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HK1078849B - Pyridine and pyrimidine derivatives and their use as inhibitors of cytokine mediated disease - Google Patents

Pyridine and pyrimidine derivatives and their use as inhibitors of cytokine mediated disease Download PDF

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Publication number
HK1078849B
HK1078849B HK05110610.4A HK05110610A HK1078849B HK 1078849 B HK1078849 B HK 1078849B HK 05110610 A HK05110610 A HK 05110610A HK 1078849 B HK1078849 B HK 1078849B
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Hong Kong
Prior art keywords
pyrimidinyl
alkyl
formula
group
ring
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HK05110610.4A
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Chinese (zh)
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HK1078849A1 (en
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Graham Cumming John
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Astrazeneca Ab
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Priority claimed from GBGB9906566.6A external-priority patent/GB9906566D0/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of HK1078849A1 publication Critical patent/HK1078849A1/en
Publication of HK1078849B publication Critical patent/HK1078849B/en

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Pyridine and pyrimidine derivatives and their use as inhibitors of cytokines mediating diseases
This application is a divisional application of an application entitled "pyridine and pyrimidine derivatives and their use as inhibitors of cytokines that mediate diseases" filed on international filing date No. 00807798.3, 3/17/2000 (international filing number PCT/GB 00/01006).
Technical Field
The present invention relates to certain amide derivatives and their use as inhibitors of cytokines that mediate diseases. The invention also relates to processes for the preparation of the novel amide derivatives, pharmaceutical compositions containing them and their use in methods of treatment, e.g. by inhibition of disease-mediating cytokines.
Background
The amide derivatives disclosed in the present invention are inhibitors of cytokine production such as tumor necrosis factor (hereinafter TNF), e.g., TNF α, and various members of the interleukin (hereinafter IL) family, e.g., IL-1, IL-6, and IL-8 production. Thus, the compounds of the present invention are useful in the treatment of diseases or medical conditions in which overproduction of cytokines occurs, for example, overproduction of TNF α or IL-1. Cytokines are known to be produced by a wide variety of cells such as monocytes and macrophages and they elicit a variety of physiological effects which are believed to be important in diseases or medical conditions such as inflammation and immunomodulation. For example, TNF α and IL-1 are involved in the amplification of cellular signaling cascades that are thought to be causative of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is also known that TNF α is preferentially produced in certain cell systems and mediates the production of other cytokines such as IL-1.
Abnormal levels of cytokines are also involved, for example, in the production of physiologically active eicosanoids such as prostaglandins and leukotrienes, in the stimulation of the release of proteolytic enzymes such as collagenase, in the activation of the immune system, for example by stimulation of T-helper cells, in the activation of osteoclast activity leading to calcium absorption, in the stimulation of proteoglycan release from, for example, cartilage, in the stimulation of cell proliferation and leading to angiogenesis.
Cytokines are also believed to be involved in the development and progression of disease states such as inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, crohn's disease and gastritis), skin diseases (especially psoriasis, eczema and dermatitis) and respiratory diseases (especially asthma, bronchitis, allergic rhinitis, adult respiratory distress syndrome and chronic obstructive pulmonary disease), and in a variety of cardiovascular and cerebrovascular diseases such as congestive heart failure, myocardial infarction, atherosclerotic plaque formation, hypertension, platelet aggregation, angina, stroke, alzheimer's disease, reperfusion injury, vascular injury including restenosis and peripheral vascular disease and for example a variety of bone metabolic diseases such as osteoporosis (including senile and post-menopausal osteoporosis), Paget's disease, bone metastasis, hypercalcemia, hyperparathyroidism, bone sclerosis, osteoporosis, and periodontitis, as well as abnormal changes in bone metabolism that may be accompanied by the development and progression of rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating complications of some bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in some complications of central nervous system surgery or injury such as neurotrauma and ischemic stroke. Excessive cytokine production has also been implicated in mediating or exacerbating the development of diseases including cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, cachexia found in certain chronic cases such as malignant disease and Acquired Immune Deficiency Syndrome (AIDS), tumor invasion and tumor metastasis and multiple sclerosis.
Evidence for the major role played by TNF α in the amplification of the cell signaling cascade leading to rheumatoid arthritis is provided by efficacy in clinical studies of TNF α antibodies: ( The Lancet，1994， 3441125 andBritish Journal of Rheumatology，1995， 34，334)。
thus, cytokines such as TNF α and IL-1 are believed to be important mediators of a considerable range of diseases and medical conditions. Therefore, it is expected that inhibition of the production and/or action of these cytokines would be advantageous for the prevention, control or treatment of such diseases and medical conditions.
It is not intended to suggest that the compounds disclosed in this invention have pharmacological activity through action on a single biological process only, and that the compounds are thought to inhibit the action of cytokines through inhibition of the enzyme p38 kinase. p38 kinase, otherwise known as cytokine inhibitory binding protein (hereinafter CSBP) and reactivation kinase (hereinafter RK), is a member of the enzyme family of mitogen-activated protein (hereinafter MAP) kinases, which are known to be activated by physiological stress, e.g. by ionizing radiation, cytotoxic drugs and toxins such as endotoxins like bacterial lipopolysaccharides and by a variety of drugs such as cytokines like TNF α and IL-1. P38 kinase is known to phosphorylate certain intracellular proteins involved in a cascade of enzymatic steps, which leads to the biosynthesis and secretion of cytokines such as TNF α and IL-1. G J Hanson inExpert Opinions on Therapeutic Patents，1997， 7729-733 known p38 kinase inhibitors have been reviewed. P38 kinase is known to exist as isoforms identified as p38 α and p38 β.
The compounds disclosed in the present invention are inhibitors of the production of cytokines such as TNF, particularly TNF α, and various interleukins, particularly IL-1.
J.Medicinal Chemistry，1995， 383780-3788 discloses certain 4-anilinopyridino [4, 3-d-]Pyrimidines are inhibitors of the tyrosine kinase activity of epidermal growth factor receptors. One of the compounds disclosed is 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d]A pyrimidine.
Disclosure of Invention
Accordingly, the present invention provides a bicyclic compound of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof:
wherein:
g is N, CH or C (CN);
ring X is a 5-or 6-membered fused heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulphur and nitrogen;
m is 0, 1 or 2;
R1is hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, aminosulfonyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, -O- (C)1-3Alkyl) -O-, C1-6Alkyl S (O)n- (wherein N is 0-2), N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group, C1-6Alkoxycarbonyl, N-C1-6Alkylcarbamoyl, N- (C)1-6Alkyl radical)2Carbamoyl radical, C2-6Alkanoyl radical, C1-6Alkanoyloxy radical, C1-6Alkanoylamino, N-C1-6Alkylaminosulfonyl, N- (C)1-6Alkyl radical)2Aminosulfonyl radical, C1-6Alkylsulfonylamino group, C1-6alkylsulfonyl-N- (C)1-6Alkyl) amino, or R1Is of formula (IA):
A-(CH2)p-B- (IA)
wherein A is halogen, hydroxy, C1-6Alkoxy radical, C1-6Alkyl S (O)n- (wherein N is 0-2), cyano, amino, N-C1-6An alkylamino group, N, or a substituted alkylamino group,N-(C1-6alkyl radical)2Amino, carboxyl, C1-6Alkoxycarbonyl, carbamoyl, N-C1-6Alkylcarbamoyl or N, N- (C)1-6Alkyl radical)2Carbamoyl, p is 1-6, B is a bond, oxy, imino, N- (C)1-6Alkyl) imino or-C (O) NH-, with the proviso that if B is not a bond or-C (O) NH-, p is equal to or greater than 2, or R1Is of formula (IB):
D-E- (IB)
wherein D is aryl, heteroaryl or heterocyclyl, E is a bond, C1-6Alkylene radical, C1-6Alkylene oxide, imide, N- (C)1-6Alkyl) imino, C1-6Alkylideneimino, N- (C)1-6Alkyl) -C1-6Alkylideneimino, C1-6Alkylene oxy-C1-6Alkylene radical, C1-6alkylideneimino-C1-6Alkylene, N- (C)1-6Alkyl) -C1-6alkylideneimino-C1-6Alkylene, -C (O) NH-, -SO2NH-、NHSO2-or C2-6An alkanoylimino group, and R1Any aryl, heteroaryl or heterocyclyl group in (a) may optionally be substituted by one or more groups selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, carbamoyl, N-C1-6Alkylcarbamoyl, N- (C)1-6Alkyl radical)2Carbamoyl radical, C2-6Alkanoyl, amino, N-C1-6Alkylamino and N, N- (C)1-6Alkyl radical)2The substituent of the amino group is substituted,
R1any of the heterocyclic groups in (a) may be optionally substituted with one or two oxo or thioxo substituents,
any containing CH bound to two carbon atoms2Or CH bound to a carbon atom3R of the above definition1At each of said CH2Or CH3Optionally carrying a group selected from hydroxy, amino, C1-6Alkoxy, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Substituents for amino and heterocyclic groups;
R2is hydrogen, halogen, C1-6Alkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
R3is hydrogen, halogen, C1-6Alkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
R4is hydrogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, amino, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C2-6Alkoxy, N-C1-6Alkylamino radical C2-6Alkoxy, N- (C)1-6Alkyl radical)2Amino group C2-6Alkoxy or C3-7A cycloalkyl group,
or R4Is of formula (IC):
-K-J (IC)
wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxo, imino, N- (C)1-6Alkyl) imino, oxy C1-6Alkylene, imino C1-6Alkylene, N- (C)1-6Alkyl) imino C1-6Alkylene, -NHC (O) -, -SO2NH-、NHSO2-or-NHC (O) -C1-6An alkylene-,
and R is4Any aryl, heteroaryl or heterocyclyl in (a) may optionally be substituted by one or more groups selected from hydroxy, halogen, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, aminosulfonyl, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, -O- (C)1-3Alkyl) -O-, C1-6Alkyl S (O)n- (wherein N is 0-2), N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group, C1-6Alkoxycarbonyl, N-C1-6Alkylcarbamoyl, N- (C)1-6Alkyl radical)2Carbamoyl radical, C2-6Alkanoyl radical, C1-6Alkanoyloxy radical, C1-6Alkanoylamino, N-C1-6Alkylaminosulfonyl, N- (C)1-6Alkyl radical)2Aminosulfonyl radical, C1-6Alkylsulfonylamino and C1-6alkylsulfonyl-N- (C)1-6Alkyl) amino group, or R4Any aryl, heteroaryl or heterocyclyl group in (a) may be optionally substituted by one or more groups of formula (IA'):
-B1-(CH2)p-A1 (IA’)
wherein A is1Is halogen, hydroxy, C1-6Alkoxy, cyano, amino, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino, carboxyl, C1-6Alkoxycarbonyl, carbamoyl, N-C1-6Alkylcarbamoyl or N, N- (C)1-6Alkyl radical)2Carbamoyl, p is 1-6, B1Is a bond, oxy, imino, N- (C)1-6Alkyl) imino or-NHC (O) -, with the proviso that if B is1Is not a bond or-NHC (O) -, p is equal to or greater than 2,
or R4Any aryl, heteroaryl or heterocyclyl group in (a) may be optionally substituted by one or more groups of formula (IB'):
-E1-D1 (IB’)
wherein D1Is aryl, heteroaryl or heterocyclyl, E1Is a bond, C1-6Alkylene, oxy C1-6Alkylene, oxy, imino, N- (C)1-6Alkyl) imino, imino C1-6Alkylene, N- (C)1-6Alkyl) -imino C1-6Alkylene radical, C1-6Alkylene-oxy C1-6Alkylene radical, C1-6Alkylene radical-imino radical C1-6Alkylene radical, C1-6alkylene-N- (C)1-6Alkyl) -imino C1-6Alkylene, -NHC (O) -, NHSO2、-SO2NH-or-NHC (O) -C1-6An alkylene-,
and R is4Any aryl, heteroaryl or heterocyclyl group in the above substituents may optionally be substituted by one or more groups selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, carbamoyl, N-C1-6Alkylcarbamoyl, N- (C)1-6Alkyl radical)2Carbamoyl radical, C2-6Alkanoyl, amino, N-C1-6Alkylamino and N, N- (C)1-6Alkyl radical)2The substituent of the amino group is substituted,
R4any of C in3-7The cycloalkyl or heterocyclyl group may be optionally substituted by one or two oxo or thioxo substituents,
any containing CH bound to two carbon atoms2Or CH bound to a carbon atom3R of the above definition4At each of said CH2Or CH3Optionally carrying a group selected from hydroxy, amino, C1-6Alkoxy, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Substituents for amino and heterocyclic groups;
R5is hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, hydroxy, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, N-C1-6Alkylamino or N, N- (C)1-6Alkyl radical)2An amino group;
q is 0, 1, 2, 3 or 4;
with the proviso that 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine is excluded.
