Patent Application
20080153799
The present invention relates to novel compounds which are JAK3 Kinase inhibitors, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Janus Kinase 3 (JAK3) is a member of the Janus family of protein kinases. Although the other members of this family are expressed by essentially all tissues, JAK3 expression is limited to hematopoetic cells. This is consistent with its essential role in signaling through the receptors for IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors. These cytokines all have a shared function in that they are involved in lymphocyte differentiation and proliferation. XSCID patient populations have been identified with severely reduced levels of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immunosupression should result from blocking signaling through the JAK3 pathway. Animal studies have suggested that JAK3 not only play a critical role in B- and T-lymphocyte maturation, but that JAK3 is constitutively required to maintain T-cell function. Modulation of immune activity through this novel mechanism can prove useful in the treatment of T-cell proliferative disorders such as transplant rejection and autoimmune diseases.
The role of JAK3 in mast cells has been described in knockout mice. Thus, IgE/antigen induced degranulation and mediator release were substantially reduced in mast cells generated from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation in vitro, it has also been shown that IgE receptor levels and mediator contents are identical in JAK3−/− and JAK3+/+ mast cells. Therefore, JAK3 appears essential for the complete response of IgE challenged mast cells. The role of JAK3 in mast cell activation has been well established in murine system, however, there is no published data on mast cell function in the AR-SCID patients. Targeting JAK3 provides the basis for new and effective treatment of mast cell mediated allergic reactions.
JAK3 inhibitors which have been disclosed to date include quinazolines (Sudbeck, E. A. et al. Clinical Cancer Res. 5 (1999) 1569-82, WO 00/0202) and pyrrolo[2,3-d]pyrimidines (Blumenkopf, T. A. et al. WO 99/65909). 4-anilinoquinoline-3-carboxamides having JAK3 inhibitory activity are described in WO 02/092571. In WO 00/18761 and WO 98/43960 there are disclosed substituted quinoline-3-carbonitrile derivatives which are stated to have kinase inhibitory activity.
Quinoline derivatives having other pharmaceutical uses, for example as antiulcer agents, phosphodiesterase inhibitors or gastric acid secretion inhibitors are described in EP 0 259 174, EP 0 346 208, EP 0 480 052 and WO 2004/103998.
The present invention provides a compound of formula (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 and R2, which may be the same or different, represent nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR32)pOR6, Y(CR32)pR6, Y(CR32)pOCOR6
or R1 and R2 are linked together as —OCH2O— or —OCH2CH2O—;
R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen;
p is 0, 1, 2, 3, 4 or 5;
Y is oxygen, CH2′—OSO2— or NR7
R4 and R5 each independently represent hydrogen or a group selected from C1-C8 alkyl, —C1-C8 alkoxy, —CO—(C1-C8)alkyl, —CO—(C1-C8) cycloalkyl, —SO2—(C1-C8)alkyl, —CO—(C1-C8) alkoxy, —CO—NR7(C1-C8)alkyl, C3-C8 cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, —CONH2 or —CO—(C1-C8) alkoxy groups, or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, ═O, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—, or one of R4 and R5 is hydrogen or C1-C8 alkyl and the other is a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
R6 is hydrogen, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, cyano, halogen or amino groups), phenyl, benzyl, —CO(C1-C8)alkyl or a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, ═O, C1-C8 alkyl —CO—, or (C1-C8 alkoxy)-CO— where any C1-C8 alkyl is optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
R7 is hydrogen or C1-C8 alkyl;
Ra is hydrogen or C1-C8 alkyl;
Rx is a group selected from C1-C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring comprising one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered ring is optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, —CONH2—, C1-C8 alkyl, (C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO—, and any C1-C8 alkyl, C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO— group is itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl; or Rx is a group Ar;
Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl, indazolyl, dihydroisoquinolyl, oxodihydroisoquinolyl, tetrahydroisoquinolyl or oxotetrahydroisoquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, cyano, C1-C8 alkoxy, CO2R8, CONR9R10, C1-C8 alkyl-NR8—C1-C8 alkyl, C1-C8 alkyl-CONR8—C1-C8 alkyl, C1-C8 alkyl-CONR9R10, NR8COC1-C8 alkyl, C1-C8 thioalkyl, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1-C8 alkyl-NR11R12, C1-C8 alkyl-OR12, C1-C8 alkyl-SR12;
R8 is hydrogen or C1-C8 alkyl;
R9 and R10 are each independently hydrogen or C1-C8 alkyl
R11 is hydrogen or C1-C8 alkyl;
R12 is hydrogen or a group selected from C1-C8 alkyl, —(CR132)nR14, —CO—(CR132)nR14, —SO2—(CR132)nR14;
n is between 0 and 5;
R13 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, hydroxy(C1-C8)alkyl, amino or halogen;
R14 is hydrogen or a group selected from —NR15R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —COOH, —S(C1-C8 alkyl), —SO(C1-C8 alkyl), —CONR15R16, —CO(C1-C8 alkyl), —CO—O—(C1-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl (which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), C1-C8 alkoxy, C1-C8 hydroxyalkyl, —C═O, cyano, amino, nitro, halogen, C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur;
or R11 and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl (which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), nitro, cyano, —CONH2, amino, ═O or —COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—; and
R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, —CONH2 or —C(NH2)═NH;
provided that when
Rx is Ar, X is —CO and R1 and R2 are independently nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR32)pOR6, Y(CR32)pR6, —CH2(CH2)pOCOR6 or R1 and R2 are linked together as —OCH2O— or —OCH2CH2O—,
where each R3 group is independently hydrogen, C1-C8 alkyl, hydroxy, or halogen,
R4 and R5 each independently represent hydrogen or C1-C8 alkyl or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted 4- to 7-membered saturated or aromatic heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group or one of R4 and R5 is hydrogen or C1-C8 alkyl and the other is a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
and R6 is selected from hydrogen, (C1-C8)alkyl, —CO(C1-C8)alkyl, hydroxy substituted (C1-C8)alkyl, halogen substituted (C1-C8)alkyl, phenyl or benzyl,
then
Ar is selected from dihydroisoquinolyl, oxodihydroisoquinolyl, tetrahydroisoquinolyl or oxotetrahydroisoquinolyl, each of which may be optionally substituted,
or Ar is phenyl substituted by at least one substituent selected from azido substituted C1-C8 alkyl, C1-C8 alkyl-NR11R12, C1-C8 alkyl-OR12 or C1-C8 alkyl-SR12,
wherein R12 is selected from —(CR132)nR14, —CO—(CR132)nR14, —SO2—(CR132)nR14 or R11 and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl (which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), nitro, cyano, —CONH2, amino, ═O or —COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—,
provided that Ar is not phenyl substituted by one or more groups selected from C1-C8 alkyl-NR11—C1-C8 alkyl, C1-C8 alkyl-O—C1-C8 alkyl or C1-C6 alkanoyloxy C1-C6 alkyl
Unless otherwise indicated, the term ‘alkyl’ when used alone or in combination, refers to a straight chain or branched chain alkyl moiety. A C1-C8 alkyl group has from one to eight carbon atoms including methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, n-hexyl and the like. References to individual alkyl groups such as “propyl” are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
Analogously, the term ‘C1-C8 alkoxy’, when used alone or in combination, will be understood to refer to straight or branched chain groups having from one to eight or from one to four carbon atoms respectively and includes such groups as methoxy, ethoxy, propoxy, isopropoxy and butoxy.
The term ‘cycloalkyl’, when used alone or in combination, refers to a saturated alicyclic moiety having from three to eight carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term aryl includes phenyl and naphthyl groups.
A C2-C4 alkenyl group is for example vinyl or allyl. A C2-C4 alkynyl group is for example ethynyl or propyn-2-yl.
‘Optionally substituted’ is used herein to indicate optional substitution by the group or groups specified at any suitable available position.
A ‘heteroatom’ is a nitrogen, sulphur or oxygen atom. Where rings include nitrogen atoms, these may be substituted as necessary to fulfil the bonding requirements of nitrogen or they may be linked to the rest of the structure by way of the nitrogen atom. Nitrogen atoms may also be in the form of N-oxides. Sulphur atoms may be in the form of S, S(O) or SO2. In a heterocyclic ring, a —CH2— group can optionally be replaced by a —C(O).
As used herein, the term ‘halogen’ includes fluorine, chlorine, bromine and iodine.
A ‘saturated or unsaturated 4- to 10-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur’ may be a saturated, partially saturated or unsaturated monocyclic or bicyclic ring. The ring may be a carbocylic (that is an alicyclic ring having ring carbon atoms only) or is a heterocyclic ring containing four to ten atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur and which ring may, unless otherwise specified, be carbon or nitrogen linked. Examples of suitable carbocyclic rings include cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Suitably a 4- to 10-membered heterocyclic ring may be pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, triazolyl, tetrazolyl, thienyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, morpholinyl, tetrahydrofuranyl, piperazinyl, imidazopyrrole, indole, isoindole, indoline, isoindazole, benzimidazole, purine, quinolyl (for example, 1,2-dihydroquinolinyl or 1,2,3,4-tetrahydroquinolinyl), isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazole, benzothiazole, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl. A saturated monocyclic 4- to 7-membered ring comprising one or more heteroatoms selected from nitrogen, oxygen and sulphur will accordingly be understood to mean a heterocyclic ring containing four to seven atoms and which may, unless otherwise specified, be carbon or nitrogen linked. Particular examples of such ring systems include pyrrolidinyl and piperidinyl as included in the above list.
A ‘4- to 7-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur’ is a fully unsaturated, aromatic monocyclic ring containing from four to seven atoms of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which ring may, unless otherwise specified, be carbon or nitrogen linked. Particular examples of such ring systems include pyridyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, triazolyl, tetrazolyl or thienyl as given above.
It will be appreciated that the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.
