartilage Degradation
The ability of the compounds of this invention to inhibit the degradation of the aggrecan or collagen components of cartilage can be assessed essentially as described by K. M. Bottomley et al., (1997) Biochem J. 323:483-488.
In Vivo Assessment
Test as an Anti-TNF Agent
The ability of the compounds of this invention as in vivo TNF-α inhibitors is assessed in the rat. Briefly, groups of female Wistar Alderley Park (AP) rats (90-100 g) are dosed with compound (5 rats) or drug vehicle (5 rats) by the appropriate route e.g. peroral (p.o.), intraperitoneal (i.p.), subcutaneous (s.c.) 1 hour prior to lipopolysaccharide (LPS) challenge (30 μg/rat i.v.). Sixty minutes following LPS challenge rats are anaesthetised and a terminal blood sample taken via the posterior vena cavae. Blood is allowed to clot at room temperature for 2 hours and serum samples obtained. These are stored at −20° C. for TNF-α ELISA and compound concentration analysis.
Data analysis by dedicated software calculates for each compound/dose:
Test as an Anti-Arthritic Agent
Activity of a compound as an anti-arthritic is tested in the collagen-induced arthritis (CIA) as defined by D. E. Trentham et al., (1977) J. Exp. Med. 146:857. In this model acid soluble native type II collagen causes polyarthritis in rats when administered in Freunds incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates.
Pharmaceutical Compositions
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The composition may also be in a form suitable for inhalation.
In general the above compositions may be prepared in a conventional manner using conventional excipients.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.5 to 75 mg/kg body weight (and preferably 0.5 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
Therefore in a further aspect of the present invention there is provided a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use in a method of treatment of a warm-blooded animal such as man by therapy.
Also provided is a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use in a method of treating a disease condition mediated by one or more metalloproteinase enzymes and in particular a disease condition mediated by TNF.
Further provided is a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use in a method of treating inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal such as man. In particular a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, is provided for use in a method of treating rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis in a warm-blooded animal such as man. Also provided is a compound of formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use in a method of treating a respiratory disorder such as asthma or COPD in a warm-blooded animal such as man.
According to an additional aspect of the invention there is provided a compound of formula (I), (IA) or (IB) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use as a medicament. Also provided is a compound of the formula (I), (IA) or (IB) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use as a medicament in the treatment of a disease condition mediated by one or more metalloproteinase enzymes and in particular a disease condition mediated by TNF-α. Further provided is a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use as a medicament in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal such as man. In particular a compound of the formula (I1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, is provided for use as a medicament in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis in a warm-blooded animal such as man. Also provided is a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, for use as a medicament in the treatment a respiratory disorder such as asthma or COPD in a warm-blooded animal such as man.
According to this another aspect of the invention there is provided the use of a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of a disease condition mediated by one or more metalloproteinase enzymes and in particular a disease condition mediated by TNF-α in a warm-blooded animal such as man. Also provided is the use of a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of inflammatory diseases, autoimmune diseases, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal such as man. In particular the use of a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore, is provided in the manufacture of a medicament in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis in a warm-blooded animal such as man. Further provided is the use of a compound of the formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment a respiratory disorder such as asthma or COPD in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method of producing a metalloprotienase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), (IA) or (IB). According to a further feature of this aspect of the invention there is provided a method of producing a TACE inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), (A) or (IB). According to this further feature of this aspect of the invention there is provided a method of treating autoimmune disease, allergic/atopic diseases, transplant rejection, graft versus host disease, cardiovascular disease, reperfusion injury and malignancy in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), (IA) or (IB). Also provided is a method of treating rheumatoid arthritis, Crohn's disease and psoriasis, and especially rheumatoid arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), (IA) or (IB). Further provided is a method of treating a respiratory disorder such as asthma or COPD in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), (IA) or (IB).
In addition to their use in therapeutic medicine, the compounds of formula (I), (IA) or (IB) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.
The compounds of this invention may be used in combination with other drugs and therapies used in the treatment of various immunological, inflammatory or malignant disease states which would benefit from the inhibition of TACE.