It is clear that: the bicyclic ring in the compound of formula (I) is represented by a bicyclic ring having a hydrogen atom bonded to a carbon atom between the N atom and the G atomThe intention is to indicate that this position is unsubstituted. Thus, it is to be understood that the hydrogen atom may not be replaced by R1And (4) substituent substitution. But it should also be clear that: when G is a CH group, the CH group may carry any R1And (4) a substituent.
It will be appreciated that since certain compounds of formula (I) as defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the present invention includes within its definition any such optically active or racemic form which has cytokine inhibitory properties, particularly TNF. The synthesis of the optically active form can be carried out according to standard techniques of organic chemistry well known in the art, such as by synthesis using optically active starting materials or by resolution of the racemic form. Similarly, its inhibitory properties against TNF can be assessed using standard laboratory techniques referenced below.
For the avoidance of doubt, it should be clear that: when for example R1Is a group of formula (IB):
D-E- (IB)
and the linking group E is, for example, C1-6Alkyleneoxy radicals (e.g. -CH)2CH2O-) is CH which is bound to D and to the O atom of the bicyclic ring of formula (I)2And (4) a base. Similarly, when for example R4When it is a group of formula (IB'):
-E1-D1 (IB’)
and a linking group E1For example imino group C1-6Alkylene (e.g. -NHCH)2CH2-) it is with D1And CH linked to NH attached to the bicyclic ring in formula (I)2And (4) a base. Similar rules apply to other bidentate linking groups.
In this specification, the term "alkyl" includes both straight and branched chain alkyl groups, but only straight chain groups are specified for individual alkyl groups such as "propyl". For example, "C1-6Alkyl "includes propyl, isopropyl and tert-butyl. But instead of the other end of the tubeA straight chain group is specified for individual alkyl groups such as "propyl" and a branched chain group is specified for individual branched chain alkyl groups such as "isopropyl". Similar rules apply to other groups, e.g. "amino C2-6Alkoxy "includes 2-aminoethoxy, 2-aminopropoxy and 3-amino-2-methylpropoxy. The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to phenyl or naphthyl. When R is4Comprising D1And D1When aryl, the "aryl" refers to phenyl, indenyl, 2, 3-indanyl, naphthyl, tetrahydronaphthyl or fluorenyl.
Unless otherwise specified, the term "heteroaryl" refers to an unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic 5-14 membered ring having 1-5 ring heteroatoms selected from nitrogen, oxygen and sulfur, wherein-CH2Optionally substituted by-C (O) -and the ring nitrogen atom optionally carries C1-6The alkyl groups or the ring nitrogen and/or sulfur atoms may optionally be oxidized to form N-oxides and/or S-oxides. Examples of "heteroaryl" include thienyl, furyl, pyranyl, pyrrolyl, pyrazolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl-N-oxide, oxopyridyl, oxoquinolinyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolinyl, N-methyloxoquinolinyl, isoquinolinyl, quinazolinyl, thioxanthyl, quinoxalinyl, indazolyl, benzofuranyl, cinnolinyl, carbazolyl, dibenzofuranyl, dibenzothienyl, S-dioxodibenzothienyl, dibenzo-1, 4-dioxinyl, Phenoxathiinyl, phenoxazinyl, dibenzithinyl, phenothiazinyl, thianthrenyl, benzofuropyridyl, thiazyl, and thiazyl, Pyridoindolyl, acridinyl and phenanthridinyl. When R is4Comprising D1And D1When it is heteroaryl, the term "heteroaryl" preferably means furyl, thienyl, pyrrolyl, pyrrolinyl, oxazolyl, isoxazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, thiazolyl, isothiazolyl, pyridyl, pyridazineA group selected from the group consisting of a phenyl group, a pyrimidinyl group, a pyrazinyl group, a benzofuranyl group, an indolyl group, a benzothiophenyl group, a benzoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, an indazolyl group, a benzofurazanyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalinyl group, a diazonaphthyl group, a carbazolyl group, a dibenzofuranyl group, a dibenzothiophenyl group or a xanthenyl group or a benzoderivative such as a 2, 3-dihydrobenzofuranyl group, a 2, 3-dihydrobenzothiophenyl group, an indolinyl group, an isoindolinyl group, a chromanyl group and an isochromanyl group, more preferably the "heteroaryl" means a furanyl group, a thienyl group, a 3-pyrrolinyl group, an isoxazolyl group, a thiazolyl group, a pyridyl group, a benzothiophenyl group, a benzofurazanyl group, a quinolyl group, a carbazolyl group.
Ring X is a 5-or 6-membered fused heteroaryl ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen. Suitably ring X is unsaturated or partially unsaturated, wherein-CH2Optionally substituted by-C (O) -and the ring nitrogen atom optionally carries C1-6The alkyl groups or the ring nitrogen and/or sulfur atoms may optionally be oxidized to form N-oxides and/or S-oxides. Examples of suitable diradicals of fused heteroaryl rings include thiophenediyl, furandiyl, imidazoldiyl, pyrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl, 1, 2, 3-oxadiazoldyl, 1, 2, 3-triazolediyl, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazindiyl, and 1, 3, 4-triazinediyl. Examples of suitable bicyclic monoradicals of formula (I) wherein Ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring include furopyridinyl, furopyrimidinyl, thienopyridinyl, thienopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrroliopyrimidyl, pyrrolinopyrimidinyl, oxopyrrolopyridinyl, oxopyrrolopyrimidinyl, oxazolopyrimidinyl, oxooxazolopyrimidinyl, isoxazolopyridinyl, isoxazolopyrimidinyl, thiazolopyridinyl, thiazolopyrimidinyl, oxothiazolopyridinyl, oxothiazolopyrimidinylIsothiazolopyridyl, isothiazolopyrimidinyl, imidazopyridyl, imidazolinopyridyl, oxoimidazolinopyridyl, purinyl, imidazolinopyrimidinyl, oxoimidazolinopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, oxopyrazolopyrimidinyl, dinitrogen naphthyl, pyridopyrimidinyl, pyrimidopyrimidinyl and pteridinyl.
Unless otherwise specified, the term "heterocyclyl" refers to a fully saturated mono-or di-3-14 membered ring having up to 5 heteroatoms selected from nitrogen, oxygen and sulfur rings, wherein-CH2Optionally substituted by-C (O) -or the ring nitrogen atom optionally carries C1-6An alkyl group. Examples of such heterocyclyl groups include morpholinyl, N-methylmorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, N-methylpiperidinyl, piperazinyl, and quinuclidinyl. When R is4Comprising D1And D1When it is a heterocyclic group, the "heterocyclic group" preferably means an oxirane group, oxetanyl group, azetidinyl group, tetrahydrofuryl group, tetrahydropyranyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, 1-dioxoisothiazolidinyl group, morpholinyl group, tetrahydro-1, 4-thiazinyl group, 1-dioxotetrahydro-1, 4-thiazinyl group, piperidinyl group, homopiperidinyl group, piperazinyl group or homopiperazinyl group, preferably azetidin-1-yl group, pyrrolidin-2-yl group, 1-dioxoisothiazolidin-2-yl group, morpholino group, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl group, piperidin-3-yl group, piperidin-4-yl group, piperidino-1, 1-dioxotetrahydro-4H-1, 4-thiazin, Homopiperidin-1-yl, piperidinyl, piperazin-1-yl, or homopiperazin-1-yl. Suitable radicals for this type which bear 1 or 2 oxo or thioxo substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2, 5-dioxopyrrolidinyl, 2, 5-dioxoimidazolidinyl or 2, 6-dioxopiperidinyl.
When optional substituents are selected from "one or more" groups, it is to be understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. Generally canThere are 1, 2 or 3 such optional substituents. For example, when the optional substituents are selected from one or more of halogen, C1-6Alkoxy and C1-6Examples of substituents that may be combined in the case of alkyl groups include 1) bromo, 2) two chloro, 3) methoxy, ethoxy and propoxy substituents, 4) fluoro and methoxy, 5) methoxy, methyl and ethyl, and 6) chloro, methoxy and ethyl.
C1-4Examples of alkyl groups include methyl, ethyl and isopropyl. C1-6Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, n-and t-butoxycarbonyl. C1-6Examples of alkoxy groups include C1-4Alkoxy and C2-4Alkoxy groups, including methoxy, ethoxy, propoxy, and tert-butoxy. C1-6Examples of alkanoylamino groups include carboxamido, acetylamino, and propionamido. C wherein n is 0-21-6Alkyl S (O)nExamples of (b) include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl. C2-6Examples of alkanoyl groups include propionyl and acetyl. N-C1-6Examples of alkylamino groups include N-methylamino and N-ethylamino. N, N- (C)1-6Alkyl radical)2Examples of the amino group include an N, N-dimethylamino group, an N, N-diethylamino group and an N-ethyl-N-methylamino group. C1-6Alkoxy radical C2-6Examples of alkoxy groups include methoxyethoxy and propoxybutoxy. N- (C)1-6Alkyl) amino C2-6Examples of alkoxy groups include 3- (N-methylamino) propoxy and 4- (N-ethylamino) butoxy. N, N- (C)1-6Alkyl radical)2Amino group C2-6Examples of alkoxy groups include 2- (N, N-dimethylamino) ethoxy and 3- (N-methyl-N-ethylamino) propoxy. C3-7Examples of cycloalkyl groups include cyclopropyl and cyclohexyl. C2-6Examples of alkenyl groups include vinyl, allyl, and 1-propenyl. C2-6Examples of alkynyl groups include ethynyl, 1-propynyl and 2-propynyl. Hydroxy radical C2-6Examples of alkoxy groups include 2-hydroxyethoxy and 2-hydroxypropoxy. C1-6Examples of the alkylsulfonamide group include a methanesulfonamide group and an ethanesulfonamideAnd (4) a base. C1-6alkylsulfonyl-N- (C)1-6Alkyl) amino groups include N-ethylmethanesulfonamide group and N-butylethanesulfonamide group. N- (C)1-6Alkyl) aminosulfonyl includes N-methylaminosulfonyl and N-ethylaminosulfonyl. N, N- (C)1-6Alkyl radical)2Examples of the aminosulfonyl group include an N, N-dimethylaminosulfonyl group and an N-methyl-N-ethylaminosulfonyl group. N- (C)1-6Alkyl) carbamoyl group include N-methylcarbamoyl and N-ethylcarbamoyl. N, N- (C)1-6Alkyl radical)2Examples of the carbamoyl group include an N, N-dimethylcarbamoyl group and an N-methyl-N-ethylcarbamoyl group. C1-6Examples of alkanoyloxy groups include propionyloxy, acetoxy, and formyloxy. -O-C1-3Examples of alkyl-O-include-oxyethoxy-and-oxymethoxy- (i.e. a bidentate substituent, which is attached to the ring at two adjacent positions).