In one particular embodiment, the invention provides a compound of formula (Ia)
or a pharmaceutically acceptable salt or solvate thereof, wherein
one of R1 and R2 represents nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR32)pOR6, Y(CR32)pR6, Y(CR32)pOCOR6
or R1 and R2 are linked together as —OCH2O— or —OCH2CH2O—;
R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen;
p is 0, 1, 2, 3, 4 or 5;
Y is oxygen, CH2′—OSO2— or NR7
R4 and R5 each independently represent hydrogen or a group selected from C1-C8 alkyl, C1-C8 alkoxy, —CO—(C1-C8)alkyl, —CO—(C1-C8)cycloalkyl, —SO2—(C1-C8)alkyl, —CO—(C1-C8)alkoxy, —CO—NR7(C1-C8)alkyl, C3-C8 cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, —CONH2 or —CO—(C1-C8)alkoxy groups,
or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, ═O, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—, or one of R4 and R5 is hydrogen or C1-C8 alkyl and the other is a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
R6 is hydrogen, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, cyano, halogen or amino groups), phenyl, benzyl, —CO(C1-C8)alkyl or a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, ═O, C1-C8 alkyl —CO—, or (C1-C8 alkoxy)-CO— where any C1-C8 alkyl is optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
R7 is hydrogen or C1-C8 alkyl;
Ra is hydrogen or C1-C8 alkyl;
Rx is a group selected from C1-C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring comprising one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered ring is optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, —CONH2—, C1-C8 alkyl, (C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO—, and any C1-C8 alkyl, C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO— group is itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl; or Rx is a group Ar;
Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl, indazolyl, dihydroisoquinolyl, oxodihydroisoquinolyl, tetrahydroisoquinolyl or oxotetrahydroisoquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, cyano, C1-C8 alkoxy, CO2R8, CONR9R10, C1-C8 alkyl-NR8—C1-C8 alkyl, C1-C8 alkyl-CONR8—C1-C8 alkyl, C1-C8 alkyl-CONR9R10, NR8COC1-C8 alkyl, C1-C8 thioalkyl, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1-C8alkyl-NR11R12, C1-C8alkyl-OR12, C1-C8alkyl-SR12;
R8 is hydrogen or C1-C8 alkyl;
R9 and R10 are each independently hydrogen or C1-C8 alkyl
R11 is hydrogen or C1-C8 alkyl;
R12 is hydrogen or a group selected from C1-C8 alkyl, —(CR132)nR14, —CO—(CR132)nR14, —SO2—(CR132)nR14;
n is between 0 and 5;
R13 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, hydroxy(C1-C8)alkyl, amino or halogen;
R14 is hydrogen or a group selected from —NR15R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —COOH, —S(C1-C8 alkyl), —SO(C1-C8 alkyl), —CONR15R16, —CO(C1-C8 alkyl), —CO—O—(C1-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl (which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), C1-C8 alkoxy, C1-C8 hydroxyalkyl, —C═O, cyano, amino, nitro, halogen, C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur;
or R11 and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), nitro, cyano, —CONH2, amino, ═O or —COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—; and
R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, —CONH2 or —C(NH2)═NH;
and the other of R1 and R2 is Y(CR32)pNR4R5, Y(CR32)nCONR4R5, Y(CR32)p—C2R6, Y(CR32)pOR6, Y(CR32)pR6 or Y(CR32)pOCOR6,
where at least one R3 is C1-C8 alkoxy, or one of R4 and R5 is selected from optionally substituted —CO—(C1-C8)alkyl, —CO—(C1-C8)cycloalkyl, —SO2—(C1-C8)alkyl, —CO—(C1-C8)alkoxy, —CO—NR7(C1-C8)alkyl or C3-C8 cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a substituted 4- to 7-membered saturated or aromatic heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group, or R6 is selected from —CO(C1-C8)alkyl, or an optionally substituted saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, and which may be optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkyl —CO—, ═O or (C1-C8 alkoxy)-CO— where any C1-C8 alkyl is optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
In another particular embodiment, the invention provides a compound of formula (Ib)
or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 and R2, which may be the same or different, represent nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR32)pOR6, Y(CR32)pR6, Y(CR32)pOCOR6
or R1 and R2 are linked together as —OCH2O— or —OCH2CH2O—;
R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen;
p is 0, 1, 2, 3, 4 or 5;
Y is oxygen, CH2′—OSO2— or NR7
R4 and R5 each independently represent hydrogen or a group selected from C1-C8 alkyl, C1-C8 alkoxy, —CO—(C1-C8)alkyl, —CO—(C1-C8)cycloalkyl, —SO2—(C1-C8)alkyl, —CO—(C1-C8)alkoxy, —CO—NR7(C1-C8)alkyl, C3-C8 cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, —CONH2 or —CO—(C1-C8)alkoxy groups,
or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, ═O, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—, or one of R4 and R5 is hydrogen or C1-C8 alkyl and the other is a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
R6 is hydrogen, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, cyano, halogen or amino groups), phenyl, benzyl, —CO(C1-C8)alkyl or a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, ═O or (C1-C8 alkoxy)-CO—; C1-C8 alkyl —CO—, where any C1-C8 alkyl is optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
R7 is hydrogen or C1-C8 alkyl;
Ra is hydrogen or C1-C8 alkyl;
Rx is a group selected from C1-C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring comprising one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered ring is optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, —CONH2—, C1-C8 alkyl, (C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO—, and any C1-C8 alkyl, C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO— group is itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl; or Rx is a group Ar;
Ar is selected from dihydroisoquinolyl, oxodihydroisoquinolyl, tetrahydroisoquinolyl or oxotetrahydroisoquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, cyano, C1-C8 alkoxy, CO2R8, CONR9R10, C1-C8 alkyl-NR8—C1-C8 alkyl, C1-C8 alkyl-CONR8—C1-C8 alkyl, C1-C8 alkyl-CONR9R10, NR8COC1-C8 alkyl, C1-C8 thioalkyl, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1-C8 alkyl-NR11R12, C1-C8 alkyl-OR12, C1-C8 alkyl-SR12;
or Ar is phenyl substituted by at least one substituent selected from azido substituted C1-C8 alkyl, C1-C8 alkyl-NR11R12a, C1-C8 alkyl-OR12a, C1-C8 alkyl-SR12a,
wherein R12a is selected from —(CR132)nR14, —CO—(CR132)nR14, —SO2—(CR132)nR14;
R8 is hydrogen or C1-C8 alkyl;
R9 and R10 are each independently hydrogen or C1-C8 alkyl
R11 is hydrogen or C1-C8 alkyl;
R12 is hydrogen or a group selected from C1-C8 alkyl, —(CR132)nR14, —CO—(CR132)nR14, —SO2—(CR32)nR14;
n is between 0 and 5;
R13 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, hydroxy(C1-C8)alkyl, amino or halogen;
R14 is hydrogen or a group selected from —NR15R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —COOH, —S(C1-C8 alkyl), —SO(C1-C8 alkyl), —CONR15R16, —CO(C1-C8 alkyl), —CO—O—(C1-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), C1-C8 alkoxy, C1-C8 hydroxyalkyl, —C═O, cyano, amino, nitro, halogen, C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur;
or R11 and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl (which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), nitro, cyano, —CONH2, amino, ═O or —COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—; and
R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl —CONH2 or —C(NH2)═NH,
provided that Ar is not phenyl substituted by one or more groups selected from C1-C8 alkyl-NR11—C1-C8 alkyl, C1-C8 alkyl-O—C1-C8 alkyl or C1-C6 alkanoyloxy C1-C6 alkyl.
Suitably X is —CHOH or —C═O, preferably —C═O.
In one embodiment, Rx is a group selected from C1-C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring comprising one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered ring is optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, —CONH2—, C1-C8 alkyl, (C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO—, and any C1-C8 alkyl, (C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO— group is itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl.
In one preferred embodiment, Rx is C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring comprising one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups is optionally substituted as described above. Preferably Rx is cyclohexyl, pyrrolidinyl or piperidinyl, optionally substituted as described above.
Substituents may be present on any suitable position of the Rx group and more than one substitutent, which may be the same or different, may be present. Where Rx is substituted, this is preferably by one or two substituents.
Preferred substituents on Rx include C1-C8 alkyl, (C1-C8 alkyl)CO—, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO—, optionally substituted with one or more substituents selected from hydroxy, azido, cyano, amino, halogen, —CONH2, C1-C8 alkoxy, (C1-C8 alkoxy)-CO— or phenyl.
Particularly preferred substituents on Rx include methyl, ethyl, benzyl, (CH3)C—O—CO—, —COCN.
In another embodiment, Rx is a group Ar.
Suitably Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indazolyl optionally substituted as described above. Substituents can be present on any suitable position of the Ar group. More than one substituent can be present, and these can be the same or different. Preferably Ar is optionally substituted dihydroisoquinolyl, oxodihydroisoquinolyl, tetrahydroisoquinolyl, oxotetrahydroisoquinolyl or phenyl, most preferably phenyl.
Where Ar is phenyl, this is preferably substituted by one and especially two substitutents. Preferred substituents include C1-C8 alkyl, such as methyl or ethyl, hydroxy(C1-C8)alkyl, for example hydroxymethyl or hydroxyethyl, or a C1-C8 alkyl-NR11R12, C1-C8 alkyl-OR12, C1-C8 alkyl-SR12 group such as CH2SR12, CH2OR12 or especially —CH2NR11R12.
In one preferred embodiment, Ar is phenyl substituted by at least one substituent selected C1-C8 alkyl-NR11R12a, C1-C8, alkyl-OR12a, C1-C8 alkyl-SR12a,
wherein R12a is selected from —(CR132)nR14, —CO—(CR132)nR14, —SO2—(CR132)nR14;
provided that Ar is not phenyl substituted by one or more groups selected from C1-C8 alkyl-NR11—C1-C8 alkyl, C1-C8 alkyl-O—C1-C8 alkyl or C1-C6 alkanoyloxy C1-C6 alkyl.
In one embodiment, R11 is preferably hydrogen
In another embodiment, R12 is preferably a group —(CR132)nR14
R13 is preferably hydrogen
R14 may be hydrogen, —NR15R16 or C1-C8 alkyl but is preferably a saturated or unsaturated 4- to 10-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), C1-C8 alkoxy, C1-C8 hydroxyalkyl, —C═O, cyano, amino, nitro, halogen, C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur;
In a particular embodiment, R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, —CONH2 groups), nitro, cyano, —CONH2, amino or —COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—;
Ra is hydrogen or C1-C8 alkyl such as methyl or ethyl. Where Ra is C1-C8 alkyl, it is preferably methyl.
In one embodiment, Ra is C1-C8 alkyl, especially methyl.
In a particular embodiment, Ra is hydrogen.
Suitably R1 and R2 are independently selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR32)pOR6, Y(CR32)pR6, Y(CR32)pOCOR6; or R1 and R2 are linked together as —OCH2O— or —OCH2CH2O—.
In one embodiment, R1 and R2 independently preferably represent C1-C8 alkoxy, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR32)pOR6, Y(CR32)pOCOR6, Y(CR32)pR6.
In one embodiment, one or both of R1 and R2 is Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR32)pOR6, Y(CR32)pR6 or Y(CR32)pOCOR6, wherein at least one R3 is alkoxy, or one of R4 and R5 is a group selected from —CO—(C1-C8)alkyl, —CO—(C1-C8)cycloalkyl, —SO2—(C1-C8)alkyl, —CO—(C1-C8)alkoxy, —CO—NR7(C1-C8)alkyl or C3-C8 cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, —CONH2 or —CO—(C1-C8)alkoxy groups, or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated or aromatic heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, which ring system is substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, ═O, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—, or R6 is selected from —CO(C1-C8)alkyl or a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO—.