If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
A mixture of [4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (200 mg), 4-((2-methylquinolin-4-yl)methoxy)aniline (150 mg) and triethylamine (0.1 ml) in DMF (3 ml) was stirred at ambient temperature for 18 h. Additional [4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (150 mg) and triethylamine (0.1 ml) were added and the mixture was stirred for 4 h before partitioning between water (50 ml) and EtOAc (100 ml). The organic phase was dried (MgSO4), evaporated under vacuum and purified by column chromatography using DCM to 6% MeOH in DCM as the eluant. The product (127 mg) was triturated with diethylether to yield 1-(4-methyl-2,5-dioxoimidazolidin-4-yl)-N-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}methanesulphonamide as a cream solid (71 mg); NMR DMSOd6 2.65 (3H, s), 1.29 (3H, s), 3.25 (1H, d), 3.45 (1H, d), 5.56 (2H, s), 7.07-7.18 (4H, m), 7.52-7.59 (2H, m), 7.72 (1H, t), 7.93-7.98 (2H, m), 8.09 (1H, d), 9.60 (1H, s), 10.69 (1H, bs); MS 455 (MH+).
The starting material [4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride was prepared as follows:
Purity by HPLC=99%, NMR supported that purity; 1H NMR (THF-d8): δ 9.91 (1H, bs); 7.57 (1H, s); 4.53, 4.44 (1H each, ABq, J=14.6 Hz); 1.52 (s, 3H, CH3); 13C NMR (THF-d8): δ 174.96; 155.86; 70.96; 61.04; 23.66.
The starting material 4-[(2-methylquinolin-4-yl)methoxy]aniline was prepared as follows:
A mixture of [4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (211 mg), 4-((2-methylquinolin-4-yl)methoxy)aniline (example 1A, 150 mg) and triethylamine (0.1 ml) in DMF (3 ml) was stirred at ambient temperature for 18 h. Additional 4-[(2-methylquinolin-4-yl)methoxy]benzenesulphonyl chloride (150 mg) and triethylamine (0.1 ml) were added and the mixture was stirred for 4 h before partitioning between water (50 ml) and EtOAc (100 ml). The organic phase was dried (MgSO4), evaporated under vacuum and purified by column chromatography using DCM to 6% MeOH in DCM as the eluant. The product (127 mg) was triturated with diethylether to yield 1-(4-ethyl-2,5-dioxoimidazolidin-4-yl)-N-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}methanesulphonamide as a cream solid (71 mg); NMR DMSOd6 0.73 (3H, t), 1.52-1.66 (2H, m), 2.65 (3H, s), 3.23 (1H, d), 3.45 (1H, d), 5.55 (2H, s), 7.06-7.20 (4H, m), 7.51-7.60 (2H, m), 7.72 (1H, t), 7.90-7.98 (2H, m), 8.09 (1H, d), 9.58 (1H, bs), 10.707 (1H, bs); MS 469 (MH+).
The starting material [4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride was prepared by an analogous method to that described in example 1A using steps i) and ii) for the preparation of [4-methyl-2,5-dioxoimidazolidin-4-yl]methylsulphonyl chloride except that 1-(benzylthio)butan-2-one (Tetrahedron Letters (1998), 39(20), 3189-3192) was used in place of benzylthioacetone; NMR (THFd8) 0.9 (3H, t), 1.9 (2H, m), 4.4 (1H, d), 4.5 (1H, d), 7.4 (1H, s), 9.9 (1H, s).
An analogous method to that used in example 1A was used except that [4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride was replaced with 2-(2,5-dioxoimidazolidin-4-yl)ethanesulphonyl chloride to afford 2-(2,5-dioxoimidazolidin-4-yl)-N-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}ethanesulphonamide as an off white solid; NMR 1.81-1.94 (1H, m), 2.02-2.05 (1H, m), 2.65 (3H, s), 3.02-3.18 (2H, m), 4.07-4.13 (1H, m), 5.56 (2H, s), 7.08-7.20 (4H, m), 7.52-7.60 (2H, m), 7.69-7.76 (1H, m), 7.92-7.97 (2H, m), 8.09 (1H, d); MS 455 (MH+).
The starting material 2-(2,5-dioxoimidazolidin-4-yl)ethanesulphonyl chloride was prepared as follows:
An analogous method to that described in example 1A was used except that 4-((2-methylquinolin-4-yl)methoxy)aniline was replaced with {4-[(2,5-dimethylbenzyl)oxy]phenyl}amine to afford N-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-1-(4-methyl-2,5-dioxoimidazolidin-4-yl)methanesulphonamide as a white solid.