At R1And R4Linking group B, E, B within definition1、E1And K, examples of generic terms include the following. C1-6Examples of alkylene groups include-CH2CH2-and-CH2CH(CH3)CH2-。C1-6Examples of the alkyleneoxy group include-CH2CH2O-and-CH2CH(CH3)CH2O-。N-(C1-6Examples of alkyl) imino groups include-N- (Me) -and-N- (Me)iPr)-。C1-6Examples of alkylideneimino include-CH2CH2NH-and-CH2CH(CH3)CH2NH-。N-(C1-6Alkyl) -C1-6Examples of alkylideneimino include-CH2CH2N (Me) -and-CH2CH(CH3)CH2N(iPr)-。C2-6Examples of alkanoylimino groups include-CH2CH2C (O) NH-and-CH2CH(CH3)CH2C (O) NH-. Oxy radical C1-6Examples of alkylene groups include-OCH2CH2-and-OCH2CH(CH3)CH2-. Imino radical C1-6Examples of alkylene groups include-NHCH2CH2-and-NHCH2CH(CH3)CH2-。N-(C1-6Alkyl) imino C1-6Examples of alkylene groups include-N (Me) CH2CH2-and-N: (iPr)CH2CH(CH3)CH2-。-NHC(O)C1-6Examples of alkylene-include-NHC (O) CH2CH2-and-NHC (O) CH2CH(CH3)CH2-。
As defined above, when containing CH attached to two carbon atoms2Or CH bound to a carbon atom3R of any of the above definitions1Or R4In each of said CH2Or CH3Optionally carrying a group selected from hydroxy, amino, C1-6Alkoxy, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2When substituents are present on amino and heterocyclyl groups, suitable substituents so formed include, for example, substituted heterocyclyl C1-6Alkoxy, e.g. 2-hydroxy-3-piperidinylpropoxy and 2-hydroxy-3-morpholinopropyloxy, substituted amino C1-6Alkoxy, e.g. 3-amino-2-hydroxypropoxy, substituted N-C1-6Alkylamino radical C1-6Alkoxy, e.g. 2-hydroxy-3-methylaminopropoxy, substituted N, N- (C)1-6Alkyl radical)2Amino group C1-6Alkoxy, e.g. 3-dimethylamino-2-hydroxypropoxy, 3- [ N- (3-dimethylaminopropyl) -N-methylamino]Propoxy and 3- [ N- (3-dimethylaminopropyl) -N-methylamino]2-hydroxypropoxy, substituted heterocyclyl C1-6Alkylamino radicals, e.g. 2-hydroxy-3-piperidinylpropylamino and 2-hydroxy-3-morpholinopropylamino, substituted amino radicals C1-6Alkylamino, e.g. 3-amino-2-hydroxypropylamino, substituted N-C1-6Alkylamino radical C1-6Alkylamino, e.g. 2-hydroxy-3-methylaminopropylamino, substituted N, N- (C)1-6Alkyl radical)2Amino group C1-6Alkylamino radicals, e.g. 3-dimethylamino-2-hydroxypropylamino, 3- [ N- (3-dimethylaminopropyl) -N-methylamino]Propylamino and 3- [ N- (3-dimethylaminopropyl) -N-methylamino]-2-hydroxypropylamino, substituted N-C1-6Alkylamino radical C1-6Alkyl radicals, e.g. 2-dimethylaminoethylaminomethyl, 3-bisMethylaminopropylaminomethyl, 3-dimethylamino-2, 2-dimethylpropylaminomethyl, 2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl, and 3-morpholinopropylaminomethyl.
R1、R2、R3、R4、R5Preferred meanings of G, X, q and m are as follows.
G is preferably N or C (CN), more preferably G is N.
For ring X, preferred examples of suitable diyl groups of fused heteroaryl rings are thiophenediyl, furandiyl, imidazolediyl, pyrazolediyl, oxazolediyl, thiazolediyl, pyridinediyl, pyrimidinediyl or pyrazinediyl.
For ring X, more preferred examples of suitable fused heteroaryl ring diradicals are thiophenediyl, thiazolediyl, pyridinediyl, or pyrazinediyl.
Preferred examples of suitable bicyclic mono-groups of formula (I) wherein ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring are furopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, pyrrolipyrimidinyl, oxopyrrolopyrimidinyl, oxazolopyrimidinyl, oxooxazolopyrimidinyl, isoxazolopyrimidinyl, thiazolopyrimidinyl, oxothiazolopyrimidinyl, isothiazolopyrimidinyl, purinyl, imidazolinopyrimidinyl, oxoimidazolinopyrimidinyl, pyrazolopyrimidinyl, oxopyrazolopyrimidinyl, pyridopyrimidinyl, pyrimidyl or pteridinyl.
More preferred examples of suitable bicyclic mono-groups of formula (I) wherein ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring are furopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl or pteridinyl.
Further more preferred examples of suitable bicyclic mono-groups of formula (I) wherein ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring are furo [3, 2-d ] pyrimidinyl, furo [2, 3-d ] pyrimidinyl, thieno [3, 2-d ] pyrimidinyl, thieno [2, 3-d ] pyrimidinyl, pyrrolo [3, 2-d ] pyrimidinyl, pyrrolo [2, 3-d ] pyrimidinyl, oxazolo [5, 4-d ] pyrimidinyl, oxazolo [4, 5-d ] pyrimidinyl, thiazolo [5, 4-d ] pyrimidinyl, thiazolo [4, 5-d ] pyrimidinyl, purinyl, pyrido [2, 3-d ] pyrimidinyl, pyrido [3, 4-d ] pyrimidinyl, pyrido [4, 3-d ] pyrimidinyl, pyrido [3, 2-d ] pyrimidinyl, pyrimido [4, 5-d ] pyrimidinyl, pyrimido [5, 6-d ] pyrimidinyl or pteridinyl.
Particularly preferred examples of suitable bicyclic monoradicals of the formula (I) in which the ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring are 6-oxopyrrolino [2, 3-d ] pyrimidin-4-yl, 6-oxopyrrolino [3, 2-d ] pyrimidin-4-yl, 2-oxooxazolino [5, 4-d ] pyrimidin-7-yl, 2-oxothiazolino [5, 4-d ] pyrimidin-7-yl, 2-oxooxazolino [4, 5-d ] pyrimidin-7-yl, 2-oxothiazolino [4, 5-d ] pyrimidin-7-yl, 2-oxoimidazolino [4, 5-d ] pyrimidin-7-yl, 3-oxopyrazolo [3, 4-d ] pyrimidin-4-yl or 3-oxopyrazolo [4, 3-d ] pyrimidin-7-yl.
Further more preferred examples of suitable bicyclic mono-radicals of formula (I) wherein ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring are thieno [3, 2-d ] pyrimidinyl, thieno [2, 3-d ] pyrimidinyl, thiazolo [5, 4-d ] pyrimidinyl, pyrido [2, 3-d ] pyrimidinyl, pyrido [3, 4-d ] pyrimidinyl, pyrido [4, 3-d ] pyrimidinyl, pyrido [3, 2-d ] pyrimidinyl or pteridinyl.
In particular, more preferred examples of suitable bicyclic mono-groups of formula (I) wherein ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring are thieno [3, 2-d ] pyrimidin-4-yl, thieno [2, 3-d ] pyrimidin-4-yl, thiazolo [5, 4-d ] pyrimidin-7-yl, pyrido [2, 3-d ] pyrimidin-4-yl, pyrido [3, 4-d ] pyrimidin-4-yl, pyrido [4, 3-d ] pyrimidin-4-yl, pyrido [3, 2-d ] pyrimidin-4-yl or pteridin-4-yl.
Preferably m is 0 or m is 1 or 2, R1Each independently of the others being hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl S (O)n- (wherein N is 0-2), N- (C)1-6Alkyl radical)2Amino group C1-6Alkyl, N- (C)1-6Alkyl radical)2Carbamoyl radical C1-6Alkoxy, N- (C)1-6Alkyl radical)2Amino group C1-6Alkoxy radical, C1-6Alkyl S (O)2-C1-6Alkoxy, N- (C)1-6Alkyl radical)2amino-N- (C)1-6Alkyl) C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group C1-6Alkylamino radical C1-6Alkyl, heterocyclic radical C1-6Alkyl, heterocyclic radical C1-6Alkoxy, heterocyclyloxy, heterocyclylC1-6Alkylamino radical C1-6Alkyl or heteroaryl C1-6An alkoxy group.
More preferably m is 0 or m is 1, R1Each independently of the others being hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl S (O)n- (wherein N is 0-2), N- (C)1-6Alkyl radical)2Amino group C1-6Alkyl, N- (C)1-6Alkyl radical)2Carbamoyl radical C1-6Alkoxy, N- (C)1-6Alkyl radical)2Amino group C1-6Alkoxy radical, C1-6Alkyl S (O)2-C1-6Alkoxy, N- (C)1-6Alkyl radical)2amino-N- (C)1-6Alkyl) C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group C1-6Alkylamino radical C1-6Alkyl, piperidin-1-yl C1-6Alkyl, homopiperidin-1-yl C1-6Alkyl, N- (C)1-6Alkyl) piperidin-1-yl C1-6Alkyl, N- (C)1-6Alkyl) homopiperidin-1-yl C1-6Alkyl, piperazin-1-yl C1-6Alkyl, 4-C1-6Alkylpiperazin-1-yl C1-6Alkyl, homopiperazin-1-yl C1-6Alkyl, 4-C1-6Alkyl homopiperazin-1-yl C1-6Alkyl, pyrrolidinyl C1-6Alkoxy, piperidinyl C1-6Alkoxy, homopiperidinyl C1-6Alkoxy, N- (C)1-6Alkyl) pyrrolidinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperidinyl C1-6Alkoxy, N- (C)1-6Alkyl) homopiperidinyl C1-6Alkoxy, morpholinyl C1-6Alkoxy, piperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperazinyl C1-6Alkoxy, homopiperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) homopiperazinyl C1-6Alkoxy, pyrrolidinyloxy, N- (C)1-6Alkyl) pyrrolidinyloxy, piperidinyloxy, N- (C)1-6Alkyl) piperidinyloxy, homopiperidinyloxy, N- (C)1-6Alkyl) homopiperidinyloxy, morpholinyl C1-6Alkylamino radical C1-6Alkyl, thiazolyl C1-6Alkoxy or pyridyl C1-6An alkoxy group.
Even more preferably m is 0 or m is 1, R1Each independently of the others being hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl S (O)n- (wherein N is 0-2), N- (C)1-6Alkyl radical)2Amino group C1-6Alkyl, N- (C)1-6Alkyl radical)2Carbamoyl radical C1-6Alkoxy, N- (C)1-6Alkyl radical)2Amino group C1-6Alkoxy radical, C1-6Alkyl S (O)2-C1-6Alkoxy, N- (C)1-6Alkyl radical)2amino-N- (C)1-6Alkyl) C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group C1-6Alkylamino radical C1-6Alkyl, piperazin-1-yl C1-6Alkyl, 4-C1-6Alkylpiperazin-1-yl C1-6Alkyl, homopiperazin-1-yl C1-6Alkyl, 4-C1-6Alkyl homopiperazin-1-yl C1-6Alkyl, pyrrolidinyl C1-6Alkoxy, piperidinyl C1-6Alkoxy, N- (C)1-6Alkyl) pyrrolidinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperidinyl C1-6Alkoxy, morpholinyl C1-6Alkoxy, piperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperazinyl C1-6Alkoxy, homopiperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) homopiperazinyl C1-6Alkoxy radicalPyrrolidinyloxy, piperidinyl oxy, morpholinyl C1-6Alkylamino radical C1-6Alkyl or pyridyl C1-6An alkoxy group.
More particularly preferably m is 0 or m is 1, R1Each independently of the others being methyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-diisopropylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy, N-methylpiperidin-2-ylmethoxy, N-methylpiperidin-3-ylmethoxy, 2-pyrrolidin-1-ylethoxy, 2- (N-methylpyrrolidin-2-yl) ethoxy, N-methyl-5-oxopyrrolidin-2-ylmethoxy, 3-pyrrolidin-1-ylpropoxy, methyl-N-propyloxy, methyl, 2- (2-oxoimidazolidin-1-yl) ethoxy, 2- (4-methylpiperazin-1-yl) ethoxy or 3-pyridin-3-ylpropoxy.
Even more particularly preferably m is 0 or m is 1, R1Each independently being methyl, methoxy, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy.
Even more particularly preferably m is 0 or m is 1, R1Is methyl or methylthio.
Preferably R2Is hydrogen, C1-6Alkyl or halogen.
More preferably R2Is hydrogen, C1-4Alkyl or halogen.
Particular preference is given to R2Is hydrogen, methyl, fluorine or chlorine, more particularly methyl.
Preferably R3Is hydrogen, C1-6Alkyl or halogen.
More preferably R3Is hydrogen, C1-4Alkyl or halogen.
Particular preference is given to R3Is hydrogen, methyl, fluorine or chlorine, more particularly hydrogen.
Preferably q is 0 or 1, more preferably q is 0.
Preferably R4Is aryl or heteroaryl, optionally substituted by one or more groups selected from halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, N- (C)1-6Alkyl radical)2Amino or heterocyclic radical.
More preferably R4Is aryl or heteroaryl, optionally substituted by one or more groups selected from halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, N- (C)1-6Alkyl radical)2Amino, pyrrolidin-1-yl, piperidinyl, morpholino, piperazinyl, 4-C1-6Alkyl piperazin-1-yl, homopiperazin-1-yl or 4-C1-6Alkyl homopiperazin-1-yl.
Even more preferably R4Is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidinyl or pyridyl, optionally substituted by one or two halogens, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy, -O- (C)1-3Alkyl) -O-, N- (C)1-4Alkyl radical)2Amino group, C1-6Alkanoylamino group, C1-6alkylsulfonyl-N- (C)1-6Alkyl) amino, phenyl (optionally substituted with one or two halogens), furyl, azetidinyl, pyrrolidinyl, 3-pyrrolinyl, piperidinyl, homopiperidinyl, morpholino, piperazinyl, homopiperazinyl, N- (C)1-6Alkyl) piperazinyl and N- (C)1-6Alkyl) homopiperazinyl, or R4Is fluorenyl or dibenzofuranyl.