In a further embodiment, R1 and R2 independently preferably represent methoxy, ethoxy, —O(CH2)2NR4R5, O(CH2)3 NR4R5, —OR6, —O(CH2)2R6, —N(CR3)2NR4R5, —N(CR3)3NR4R5, —N(CR3)2OR6, —N(CR3)3OR6.
Each R3 group independently may suitably represent hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen but preferably each R3 independently represents hydrogen or C1-C8 alkoxy such as methoxy or ethoxy.
R4 and R5 each independently preferably represent hydrogen or a group selected from C1-C8 alkyl, —CO—(C1-C8)alkyl, —SO2—(C1-C8)alkyl, C3-C8 cycloalkyl, each of which groups may be optionally substituted as described above, or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, substituted or unsubstituted, saturated or aromatic heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group. Particularly preferably, R4 and R5 each independently represent hydrogen, —CH3, —(CH2)2CN, —COCH3—COCH(CH3)2, —CH(CH3)2, cyclopropyl, —CO-cyclopropyl, —SO2CH3, —C(═O)—O—C(CH3)3, or R4 and R5 together represent an optionally substituted piperidinyl, pyrrolidinyl, piperazinyl, 1,2,4-triazolyl, 2,5-dioxopyrrolidinyl or 2,5-dioxoimidazolidinyl group.
In a particular embodiment, R1 and R2 are both C1-C8 alkoxy, or one of R1 and R2 is C1-C8 alkoxy and the other is Y(CR32)nNR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, Y(CR62)pOR6, Y(CR32)pR6 or Y(CR32)pOCOR6.
Where R1 and R2 are both C1-C8 alkoxy, this is preferably methoxy or ethoxy. In one particular embodiment, R1 and R2 are both methoxy or ethoxy.
Preferred compounds of the invention include:—
Where the compounds according to the invention contain one or more asymmetrically substituted carbon atoms, the invention includes all stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof. Tautomers and mixtures thereof are also included.
Racemates may be separated into individual enantiomers using known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, p 104-107). A suitable procedure involves formation of diastereomeric derivatives by reaction of the racemic material with a chiral auxiliary, followed by separation, for example by chromatography, of the diastereomers and then cleavage of the auxiliary species.
The compounds according to the invention may be provided as pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. In another aspect, where the compound is sufficiently basic, suitable salts include acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, which comprises:
(a) reaction of a compound of formula (II):
in which R1 and R2 are as defined in formula (I) or are protected derivatives thereof and R20 is a leaving group, with a compound of formula (III):
Rx—N(Ra)H (III)
in which Rx and Ra are as defined in formula (I) or a protected derivative thereof, or (b) for compounds of formula (I) where R1 and/or R2 are groups Y(CR32)pNR4R5, Y(CR12)pCONR4R5, Y(CR3)pCO2R6, Y(CR32)pOR6 or Y(CR32)pR6 where Y is oxygen, reaction of a compound of formula (IV):
where the R1′ or R2′ to be converted into a group Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR3)pCO2R6, Y(CR32)pOR6 or Y(CR32)pR6 is hydroxy and the other R1′ or R2′ together with Rx are as defined above for process (a) with a compound of formula (V):
L-(CR32)pR21 (V)
where R21 is NR4R5, CONR4R5, CO2R6, OR6 or R6 and R4, R5 and R6 are as defined in formula (I) or are protected derivatives thereof,
and optionally thereafter process (a) or (b)
In process (a) the group R20 is a leaving group such as halogen, in particular chloro. The reaction can be carried out in an inert solvent such as DMF at elevated temperature, for example at about 100° C.
In process (b) the leaving group L is preferably halogen, in particular chloro. The reaction can be carried out in the presence of a base such as cesium carbonate in an inert solvent such as DMF or ethanol.
Compounds of formula (II) can be prepared by reacting compounds of formula (VI):
in which R1, R2 and R20 are as defined in formula (II) with a chlorinating agent such as thionyl chloride, and reaction of the corresponding acid chloride with ammonia.
Compounds of formula (VI) can be prepared using methods conventional in the art.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures conventional in the art.
Examples of the types of conversion reactions that may be used include 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 and are illustrated in the Examples below. By way of example, a hydroxy group may be replaced with a chloro group by reaction with a chlorinating agent such as thionyl chloride and the chloro group may itself undergo nucleophilic substitution. Alternatively a chloro substituent may be treated with sodium azide to replace the chloro group with an azido group which in turn may be reduced to an amine group. Amine groups may conveniently be acylated with acid chlorides or isocyanates and converted into amides by treatment with appropriate acids.
It will be appreciated that certain functional groups may need to be protected using standard protecting groups. The protection and deprotection of functional groups is for example, described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 3rd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1999).
Diseases mediated by JAK3 include inflammatory, immunological, and bronchopulmonary disorders.
The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and other autoimmune diseases or (b) the inhibition of protein tyrosine kinases or Janus kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in such disorders or conditions and a pharmaceutically acceptable carrier.
Preferably the compounds of the invention are used for the treatment of asthma, rheumatoid arthritis, and host versus graft rejection/transplantation.
The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cane, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and other autoimmune diseases or (b) the inhibition of protein tyrosine kinases or Janus kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with a T-cell immunosuppresant or anti-inflammatory agents, effective in such disorders or conditions and a pharmaceutically acceptable carrier.
The present invention also relates to a method for the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. The dosage will preferably be in the range of from 0.1 mg/kg to 100 mg/kg.
The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, e.g. formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration, e.g. in the form of sterile parenteral solutions or suspensions, or by rectal administration, e.g. in the form of suppositories.
The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 μm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (e.g. oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol, or an other polyol. Suitable carriers are sugars, e.g. lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound, with or without a carrier substance, is delivered to the patient.
For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol; a starch, e.g. potato starch, corn starch or amylopectin; a cellulose derivative; a binder, e.g. gelatine or polyvinylpyrrolidone, and/or a lubricant, e.g. magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
The term ‘medical therapy’ as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. The terms “therapeutic” and “therapeutically” will be understood accordingly.
The following Examples illustrate the invention.
All reactions were performed in dried glassware in an argon atmosphere at room temperature, unless otherwise noted. All solvents and reagents and solvents were used as received. Merck Silica gel 60 (0.040-0.063 mm) was used for preparative silica gel chromatography. A Kromasil KR-100-5-C18 column (250×20 mm, Akzo Nobel) and mixtures of acetonitrile/water at a flow rate of 10 ml/min was used for preparative HPLC. Reactions were monitored at 254 nm by analytical HPLC, using a Kromasil C-18 column (150×4.6 mm) and a gradient (containing 0.1% trifluoroacetic acid) of 5 to 100% of acetonitrile in water at a flow rate of 1 ml/min. Evaporations of solvents were performed under reduced pressure using a rotary evaporator at a maximum temperature of 40° C. Products were dried under reduced pressure at 40° C.
1H-NMR spectra were recorded on a Varian Inova-400 or Unity-500+ instrument. The central solvent peak of chloroform-d (δH 7.27 ppm), dimethylsulfoxide-d6 (δH 2.50 ppm) or methanol-d4 (δH 3.35 ppm) were used as internal references. Low resolution mass spectra obtained on a Hewlett Packard 1100 LC-MS system equipped with a APCI ionisation chamber.
Merck Silica gel 60 (0.040-0.063 mm) was used for preparative silica gel chromatography. A Kromasil KR-100-5-C18 column (250×20 mm, Akzo Nobel) and mixtures of acetonitrile/water at a flow rate of 10 ml/min was used for preparative HPLC. Reactions were monitored at 254 nm by analytical HPLC, using a Kromasil C-18 column (150×4.6 mm) and a gradient (containing 0.1% trifluoroacetic acid) of 5 to 100% of acetonitrile in water at a flow rate of 1 ml/min. Evaporations of solvents were performed under reduced pressure using a rotary evaporator at a maximum temperature of 40° C. Products were dried under reduced pressure at 40° C.
The title compound was prepared according to the method described in WO 02/092571
To a suspension of 6,7-diethoxy-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}quinoline-3-carboxamide (1.1 g, 2.7 mmol) in CH2Cl2 (7 ml) was added thionyl chloride (0.7 g, 5.77 mmol). After fifteen minutes the suspension was dissolved. Azeotropic evaporation of excess thionyl chloride with toluene gave the title compound 1.15 g (100%) as a yellow powder.
1H NMR (400 MHz, CDCl3): δ 12.5 (1H, s); 9.12 (1H, s); 8.69 (1H, br s); 8.08 (1H, br s); 7.52 (1H, d); 7.45 (1H, s); 7.33 (1H, t); 7.23 (1H, d); 6.63 (1H, s); 4.92 (2H, s); 4.18 (2H, q); 3.72 (2H, br s); 2.83 (2H, br s); 1.39 (3H, t); 1.17 (3H, t); 1.05 (3H, t);
APCI-LC/MS m/z: 428.4 [MH+]
Imidazole (110 mg, 1.6 mmol) was added to a solution of 4-{[3-(chloromethyl)-2-ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide (40.2 mg, 0.094 mmol) In 1-methyl-2-pyrrolidinone (2 ml) The mixture was heated for two hours at 70 C, cooled to room temperature and diluted with water. The product was purified by preparative HPLC. After freeze-drying the title compound was obtained as a white powder.
1H NMR (400 MHz, DMSO-d6) δ 10.96 (1H, s), 8.88 (1H, s), 8.30 (1H, s), 7.70 (1H, s), 7.63 (1H, s), 7.22 (1H, s), 7.09 (1H, s), 7.04 (2H, t), 6.93 (1H, s), 6.87 (1H, d), 6.60 (2H, d), 6.55 (1H, s), 5.31 (2H, s), 4.14 (2H, q), 2.85 (2H, q), 1.36 (3H, t), 1.02 (5H, dd)
APCI-LC/MS m/z: 460.2 [MH+]
The title compounds of examples 2-115 were prepared in analogous manner to example 1.