The starting material {4-[(2,5-dimethylbenzyl)oxy]phenyl}amine was prepared as follows:
An analogous method to that described in example 2A was used except that 4-((2-methylquinolin-4-yl)methoxy)aniline was replaced with {4-[(2,5-dimethylbenzyl)oxy]phenyl}amine (example 4A step ii)) to afford N-{4-[(2,5-dimethylbenzyl)oxy]phenyl}-1-(4-ethyl-2,5-dioxoimidazolidin-4-yl)methanesulphonamide as a white solid; NMR δ 0.72 (s, 3H), 1.60 (m, 2H), 2.25 (s, 6H), 3.32 (dd, 2H), 4.98 (s, 2H), 6.96 (d, 2H), 7.01-7.10 (m, 2H), 7.13 (d, 2H), 7.22 (s, 1H), 8.01 (s, 1H), 9.55 (s, 1H), 10.71 (s, 1H); MS 430.3 (MH−).
N-methyl-4-[(2-methylquinolin-4-yl)methoxy]aniline (67 mg), (4-methyl-2,5-dioxoimidazolidin-4-yl)methanesulphonyl chloride (example 1A) (82 mg) and triethylamine (67 μl) were stirred under argon in DCM (10 ml) for 16 h. The mixture was washed with water (20 ml), dried (MgSO4), concentrated in vacuo and purified by prep-HPLC, eluting with a gradient of 5-30% acetonitrile/water to give N-methyl-1-(4-methyl-2,5-dioxoimidazolidin-4-yl)-N-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}methanesulphonamide as a white solid (30 mg); NMR (DMSO-d6) δ 1.25 (s, 1H), 1.33 (s, 3), 2.90 (s, 3H), 3.20 (s, 3H), 3.30 (m, 1H), 3.65 (m, 1H), 5.80 (s, 2), 7.22 (m, 2H), 7.42 (m, 2H), 7.80 (m, 1H), 7.90 (s, 1H), 8.00 (m, 2H), 8.13 (m, 1H), 8.30 (m, 1H), 10.70 (s, 1H); MS 469 (MH+).
The starting material N-methyl-4-[(2-methylquinolin-4-yl)methoxy]aniline was prepared as follows:
2,4-dioxo-1,3-diazaspiro[4.5]decane-6-sulphonyl chloride (104 mg) was added to a stirred solution 4-[(2-methylquinolin-4-yl)methoxy]aniline (example 1A, 102 mg) in DMSO (2 ml). Triethylamine (0.11 ml) and 4-dimethylaminopyridine (10 mg) were added and the mixture was stirred for 18 h at 20° C. and then for 3 h at 60° C. The mixture was cooled and saturated KH2PO4 (5 ml) and water (2 ml) added; a solid formed upon stirring. The solid was filtered off, washed with water, dried, dissolved in a minimum volume of DCM and purified by eluting from a silica column in MeOH/DCM mixtures affording the title compound as a solid. (78 mg); 1H NMR (DMSOd6) 1.0-2.4 (m, 8H), 2.65 (s, 3H), 4.05 (m, 1H), 5.55 (s, 2H), 7.1, 7.2 (d, d, 4H), 7.55 (s, 1H), 7.6 (m, 1H), 7.65 (m, 1H), 7.95 (d, 1H), 8.1 (d, 1H), 8.65 and 7.75 (s, s 2:3, 1H), 9.7 (s, 1H), 10.5 and 10.6 (s, s, 2:3, 1H); MS (ES)+495.1 (M+H)+(ES)−493.1 (M−H)−.
The starting material 2,4-dioxo-1,3-diazaspiro[4.5]decane-6-sulphonyl chloride was prepared as a mixture of isomers as follows:
An analogous method to that used in example 7A was used except that 2,4-dioxo-1,3-diazaspiro[4.5]decane-6-sulphonyl chloride was replaced with 2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-sulphonyl chloride to afford N-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-sulphonamide as a white solid; NMR DMSOd6 1.6-2.2 (m, 6H), 2.65 (s, 3H), 3.5 3.65 (t, t, 1:1, 1H), 5.55 (s, 2H), 7.0-7.2 (s, 4H), 7.5-7.6 (m, 2H), 7.7 (t, 1H), 7.7 8.4 (s, s, 1:1, 1H), 7.95 (d, 1H), 8.1 (d, 1H), 9.6 (s, 1H), 10.6 10.7 (s, s, 1:1, 1H); MS 481.1 (MH+), MS 479.1 (MH−).