Even more preferably R4Is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidinyl or pyridyl, optionally substituted by one or two halogens, cyano, C1-4Alkyl radical, C1-4Alkoxy, N- (C)1-4Alkyl radical)2Amino, piperidinyl, morpholino, or piperazinyl.
Particular preference is given to R4Is phenyl, furyl, isoxazolyl or pyridyl, which are optionally substituted by one or more substituents selected from the group consisting of fluorine, chlorine, cyano, methyl,Methoxy, N-dimethylamino or morpholino.
Further, R is particularly preferable4Is phenyl, furyl, thienyl or pyridyl, which is optionally substituted by one or two radicals selected from the group consisting of fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N-dimethylamino, acetylamino, N-methylmethanesulfonamido, phenyl, 4-fluorophenyl, 4-chlorophenyl, furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidinyl, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylpiperazin-1-yl.
Further, R is particularly preferable4Is phenyl, which is optionally substituted by one or two groups selected from fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N-dimethylamino, acetylamino, N-methylmethanesulfonamido, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidinyl, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylpiperazin-1-yl.
Further, R is particularly preferable4Is a 1-fluorenyl or dibenzofuran-4-yl group.
More particularly, R is preferred4Is phenyl, 2-methylphenyl, 3- (N, N-dimethylamino) phenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-cyanophenyl, 3, 4-dimethoxyphenyl, 3-morpholinophenyl, 2-furyl, 2-chloropyridin-5-yl, 2-morpholinopyridin-4-yl or isoxazol-5-yl.
Even more particularly R is4Is phenyl, 3-fluorophenyl, 4-cyanophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-ethoxyphenyl, 3, 4-dimethoxyphenyl, 3, 4-methylenedioxyphenyl, 3- (N, N-dimethylamino) phenyl, 3-acetamidophenyl, 3- (4-fluorophenyl) phenyl, 3- (2-furyl) phenyl, 3-pyrrolidin-1-ylphenyl, 3-morpholinophenyl, 3-fluoro-5-pyrrolidine-1-ylphenyl, 3-fluoro-5-piperidinylphenyl, 3-fluoro-5-morpholinophenyl or 3-morpholino-5-trifluoromethylphenyl.
Even more particularly R is4Is pyridyl, optionally substituted with N, N-dimethylamino, N-diethylamino, pyrrolidin-1-yl, piperidinyl or morpholino.
Even more particularly R is4Is pyridyl, which is optionally substituted by N, N-dimethylamino, N-diethylamino, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidinyl, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl or 4-methylpiperazin-1-yl.
Even more particularly preferred is R4Is 2-morpholinopyridin-4-yl.
Preferably R4Is hydrogen or C1-6Alkoxy, more preferably C1-4Alkoxy, especially hydrogen or methoxy.
Preferably R5Is hydrogen.
A preferred aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof, wherein:
the bicyclic ring of formula (I) wherein Ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring is furopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, or pteridinyl;
m is 0 or m is 1, R1Each independently of the others being hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl S (O)n- (wherein N is 0-2), N- (C)1-6Alkyl radical)2Amino group C1-6Alkyl, N- (C)1-6Alkyl radical)2Carbamoyl radical C1-6Alkoxy, N- (C)1-6Alkyl radical)2Amino group C1-6Alkoxy radical, C1-6Alkyl S (O)2-C1-6Alkoxy, N- (C)1-6Alkyl radical)2amino-N- (C)1-6Alkyl) C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group C1-6Alkylamino radical C1-6Alkyl, piperidin-1-yl C1-6Alkyl, homopiperidin-1-yl C1-6Alkyl, N- (C)1-6Alkyl) piperidin-1-yl C1-6Alkyl, N- (C)1-6Alkyl) homopiperidin-1-yl C1-6Alkyl, piperazin-1-yl C1-6Alkyl, 4-C1-6Alkylpiperazin-1-yl C1-6Alkyl, homopiperazin-1-yl C1-6Alkyl, 4-C1-6Alkyl homopiperazin-1-yl C1-6Alkyl, pyrrolidinyl C1-6Alkoxy, piperidinyl C1-6Alkoxy, homopiperidinyl C1-6Alkoxy, N- (C)1-6Alkyl) pyrrolidinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperidinyl C1-6Alkoxy, N- (C)1-6Alkyl) homopiperidinyl C1-6Alkoxy, morpholinyl C1-6Alkoxy, piperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperazinyl C1-6Alkoxy, homopiperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) homopiperazinyl C1-6Alkoxy, pyrrolidinyloxy, N- (C)1-6Alkyl) pyrrolidinyloxy, piperidinyloxy, N- (C)1-6Alkyl) piperidinyloxy, homopiperidinyloxy, N- (C)1-6Alkyl) homopiperidinyloxy, morpholinyl C1-6Alkylamino radical C1-6Alkyl, thiazolyl C1-6Alkoxy or pyridyl C1-6An alkoxy group;
R2is hydrogen, C1-4Alkyl or halogen;
R3is hydrogen, C1-4Alkyl or halogen;
q is 0;
R4is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidinyl or pyridyl, optionally substituted by one or two halogens, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy, -O- (C)1-3Alkyl) -O-, N- (C)1-4Alkyl radical)2Amino group, C1-6Alkanoylamino group, C1-6alkylsulfonyl-N- (C)1-6Alkyl) amino, phenyl (optionally substituted with one or two halogens), furyl, azetidinyl, pyrrolidinyl, 3-pyrrolinyl, piperidinyl, homopiperidinyl, morpholino, piperazinyl, homopiperazinyl, N- (C)1-6Alkyl) piperazinyl and N- (C)1-6Alkyl) homopiperazinyl substitution, or R4Is fluorenyl or dibenzofuranyl; and
R5is hydrogen.
Another preferred aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof wherein:
the bicyclic ring of formula (I) wherein Ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring is furopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, or pteridinyl;
m is 0 or m is 1, R1Each independently of the others being hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl S (O)n- (wherein N is 0-2), N- (C)1-6Alkyl radical)2Amino group C1-6Alkyl, N- (C)1-6Alkyl radical)2Carbamoyl radical C1-6Alkoxy, N- (C)1-6Alkyl radical)2Amino group C1-6Alkoxy radical, C1-6Alkyl S (O)2-C1-6Alkoxy, N- (C)1-6Alkyl radical)2amino-N- (C)1-6Alkyl) C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group C1-6Alkylamino radical C1-6Alkyl, piperazin-1-yl C1-6Alkyl, 4-C1-6Alkylpiperazin-1-yl C1-6Alkyl, homopiperazin-1-yl C1-6Alkyl, 4-C1-6Alkyl homopiperazin-1-yl C1-6Alkyl, pyrrolidinyl C1-6Alkoxy, piperidinyl C1-6Alkoxy, N- (C)1-6Alkyl) pyrrolidinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperidinyl C1-6Alkoxy, morpholinyl C1-6Alkoxy, piperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) piperazinyl C1-6Alkoxy, homopiperazinyl C1-6Alkoxy, N- (C)1-6Alkyl) homopiperazinyl C1-6Alkoxy, pyrrolidinyloxy, piperidinyloxy, morpholinyl C1-6Alkylamino radical C1-6Alkyl or pyridyl C1-6An alkoxy group;
R2is hydrogen, C1-4Alkyl or halogen;
R3is hydrogen, C1-4Alkyl or halogen;
q is 0;
R4is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidinyl or pyridyl, optionally substituted by one or two halogens, cyano, C1-4Alkyl radical, C1-4Alkoxy, N- (C)1-4Alkyl radical)2Amino, piperidinyl, morpholino, or piperazinyl substitution; and
R5is hydrogen.
A more preferred aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof wherein:
bicyclic ring formed by the fusion of ring X in formula (I) with an adjacent nitrogen-containing 6-membered heteroaromatic ring is furo [3, 2-d ] pyrimidinyl, furo [2, 3-d ] pyrimidinyl, thieno [3, 2-d ] pyrimidinyl, thieno [2, 3-d ] pyrimidinyl, pyrrolo [3, 2-d ] pyrimidinyl, pyrrolo [2, 3-d ] pyrimidinyl, oxazolo [5, 4-d ] pyrimidinyl, oxazolo [4, 5-d ] pyrimidinyl, thiazolo [5, 4-d ] pyrimidinyl, thiazolo [4, 5-d ] pyrimidinyl, purinyl, pyrido [2, 3-d ] pyrimidinyl, pyrido [3, 4-d ] pyrimidinyl, pyrido [4, 3-d ] pyrimidinyl, pyrido [3, 2-d ] pyrimidinyl, pyrimido [4 ], 5-d ] pyrimidinyl, pyrimido [5, 6-d ] pyrimidinyl or pteridinyl;
m is 0 or m is 1, R1Each independently is methyl or methoxyA group selected from the group consisting of methyl, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy and 3-pyrrolidin-1-ylpropoxy;
R2is hydrogen, methyl, fluorine or chlorine;
R3is hydrogen;
q is 0;
R4is phenyl, which is optionally substituted by one or two radicals selected from the group consisting of fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N-dimethylamino, acetylamino, N-methylmethanesulfonamido, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidinyl, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylpiperazin-1-yl,
or R4Is pyridyl, optionally substituted by N, N-dimethylamino, N-diethylamino, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidinyl, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl or 4-methylpiperazin-1-yl, or R4Is 1-fluorenyl or dibenzofuran-4-yl; and
R5is hydrogen.
Another more preferred aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof wherein:
bicyclic ring formed by the fusion of ring X in formula (I) with an adjacent nitrogen-containing 6-membered heteroaromatic ring is furo [3, 2-d ] pyrimidinyl, furo [2, 3-d ] pyrimidinyl, thieno [3, 2-d ] pyrimidinyl, thieno [2, 3-d ] pyrimidinyl, pyrrolo [3, 2-d ] pyrimidinyl, pyrrolo [2, 3-d ] pyrimidinyl, oxazolo [5, 4-d ] pyrimidinyl, oxazolo [4, 5-d ] pyrimidinyl, thiazolo [5, 4-d ] pyrimidinyl, thiazolo [4, 5-d ] pyrimidinyl, purinyl, pyrido [2, 3-d ] pyrimidinyl, pyrido [3, 4-d ] pyrimidinyl, pyrido [4, 3-d ] pyrimidinyl, pyrido [3, 2-d ] pyrimidinyl, pyrimido [4 ], 5-d ] pyrimidinyl, pyrimido [5, 6-d ] pyrimidinyl or pteridinyl;
m is 0 or m is 1, R1Each independently is methyl, methoxy, methylthio, 2-diisopropylaminoethoxy, 3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy;
R2is hydrogen, methyl, fluorine or chlorine;
R3is hydrogen;
q is 0;
R4is pyridyl, optionally substituted with N, N-dimethylamino, N-diethylamino, pyrrolidin-1-yl, piperidinyl or morpholino; and
R5is hydrogen.
A particularly preferred aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof wherein:
the bicyclic ring in which ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring in formula (I) is thieno [3, 2-d ] pyrimidin-4-yl, thieno [2, 3-d ] pyrimidin-4-yl, thiazolo [5, 4-d ] pyrimidin-7-yl, 6-purinyl, pyrido [2, 3-d ] pyrimidin-4-yl, pyrido [3, 4-d ] pyrimidin-4-yl, pyrido [4, 3-d ] pyrimidin-4-yl, pyrido [3, 2-d ] pyrimidin-4-yl or pteridin-4-yl;
m is 0 or m is 1, R1Is methyl or methylthio;
R2is methyl;
R3is hydrogen;
q is 0;
R4is phenyl, 3-fluorophenyl, 4-cyanophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-ethoxyphenyl, 3, 4-dimethoxyphenyl, 3, 4-methylenedioxyphenyl, 3- (N, N-dimethylamino) phenyl, 3-ethylphenylAcylaminophenyl, 3- (4-fluorophenyl) phenyl, 3- (2-furyl) phenyl, 3-pyrrolidin-1-ylphenyl, 3-morpholinophenyl, 3-fluoro-5-pyrrolidin-1-ylphenyl, 3-fluoro-5-piperidinylphenyl, 3-fluoro-5-morpholinophenyl or 3-morpholino-5-trifluoromethylphenyl, or R4Is 2-morpholinopyridin-4-yl, or R4Is 1-fluorenyl or dibenzofuran-4-yl; and
R5is hydrogen.