APCI LC-MS m/z: 447.5-[MH+]
1H NMR (400 MHz, DMSO-d6) δ 10.97 (1H, s), 8.87 (1H, s), 8.29 (1H, s), 7.60 (1H, s), 7.21 (1H, s), 7.03 (2H, d), 6.98 (2H, t), 6.61 (1H, s), 6.56 (2H, d), 4.14 (2H, q), 3.57 (5H, s), 3.51 (3H, s), 2.87 (2H, q), 2.38 (4H, s), 1.36 (3H, t), 1.24 (3H, t), 1.01 (3H, t)
APCI LC-MS m/z: 479.4 [MH+]
APCI LC-MS m/z: 446.5-[MH+]
APCI LC-MS m/z: 421.5 [MH+]
APCI LC-MS m/z: 447.5 [MH+]
APCI LC-MS m/z: 550.4 [MH+]
APCI LC-MS m/z: 448.2 [MH+]
1H NMR (399.99 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.90 (s, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.25 (s, 1H), 7.09 (s, 1H), 7.06 (d, 1H), 6.93 (s, 1H), 6.87 (d, 1H), 6.64 (d, 1H), 6.56 (s, 1H), 5.33 (s, 2H), 3.88 (s, 3H), 3.17 (s, 3H), 2.86 (q, 2H), 1.03 (t, 3H)
APCI LC-MS m/z: 432.4 [MH+]
APCI LC-MS m/z: 487.1 [MH+]
APCI LC-MS m/z: 507.5 [MH+]
APCI LC-MS m/z: 505.6 [MH+]
APCI LC-MS m/z: 492.6 [MH+]
APCI LC-MS m/z: 495.6 [MH+]
APCI LC-MS m/z: 505.6 [MH+]
APCI LC-MS m/z: 477.2 [MH+]
APCI LC-MS m/z: 462.5 [MH+]
APCI LC-MS m/z: 446.5 [MH+]
APCI LC-MS m/z: 476.5 [MH+]
1NMR (400 MHz, DMSO-d6) δ 11.03 (1H, s), 8.87 (1H, s), 8.28 (1H, s), 7.59 (1H, s), 7.22 (1H, s), 7.12 (1H, d), 7.00 (1H, t), 6.63 (1H, s), 6.57 (1H, d), 3.87 (3H, s), 3.73 (2H, s), 3.19 (3H, s), 3.03 (1H, t), 2.86 (2H, q), 1.73 (2H, mult), 1.61 (2H, mult), 1.46 (2H, mult), 1.35 (2H, mult), 1.21 (3H, t)
APCI LC-MS m/z: 449.2 [MH+]
1H NMR (400 MHz, DMSO-d6) δ 9.20 (1H, s), 9.00 (2H, d), 8.60 (1H, s), 8.07 (1H, s), 7.52 (2H, s), 7.48 (2H, d), 7.37 (2H, mult), 7.23 (1H, d), 6.67 (1H, s), 4.34 (2H, s), 3.94 (4H, s), 3.40 (3H, t), 3.20 (4H, s), 3.11 (3H, t), 2.81 (2H, s), 1.14 (3H, t)
APCI LC-MS m/z: 475.2 [MH+]
1H NMR (400 MHz, DMSO-d6) δ 11.03 (1H, s), 8.87 (1H, s), 8.28 (1H, s), 7.59 (1H, s), 7.22 (1H, s), 7.12 (1H, d), 7.00 (1H, t), 6.62 (2H, s), 6.58 (2H, d), 4.59 (1H, s), 3.86 (3H, s), 3.68 (2H, s), 3.25 (2H, d), 3.19 (3H, s), 2.87 (2H, d), 1.23 (3H, t), 1.02 (6H, s).
APCI LC-MS m/z: 453.1 [MH+]
APCI LC-MS m/z: 464.1 [MH+]
APCI LC-MS m/z: 439.3 [MH+]
APCI LC-MS m/z: 501.3 [MH+]
1H NMR (399.99 MHz, dmso-d6) δ 11.03 (1H, s), 8.88 (1H, s), 8.34 (1H, s), 7.88 (2H, d), 7.63 (2H, d), 7.57 (1H, s), 7.22 (1H, s), 7.16 (1H, d), 7.03 (1H, t), 6.63 (1H, s), 6.59 (1H, d), 3.87 (3H, s), 3.84 (2H, s), 3.76 (2H, s), 3.18 (6H, s), 2.83 (2H, d), 1.17 (3H, t)
APCI LC-MS m/z: 549.3 [MH+]
1H NMR (399.99 MHz, DMSO-d6) δ 11.03 (1H, s), 8.88 (1H, br s), 8.27 (1H, br s), 7.60 (1H, s), 7.33 (4H, mult), 7.22 (2H, mult), 7.16 (1H, d), 7.03 (1H, t), 6.63 (1H, s), 6.59 (1H, d), 3.87 (3H, s), 3.73 (4H, d), 3.18 (3H, s), 2.81 (2H, q), 1.16 (3H, t)
APCI LC-MS m/z 471.3 [MH+]
APCI LC-MS m/z 478.5 [MH+]
APCI LC-MS m/z 449.2 [MH+]
APCI LC-MS m/z 449.2 [MH+]
1H NMR (399.99 MHz, DMSO-d6) δ 11.03 (1H, s), 8.87 (1H, s), 8.28 (1H, br s), 7.60 (1H, br s), 7.22 (1H, s), 7.13 (1H, d), 7.01 (1H, t), 6.62 (1H, s), 6.58 (1H, d), 6.22 (1H, s), 3.87 (3H, s), 3.77 (2H, s), 3.29 (2H, t), 3.19 (5H, mult), 3.14 (2H, t), 2.85 (2H, q).
APCI LC-MS m/z 493.3 [MH+]
APCI LC-MS m/z 479.3 [MH+]
APCI LC-MS m/z 464.3 [MH+]
APCI LC-MS m/z 481.5 [MH+]
APCI LC-MS m/z: 584.6 [MH+]
APCI LC-MS m/z: 507.5 [MH+]
APCI LC-MS m/z: 507.6 [MH+]
APCI LC-MS m/z: 560.7 [MH+]
APCI LC-MS m/z: 520.5 [MH+]
APCI LC-MS m/z: 579.7 [MH+]
APCI LC-MS m/z: 580.6 [MH+]
APCI LC-MS m/z: 489.5 [MH+]
APCI LC-MS m/z: 522.6 [MH+]
APCI LC-MS m/z: 493.5 [MH+]
APCI LC-MS m/z: 557.6 [MH+]
APCI LC-MS m/z: 519.5 [MH+]
APCI LC-MS m/z: 517.6 [MH+]
APCI LC-MS m/z: 534.6 [MH+]
APCI LC-MS m/z: 547.5 [MH+]
APCI LC-MS m/z: 547.6 [MH+]
APCI LC-MS m/z: 547.6 [MH+]
APCI LC-MS m/z: 529.6 [MH+]
APCI LC-MS m/z: 477.5 [MH+]
APCI LC-MS m/z: 503.6 [MH+]
APCI LC-MS m/z: 591.7 [MH+]
APCI LC-MS m/z: 523.5 [MH+]
APCI LC-MS m/z: 492.5 [MH+]
APCI LC-MS m/z: 481.5 [MH+]
APCI LC-MS m/z: 514.5 [MH+]
APCI LC-MS m/z: 476.6 [MH+]
APCI LC-MS m/z: 581.5 [MH+]
APCI LC-MS m/z 578.6 [MH+]
APCI LC-MS m/z: 552.6 [MH+]
APCI LC-MS m/z: 549.7 [MH+]
APCI LC-MS m/z: 520.6 [MH+]
APCI LC-MS m/z: 569.6 [MH+]
APCI LC-MS m/z: 500.6 [MH+]
APCI LC-MS m/z: 500.6 [MH+]
APCI LC-MS m/z: 499.5 [MH+]
APCI LC-MS m/z: 489.6 [MH+]
APCI LC-MS m/z: 467.5 [MH+]
APCI LC-MS m/z: 467.5 [MH+]
APCI LC-MS m/z: 565.6 [MH+]
APCI LC-MS m/z: 592.7 [MH+]
APCI LC-MS m/z: 520.7 [MH+]
APCI LC-MS m/z: 533.5 [MH+]
APCI LC-MS m/z: 582.7 [MH+]
APCI LC-MS m/z: 529.5 [MH+]
APCI LC-MS m/z: 529.7 [MH+]
APCI LC-MS m/z: 517.6 [MH+]
APCI LC-MS m/z 541.5 [MH+]
APCI LC-MS m/z 582.5 [MH+]
APCI LC-MS m/z 524.5 [MH+]
APCI LC-MS m/z 529.5 [MH+]
APCI LC-MS m/z 497.3 [MH+]
APCI LC-MS m/z 497.5 [MH+]
APCI LC-MS m/z 511.3 [MH+]
APCI LC-MS m/z 483.5 [MH+]
APCI LC-MS m/z 509.5 [MH+]
APCI LC-MS m/z 506.5 [MH+]
APCI LC-MS m/z 497.3 [MH+]
APCI LC-MS m/z 509.5 [MH+]
APCI LC-MS m/z 495.5 [MH+]
APCI LC-MS m/z 510.4 [MH+]
APCI LC-MS m/z 557.5 [MH+]
APCI LC-MS m/z 543.5 [MH+]
APCI LC-MS m/z 561.5 [MH+]
APCI LC-MS m/z 467.5 [MH+]
APCI LC-MS m/z 467.5 [MH+]
APCI LC-MS m/z 453.5 [MH+]
APCI LC-MS m/z 483.5 [MH+]
APCI LC-MS m/z 515.4 [MH+]
APCI LC-MS m/z 549.6 [MH+]
APCI LC-MS m/z 543.5 [MH+]
APCI LC-MS m/z 480.4 [MH+]
APCI LC-MS m/z 563.5 [MH+]
APCI LC-MS m/z 529.5 [MH+]
APCI LC-MS m/z 493.5 [MH+]
APCI LC-MS m/z 559.5 [MH+]
APCI LC-MS m/z 522.4 [MH+]
APCI LC-MS m/z 559.5 [MH+]
APCI LC-MS m/z 559.5 [MH+]
APCI LC-MS m/z 462.5 [MH+]
APCI LC-MS m/z 495.5 [MH+]
APCI LC-MS m/z 577.5 [MH+]
A mixture of 4-chloro-6,7-diethoxyquinoline-3-carboxamide (96.5 mg, 0.33 mmole), tert-butyl 3-amino-2-ethylbenzylcarbamate (prepared according to WO 02/092571) (119 mg, 0.476) in NMP (2 ml) was heated over night at 115 C. After cooling the solution was diluted with water and basified with NaHCO3. The compound was extracted from the aqueous solution with ethylacetate (3×). The extracts were washed with water (2×), brine (2×), dried (Na2SO4), and evaporated. The residue was purified by silica chromatography (CH2Cl2/MeOH) to give 105 mg (62%) of the title compound as a white powder.