The starting material 2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-sulphonyl chloride was prepared by an analogous method to that described in example 7A using steps i) and ii) for the preparation of 2,4-dioxo-1,3-diazaspiro[4.5]decance-6-sulphonyl chloride except that 2-benzylthiocyclopentane was used instead of 2-benzylthiocyclohexane in step i) to yield 6-(benzylthio)-1,3-diazaspiro[4.4]nonane-2,4-dione; NMR DMSOd6 1.5-2.1 (m, 6H), 3.1 3.2 (m, m, 3:7, 1H), 3.7 3.85 (s, s, 7:3, 2H), 7.2-7.4 (m, 5H), 7.9 8.3 (s, s, 3:7, 1H), 10.7 10.8 (s, s, 3:7, 1H); MS 275.2 (MH−) and from step ii) 2,4-dioxo-1,3-diazaspiro[4.4]nonane-6-sulphonyl chloride; NMR DMSOd6 1.8-2.5 (m, 6H), 4.7 4.8 (t, t, 0.33H, 0.66H) 8.15 8.7 (s, s, 0.33H, 0.66H), 10.9 11.5. (s, s, 0,33H, 0.66H).
An analogous method to that used in example 7A was used except that 2,4-dioxo-1,3-diazaspiro[4.5]decane-6-sulphonyl chloride was replaced with 2,4-dioxo-7-oxa-1,3-iazaspiro[4.4]nonane-9-sulphonyl chloride to afford N-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-2,4-dioxo-7-oxa-1,3-diazaspiro[4.4]nonane-9-sulphonamide as a white solid; NMR DMSOd6 2.55 2.65 (s, s, 1:3, 2H), 3.74.1 (m, 5H), 5.55 5.65 (s, s, 3:1, 2H), 7.1-7.2 (m, 4H), 7.25-7.31 (m, 2H), 7.7 (t, 1H), 7.95 (d, 1H), 8.1-8.2 8.6 (s, s 3:1, 2H), 9.8 (s, 1H), 10.8 10.95 (s, s, 3:1, 1H); MS 483.2 (MH+), MS 481.1 (MH−).
The starting material 2,4-dioxo-7-oxa-1,3-diazaspiro[4.4]nonane-9-sulphonyl chloride was prepared as follows:
1-{4-[(2-Methylquinolin-4-yl)methoxy]sulphonyl}pyrrolidin-2-ylcarbaldehyde (prepared as described below) (198 mg, 0.48 mmol) was stirred in ethanol (5 ml) and water (4 ml). Ammonium carbonate (232 mg, 2.41 mmol) was added followed by potassium cyanide (38 mg, 0.58 mmol) and the reaction mixture was heated at 60 to 65° C. for 5 h. The mixture was then concentrated in vacuo, diluted with water (15 ml) and extracted with EtOAc (3×15 ml). The combined organic extracts were washed with brine (15 ml), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (20 g silica bond elut, eluent 0-4% MeOH in DCM) to give the product 5-[1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)pyrrolidin-2-yl]imidazolidine-2,4-dione as a mixture of 4 diastereoisomers (77 mg, 0.16 mmol). NMR: 1.20-1.82 (m, 4H), 2.66 (s, 3H), 3.15-3.41 (m, 2H), 3.73-3.81 (m, A 1H), 3.81-3.89 (m, B 1H), 4.15 (d, B 1H), 4.47 (s, A 1H), 5.72 (s, 2H), 7.35 (d, B 2H), 7.40 (d, A 2H), 7.55 (s, 1H), 7.58 (t, 1H), 7.74 (t, 1H), 7.82 (d, 2H), 7.88 (s, B 1H), 7.95 (d, 1H), 8.10 (d, 1H), 8.25 (s, A 1H), 10.66 (s, B 1H), 10.76 (s, A 1H); MS (M+H) 481.
The starting material 1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)pyrrolidin-2-ylcarbaldehyde was prepared as described below:
An analogous method to that described in example 1B was used to yield a mixture of 4 diastereoisomers except that 1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)pyrrolidin-2-ylcarbaldehyde was replaced with 1-{4-[(2-methylquinolin-4-yl)methoxy]benzoyl}pyrrolidin-2-ylcarbaldehyde (prepared as described below). The product was purified by chromatography (10 g silica bond elut, eluent 0-4% MeOH in DCM). Fraction 1: (A:B 5:1) NMR: 1.46-2.16 (m, 4H), 2.68 (s, 3H), 3.30-3.59 (m, 2H), 4.35-4.50 (m, 1H+ B 1H), 4.76 (s, A 1H), 5.67 (s, 2H), 7.22 (d, 2H), 7.55 (d, B 2H), 7.58 (s, 1H), 7.60 (t, 1H), 7.66 (d, A 2H), 7.76 (t, 1H), 7.99 (d, 1H), 7.99 (s, B 1H), 8.12 (d, 1H), 8.21 (s, A 1H), 10.60 (s, B 1H), 10.74 (s, A 1H); MS 445 (MH+) Fraction 2: (A:B 4:3) MS 445 (MH+).