Another particularly preferred aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof wherein:
the bicyclic ring in which ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring in formula (I) is thieno [3, 2-d ] pyrimidin-4-yl, thieno [2, 3-d ] pyrimidin-4-yl, thiazolo [5, 4-d ] pyrimidin-7-yl, pyrido [2, 3-d ] pyrimidin-4-yl, pyrido [3, 4-d ] pyrimidin-4-yl, pyrido [4, 3-d ] pyrimidin-4-yl, pyrido [3, 2-d ] pyrimidin-4-yl or pteridin-4-yl;
m is 0 or m is 1, R1Is methyl or methylthio;
R2is methyl;
R3is hydrogen;
q is 0;
R4is 2-morpholinopyridin-4-yl; and
R5is hydrogen.
Preferred compounds of the invention are the compounds of examples 1-3 or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof.
Particularly preferred compounds of the invention are, for example, compounds of formula (I) or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof selected from:
4- [ 2-methyl-5- (2-morpholinopyridine-4-formamido) anilino ] thieno [3, 2-d ] pyrimidine,
4- [ 2-methyl-5- (2-morpholinopyridine-4-formamido) anilino ] pyrido [4, 3-d ] pyrimidine,
4- [ 2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino ] pteridine and
6- [ 2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino ] purine.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) are, for example, acid addition salts of the compounds of formula (I) which are sufficiently basic, for example with inorganic or organic acids, such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt (such as a calcium or magnesium salt) or an ammonium salt, or a salt with an organic base (such as methylamine, dimethylamine, trimethylamine, pyridine, morpholine or tris- (2-hydroxyethyl) amine).
Various forms of prodrugs are known in the art. Examples of such prodrug derivatives can be found in: a) H.Burdgaard edited prodrug design (Elsevier, 1985) and K.Widder et al edited enzymatic methods, Vol.42, page 309-396 (Academic Press, 1985);
b) a Textbook of Drug design and Development edited by Krogsgaard-Larsen and H.Bundgaard, Chapter H.Bundgaard, "design and application of prodrugs" pp.113-191 (1991);
c)H.Bundgaard，Advanced Drug Delivery Reviews， 8，1-38(1992)；
d) bundgaard et al, Journal of Pharmaceutical Sciences,77285 (1988); and
e) N.Kakeya et al, Chem Phann Bull,32，692(1984)。
examples of these prodrugs can be used to form in vivo cleavable esters of the compounds of formula (I). The in vivo cleavable ester of a compound of formula (I) containing a carboxy group is, for example, a pharmaceutically acceptable ester cleavable in the human or animal body to the parent acidAn ester of (a). Suitable pharmaceutically acceptable esters of carboxy include C1-6Alkoxymethyl esters (such as methoxymethyl esters); c1-6Alkanoyloxymethyl esters (such as pivaloyloxymethyl ester); 2-benzo [ c ]]Furanone ester; c3-8Cycloalkoxy-carbonyloxy group C1-6Alkyl esters (e.g., 1-cyclohexylcarbonyloxyethyl ester); 1, 3-dioxolan-2-ylmethyl ester (e.g., 5-methyl-1, 3-dioxolan-2-ylmethyl ester); and C1-6Alkoxycarbonyloxyethyl esters (such as 1-methoxycarbonyloxyethyl ester); and may be formed on any carboxyl group in the compounds of the present invention.
For use in the treatment (including prophylaxis) of mammals (including humans), a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, it will generally be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
In one aspect the present invention provides a pharmaceutical composition which comprises a bicyclic compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, in association with a pharmaceutically acceptable diluent or carrier.
The compositions of the present invention may be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oil-soluble suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., creams, ointments, gels, or aqueous or oil-soluble solutions or suspensions), inhalation administration (e.g., uniformly dispersed powders or liquid aerosols), insufflation administration (e.g., uniformly dispersed powders), or parenteral administration (e.g., sterile aqueous or oil-soluble solutions for intravenous, subcutaneous, intramuscular, or rectal administration).
The compositions of the present invention may be prepared by conventional methods well known in the art using conventional pharmaceutical excipients. Thus, compositions intended for oral administration may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for tablets include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl paraben, and antioxidants such as ascorbic acid. Tablets may be plain tablets or they may be coated by conventional coating agents and methods well known in the art, in either case to modify their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and/or appearance.
Compositions for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions generally contain the active ingredient in a homogeneous powder form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example, lecithin or condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g. polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g. polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives (e.g. ethyl or propyl p-hydroxybenzoate), antioxidants (e.g. ascorbic acid), colouring, flavouring and/or sweetening agents (e.g. sucrose, saccharin or aspartame).
Oil-soluble suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oil-soluble suspension may also contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be protected by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally comprise the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents have been mentioned above by way of example. Other excipients, such as sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or a mixture of any of these oils. Suitable emulsifying agents may be, for example, naturally-occurring gums (e.g. gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g. soy bean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. sorbitan monooleate) and condensation products of the partial esters with ethylene oxide (e.g. polyoxyethylene sorbitan monooleate). The emulsion may also contain sweetening agents, flavoring agents and preservatives.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may contain demulcents, preservatives, flavouring and/or colouring agents.
Pharmaceutical compositions may also be presented as sterile injectable aqueous or oleaginous suspensions, which may be prepared according to known methods using one or more of the appropriate dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
Suppositories can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations such as creams, ointments, gels, and water-or oil-soluble solutions or suspensions can generally be obtained by formulating the active ingredient with a conventional topically acceptable vehicle or diluent according to methods well known in the art.
Compositions for insufflation may be in the form of a uniformly dispersed powder having an average particle size, e.g. 30 μm or less, which may itself contain the active ingredient alone or may be diluted with one or more physiologically acceptable carriers, e.g. lactose. The insufflation powder is then typically placed in a capsule containing, for example, 1-50mg of the active ingredient for use with a pressurized inhaler device, such as the known drug cromolyn sodium for insufflation.
Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol containing uniformly dispersed solid or liquid droplets of the dispersed active ingredient. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used, and aerosol devices are typically provided with means for quantitatively dispersing the active component.
For information on other formulations, the reader is referred to the fifth volume, chapter 25.2 of Comprehensive medicinal chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, formulations for oral administration to humans typically contain, for example, 0.5mg to 2g of the active ingredient, formulated with appropriate and conventional amounts of excipients, which comprise about 5 to 98% by weight of the total composition. Unit dosage forms typically contain from about 1mg to about 500mg of the active ingredient. For information on other routes of administration and dosage regimens, the reader is referred to the Comprehensive Medicinal Chemistry, volume V, chapter 25.3 (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The dosage of the compounds of formula (I) for therapeutic or prophylactic purposes will generally vary according to well-known principles of administration, depending on the nature and severity of the symptoms, the age and sex of the animal or patient and the route of administration.
In the use of the compounds of formula (I) for therapeutic or prophylactic purposes, they are generally administered in a daily dose in the range of from 0.5mg to 75mg per kg body weight, preferably from 0.5mg to 40mg per kg body weight, and may be administered in divided doses if desired. When the parenteral route is used, lower doses are generally administered. Thus, for example, for intravenous administration, a dosage range of, for example, 0.5mg to 30mg per kg body weight is generally employed. Similarly, for administration by inhalation, the dosage range employed is, for example, in the range of 0.5mg to 25mg per kg body weight. But is preferably administered orally, particularly in tablet form. Typically, a unit dosage form contains about 1-500mg of a compound of the invention.
The compounds of the present invention may be used in combination with other drugs and therapies for the treatment of diseases that benefit from the inhibition of cytokines, particularly TNF and IL-1. For example, the compounds of formula (I) may be used in combination with drugs and therapies for the treatment of rheumatoid arthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, ischemic heart disease, psoriasis and other diseases mentioned earlier in this specification.
For example, due to their ability to inhibit cytokines, the compounds of formula (I) are useful in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with cyclooxygenase-inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Administration of a compound of formula (I) in combination with an NSAID reduces the amount of the latter required to produce a therapeutic effect. Thus, the likelihood of adverse side effects (such as gastrointestinal reactions) caused by NSAIDs may be reduced. Accordingly, in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof in association with or in admixture with a cyclooxygenase-inhibiting non-steroidal anti-inflammatory drug and a pharmaceutically acceptable diluent or carrier.
The compounds of the invention may also be used in combination with anti-inflammatory agents, such as 5-lipoxygenase inhibitors (such as those disclosed in european patent applications 0351194, 0375368, 0375404, 0375452, 0375457, 0381375, 0385662, 0385663, 0385679, 0385680).
The compounds of formula (I) may also be used in combination with antiarthritics, such as gold, methotrexate, steroids and penicillamine, for example, for the treatment of rheumatoid arthritis, and in combination with steroids for the treatment of diseases such as osteoarthritis.
The compounds of the present invention may also be used in combination with cartilage protectors, antidegradants and/or repair drugs such as diacerein (diacerein), hyaluronic acid preparations (e.g. Hyalan), Rumalon, artparamon and glucosamine salts (e.g. Antril) for the treatment of degenerative diseases such as osteoarthritis.
The compounds of formula (I) may also be used in combination with anti-asthmatics such as bronchodilators and leukotriene antagonists in the treatment of asthma.
If formulated as a fixed dose formulation, the composition contains the compound of the invention in the dosage range described herein, as well as other pharmaceutically active agents in approved dosages. When it is not appropriate to make a combined preparation, the sequential administration is adopted.
Although the compounds of formula (I) are useful primarily as therapeutic agents in warm-blooded animals, including humans, other agents which inhibit the action of cytokines may be used. They are therefore useful as pharmacological standards, in the development of new biological experiments and in the study of new drugs.
In a further aspect the invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, which process (unless otherwise specified, wherein G, R1、R2、R3、R4、R5Ring X, m and q are defined by formula (I) include:
a) reacting an aniline of formula (II):
with an acyl compound of formula (III):
wherein L is a displaceable group as defined below;
b) reacting an activated bicyclic heteroaryl ring of formula (IV):
wherein L is a displaceable group as defined below, with an aniline of formula (V):
or c) for the preparation of compounds of the formula (I), in which R is1Or R4The substituent on is C1-6Alkoxy or substituted C1-6Alkoxy radical, C1-6Alkyl S-, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino or substituted C1-6Alkylamino, wherein R can be generally defined as1Or R4Alkylation of compounds of formula (I) wherein the substituents are suitably hydroxy, mercapto or amino;
then, if necessary:
i) converting a compound of formula (I) into another compound of formula (I);
ii) removing any protecting groups; and
iii) forming a pharmaceutically acceptable salt or an in vivo cleavable ester.
The specific reaction conditions for the above process variants are as follows:
suitable displaceable groups L for process variant a) are, for example, halogen, active phenoxy or sulfonyloxy, such as chloro, bromo, pentafluorophenoxy or methanesulfonyloxy or toluene-4-sulfonyloxy. Particularly preferred displaceable groups are chlorine and pentafluorophenoxy.
Aniline of formula (II) may be reacted with an acyl compound of formula (III) in a suitable inert solvent or diluent, such as dichloromethane, acetonitrile, butanol, sulfolane, tetrahydrofuran, 1, 2-dimethoxyethane, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidin-2-one, optionally in the presence of a base such as an alkali or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium or potassium carbonate, or such as an organic amine base, such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0] undec-7-ene, at a temperature in the range of e.g. 0-50 ℃, often at or near room temperature.
The aniline of formula (II) can be prepared according to the following scheme:
q is-NH2Or if R is2And R3Not identical and requiring a stereospecific reaction, Q may be an amino group protected by a suitable protecting group (such as those defined below) or a nitro group. Following the above reaction, the protecting group is removed or the nitro group is reduced (e.g., with iron powder and acetic acid) to produce the aniline of formula (II).
The active heteroaryl compounds of formula (IV) are known compounds and may be provided commercially or prepared according to methods known in the art. For example, where L is chloro or pentafluorophenoxy, the compound of formula (IV) may be prepared according to the following scheme:
suitable displaceable groups L for process variant b) are as defined above.
The reactive heteroaryl compounds of formula (IV) can be reacted with the anilines of formula (V) together in the presence of a protic solvent such as isopropanol and in the presence of an acid such as ethereal hydrogen chloride or hydrochloric acid at a temperature in the range of, for example, 0-150 deg.C, usually at or near reflux temperature.