1H NMR (299.946 MHz, DMSO-d6) δ10.98 (1H, s), 8.86 (1H, s), 8.27 (1H, s), 7.58 (1H, s), 7.19 (1H, s), 7.00 (2H, mult), 6.56 (2H, mult), 4.22 (2H, d), 4.12 (4H, mult), 3.40 (1H, s), 2.81 (2H, d), 1.39 (9H, s), 1.33 (3H, t), 1.17 (3H, t), 1.02 (3H, t)
APCI-LC/MS m/z: 509.4 [MH+]
To a cooled solution of tert-butyl 3-{[3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino}-2-ethylbenzylcarbamate (105 mg, 0.21 mmole) in CH2Cl2 (4 ml) was added TFA (4 ml). After 40 minutes at 0° C. the solvent was evaporated of. The residue was dissolved in CH3CN/NH3-aq solution and purified by preparative HPLC After freeze-drying (36 mg, 42%) of the title compound was obtained as a white powder.
1H NMR (399.99 MHz, DMSO-d6) δ 10.97 (1H, s), 8.85 (1H, s), 8.27 (1H, s), 7.57 (1H, s), 7.19 (1H, s), 7.17 (1H, s), 7.01 (1H, t), 6.63 (1H, s), 6.54 (1H, d), 4.13 (2H, q), 3.80 (2H, s), 2.81 (2H, q), 1.35 (3H, t), 1.18 (3H, t), 1.01 (3H, t)
APCI-LC/MS m/z: 409.2 [MH+]
The title compound was prepared in an analogues way to example 117.
APCI-LC/MS m/z: 395.2 [MH+]
To a mixture of boc-L-tyrosine (45 mg, 0.16 mmol), HATU (61 mg, 0.16 mmol), and DIEA (26 mg, 0.2 mmol) in NMP/dichloromethane (1 ml) 4-{[3-(aminomethyl)-2-ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide (15 mg, 0.039 mmol) was added. The reaction was stirred for 1 h at room temperature. TFA (50% in DCM, 1 ml) was then added and the reaction mixture was stirred further for 1 h. The mixture was then diluted with water (1.0 ml) and purified by preparative HPLC using a gradient of acetonitrile/water at a flow rate of 20 ml/min. Freeze drying of the mixture afforded the title compound in 20% yield.
1H NMR (400 MHz, DMSO-d6) δ 9.39 (1H, s,); 8.98 (1H, s,); 8.85 (1H, s,); 8.54 (1H, s,); 8.20 (3H, s,); 8.02 (1H, s,); 7.28 (1H, s,); 7.16 (1H, s,); 7.04 (2H, d, J=8.5 Hz); 6.72 (2H, d, J=8.5 Hz); 6.65 (1H, s,); 4.49 (1H, s,); 4.34 (1H, d, J=11.3 Hz); 4.20 (2H, q, J=7.0 Hz); 3.99 (1H, s,); 2.96 (2H, t, J=6.7 Hz); 2.70 (1H, d, J=27.3 Hz); 1.39 (3H, t, J=7.0 Hz); 1.13 (6H, t, J=7.5 Hz); 1.07 (9H, t, J=6.7 Hz).
APCI-LC/MS m/z: 572.6 [MH+]
The title compounds of examples 120-183 were prepared in analogous manner to example 119 using 4-{[3-(aminomethyl)-2-ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide, 4-{[3-(aminomethyl)-2-ethylphenyl]amino}-6,7-dimetoxyquinoline-3-carboxamide or 4-{[3-(aminomethyl)-2-methylphenyl]amino}-6,7-dimetoxyquinoline-3-carboxamide and an appropriate amino acid, acid chloride or isocyanate.
APCI LC-MS m/z: 466.5 [MH+]
APCI LC-MS m/z: 437.4 [MH+]
APCI LC-MS m/z: 585.1 [MH+]
APCI LC-MS m/z: 423.4 [MH+]
APCI LC-MS m/z: 585.1 [MH+]
APCI LC-MS m/z: 459.2 [MH+]
APCI LC-MS m/z: 480.2 [MH+]
APCI LC-MS m/z: 534.5 [MH+]
APCI LC-MS m/z: 540.5 [MH+]
APCI LC-MS m/z: 506.4 [MH+]
APCI LC-MS m/z: 510.4 [MH+]
APCI LC-MS m/z: 538.5 [MH+]
APCI LC-MS m/z: 508.5 [MH+]
APCI LC-MS m/z: 565.6 [MH+]
APCI LC-MS m/z: 480.4 [MH+]
APCI LC-MS m/z: 496.4 [MH+]
APCI LC-MS m/z: 562.5 [MH+]
APCI LC-MS m/z: 524.4 [MH+]
APCI LC-MS m/z: 522.5 [MH+]
APCI LC-MS m/z: 522.5 [MH+]
APCI LC-MS m/z: 523.2 [MH+]
APCI LC-MS m/z: 520.5 [MH+]
APCI LC-MS m/z: 562.5 [MH+]
APCI LC-MS m/z 520.5 [MH+]
APCI LC-MS m/z: 506.5 [MH+]
APCI LC-MS m/z: 492.4 [MH+]
APCI LC-MS m/z: 536.5 [MH+]
APCI LC-MS m/z: 524.4 [MH+]
APCI LC-MS m/z: 601.5 [MH+]
APCI LC-MS m/z: 568.5 [MH+]
APCI LC-MS m/z: 534.5 [MH+]
APCI LC-MS m/z: 568.5 [MH+]
APCI LC-MS m/z: 570.5 [MH+]
APCI LC-MS m/z: 568.5 [MH+]
APCI LC-MS m/z: 589.6 [MH+]
APCI LC-MS m/z: 495.4 [MH+]
APCI LC-MS m/z: 556.5 [MH+]
APCI LC-MS m/z: 570.5 [MH+]
APCI LC-MS m/z: 520.5 [MH+]
APCI LC-MS m/z: 520.5 [MH+]
APCI LC-MS m/z: 542.5 [MH+]
APCI LC-MS m/z: 522.5 [MH+]
APCI LC-MS m/z: 506.5 [MH+]
APCI LC-MS m/z: 504.4 [MH+]
APCI LC-MS m/z: 466.4 [MH+]
APCI LC-MS m/z: 556.5 [MH+]
APCI LC-MS m/z: 546.5 [MH+]
APCI LC-MS m/z: 557.5 [M+]
APCI LC-MS m/z: 562.4 [MH+]
APCI LC-MS m/z: 563.5 [MH+]
APCI LC-MS m/z: 534.5 [MH+]
APCI LC-MS m/z: 504.4 [MH+]
APCI LC-MS m/z: 508.5 [MH+]
APCI LC-MS m/z: 542.5 [MH+]
APCI LC-MS m/z: 522.4 [MH+]
APCI LC-MS m/z: 480.4 [MH+]
APCI LC-MS m/z: 557.5 [MH+]
APCI LC-MS m/z: 557.5 [MH+]
APCI LC-MS m/z: 566.5 [MH+]
APCI LC-MS m/z: 536.5 [MH+]
APCI LC-MS m/z: 554.5 [MH+]
APCI LC-MS m/z: 522.5 [MH+]
APCI LC-MS m/z: 508.5 [MH+]
APCI LC-MS m/z: 520.5 [MH+]
To a solution of 4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-[3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide, prepared according to the procedure described in WO 02/092571, 10 mg, 0.021 mmole), triethylamine (0.2 ml) in NMP (1 ml) was added isobutiric anhydride (3.8 mg, 0.024 mmole). The mixture was stirred overnight at ambient temperature. The solution was diluted with water and the product was purified by preparative HPLC. After freeze-drying 6.7 mg (59%) was obtained of the title compound as a white powder.
1H NMR (399.99 MHz, DMSO-d6) δ 11.03 (1H, s), 8.87 (1H, s), 8.28 (1H, s), 7.60 (1H, s), 7.21 (2H, mult), 7.04 (1H, t), 6.65 (1H, d), 6.59 (1H, d), 5.16 (1H, t), 4.60 (2H, d), 4.46 (1H, quintet), 4.13 (2H, mult), 3.23 (1H, t), 3.21 (3H, d), 2.81 (3H, mult), 1.96 (2H, s), 1.19 (3H, t), 1.12 (3H, t), 1.05 (3H, d), 0.98 (3H, d), 0.90 (3H, d)
APCI-LC/MS m/z: 537.3 [MH+]
Following examples 185-202 were prepared in analogous manner to example 184 using the appropriate anhydride, acid chloride or isocyanate.
1H NMR (399.99 MHz, DMSO-d6) δ 11.07 (1H, s), 8.87 (1H, s), 8.29 (1H, s), 7.61 (1H, s), 7.24 (1H, s), 7.19 (2H, d), 7.05 (1H, t), 6.65 (1H, d), 6.60 (1H, d), 5.16 (1H, t), 4.59 (2H, d), 4.44 (0.5H, t), 4.12 (2H, dt), 4.00 (0.5H, quintet), 3.23 (1H, t), 3.21 (3H, d), 2.79 (2H, q), 1.97 (5H, mult), 1.19 (3H, t), 1.08 (6H, mult)
APCI LC-MS m/z: 509.3 [MH+]
APCI LC-MS m/z: 423.2 [MH+]
APCI LC-MS m/z: 437.2 [MH+]
APCI LC-MS m/z: 465.2 [MH+]
APCI LC-MS m/z: 465.2 [MH+]
APCI LC-MS m/z: 493.3 [MH+]
APCI LC-MS m/z: 481.5 [MH+]
APCI LC-MS m/z: 509.6 [MH+]
APCI LC-MS m/z: 507.6 [MH+]
APCI LC-MS m/z: 534.7 [MH+]
APCI LC-MS m/z: 467.3 [MH+]
APCI LC-MS m/z: 494.7 [MH+]
APCI LC-MS m/z: 463.2 [MH+]
APCI LC-MS m/z: 491.2 [MH+]
APCI LC-MS m/z: 545.3 [MH+]
APCI LC-MS m/z: 503.6 [MH+]
1H NMR (399.99 MHz, CD3OD) δ 8.79 (s, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.20 (s, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.81-6.74 (m, 2H), 4.75 (s, 2H), 4.16 (t, J=5.9 Hz, 3H), 3.36-3.31 (m, 2H), 3.28 (s, 3H), 2.94 (q, J=7.4 Hz, 2H), 2.14-2.04 (m, 2H), 1.42 (s, 9H), 1.30 (t, J=7.5 Hz, 3H), 1.16 (d, J=6.8 Hz, 6H).