The starting material 1-{4-[(2-methylquinolin-4-yl)methoxy]benzoyl}pyrrolidin-2-ylcarbaldehyde was prepared as described below:
An analogous method to that described in example 1B was used to obtain a mixture of 4 diastereomers except that 1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)pyrrolidin-2-ylcarbaldehyde was replaced with 1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)piperidin-2-ylcarbaldehyde (prepared as described below). The product was purified by chromatography (10 g silica bond elut, eluent 0-3% MeOH in DCM); Fraction 1: (A:B 5:3) NMR: 0.80-2.03 (m, 6H), 2.67 (s, 3H), 3.07-3.20 (m, 1H), 3.62-3.78 (m, 1H), 3.97-4.12 (m, 1H), 4.31-4.44 (m, 1H), 5.74 (s, 2H), 7.30-7.39 (m, 2H), 7.56 (s, 1), 7.60 (t, 1H), 7.76 (t, 1H), 7.85 (d, 2H), 7.88 (s, A 1H), 7.99 (d, 1H), 8.12 (d, 1H), 8.14 (s, B 1H), 10.67 (s, A 1H), 10.75 (s, B 1H); MS 495 (MH+).
The starting material 1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)piperidin-2-ylcarbaldehyde was prepared as described below:
Thionyl chloride (0.85 ml, 12.00 mmol) was added dropwise to methanol (8 ml), stirred and cooled in a water bath. Stirring was continued at RT for 50 min then tert-butyl (2R)-[(4R)-4-methyl-2,5-dioxoimidazolidin-4-yl]pyrrolidin-1-ylcarboxylate (prepared as described below) (133 mg, 0.468 mmol) was added in one portion. After stirring for a further 30 min the solution was evaporated to dryness and re-evaportaed twice with EtOH (2×3 ml), then dried in vacuo. The residual solid was dissolved in DCM (5 ml) under argon, to this was added triethylamine (80 μl, 0.574 mmol) and the mixture was stirred at RT for 10 min. 4-[2-Methylquinolin-4-yl)methoxy]benzenesulphonyl chloride hydrochloride (example 1B step v)) (180 mg, 0.468 mmol) was suspended in DCM (5 ml) and to this was added triethylamine (130 μl, 0.933 mmol); the resulting solution was then added dropwise to the amine solution and stirring continued under argon for 16 h. The solution was diluted with DCM (20 ml) and washed with water (15 ml). The organic layer was evaporated and purified by column chromatography (log silica bond elut, eluent 0-2% MeOH in DCM). Product fractions were evaporated, triturated with ether and collected by filtration to give (5R)-5-methyl-5-[(2R)-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)piperidin-2-yl]imidazoline-2,4-dione as a white solid (113 mg, 0.228 mol). NMR: 1.02-1.15 (m, 1H), 1.23-1.48 (m, 2H), 1.44 (s, 3H), 1.60-1.74 (m, 1H), 2.66 (s, 3H), 3.22-3.50 (m, 2H), 3.95-4.02 (m, 1 μl), 5.74 (s, 2H), 7.36 (d, 2H), 7.55 (s, 1H), 7.60 (t, 1H), 7.76 (t, 1H), 7.84 (d, 2H), 7.99 (d, 1H), 8.07 (s, 1H), 8.12 (d, 1H), 10.80 (s, 1H); MS (M+H) 495.
The starting material tert-butyl (2R)-[(4R)-methyl-2,5-dioxoimidazolidin-4-yl]pyrrolidin-1-ylcarboxylate was prepared as described below:
To a solution of 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-1,3-diazaspiro[4.6]undecane-2,4-dione (140 mg) in MeOH (10 ml) at 0° C. was added a suspension of potassium peroxymonosulphate (300 mg) in water (10 ml). The resultant suspension was stirred for 1 h, diluted with water (50 ml) and portioned with DCM (3×80 ml). The combined organic extracts were treated with water (50 ml) and brine (50 ml), dried and concentrated in vacuo. The crude product was chromatographed on silica (10 g) using a 0-10% EtOH/DCM gradient over 50 min as eluent to give 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)-1,3-diazaspiro[4.6]undecane-2,4-dione as a white solid (123 mg); NMR δ 1.4 (m, 7H), 2.0 (m, 4H), 2.8 (s, 3H), 5.8 (s, 2H), 7.5 (m, 2H), 7.8 (m, 4H), 7.9 (s, 1H), 8.1 (d, 1H), 8.3 (d, 1H), 8.4 (s, 1H), 10.6 (m, 1H), diastereoisomeric enrichment approximately 2.2:1; MS 493.95 (MH+).