The anilines of formula (V) are known compounds and can be provided commercially or prepared according to methods known in the art. For example, anilines of formula (V) can be prepared according to the following scheme
Wherein Q is as defined above.
The compounds of formulae (IIB), (III), (VA) and (VB) are known compounds and may be supplied commercially or prepared according to methods known in the art.
Suitable alkylating agents for process variant C) are, for example, any of the art-known reagents for the hydroxyalkylation to produce alkoxy or substituted alkoxy, or for the mercaptoalkylation to produce alkylthio, or for the aminoalkylation to produce alkylamino or substituted alkylamino (the alkylation being carried out in the presence of a suitable base as defined below in a suitable inert solvent or diluent as defined above for process variant a)), for example alkyl or substituted alkyl halides, such as C1-6Chlorides, bromides or iodides of alkyl groups or substituted C1-6Chlorides, bromides or iodides of alkyl groups.
Suitable bases are, for example, alkali metal or alkaline earth metal carbonates, alkoxides, hydroxides or hydrides, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or organometallic bases, for example alkyllithium (e.g.n-butyllithium) or dialkylaminolithium (e.g.lithium diisopropylamide), or, for example, organic amine bases, such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0] undec-7-ene. The reaction is generally carried out at a temperature in the range of, for example, 10 to 150 ℃ and preferably 20 to 80 ℃.
Any necessary protecting group may be selected from any group described in the appropriate literature or known to the skilled chemist to protect the group discussed above and these protecting groups may be introduced according to conventional methods. The protecting groups may be removed according to any conventional method described in the appropriate literature or known to the skilled chemist to remove the protecting groups discussed above, and such methods should be selected to remove only the protecting groups with minimal effect on other groups in the molecule.
For convenience, specific examples of protecting groups are given below, wherein "lower", as in lower alkyl, means that the group used preferably has from 1 to 4 carbon atoms. It is to be understood that these examples are not intended to be exhaustive. In the specific examples of protecting group removal methods given below, these examples are likewise not exhaustive. Of course, the use of protecting groups and methods of deprotection not specifically mentioned are also within the scope of the present invention.
The carboxyl protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (which alcohol or silanol preferably contains 1 to 20 carbon atoms).
Examples of carboxyl protecting groups include straight or branched C1-12Alkyl (e.g., isopropyl, tert-butyl); lower alkoxy lower alkyl (e.g., methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl (e.g., acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl (e.g., 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl (e.g. benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and 2-benzo [ c ]]Furanone group); tri (lower alkyl) silyl (e.g., trimethylsilyl and t-butyldimethylsilyl); tri (lower alkyl) silyl lower alkyl (e.g., trimethylsilylethyl);and C2-6Alkenyl groups (such as allyl and vinyl ethyl).
Particularly suitable methods for removing the carboxyl protecting group include, for example, acid-, base-, metal-or enzyme-catalyzed hydrolysis.
Examples of hydroxy protecting groups include lower alkyl (e.g., t-butyl); lower alkenyl (e.g., allyl); lower alkanoyl (e.g., acetyl); lower alkoxycarbonyl (such as tert-butoxycarbonyl); lower alkenyloxycarbonyl (e.g., allyloxycarbonyl); aryl lower alkoxycarbonyl (e.g., benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri-lower alkyl silyl (e.g., trimethylsilyl, t-butyldimethylsilyl) and aryl lower alkyl (e.g., benzyl).
Examples of amino protecting groups include formyl, arylalkyl (such as benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2, 4-dimethoxybenzyl, and triphenylmethyl); di-p-methoxybenzyl and furylmethyl; lower alkoxycarbonyl (such as tert-butoxycarbonyl); lower alkenyloxycarbonyl (e.g., allyloxycarbonyl); aryl lower alkoxycarbonyl (e.g., benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); trialkylsilyl groups (e.g., trimethylsilyl and t-butyldimethylsilyl); alkylene (e.g., methylene); benzylidene and substituted benzylidene.
Suitable methods for removing hydroxy and amino protecting groups include, for example, acid-, base-, metal-, or enzymatically hydrolyzed groups such as p-nitrobenzyloxycarbonyl; hydrogenated groups, such as benzyl; and photolytic groups such as o-nitrobenzyloxycarbonyl.
For general guidance on reaction conditions and reagents, the reader is referred to the higher organic chemistry, fourth edition, edited by Jerry March, published by John Wiley & Sons 1992. For a general guidance on protecting groups, the reader is referred to the protecting groups in organic synthesis, second edition, edited by Green et al, published by John Wiley & Sons.
A further aspect of the invention provides a bicyclic compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, for use in a method of treatment of the human or animal body.
In a further aspect the present invention provides a bicyclic compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof or an in vivo cleavable ester thereof for use as a medicament.
In a further aspect the present invention provides the use of a bicyclic compound of formula (I), or a pharmaceutically acceptable salt or in vivo cleavable ester thereof, as defined above, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for the treatment of diseases or medical conditions mediated by cytokines.
In a further aspect, the present invention provides a method of treating a disease or medical condition mediated by a cytokine, which comprises administering to a warm-blooded animal an effective amount of a bicyclic compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as defined above or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine.
In a further aspect the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for the treatment of a disease or medical condition mediated by TNF, IL-1, IL-6 or IL-8.
In a further aspect, the present invention provides a method of treating a disease or medical condition mediated by TNF, IL-1, IL-6 or IL-8, which method comprises administering to a warm-blooded animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as defined above or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine.
In a further aspect the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for the treatment of a disease or medical condition mediated by TNF.
In a further aspect, the present invention provides a method of treating a disease or medical condition mediated by TNF which comprises administering to a warm-blooded animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as defined above or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine.
In a further aspect the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for the inhibition of TNF, IL-1, IL-6 or IL-8.
In another aspect, the present invention provides a method of inhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to a warm-blooded animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as defined above or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine.
In a further aspect the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for the inhibition of TNF.
In another aspect, the present invention provides a method of inhibiting TNF which comprises administering to a warm-blooded animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as defined above or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine.
In a further aspect the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for the treatment of a disease or medical condition mediated by p38 kinase.
In a further aspect, the present invention provides a method of treating a disease or medical condition mediated by p38 kinase, which method comprises administering to a warm-blooded animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof as defined above or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine.
In a further aspect the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for use in the production of a p38 kinase inhibitory effect.
In a further aspect, the present invention provides a method for the production of a p38 kinase inhibitory effect, which method comprises administering to a warm-blooded animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo cleavable ester thereof or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, as defined above.
In a further aspect the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an in vivo cleavable ester thereof, as defined above, or the use of the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine, for the manufacture of a medicament for the treatment of rheumatoid arthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, ischaemic heart disease or psoriasis.
Detailed Description
The following biological tests and examples are illustrative of the present invention.
Biological assay
The following assays can be used to measure p38 kinase inhibition, TNF inhibition, and anti-arthritic effects of the compounds of the present invention.
In vitro enzyme assay
The ability of the compounds of the invention to inhibit the enzyme p38 kinase was evaluated. The activity of the test compound against each of the isoforms p38 α and p38 β of the enzyme was determined.
The use of the instant messaging was described by j.han et al,Journal of Biological Chemistry，1996， 2712886-2891 from Image clone 45578(Genomics，1996， 33151) human recombinant MKK6(GenBank Accession number g1209672) was isolated and used to generate proteins in the form of GST fusion proteins in pGEX vectors. The use of the instant messaging was described by j.han et al,Biochimica et Biophysica Acta，1995， 1265224-,Journal of Biological Chemistry，1996， 271similar to those described in 17920-17926, human lymphoblast cDNA (GenBank Accession Number GM1416) and human fetal brain cDNA were PCR amplified using oligonucleotides designed for the 5 'and 3' ends of the human p38 α and p38 β genes, respectively [ synthesized from mRNA (Clontech, catalog No. 6525-1) using the Gibco superscript cDNA Synthesis kit ]]P38 alpha (GenBank Accession Number G529039) and p38 beta (GenBank Accession Number G1469305) were isolated.
Two p38 protein isoforms were expressed on E.coli in PET vectors. Human recombinant p38 α and p38 β isoforms were produced as 5' c-myc, 6 His-tagged proteins. MKK6 and p38 proteins were purified using standard protocols: GSTMKK6 was purified using a glutathione sepharose column and p38 protein was purified using a nickel chelate column.
The p38 enzyme was activated prior to use by incubation with MKK6 for 3 hours at 30 ℃. Unactivated escherichia coli expressing MKK6 retained sufficient activity to fully activate both isoforms of p 38. Activation incubations contained a mixture of MKK6(10 μ l, 1mg/ml), a "kinase buffer" [100 μ l; pH 7.4 buffer containing Tris (50mM), EGTA (0.1mM), sodium orthovanadate (0.1mM) and beta-mercaptoethanol (0.1%)]And MgATP (30. mu.l of 50mM Mg (OCOCH)3)2P38 alpha (10. mu.l, 10mg/ml) or p38 beta (10. mu.l, 5mg `) together with 0.5mM ATP)ml). This resulted in an activated p38 enzyme sufficient for 3 microtiter plates.
Test compounds were dissolved in DMSO and 10. mu.l of a 1: 10 dilution in "kinase buffer" was added to one well of a microtiter plate. For single dose assays, compounds were tested at 10 μ M. Then add "kinase assay mix" [30 μ l; comprising myelin basic protein (Gibco BRL Cat. No. 1322B-010; 1ml of a 3.33mg/ml solution in water), activated p38 enzyme (50. mu.l) and "kinase buffer" (2ml)]Followed by the addition of "labelled ATP" [10 μ l; contains 50. mu.M ATP, 0.1. mu. Ci33PATP (Amersham International Cat number BF1000) and 50mM Mg (OCOCH)3)2]. Plates were incubated at room temperature with gentle stirring. Plates containing p38 α were incubated for 90 minutes and plates containing p38 β were incubated for 45 minutes. The incubation was stopped by adding 50. mu.l of 20% trichloroacetic acid (TCA). The precipitated protein was phosphorylated by p38 kinase and the ability of the test compound to inhibit this phosphorylation was evaluated. The plates were filtered using a Canberra Packard Unifilter and washed with 2% TCA, dried overnight and counted on a Top Count scintillation counter.
Test compounds were initially tested at a single dose and the active compounds were tested again to determine IC50The value is obtained.
In vitro cell-based assays
(i)PBMC
The ability of the compounds of the present invention to inhibit TNF α production was evaluated by using human peripheral blood mononuclear cells, which synthesize and secrete TNF α when stimulated with lipopolysaccharide.
From density centrifugation (Lymphoprep)TM(ii) a Nychomed) heparinized (10 units/ml heparin) human blood Peripheral Blood Mononuclear Cells (PBMCs) were isolated. The monocytes were resuspended in medium [ RPMI1640 medium (Gibco) supplemented with 50 units/ml penicillin, 50. mu.g/ml streptomycin, 2mM glutamine and 1% heat-inactivated human AB serum (Sigma H-1513) ]]In (1). Compounds were dissolved in DMSO at a concentration of 50mM, diluted 1: 100 in medium and subsequently inSerial dilutions were made in medium containing 1% DMSO. At 37 ℃ in the presence of moisture (5% CO)2/95% air) incubator (Falcon 3072; 96-well flat-bottom tissue culture plates), PBMCs (2.4X 10 in 160. mu.l medium) are plated with 20. mu.l of varying concentrations of test compound (triplicate cultures) or 20. mu.l of medium containing 1% DMSO (control wells)5Cells) were incubated for 30 minutes. Mu.l lipopolysaccharide dissolved in the medium [ LPS E.coli 0111: b4(Sigma L-4130) at a final concentration of 10. mu.g/ml]Added to the appropriate wells. Add 20. mu.l of medium to the control wells of "Medium alone". Six "LPS alone" and four "medium alone" controls were included on each 96-well plate. Known TNF α inhibitors, i.e., PDE type IV enzyme inhibitors, were included at varying concentrations in each assay (see, e.g., Semmler, j.wachtel. h and Endres, s.,Int.J.Immunopharmac.(1993)， 15(3) 409-Asahne 413) or inhibitors of the pro-TNF α convertase (see, e.g., McGeehan, G.M., etc.)Nature(1994) 370,558-561). The plates were incubated at 37 deg.C (wet incubator) for 7 hours, after which 100. mu.l of supernatant was removed from each well and stored at-70 deg.C (96-well round bottom plate; Corning 25850). Human TNF α ELISA (see WO 92/10190 and Frederick m.ausbel et al,Current Protocols in Molecular Biologyvol.2, John Wiley and Sons), TNF α levels were determined in each sample.