APCI LC-MS m/z: 567.3 [MH+]
1H NMR (399.99 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.29 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.05 (t, J=7.7 Hz, 1H), 6.66 (s, 1H), 6.60 (d, J=7.6 Hz, 1H), 5.61 (d, J=7.8 Hz, 1H), 5.17 (t, J=5.4 Hz, 1H), 4.61 (d, J=5.4 Hz, 2H), 4.22 (quintet, J=6.7 Hz, 1H), 4.12 (t, J=6.2 Hz, 2H), 3.76 (quintet, J=6.8 Hz, 1H), 3.22 (s, 3H), 3.18 (t, J=7.3 Hz, 2H), 2.80 (q, J=7.5 Hz, 2H), 1.99-1.87 (m, 2H), 1.20 (t, J=7.4 Hz, 3H), 1.06-0.97 (m, 12H)
APCI LC-MS m/z: 552.3 [MH+]
Following examples 203-233 are prepared according to the procedure described in WO 02/092571
APCI LC-MS m/z: 465.4 [MH+]
1H NMR (399.99 MHz, DMSO-d6): δ 11.02 (1H, s); 8.88 (1H, s); 8.29 (1H, br s); 7.61 (1H, br s); 7.23 (1H, s); 7.18 (1H, d, J=7.4 Hz); 7.04 (1H, t, J=7.8 Hz); 6.65 (1H, s); 6.60 (1H, d, J=7.7 Hz); 5.19 (1H, br s); 4.61 (2H, s); 3.88 (3H, s); 3.37 (2H, s); 2.80 (2H, q, J=7.4 Hz); 1.99 (1H, dquintet, J=6.7, 3.4 Hz); 1.57 (2H, quintet, J=6.6 Hz); 1.20 (3H, t, J=7.5 Hz); 0.34 (2H, td, J=6.4, 4.2 Hz); 0.15 (2H, dt, J=6.1, 3.7 Hz).
APCI-LC/MS m/z: 465.4 [MH+]
APCI LC-MS m/z: 478.3 [MH+]
APCI LC-MS m/z: 493.3 [MH+]
APCI LC-MS m/z: 478.2 [MH+]
APCI LC-MS m/z: 495.3 [MH+]
APCI LC-MS m/z: 495.3 [MH+]
APCI LC-MS m/z: 463.3 [MH+]
APCI LC-MS m/z: 465.3 [MH+]
APCI LC-MS m/z: 465.3 [MH+]
APCI LC-MS m/z: 481.1 [MH+]
APCI LC-MS m/z: 477.6 [MH+]
APCI LC-MS m/z: 437.5 [MH+]
APCI LC-MS m/z: 437.2 [MH+]
APCI LC-MS m/z: 421.5 [MH+]
APCI LC-MS m/z: 421.5 [MH+]
APCI LC-MS m/z: 407.2 [MH+]
APCI LC-MS m/z: 450.2 [MH+]
APCI LC-MS m/z: 435.3 [MH+]
APCI LC-MS m/z: 434.3 [MH+]
APCI LC-MS m/z: 452.3 [MH+]
APCI LC-MS m/z: 467.3 [MH+]
APCI LC-MS m/z: 435.2 [MH+]
APCI LC-MS m/z: 568.5 [MH+]
APCI LC-MS m/z: 421.1 [MH+]
APCI LC-MS m/z: 507.6 [MH+]
APCI LC-MS m/z: 522.6 [MH+]
APCI LC-MS m/z: 550.5 [MH+]
APCI LC-MS m/z: 436.2 [MH+]
APCI LC-MS m/z: 406.5 [MH+]
To a mixture of 7-(3-chloropropoxy)-4-{[3-(hydroxymethyl)-2-methylphenyl]amino}-6-methoxyquinoline-3-carboxamide (0.050 g, 0.116 mmol) in aceton (4.0 ml) 1-methylpyrrolidine (0.040 g, 0.46 mmol) and sodium iodide was added and the mixture heated to 60° C. for 24 h. After cooling, aceton was evaporated, the reaction mixture was diluted with water (2.0 ml) and purified by preparative HPLC using a gradient of acetonitrile/water at a flow rate of 20 ml/min. Freeze drying of the mixture afforded the title compound.
1H NMR (400 MHz, CD3OD) δ 8.80 (1H, s,); 7.27 (1H, d, J=7.2 Hz); 7.22 (1H, s,); 7.14 (1H, t, J=7.6 Hz); 6.86 (1H, d, J=7.5 Hz); 6.81 (1H, s,); 4.70 (2H, s,); 4.26 (2H, t, J=5.2 Hz); 3.61 (7H, m,); 3.14 (3H, s,); 2.38 (2H, m,); 2.36 (3H, s,); 2.25 (3H, m,); 1.91 (3H, s,)
APCI-LC/MS m/z: 479.4 [M+]
A mixture of 4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-hydroxy-6-methoxyquinoline-3-carboxamide (112.6 mg, 0.31 mmole), prepared according to the procedure described in WO 02/092571, tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (99.7 mg, 0.36 mg) and cesium carbonate (158.5 mg, 0.49 mg) in dimethyl sulfoxide (2 ml) was heated at 70° C. for 10 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water dried over sodium sulfate, filtrated and concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane/methanol (9.6:0.4) to give the title compound as a yellow powder (39 mg, 23%).
1H NMR (399.99 MHz, DMSO-d6) δ 11.06 (1H, s), 8.87 (1H, s), 8.37 (1H, s), 7.69 (1H, s), 7.32 (1H, s), 7.17 (1H, s), 7.05 (1H, s), 6.65 (2H, s), 6.62 (2H, d), 5.16 (1H, s), 4.59 (2H, d), 3.69 (2H, mult), 3.19 (5H, s), 2.79 (2H, d), 2.02 (1H, s), 1.53 (2H, mult), 1.39 (9H, s), 1.19 (3H, t)
APCI-LC/MS m/z: 551.4 [MH+]
The title compound was prepared as described in example 235.
APCI-LC/MS m/z: 521.4 [MH+]
To a solution of 4-[(2-ethylphenyl)amino]-6-hydroxy-7-methoxyquinoline-3-carboxamide trifluoroacetate, prepared according to the procedure described in WO 02/092571, (77.2 mg, 0.17 mmole), triethylamine (0.5 ml, 3.6 mmole) in 1-methyl-2-pyrrolidinone was added propane-2-sulfonyl chloride (0.1 ml, 0.89 mmole). After stirring at room temperature for 48 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a white solid (24.6 mg, 32%).
1H NMR (399.99 MHz, DMSO-d6) δ 11.14 (1H, s), 9.01 (1H, s), 8.36 (1H, s), 7.70 (1H, s), 7.45 (1H, s), 7.34 (1H, dd), 7.20 (1H, s), 7.14 (2H, t), 7.07 (1H, td), 6.75 (1H, d), 3.94 (3H, s), 3.13 (1H, t), 2.70 (2H, q), 1.17 (6H, d), 1.16 (3H, t)
APCI-LC/MS m/z: 444.1 [MH+]
Tert-butyl 4-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinolin-7-yl)oxy]piperidine-1-carboxylate (32 mg, 0.06 mmole) described in example 235 was dissolved in dichloromethane (5 ml) cooled on ice and trifluoroacetic acid (5 ml) was added. After 1 h stirring at room temperature the solvent was evaporated. The residue was purified by preparative HPLC to give the title compound as a white powder (7 mg, 26%).
1H NMR (399.99 MHz, DMSO-d6) δ11.03 (1H, s), 8.84 (1H, s), 8.25 (1H, s), 7.56 (1H, s), 7.24 (1H, s), 7.16 (1H, d), 7.03 (1H, t), 6.62 (1H, s), 6.59 (1H, d), 4.63 (3H, s), 3.17 (3H, s), 2.93 (2H, q), 2.77 (2H, q), 2.60 (3H, t), 1.95 (2H, dd), 1.44 (2H, mult), 1.18 (3H, t)
APCI-LC/MS m/z: 451.2 [MH+]
The title compound was prepared as described in example 238
1H NMR (399.99 MHz, DMSO-d6) δ 10.83 (1H, s), 8.88 (1H, s), 8.29 (1H, br s), 7.62 (1H, br s), 7.32 (1H, dd), 7.25 (1H, s), 7.04 (2H, quintet), 6.67 (1H, s), 6.60 (1H, d), 3.87 (3H, s), 3.54 (1H, mult), 2.77 (4H, mult), 2.20 (2H, d), 1.48 (2H, s), 1.21 (5H, mult)
APCI-LC/MS m/z: 421.2 [MH+]
To a mixture of 4-[(2-ethylphenyl)amino]-6-hydroxy-7-methoxyquinoline-3-carboxamide, prepared according to the procedure described in WO 02/092571, (0.070 g, 0.2 mmol) and Cs2CO3 (0.100 g, 0.3 mmol) in NMP (3.0 ml) epibromohydrine (0.034 g, 0.25 mmol) was added and the mixture was heated at 90° C. for 0.5 h. After cooling cyclopropylamine (0.05 g 0.87 mmol) was added and the mixture heated at 70° C. over night. After cooling the reaction mixture was diluted with water (2.0 ml) and purified with preparative HPLC using a gradient of acetonitrile/water at a flow rate of 20 ml/min.
1H NMR (399.99 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.89 (s, 1H), 8.29 (s, 1H), 7.61 (s, 1H), 7.34-7.31 (m, 1H), 7.26 (s, 1H), 7.09-7.06 (m, 2H), 6.68-6.66 (m, 1H), 6.65 (s, 1H), 4.83 (d, 1H), 3.90 (s, 3H), 3.70 (q, 1H), 3.29-3.18 (m, 2H), 2.72 (q, 2H), 2.55-2.45 (m, 2H), 2.05-2.00 (m, 1H), 1.25 (t, 3H), 0.36-0.33 (m, 2H), 0.18-0.14 (m, 2H)
APCI-MS m/z: 451.5 [MH+]
The title compounds of examples 240-247 were prepared in analogous manner to example 239.
APCI LC-MS m/z: 464.1 [MH+]
APCI LC-MS m/z: 481.3 [MH+]
APCI LC-MS m/z: 480.3 [MH+]
APCI LC-MS m/z: 465.6 [MH+]
APCI LC-MS m/z: 465.6 [MH+]
APCI LC-MS m/z: 481.2 [MH+]
APCI LC-MS m/z: 451.5 [MH+]
APCI LC-MS m/z: 451.5 [MH+]
The title compound was prepared in an analogues way to example 236.
APCI-MS m/z: 408.4 [MH+]
The title compound was prepared as described in WO 02/092571 starting from 5-amino-4-methylisoquinolin-1(2H)-one and 4-chloro-6,7-diethoxyquinoline-3-carboxamide.
1H NMR (399.99 MHz, DMSO-d6) δ 11.28 (1H, s), 11.26 (1H, d), 8.85 (1H, s), 8.27 (1H, s), 8.11 (1H, d), 7.58 (1H, s), 7.33 (1H, t), 7.22 (1H, s), 7.11 (1H, d), 6.99 (1H, d), 6.64 (1H, s), 4.14 (2H, mult), 3.37 (3H, mult), 3.25 (2H, mult), 1.35 (3H, t), 0.92 (3H, t)
APCI-LC/MS m/z: 433.2 [MH+]
The title compound was prepared in an analogues manner as described in WO 02/092571 starting from 5-amino-4-methyl-3,4-dihydroisoquinolin-1(2H)-one and 4-chloro-6,7-diethoxyquinoline-3-carboxamide.