The starting material 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-1,3-diazaspiro[4.6]undecane-2,4-dione was prepared as follows:
An analogous method to that described in example 1 was used except that the starting material was 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-1,3-diazaspiro[4.5]decane-2,4dione. The crude product was chromatographed on a 10 g silica bond elute using a 0-25% EtOH/DCM gradient over 50 min as eluent to give 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)-1,3-diazaspiro[4.5]decane-2,4-dione as a white solid (75 mg); NMR δ 1.4 (m, 5H), 2.0 (m, 4H), 2.8 (s, 3H), 5.8 (s, 2H), 7.5 (m, 2H), 7.8 (m, 4H), 7.9 (s, 1H), 8.1 (d, 1H), 8.3 (d, 1H), 8.4 (s, 1H), 10.6 (m, 1H), diastereoisomeric enrichment approximately 4.2:1; MS 479.93 (MH+)
The starting material 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-1,3-diazaspiro[4.5]decane-2,4-dione was prepared using an analogous method to that describe in example 1 for the preparation of 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-1,3-diazaspiro[4.6]undecane-2,4-dione except that 2-cyclohexen-1-one was used instead of 2-cyclohepten-1-one in step vi) to yield 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-1,3-diazaspiro[4.5]decane-2,4-dione as a white foam (140 mg); MS 448.0 (MH+).
An analogous method to that described in example 1 was used except the starting material was 7-({4-[(2-methylquinolinfyl)methoxy]phenyl}thio)-1,3-diazaspiro[4.4]nonane-2,4-dione (70 mg). The crude product was chromatographed on a 10 g silica bond elute using a 0-20% EtOH/DCM gradient over 45 min as eluent to give 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione as a white solid (20 mg); NMR δ 2.0 (m, 6H), 2.7 (s, 3H), 3.9 (m, 1H), 5.7 (s, 2H), 7.4 (m, 2H), 7.5 (m, 2H), 7.6 (m, 1H), 7.7 (m, 2H), 7.9 (m, 2H), 8.1 (m, 1H), 10.6 (m, 1H), diastereoisomeric enrichment approximately 4.6:1; MS 465.89 (MH+).
The starting material 7-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)-1,3-diazaspiro[4.4]nonane-2,4-dione was prepared as follows:
An analogous method to that described in example 1 was used except the starting material was 5-methyl-5-[1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)ethyl]imidazolidine-2,4-dione (124 mg). The crude product was chromatographed on a 10 g silica bond elute using a 0-10% EtOH/DCM gradient as eluent to give 5-methyl-5-[1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)ethyl]imidazolidine-2,4-dione as a white solid (64 mg); NMR δ 1.1 (d, 3H), 1.5 (s, 3H), 2.7 (s, 3H), 3.7 (m, 1H), 5.8 (s, 2H), 7.4 (d, 2H), 7.6 (d, 2H), 7.7 (d, 2H), 7.8 (d, 2H), 7.95 (d, 1H), 8.1 (d, 1H), 10.8 (s, 1H); MS 454.2 (MH+).
The starting material 5-methyl-5-[1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)ethyl]imidazolidine-2,4-dione was prepared as follows:
Single Diastereoisomer
An analogous method to the described in example 1 was used except that the starting material was 5-[2-(4-fluorophenyl)-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)ethyl]-5-methylimidazolidine-2,4-dione (90 mg). The crude product was chromatographed on a 10 g silica bond elute using a 0-15% EtOH(DCM gradient over 45 min as eluent to give 5-[2-(4-fluorophenyl)-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)ethyl]-5-methylimidazolidine-2,4-dione as a white solid (29 mg); MS 548.2 (MH+).
The starting material 5-[2-(4-fluorophenyl)-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)ethyl]-5-methylimidazolidine-2,4-dione was prepared by an analogous method to that described in example 4 steps i) and ii) except that 3-bromo-2-butanone in step i) was replaced with 3-chloro-4-(4-fluorophenyl)-2-butanone to yield 4-(4-fluorophenyl)-3-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)butan-2-one as a colourless oil (470 mg); MS 445.95 (MH+) and then 5-[2-(4-fluorophenyl)-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}thio)ethyl]-5-methylimidazolidine-2,4-dione as a white solid (90 mg); MS 516.2 (MH+).