(ii) Human Whole blood
The ability of the compounds of the invention to inhibit TNF α production was also evaluated in a human whole blood assay. Human whole blood secretes TNF α when stimulated with LPS. This blood property forms the basis for an assay that is used as a secondary assay for compounds that show activity in the PBMC assay.
Heparinized (10 units/ml) human blood was obtained from volunteers. Mu.l of whole blood was added to a 96-well round bottom plate (Corning 25850). The compounds were dissolved and serially diluted in RPMI1640 medium (Gibco) supplemented with 50 units/ml penicillin, 50. mu.g/ml streptomycin and 2mM glutamine as detailed above. 20 μ l of each assay concentration was added to the appropriate wells (triplicate cultures). Mu.l of RPMI1640 medium supplemented with antibiotics and glutamine were added to the control wells. The plates were incubated at 37 deg.C (wet incubator) for 30 minutes, then 20. mu.l LPS (final concentration 10. mu.g/ml) was added. RPMI1640 medium was added to the control wells. Six "LPS alone" and four "medium alone" controls were included on each plate. Known inhibitors of TNF α synthesis/secretion were included in each assay. Plates were incubated at 37 deg.C (wet incubator) for 6 hours. The plates were centrifuged (10 min at 2000 rpm) and 100. mu.l of plasma was removed and stored at-70 ℃ (Corning 25850 plates). TNF α levels were measured by ELISA (see WO 92/10190 and Frederick m. ausbel et al,Current Protocols in Molecular Biologyvolume 2, John Wiley and Sons). From R&The D system (catalog number MAB610 anti-human TNF α coated antibody, BAF210 biotinylated anti-human TNF α detection antibody) resulted in a paired antibody used in ELISA.
In vivo/in vitro evaluation
The ability of the compounds of the invention as inhibitors of TNF α in vivo was evaluated in rats or mice. Briefly, groups of male Wista laser Park (AP) rats (180-210g) were administered either compound (6 rats) or drug vehicle (10 rats) by an appropriate route, e.g., orally (p.o.), intraperitoneally (i.p.), or subcutaneously (s.c). After 90 minutes an elevated concentration of CO was used2The rats were sacrificed and blood was bled into 5 units of sodium heparin/ml blood via the posterior vena cava. The blood samples were immediately placed on ice and centrifuged at 2000rpm for 10min at 4 ℃ and the collected plasma was frozen at-20 ℃ for subsequent testing of their effect on LPS-stimulated human blood TNF α production. Rat plasma samples were thawed and 175. mu.l of each sample was added to a set of wells in a 96-well round bottom plate (Corning 25850). Then 50 μ l of heparinized human blood was added to each well, mixed and the plates incubated at 37 ℃ for 30min (wet incubator). LPS (25. mu.l; final concentration 10. mu.g/ml) was addedInto these wells and incubation continued for another 5.5 hours. Control wells were incubated with 25 μ l of medium alone. The plates were then centrifuged at 2000rpm for 10min and 200 μ l of the supernatant was transferred to 96-well plates and frozen at-20 ℃ for subsequent analysis of TNF concentration by ELISA.
Data analysis via indicated software for each compound/dose calculation:
alternatively, mice were used in place of rats in the above methods.
Test as anti-arthritic
The compounds were tested for their activity as anti-arthritic drugs as follows. Trentham et al [1] showed that acid soluble native type II collagen is arthritic in rats; polyarthritis is caused when Freunds' incomplete adjuvant is administered. This is currently known as collagen-induced arthritis (CIA) and can induce similar symptoms in mice and primates. Recent studies have shown that anti-TNF monoclonal antibodies [2] and TNF receptor-IgG fusion proteins [3] improve established CIA, suggesting that TNF plays an important role in CIA pathophysiology. Furthermore, the significant efficacy of anti-TNF monoclonal antibodies reported in recent clinical trials of rheumatoid arthritis suggests that TNF plays a major role in chronic inflammatory diseases. Thus, CIA on DBA/1 mice as described in references 2 and 3 is a third model that can be used to demonstrate the anti-arthritic activity of the compounds. See also document 4.
Trentham, D.E. et al, (1977)J.Exp.Med.， 146，857。
Williams, R.O. et al, (1992)Proc.Natl.Acad.Sci.， 89，9784。
Williams, R.O. et al, (1995)Immunology， 84，433。
Badger, M.B. et al, (1996)The Journal of Pharmacology and Experimental Therapeutics， 279，1453-1461。
Although the pharmacological properties of the compounds of formula Ia vary with structural changes, as expected, the compounds of formula (I) generally give an inhibition of p 38. alpha. and/or p 38. beta. of more than 30% at concentrations up to 10. mu.M and an inhibition of more than 30% in the PBMC assay at concentrations up to 50. mu.M. At effective doses of the test compounds of the present invention, no physiologically unacceptable toxicity is observed. The following examples are used to illustrate:
example (Compound No.) IC50(p38α)
1 0.06
2 0.34
3(1) 0.04
3(2) 0.07
Examples
The invention is illustrated by the following non-limiting examples in which, unless otherwise indicated:
(i) unless otherwise stated, the operation is carried out at room temperature, i.e. in the range from 17 to 25 ℃, in an inert gas (e.g. argon) atmosphere;
(ii) evaporating by vacuum rotary evaporation, and carrying out a post-treatment step after filtering to remove residual solids;
(iii) column chromatography (via flash procedure) was performed on either Merck Kieselgel silica gel (Art.9385) or Merck Lichroprep RP-18(Art.9303) reverse phase silica gel from E.Merck, Darmstadt, Germany;
(iv) the yields given are for illustration only and are not necessarily the maximum yields attainable;
(v) in general, the final product of formula (I) has satisfactory microanalysis, the structure of which can be confirmed by Nuclear Magnetic Resonance (NMR) and/or mass spectrometry techniques; fast Atom Bombardment (FAB) mass spectrometry data were measured using a Platform spectrometer and, if appropriate, positive ion data or negative ion data were collected; determination of NMR chemical Shift values on the delta Scale [ proton Nuclear magnetic resonance Spectroscopy at field intensity 300MHz with a Varian Gemini 2000 spectrometer or 250MHz with a Bruker AM250 spectrometer](ii) a The following abbreviations are used: s, singlet; d, doublet; t, triplet; m, multiplet; br, wide; unless otherwise stated, deuterated dimethyl sulfoxide (DMSO-d) is used6) As a solvent.
Example 1
4- [ 2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino ] thieno [3, 2-d ] pyrimidine
Will be provided withN- (3-amino-4-methylphenyl) -2-morpholinopyridine-4-carboxamide (0.312g), 4-chlorothieno [3, 2-d)]Pyrimidine (PCT patent application WO 95/19774; 0.171g), triethylamine (0.15ml) andN，Na mixture of-dimethylformamide (5ml) was stirred and heated to 120 ℃ for 36 hours. The mixture was cooled to room temperature and poured into water. The resulting precipitate was separated and purified by silica gel column chromatography using a 19: 1 mixture of ethyl acetate and methanol as eluent. The title compound was obtained as a solid (0.216g, 48%);NMR：2.14(s，3H)，3.51(m，4H)，3.69(m，4H)，7.08(d，1H)，7.21(s，1H)，7.29(d，1H)，7.37(d，1H)，7.68(d，1H)，7.74(s，1H)，8.08(d，1H)，8.26(d，1H)，8.43(s，1H)，9.48(s，1H)，10.29(s，1H)； mass spectrometry：M+H+447。
Raw materialsN- (3-amino-4-methylphenyl) -2-morpholinopyridine-4-carboxamide is prepared as follows:
triethylamine (31.8ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (15.8g), 2-chloropyridine-4-carbonyl chloride (20g) and dichloromethane (1L), and the resulting mixture was stirred at room temperature for 16 hours. The precipitate was separated, washed with saturated aqueous sodium bicarbonate and dichloromethane and dried under vacuum at 40 ℃. Obtaining 2-chloro-N- (4-methyl-3-nitrophenyl) pyridine-4-carboxamide (10.2 g). The organic filtrate was washed with saturated aqueous sodium bicarbonate solution and dried (MgSO)4) And (4) evaporating. The residue was triturated in dichloromethane and the solid obtained was isolated and dried under vacuum at 40 ℃. Obtaining a second batch of 2-chloro-N- (4-methyl-3-nitrophenyl) pyridine-4-carboxamide (8.13 g);NMR：2.48(s，3H)，7.51(d，1H)，7.86(m，1H)，7.96(m，2H)，8.49(m，1H)，8.64(m，1H)，10.85(s，1H)； mass spectrometry：M+H+292, and 294.
The resulting mixture of pyridine-4-carboxamide and morpholine (250ml) was stirred and heated to 100 ℃ for 18 hours. The mixture was poured into water (250ml) and stirred for 10 minutes. Methylene chloride (30ml) was added to the solution, and the resulting mixture was stirred for 30 minutes. The resulting solid was collected, washed with dichloromethane and dried in a vacuum oven at 40 ℃ for 18 hours. To obtainN- (4-methyl-3-nitrophenyl) -2-morpholinopyridine-4-carboxamide (17.34 g);NMR：2.48(s，3H)，3.52(m，4H)，3.71(m，4H)，7.1(d，1H)，7.25(s，1H)，7.49(d，1H)，7.97(m，1H)，8.29(m，1H)，8.49(m，1H)，10.62(s，1H)； mass spectrometry：M+H+343。
A mixture of the resulting portion of this material (8.5g), 5% palladium on carbon catalyst (0.85g) and methanol (600ml) was stirred under hydrogen at one atmosphere for 18 hours. Dichloromethane (400ml) was added and the mixture was passed through celiteThe reaction mixture was filtered. Evaporating the filtrate to obtainN- (3-amino-4-methylphenyl) -2-morpholinopyridine-4-carboxamide (6.41 g);NMR：2.01(s，3H)，3.52(m，4H)，3.73(m，4H)，4.83(s，2H)，6.78(d，1H)，6.84(d，1H)，7.04-7.08(m，2H)，7.2(s，1H)，8.24(d，1H)，9.95(s，1H)； mass spectrometry：M+H+313。
Example 2
4- [ 2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino ] -5-methylthio [2, 3-d ] pyrimidine
A solution of 1M hydrogen chloride in diethyl ether (0.2ml) was addedN- (3-amino-4-methylphenyl) -2-morpholinopyridine-4-carboxamide (0.056g), 4-chloro-5-methylthio-eno [2, 3-d)]To a mixture of pyrimidine (Maybridge Chemical Company, Trevillet, Tintagel, Cornwall, PL340HW, GB; 0.037g) and isopropanol (2ml), the reaction mixture was stirred and heated to 88 ℃ for 18 hours. The reaction mixture was cooled to room temperature, and the precipitate was separated and washed with isohexane and diethyl ether in this order. The title compound (0.021g) was obtained;mass spectrometry：M+H+461。
Example 3
The appropriate 4-chloro heterocycle (obtained from Maybridge Chemical Company, Trevillet, Tintagel, Cornwall, PL340HW, GB, unless otherwise specified) was reacted with the appropriate aniline in a similar manner as described in example 2 to give the compounds in the following table.