1H NMR (399.99 MHz, DMSO-d6) δ 11.28 (1H, s), 11.26 (1H, d), 8.85 (1H, s), 8.27 (1H, s), 8.12 (1H, d), 7.58 (1H, s), 7.33 (1H, t), 7.22 (1H, s), 7.11 (1H, d), 6.99 (1H, d), 6.64 (1H, s), 4.14 (1H, quintetd), 3.37 (3H, dq), 3.23 (4H, mult), 1.35 (3H, t), 0.92 (3H, t)
APCI-LC/MS m/z: 435.3 [MH+]
A mixture of 4-chloro-6,7-diethoxyquinoline-3-carboxamide (178 mg, 0.61 mmole, prepared according to WO 02/092571), tert-butyl 5-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (198 mg, 0.80 mmole), acetic acid (7 μl) in NMP (3 ml) was heated over night at 110 C. The reaction mixture was cooled, partitioned between ethyl acetate and sodium hydrogen carbonate solution.
The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane/methanol (10:0.5) to give the title compound as a light brown powder (214 mg, 69%).
1H NMR (399.99 MHz, DMSO-d6) δ 10.63 (1H, s), 8.84 (1H, s), 8.24 (1H, br s), 7.58 (1H, br s), 7.22 (1H, s), 7.06 (1H, t), 6.95 (1H, d), 6.65 (2H, s), 6.61 (2H, d), 4.53 (2H, s), 4.15 (2H, q), 3.59 (2H, t), 3.49 (2H, d), 2.70 (2H, t), 1.39 (9H, s), 1.36 (3H, t), 1.06 (3H, t).
APCI-LC/MS m/z: 507.2 [MH+]
The title compound was prepared in a similar way described in example 117
1H NMR (399.99 MHz, DMSO-d6) δ 10.62 (1H, s), 8.84 (1H, s), 8.24 (1H, s), 7.58 (1H, s), 7.22 (1H, s), 6.96 (1H, d), 6.80 (1H, d), 6.70 (1H, s), 6.52 (1H, d), 4.15 (2H, d), 3.85 (2H, s), 3.51 (2H, s), 2.98 (2H, s), 2.61 (2H, s), 1.37 (3H, s), 1.15 (3H, s)
APCI-LC/MS m/z: 407.2 [MH+]
The title compound was prepared analogous manner to example 1 using sodium acid.
APCI-LC/MS m/z: 490.3 [MH+]
The title compound was prepared according to the procedure described in WO 02/092571 using 5% Palladium-charcoal and the compound described in example 253.
APCI-LC/MS m/z: 464.3 [MH+]
The title compound was prepared in an analogous manner to example 255 using the compound described in example 185.
APCI-LC/MS m/z: 536.4 [MH+]
The title compound was prepared in an analogous manner to example 240
APCI-LC/MS m/z: 506.6 [MH+]
The title compound was prepared in an analogous manner to example 254
APCI-LC/MS m/z: 480.6 [MH+]
The title compound was prepared in an analogous manner to example 119 using compound 257 and acetic acid anhydride.
APCI-LC/MS m/z: 564.6 [MH+]
The title compounds of examples 259-261 were prepared in analogous manner to example 239.
APCI-LC/MS m/z: 480.6 [MH+]
The title compound was prepared from 4-{[2-ethyl-3-(1H-imidazol-1-ylmethyl)phenyl]amino}-6-hydroxy-7-methoxyquinoline-3-carboxamide, epibromohydrine and cyclopropylamine as described in example 239.
1H NMR (400 MHz, DMSO-d6) δ 11.00 (1H, s,); 8.90 (1H, s,); 8.32 (1H, s,); 7.72 (1H, s,); 7.64 (1H, s,); 7.26 (1H, s,); 7.11 (1H, s,); 7.05 (2H, t, J=7.8 Hz); 6.94 (1H, s,); 6.77 (1H, d, J=7.6 Hz); 6.62 (2H, mult,); 5.34 (2H, s,); 4.89 (1H, d, J=4.3 Hz); 3.90 (3H, s,); 3.72 (1H, s,); 2.83 (2H, q, J=7.2 Hz); 2.06 (1H, mult,); 0.35 (2H, mult,); 0.16 (1H, d, J=1.8 Hz)
APCI-LC/MS m/z: 531.6 [MH+]
APCI-LC/MS m/z: 550.7 [MH+]
Red-A1 (5.3 mg, 0.13 mmol) was added slowly to a mixture of 6,7-diethoxy-4-[(2-ethylphenyl)amino]quinoline-3-carboxamide (10 mg, 0.26 mmol) prepared according to the procedure described in WO 02/092571 in THF under argon and stirred at 50° C. for 18 hrs. The resulting mixture was washed with water and the organic layers dried over natriumsulfate, filtered and concentrated. The resulting crude product was purified on HPLC to give 1 mg (2.62 mmol, 10%) of the desired product.
APCI-MS: m/z 382.5 [MH+]
The title compound was prepared in an analogous manner to example 253
APCI-LC/MS m/z: 515.4 [MH+]
A mixture of 4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-hydroxy-6-methoxyquinoline-3-carboxamide,) prepared according to the procedure described in WO 02/092571, (32.2 mg, 0.09 mmol), 2-bromoethyl methyl ether (23.7 mg, 0.17 mmol), cesium carbonate (45.3 mg, 0.14 mmol) and NMP (1 ml) was heated at 60° C. for 4 h. After cooling the reaction mixture was diluted with water and purified by preparative HPLC to give 19 mg of the compound
APCI-LC/MS m/z: 426.3 [MH+].
1H NMR (399.99 MHz, DMSO-d6): δ 11.02 (1H, s); 8.89 (1H, d, J=5.2 Hz); 8.31 (1H, br s); 7.72 (1H, s); 7.64 (1H, br s); 7.26 (1H, s); 7.09 (1H, s); 7.06 (1H, d, J=7.7 Hz); 6.93 (1H, s); 6.87 (2H, d, J=7.5 Hz); 6.64 (1H, d, J=7.7 Hz); 6.57 (1H, s); 5.33 (2H, s); 4.22 (2H, t, J=4.3 Hz); 3.70 (2H, t, J=4.4 Hz); 3.31 (2H, br s); 3.18 (3H, br s); 2.86 (2H, q, J=7.4 Hz); 1.03 (3H, t, J=7.4 Hz).
APCI-LC/MS m/z: 476.4 [MH+]
In a schlenk were placed ethyl 6-bromo-4-{[2-ethyl-3-(1H-imidazol-1-ylmethyl)phenyl]amino}-7-methoxyquinoline-3-carboxylate (71.2 mg, 0.14 mmol) prepared in an analogues way to example 1, tris(dibenzylideneacetone) dipalladium(0) (12.1 mg, 0.01 mmol) bis(diphenylphospino)1.1naphtalene (28.3 mg, 0.05 mmol), cesium carbonate (83 mg, 0.26 mmol), ethyl amine (0.34 mg, 7.6 mmol) and toluene (10 ml) under argon. The vessel was sealed and heated at 75° C. for 48 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtrated and concentrated in vacuum. The residue was purified by preparative HPLC to give 24 mg of the desired product.
APCI-LC/MS m/z: 474.3 [MH+]
b) Potassium cyanide (5 mg) and the product from the first step were suspended in dry methanol (10 ml) saturated with ammonia. The schlenk was sealed and heated at 65° C. for 50 h. The reaction mixture was cooled and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a white solid (8 mg, 13%).
1H NMR (399.99 MHz, DMSO-d6): δ 10.65 (1H, s); 8.73 (1H, s); 8.23 (1H, br s); 7.68 (1H, s); 7.56 (1H, br s); 7.12 (1H, s); 7.06 (1H, s); 6.98 (2H, t, J=7.8 Hz); 6.92 (1H, s); 6.81 (1H, d, J=7.5 Hz); 6.47 (1H, d, J=7.8 Hz); 6.05 (1H, s); 5.29 (3H, m); 3.91 (3H, s); 2.84 (2H, d, J=7.2 Hz); 2.52 (1H, br s); 1.02 (3H, t, J=7.4 Hz); 0.75 (3H, t, J=7.1 Hz).
APCI-LC/MS m/z: 445.3 [MH+].
The title compounds of examples 266-268 were prepared in analogous manner to example 265.
1H NMR (399.99 MHz, DMSO-d6): δ 10.61 (1H, s); 8.75 (1H, s); 8.24 (1H, s); 7.57 (1H, s); 7.28 (1H, m); 7.16 (1H, s); 7.00 (2H, m); 6.50 (1H, m); 6.24 (1H, s); 5.24 (1H, t, J=5.8 Hz); 4.15 (1H, t, J=5.5 Hz); 3.94 (3H, s); 3.12 (6H, s); 2.73 (2H, q, J=7.5 Hz); 2.65 (2H, t, J=5.7 Hz); 1.26 (3H, t, J=7.5 Hz).
APCI-LC/MS m/z: 425.4 [MH+]
1H NMR (299.946 MHz, DMSO-d6) δ 10.58 (1H, s), 8.73 (1H, s), 8.28 (1H, br s), 7.62 (1H, br s), 7.24 (1H, mult), 7.13 (1H, s), 6.98 (2H, dquintet), 6.51 (1H, mult), 6.14 (1H, s), 5.42 (1H, t), 4.32 (1H, t), 3.91 (3H, s), 3.49 (2H, mult), 3.36 (2H, mult), 2.72 (2H, q), 2.53 (2H, q), 1.51 (2H, dd), 1.25 (3H, t), 1.08 (6H, t)
APCI-LC/MS m/z: 467.4 [MH+]
APCI-LC/MS m/z: 480.3 [MH+]
A mixture of ethyl 6-bromo-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxyquinoline-3-carboxylate (406 mg, 0.89 mmol), tert-butyl(chloro) dimethylsilane (0.95 g, 6.3 mmol), imidazole (1.9 g, 27.9 mmol) in DMF (3 ml) was stirred under argon at room temperature for 48 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate, filtrated and concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane/methanol (97:3) to give the title compound as grey powder (309 mg, 60%).