To 1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)-5-pyrimidin-2-ylpentan-2-one (65 mg) dissolved in EtOH (3 ml) and water (3 ml) was added ammonium carbonate (318 mg) and potassium cyanide (18 mg). The mixture was stirred at 70° C. for 6 d. The solution was cooled to RT, partitioned between saturated brine (20 ml) and EtOAc (2×25 ml), and the combined organic extracts were concentrated in vacuo and purified on a 10 g silica bond elute using a 0-10% EtOH/DCM gradient over 50 min as eluent to give 5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]-5-(3-pyrimidin-2-ylpropyl)imidazolidine-2,4-dione as a white solid (27 mg); MS 545.96 (MH+).
The starting material 1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)-5-pyrimidin-2-ylpentan-2-one was prepared as follows:
5-Isopropyl-5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]imidazolidine-2,4-dione was prepared using an analogous method to that described in example 6 except that in step iii) ethyl 4-(2-pyrimidinyl)butyrate was replaced with methyl isobutyrate to yield the product as a white solid (37 mg); MS 468.2 (MH+).
5-(Methoxymethyl)-5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]imidazolidine-2,4-dione was prepared using an analogous method to that described in example 6 except that in step iii) ethyl 4-(2-pyrimidinyl)butyrate was replaced with methyl methoxyacetate to yield the product as a white solid (37 mg); MS 470.2 (MH+).
5-(2-Methoxyethyl)-5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]imidazolidine-2,4-dione was prepared using an analogous method to that described in example 6 except that in step iii) ethyl 4-(2-pyrimidinyl)butyrate was replaced with methyl 3-methoxypropionate to yield the product as a light brown solid (9 mg); MS 483.99 (MH+).
tert-Butyl ({4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]-2,5-dioxoimidazolidin-4-yl}methyl)carbamate was prepared using an analogous method to that described in example 6 except that ethyl 4-(2-pyrimidinyl)butyrate was replaced with methyl N-(tert-butoxycarbonyl)glycinate to yield the product as a white solid (13 mg); MS 555.2 (MH+).
tert-Butyl 4-{4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]-2,5-dioxoimidazolidin-4-yl}piperidin-1-ylcarboxylate was prepared using an analogous method to that described in example 6 except that in step iii) ethyl 4(2-pyrimidinyl)butyrate was replaced with ethyl (N-[tert-butoxycarbonyl]piperidin-4-yl)carboxylate to yield the product as a white solid (9 mg); MS 608.99 (MH+).
1-(1-Acetylpiperidin-4-yl)-2-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)ethanone (65 mg) was treated using an analogous method to that described in example 6 to yield 5-(1-acetylpiperidin-4-yl)-5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]imidazolidine-2,4-dione as a white solid (3 mg); MS 550.90 (MH+).
The starting material 1-(1-acetylpiperidin-4-yl)-2-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)ethanone was prepared as follows:
To tert-butyl({4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]-2,5-dioxoimidazolidin-4-yl}methyl)carbamate (20 mg) (example 10) dissolved in MeOH (5 ml) was added hydrogen chloride (4M in 1,4-dioxan, 1.5 ml). The solution was stirred at RT overnight and partitioned between saturated aqueous potassium carbonate (10 ml) and DCM (2×15 ml). The combined organic extracts were dried (sodium sulphate) and concentrated in vacuo to give 5-(aminomethyl)-5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]imidazolidine-2,4-dione as a white solid (10 mg); MS 454.92 (MH+).
5-Isobutyl-5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]imidazolidine-2,4-dione was prepared by an analogous method to that described in example 6 except that in step iii) ethyl 4-(2-pyrimidyl)butyrate was replaced with ethyl isovalerate to yield the product as a white solid (23 mg); MS 481.96 (MH+).
5-Cyclopropyl-5-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulphonyl)methyl]imidazolidine-2,4-dione was prepared by an analogous method to that described in example 6 except that in step iii) ethyl 4-(2-pyrimidyl)butyrate was replaced with ethyl cyclopropanecarboxylate to yield the product as a white solid (10 mg); MS 465.85 (MH+).
Sodium hydride (48 mg of 60% dispersion) was added to a solution of 3,5-dimethoxybenzyl alcohol (168 mg) in dimethylacetamide (10 ml) and the mixture stirred at ambient temperature for 20 min. 5-{[(4-fluorophenyl)sulphonyl]methyl}-5-methylimidazolidine-2,4-dione (286 mg) was added and the reaction mixture was heated for 4 h at 70° C. After cooling, the reaction was poured into water (50 ml) and the solution acidified to pH1 using 36% hydrochloric acid.