1H NMR (399.99 MHz, DMSO-d6): δ 10.24 (1H, s); 9.01 (1H, s); 7.54 (1H, s); 7.37 (1H, s); 7.29 (1H, d, J=7.4 Hz); 7.11 (1H, t, J=7.8 Hz); 6.81 (1H, d, J=7.8 Hz); 4.79 (2H, s); 4.31 (2H, q, J=7.1 Hz); 3.94 (3H, s); 2.76 (2H, q, J=7.5 Hz); 1.32 (3H, t, J=7.1 Hz); 1.15 (3H, t, J=7.5 Hz); 0.89 (9H, s, J=2.9 Hz); 0.09 (6H, s, J=3.1 Hz).
APCI-LC/MS m/z: 573.1, 574.2, 575.1 [M+], [M+1], [M+2]
A mixture of ethyl 6-bromo-4-{[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethylphenyl]amino}-7-methoxyquinoline-3-carboxylate (250 mg, 0.44 mmol) tris(dibenzylideneacetone) dipalladium(0) (21 mg, 0.02 mmol) bis(diphenylphospino)1.1naphtalene (48 mg, 0.08 mmol), cesium carbonate (230 mg, 0.71 mmol), N-(2-Aminoethyl)carbamic Acid ter-tbutylester (101 mg, 0.63 mmol) and toluene (8 ml) was placed in a schlenk under argon. The Schlenk vessel was sealed and the reaction mixture was heated at 85° C. over night. After cooling the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water dried over sodium sulphate, filtrated and concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane/methanol (100:3) to give the title compound as a yellow powder (205 mg, 73%).
1H NMR (399.988 MHz, CDCl3): δ 10.21 (1H, s); 9.03 (1H, s); 7.25 (1H, d, J=7.3 Hz); 7.21 (2H, s); 7.06 (1H, t, J=7.8 Hz); 6.76 (1H, d, J=7.8 Hz); 4.83 (2H, s); 4.64 (1H, br s); 4.54 (1H, br s); 4.43 (2H, q, J=7.1 Hz); 3.97 (3H, s); 3.00-2.83 (5H, m); 2.83-2.61 (4H, m); 1.48-1.43 (13H, m); 1.31 (3H, t, J=7.5 Hz); 0.98 (9H, s, J=2.8 Hz); 0.16 (6H, s, J=3.0 Hz);
APCI-LC/MS m/z: 653.3 [MH+]
In a high pressure flask were placed ethyl 6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-4-{[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethylphenyl]amino}-7-methoxyquinoline-3-carboxylate (148 mg, 0.23 mmol), potassium cyanide (7 mg, 0.1 mmol) and dry methanol (10 ml) saturated with ammonia. The flask was sealed and heated at 55° C. for 96 hours. After cooling the reaction mixture was concentrated in vacuum and the residue was stirred with tetrabutylammonium fluoride hydrate (150 mg, 0.57 mmol) in tetrahydrofuran (5 ml) for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate, filtered and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a light yellow powder (52 mg, 44%).
The title compound was prepared in an analogous manner to example 266 using ethyl 6-bromo-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxylate and (3-Amino-propyl)-cyclopropyl-carbamic acid tert-butyl ester. Removal of the carbamaic acid tert-butyl ester derivative was performed with TFA according to example 117.
1H NMR (399.99 MHz, DMSO-d6): δ 10.69 (1H, s); 8.73 (1H, s); 8.21 (1H, br s); 7.53 (1H, br s); 7.16-7.07 (2H, m); 6.96 (1H, t, J=7.7 Hz); 6.70 (1H, t, J=5.3 Hz); 6.45 (1H, d, J=7.8 Hz); 6.10 (1H, s); 5.37 (1H, t, J=4.8 Hz); 5.12 (1H, t, J=5.3 Hz); 4.59 (2H, d, J=5.3 Hz); 3.90 (3H, s); 2.81 (4H, m); 1.36 (9H, s); 1.27 (2H, s); 1.21 (3H, t, J=7.4 Hz);
APCI-LC/MS m/z: 510.3 [MH+]
1H NMR (399.99 MHz, DMSO-d6): δ 10.12 (1H, s); 9.01 (1H, s); 7.67 (1H, s); 7.44-7.38 (2H, m); 7.25 (1H, t, J=7.3 Hz); 7.16 (1H, t, J=12.5 Hz); 6.93 (1H, d, J=7.7 Hz); 4.27 (2H, q, J=7.1 Hz); 3.98 (3H, s); 2.71 (2H, q, J=7.5 Hz); 1.32 (3H, t, J=7.1 Hz); 1.21 (3H, t, J=7.5 Hz).
APCI-LC/MS m/z: 429.1, 431.1 [MH+]
A mixture of 3-bromopropan-1-ol (4.5 g, 32.4 mmol), cyclopropylamine (12.4 g, 216.5 mmol) and tetrahydrofuranne (40 ml) was heated at 60° C. for 7 h. The reaction was cooled to room temperature, concentrated in vacuum, diluted with a mixture of tetrahydrofuranne (20 ml)/triethylamine (10 ml) and again concentrated in vacuum.
To the residue was added di-tert-butyl dicarbonate (7.2 g, 33.0 mmol), tetrahydrofuranne (35 ml) and triethylamine (5 ml). The suspension was heated at 50° C. over night then cooled to room temperature, diluted with ether, filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane/methanol (100:3) to give the title compound as colourless oil (3.1 g, 44%).
1H NMR (299.944 MHz, CDCl3): δ 3.56 (2H, quintet, J=5.7 Hz); 3.38 (2H, t, J=6.1 Hz); 2.45 (1H, ddd, J=10.8 7.0 3.9 Hz); 1.70 (2H, quintet, J=8.1 Hz); 1.46 (9H, s); 0.77-0.68 (2H, m); 0.62-0.56 (2H, m).
To an is cooled solution of tert-butyl cyclopropyl(3-hydroxypropyl)carbamate (1.6 g, 7.4 mmol), triphenylphosphine (2.5 g, 9.7 mmol) and tetrahydrofuran (25 ml) was added carbon tetrabromide (3.2 g, 9.7 mmol) under 20 minutes. The mixture was stirred for 30 minutes at 0° C. and then allowed to reach room temperature. After 3 hours at ambient temperature the reaction mixture was diluted with diethyl ether and the precipitate was removed by filtration. The filtrate was concentrated in vacuum and the residue was purified by flash chromatography eluting with dichloromethane/heptane (2:1) to give the title compound as colourless oil (1.2 g, 59%).
1H NMR (399.988 MHz, CDCl3): δ 3.39 (2H, t, J=6.7 Hz); 3.33 (2H, t, J=7.1 Hz); 2.49 (1H, septet, J=5.1 Hz); 2.11 (2H, quintet, J=6.9 Hz); 1.45 (9H, s); 0.75 (2H, td, J=7.1 5.1 Hz); 0.60 (2H, m).
A mixture of tert-butyl 3-bromopropyl(cyclopropyl)carbamate (1.1 g, 3.9 mmol), sodium azide (0.33 g, 5.1 mmol) and 1-methyl-2-pyrrolidinone (7 ml) was stirred at ambient temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water dried over sodium sulphate, filtrated and concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane to give the title compound as colourless oil (0.92 g, 96%).
1H NMR (399.988 MHz, CDCl3): δ 3.29 (4H, q, J=13.1 Hz); 2.48 (1H, septet, J=5.7 Hz); 1.82 (2H, quintet, J=7.0 Hz); 1.45 (9H, s); 0.74 (2H, m); 0.59 (2H, m).
A mixture of tert-butyl 3-azidopropyl(cyclopropyl)carbamate (0.9 g, 3.7 mmol), 5% palladium on carbon (60 mg) in ethanol (15 ml) and ethyl acetate (15 ml) was stirred vigorously under 1 atmosphere of hydrogen for 19 h. The hydrogen atmosphere was changed twice under the period of reaction time. The catalyst was filtered off and the filtrate was concentrated to give the title compound as colourless oil (0.79 g, 98%).
1H NMR (399.988 MHz, CDCl3): δ 3.27 (2H, t, J=6.9 Hz); 2.70 (2H, t, J=6.8 Hz); 2.45 (1H, dt, J=6.9 3.4 Hz); 1.76 (2H, s); 1.69 (2H, quintet, J=6.9 Hz); 1.44 (9H, s); 0.72 (2H, dd, J=12.2 6.9 Hz); 0.57 (2H, m).
The title compound was prepared in an analogous manner to example 266 using ethyl 6-bromo-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxylate and (3-Amino-propyl)-cyclopropyl-carbamic acid tert-butyl ester. Removal of the carbamaic acid tert-butyl ester derivative was performed with TFA according to example 117.
1H NMR (399.99 MHz, DMSO-d6): δ 10.57 (1H, s); 8.73 (1H, s); 8.22 (1H, br s); 7.55 (1H, br s); 7.27 (1H, m); 7.13 (1H, s); 6.99 (2H, m); 6.50 (1H, m); 6.14 (1H, s); 5.65 (1H, t, J=5.5 Hz); 3.92 (3H, s); 2.74 (2H, q, J=7.4 Hz); 2.58 (2H, q, J=6.4 Hz); 2.40 (2H, t, J=6.2 Hz); 2.00-1.89 (2H, m); 1.35-1.22 (5H, m); 0.33 (2H, m); 0.17 (2H, m).
APCI-LC/MS m/z: 434.5 [MH+]
The title compounds of Examples 271-274 were prepared in analogous manner to the methods described above.
APCI LC-MS m/z: 364.1 [MH+]
APCI LC-MS m/z: 372.3 [MH+]
APCI LC-MS m/z: 384.1 [MH+]
APCI LC-MS m/z: 398.1 [MH+]
The JAK3 kinase assay utilizes a fusion protein (Jak3 kinase domain fused to Glutathione S-transferase, GST) coexpressed in E. Coli with GroEL/S, and purified by affinity chromatography on Glutathione Sepharose. The enzyme is diluted in 10 mM Tris-HCl, 150 mM NaCl, 5% mannitol, 2 mM 2-mercaptoethanol and 30% glycerol. The substrate in the kinase reaction is a biotinylated peptide of the autophosphorylation site of JAK3 (biotin-LPDKDYYVVREPG) used at 2 μM. Assay conditions are as follows: JAK3, compound and substrate are incubated in 25 mM Trizma base, 5 mM MgCl2, 5 mM MnCl2, 0.05% TritonX-100 and 2 μM ATP for 45 min at RT. Reaction volume is 20 μM. Stopsolution is added for a final concentration of 100 μM EDTA. Finally 0.065 mg/ml PT66-K and 10.42 μM SA-XL665 are added in 50 mM Hepes, 0.5 M KF and 0.1% BSA. The plate is read in a Discovery instrument after 60 min incubation.
The compounds of the examples have an IC50 less than 10 μM
| Number | Date | Country | Kind |
|---|---|---|---|
| 0400284-6 | Feb 2004 | SE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/SE2005/000156 | 2/7/2005 | WO | 00 | 8/10/2006 |