The resulting precipitate was filtered and washed with water. The product was then treated with ether and dried in vacuo to afford 5-[({4[(3,5-dimethoxybenzyl)oxy]phenyl}sulphonyl)methyl]-5-methylimidazolidine-2,4-dione. NMR (DMSO-d6) 1.25 (s, 3H), 3.7 (m, 2H), 3.8 (s, 6), 5.15 (s, 2H), 6.5 (m, 1H), 6.6 (m, 2H), 7.25 (m, 2H), 7.8 (m, 3H), 10.7 (s, 1H). MS 435 (MH+).
The starting material 5-{[(4-fluorophenyl)sulphonyl]methyl}-5-methylimidazolidine-2,4-dione was prepared as follows:
5-Methyl-5-({[4-(1-naphthylmethoxy)phenyl]sulphonyl}methyl)imidazolidine-2,4-dione was prepared using an analogous method to that described in example 16 except that 3,5-dimethoxybenzyl alcohol was replaced with 1-naphthylmethanol (241 mg) to afford 5-methyl-5-({[4-(1-naphthylmethoxy)phenyl]sulphonyl}methyl)imidazolidine-2,4-dione; NMR (DMSO-d6) δ 1.3 (s, 3H), 3.7 (m, 2H), 5.7 (s, 2H), 7.3 (m, 2H), 7.5 (m, 3H), 7.7 (m, 4H), 7.9 (m, 2H), 8.1 (m, 1H), 10.7 (s, 1H); MS 423 (MH−).
6-({4-[(3,5-Dimethoxybenzyl)oxy]phenyl}sulphonyl)-1,3-diazaspiro[4.4]nonane-2,4-dione was prepared by an analogous method to that described in example 16 except 6-[(4-fluorophenyl)sulphonyl]-1,3-diazaspiro[4.4]nonane-2,4-dione (311 mg) and 3,5-dimethoxybenzyl alcohol were used; NMR DMSO-d6 1.8 (m, 2H), 2.0 (m, 4H), 3.75 (s, 6H), 3.8 (m, 1H), 5.3 (s, 2H), 6.45 (m, 1H), 6.6 (m, 2H), 7.2 (m, 2H), 7.7 (m, 2H), 8.35 (s, 1H), 10.65 (br, 1H); MS 459 (MH−).
The starting material 6-[(4-fluorophenyl)sulphonyl]-1,3-diazaspiro[4.4]nonane-2,4-dione was prepared as follows:
6-{[4-(1-Naphthylmethoxy)phenyl]sulphonyl}-1,3-diazaspiro[4.4]nonane-2,4-dione was prepared by an analogous method to that described in example 18 except that 3,5-dimethoxybenzyl alcohol was replaced with 1-naphthylmethanol; NMR DMSO-d6 1.8 (m, 2H), 2.0 (m, 4H), 3.8 (m, 1H), 5.7 (s, 2H), 7.3 (m, 2H), 7.6 (m, 3H), 7.7 (m, 3H), 7.95 (m, 2H), 8.1 (m, 1H), 8.4 (s, 1H), 10.65 (br, 1H); MS 449 (MH−).
A slurry of potassium peroxymonosulphate (0.57 g) in water (5 ml) was added to a stirred solution of 5-methyl-5-({[4-(quinolin-4-ylmethoxy)phenyl]thio}methyl)imidazolidine-2,4-dione (120 mg) in MeOH (20 ml) and the mixture stirred at ambient temperature for 3 h. After filtration from the inorganic material, the filtrate was evaporated The crude product was purified initially with an SCX column (eluant gradient MeOH to 2M ammonia in MeOH) and then with a silica column (eluant gradient DCM to 10% MeOH/DCM) to give the title compound (25 mg);
NMR DMSOd6 1.3 (s, 3H), 3.7 (m, 2H), 5.75 (m, 2H), 7.4 (m, 2H), 7.7 (m, 2H), 7.8 (m, 4H), 8.2 (m, 1H), 8.6 (m, 1H), 9.0 (m, 1H), 10.7 (s, 1H); MS 424 (MH−).
The starting material 5-methyl-5-({[4-(quinolin-4-ylmethoxy)phenyl]thio}methyl)imidazolidine-2,4-dione was prepared as follows:
| Number | Date | Country | Kind |
|---|---|---|---|
| 0221246.2 | Sep 2002 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB03/03907 | 9/9/2003 | WO | 3/10/2005 |