Numbering Het R2 R4 Note
1 7-methylthioeno [3, 2-d ]]Pyrimidin-4-yl Me 2-morpholinopyridin-4-yl a)
2 Thieno [2, 3-d ]]Pyrimidin-4-yl Me 2-morpholinopyridin-4-yl b)
3 2-methylthiothiazolo [5, 4-d ]]Pyrimidin-7-yl Me 2-morpholinopyridin-4-yl c)
4 Pyrido [4, 3-d]Pyrimidin-4-yl Me 2-morpholinopyridin-4-yl d)
5 Pyrido [2, 3-d]Pyrimidin-4-yl Me 2-morpholinopyridin-4-yl e)
6 Pteridin-4-yl Me 2-morpholinopyridin-4-yl f)
7 6-purinyl radical Me 2-morpholinopyridin-4-yl g)
Note
a) The product gave the following data: mass spectrum: m + H+461。
b) The starting 4-chlorothieno [2, 3-d ] is obtained as described in PCT patent application WO 95/19774]A pyrimidine. The product gave the following data: mass spectrum: m + H+447。
c) The product gave the following data: mass spectrum: m + H+494。
d) The product gave the following data: mass spectrum: m + H+442。
The starting 4-chloropyrido [4, 3-d ] pyrimidine was prepared as follows:
a mixture of pyrido [4, 3-d ] pyrimidin-4 (1H) -one (PCT patent application WO 95/19774; 0.03g) and thionyl chloride (2ml) was stirred and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated to give the desired starting material, which was used without further purification.
e) The product gave the following data: mass spectrum: m + H+442。
The starting 4-chloropyrido [2, 3-d ] pyrimidine was prepared as follows:
a mixture of pyrido [2, 3-d ] pyrimidin-4 (1H) -one (PCT patent application WO 95/19774; 0.03g) and thionyl chloride (2ml) was stirred and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated to give the desired starting material, which was used without further purification.
f) The product gave the following data: mass spectrum: m + H+443。
g) The product gave the following data:NMR: 2.18(s, 3H), 3.52(m, 4H), 3.75(m, 4H), 7.09(m, 1H), 7.22(m, 2H), 7.55(m, 1H), 7.84 (width s, 1H), 8.18 (width s, 1H), 8.24(m, 2H), 9.14 (width s, 1H), 10.26(s, 1H); MS: m + H+431。
Example 4
Pharmaceutical composition
Representative pharmaceutical dosage forms of the invention for use in the treatment or prophylaxis of humans as defined herein (the active ingredient is referred to as "compound X") are set forth below:
(a) tablet I mg/tablet
Compound X100
Lactose ph. eur 182.75
Croscarmellose sodium 12.0
Corn starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
(b) Tablet II mg/tablet
Compound X50
Lactose ph. eur 223.75
Croscarmellose sodium 6.0
Corn starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25
Magnesium stearate 3.0
(c) Tablet III mg/tablet
Compound X1.0
Lactose ph. eur 93.25
Croscarmellose sodium 4.0
Corn starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0
(d) Capsule mg/capsule
Compound X10
Lactose ph. eur 488.5
Magnesium 1.5
(e) Injection I (50mg/ml)
Compound X5.0% w/v
1M sodium hydroxide solution 15.0% v/v
0.1M hydrochloric acid (pH adjusted to 7.6)
Polyethylene glycol 4004.5% w/v
Adding water for injection to 100%
(f) Injection II (10mg/ml)
Compound X1.0% w/v
Sodium phosphate BP 3.6% w/v
0.1M sodium hydroxide solution 15.0% v/v
Adding water for injection to 100%
(g) Injection III (1mg/ml, buffered to pH6)
Compound X0.1% w/v
Sodium phosphate BP 2.26% w/v
Citric acid 0.38% w/v
Polyethylene glycol 4003.5% w/v
Adding water for injection to 100%
(h) Aerosol I mg/ml
Compound X10.0
Sorbitan trioleate 13.5
Trichlorofluoromethane 910.0
Dichlorodifluoromethane 490.0
(i) Aerosol II mg/ml
Compound X0.2
Sorbitan trioleate 0.27
Trichlorofluoromethane 70.0
Dichlorodifluoromethane 280.0
Dichlorotetrafluoroethane 1094.0
(j) Aerosol III mg/ml
Compound X2.5
Sorbitan trioleate 3.38
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
(k) Aerosol IV mg/ml
Compound X2.5
Soybean lecithin 2.7
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
(l) Ointment ml
Compound X40 mg
300 μ l of ethanol
300 mul of water
1-dodecyl-N-Zetazepan-2-one 50. mu.l
Propylene glycol to 1ml
Remarks for note
The above formulations can be obtained by conventional methods known in the pharmaceutical field. Tablets (a) - (c) may be enteric coated by conventional methods, e.g. by providing a coating of cellulose acetate phthalate. Aerosol formulations (h) - (k) may be used in combination with standard, metered dose aerosol dispersants, and the suspending agents sorbitan trioleate and soy lecithin may be replaced by additional suspending agents such as sorbitan monooleate, sorbitan sesquioleate, polyethoxyethers, polyglycerol oleate or oleic acid.

Claims (11)

1. A bicyclic compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
g is N;
ring X is a 5-or 6-membered fused heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulphur and nitrogen;
m is 0, 1 or 2;
R1is C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy or C1-6Alkyl S (O)n-, where n is 0 to 2;
R2is C1-6An alkyl group;
R3is hydrogen;
R4is C3-7A cycloalkyl group,
or R4Is of formula (IC):
-K-J (IC)
wherein J is aryl, heteroaryl or heterocyclyl, K is a bond,
and R is4Any aryl, heteroaryl or heterocyclyl group in (a) may optionally be substituted by one or more groups selected from halogen, trifluoromethyl, cyano, C1-6Alkyl radical, C1-6Alkoxy, -O- (C)1-3Alkyl) -O-, C1-6Alkyl S (O)n-, where N is 0-2, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino group, C1-6Alkanoylamino and C1-6alkylsulfonyl-N- (C)1-6Alkyl) amino group, or R4Any aryl, heteroaryl or heterocyclyl group in (a) may be optionally substituted by one or more groups of formula (IB'):
-E1-D1 (IB’)
wherein D1Is aryl, heteroaryl or heterocyclyl, E1Is a key of the series of keys,
and R is4Any aryl, heteroaryl or heterocyclyl group in the above substituents may optionally be substituted by one or more groups selected from halogen, C1-6Alkyl and C1-6The substituent of the alkoxy group is replaced by the group,
R5is hydrogen;
q is 0;
and wherein aryl is phenyl or naphthyl,
wherein heteroaryl is a monocyclic, bicyclic or tricyclic 5-to 14-membered ring, which ring is unsaturated or partially unsaturated, having 1 to 5 ring heteroatoms selected from nitrogen, oxygen and sulfur,
wherein the heterocyclyl is a mono-or bicyclic 3-14 membered ring which is fully saturated and has up to 5 ring heteroatoms selected from nitrogen, oxygen and sulphur.
2. A bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein:
the bicyclic ring of formula (I) wherein Ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring is furopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, or pteridinyl;
m is 0 or m is 1, R1Each independently is C1-6Alkyl radical, C1-6Alkoxy or C1-6Alkyl S (O)n-, where n is 0 to 2;
R2is C1-4An alkyl group;
R3is hydrogen;
q is 0;
R4is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidinyl or pyridyl, optionally substituted by one or two halogens, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy, -O- (C)1-3Alkyl) -O-, N- (C)1-4Alkyl radical)2Amino group, C1-6Alkanoylamino group, C1-6alkylsulfonyl-N- (C)1-6Alkyl) amino, phenyl (optionally substituted with one or two halogens), furyl, azetidinyl, pyrrolidinyl, 3-pyrrolinyl, piperidinyl, homopiperidinyl, morpholino, piperazinyl, homopiperazinyl, N- (C)1-6Alkyl) piperazinyl and N- (C)1-6Alkyl) homopiperazinyl substitution, or R4Is fluorenyl or dibenzofuranyl; and
R5is hydrogen.
3. A bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein:
the bicyclic ring of formula (I) wherein Ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring is furopyrimidinyl, thienopyrimidinyl, pyrrolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, purinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, or pteridinyl;
m is 0 or m is 1, R1Each independently is C1-6Alkyl radical, C1-6Alkoxy or C1-6Alkyl S (O)n-, where n is 0 to 2;
R2is C1-4An alkyl group;
R3is hydrogen;
q is 0;
R4is phenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidinyl or pyridyl, optionally substituted by one or two halogens, cyano, C1-4Alkyl radical, C1-4Alkoxy, N- (C)1-4Alkyl radical)2Amino, piperidinyl, morpholino, or piperazinyl substitution; and
R5is hydrogen.
4. A bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein:
bicyclic ring formed by the fusion of ring X in formula (I) with an adjacent nitrogen-containing 6-membered heteroaromatic ring is furo [3, 2-d ] pyrimidinyl, furo [2, 3-d ] pyrimidinyl, thieno [3, 2-d ] pyrimidinyl, thieno [2, 3-d ] pyrimidinyl, pyrrolo [3, 2-d ] pyrimidinyl, pyrrolo [2, 3-d ] pyrimidinyl, oxazolo [5, 4-d ] pyrimidinyl, oxazolo [4, 5-d ] pyrimidinyl, thiazolo [5, 4-d ] pyrimidinyl, thiazolo [4, 5-d ] pyrimidinyl, purinyl, pyrido [2, 3-d ] pyrimidinyl, pyrido [3, 4-d ] pyrimidinyl, pyrido [4, 3-d ] pyrimidinyl, pyrido [3, 2-d ] pyrimidinyl, pyrimido [4 ], 5-d ] pyrimidinyl, pyrimido [5, 6-d ] pyrimidinyl or pteridinyl;
m is 0 or m is 1, R1Each independently is methyl, methoxy or methylthio; r2Is methyl;
R3is hydrogen;
q is 0;
R4is phenyl, which is optionally substituted by one or two radicals selected from the group consisting of fluoro, chloro, trifluoromethyl, cyano, methyl, methoxy, ethoxy, methylenedioxy, N-dimethylamino, acetylamino, N-methylmethanesulfonamido, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-furyl, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolidin-1-yl, piperidinyl, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylpiperazin-1-yl,
or R4Is pyridyl, optionally substituted by N, N-dimethylamino, N-diethylamino, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolin-1-yl, piperidinyl, homopiperidin-1-yl, morpholino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl or 4-methylpiperazin-1-yl, or R4Is 1-fluorenyl or dibenzofuran-4-yl; and
R5is hydrogen.
5. A bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein:
bicyclic ring formed by the fusion of ring X in formula (I) with an adjacent nitrogen-containing 6-membered heteroaromatic ring is furo [3, 2-d ] pyrimidinyl, furo [2, 3-d ] pyrimidinyl, thieno [3, 2-d ] pyrimidinyl, thieno [2, 3-d ] pyrimidinyl, pyrrolo [3, 2-d ] pyrimidinyl, pyrrolo [2, 3-d ] pyrimidinyl, oxazolo [5, 4-d ] pyrimidinyl, oxazolo [4, 5-d ] pyrimidinyl, thiazolo [5, 4-d ] pyrimidinyl, thiazolo [4, 5-d ] pyrimidinyl, purinyl, pyrido [2, 3-d ] pyrimidinyl, pyrido [3, 4-d ] pyrimidinyl, pyrido [4, 3-d ] pyrimidinyl, pyrido [3, 2-d ] pyrimidinyl, pyrimido [4 ], 5-d ] pyrimidinyl, pyrimido [5, 6-d ] pyrimidinyl or pteridinyl;
m is 0 or m is 1, R1Each independently is methyl, methoxy or methylthio; r2Is methyl;
R3is hydrogen;
q is 0;
R4is pyridyl, optionally substituted by N, N-dimethylamino, N-diethylamino, pyrroleAlkyl-1-yl, piperidinyl or morpholino; and
R5is hydrogen.
6. A bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein:
the bicyclic ring in which ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring in formula (I) is thieno [3, 2-d ] pyrimidin-4-yl, thieno [2, 3-d ] pyrimidin-4-yl, thiazolo [5, 4-d ] pyrimidin-7-yl, 6-purinyl, pyrido [2, 3-d ] pyrimidin-4-yl, pyrido [3, 4-d ] pyrimidin-4-yl, pyrido [4, 3-d ] pyrimidin-4-yl, pyrido [3, 2-d ] pyrimidin-4-yl or pteridin-4-yl;
m is 0 or m is 1, R1Is methyl or methylthio;
R2is methyl;
R3is hydrogen;
q is 0;
R4is phenyl, 3-fluorophenyl, 4-cyanophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-ethoxyphenyl, 3, 4-dimethoxyphenyl, 3, 4-methylenedioxyphenyl, 3- (N, N-dimethylamino) phenyl, 3-acetamidophenyl, 3- (4-fluorophenyl) phenyl, 3- (2-furyl) phenyl, 3-pyrrolidin-1-ylphenyl, 3-morpholinophenyl, 3-fluoro-5-pyrrolidin-1-ylphenyl, 3-fluoro-5-piperidinylphenyl, 3-fluoro-5-morpholinophenyl or 3-morpholino-5-trifluoromethylphenyl, or R4Is 2-morpholinopyridin-4-yl, or R4Is 1-fluorenyl or dibenzofuran-4-yl; and
R5is hydrogen.
7. A bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein:
the bicyclic ring in which ring X is fused to an adjacent nitrogen-containing 6-membered heteroaryl ring in formula (I) is thieno [3, 2-d ] pyrimidin-4-yl, thieno [2, 3-d ] pyrimidin-4-yl, thiazolo [5, 4-d ] pyrimidin-7-yl, pyrido [2, 3-d ] pyrimidin-4-yl, pyrido [3, 4-d ] pyrimidin-4-yl, pyrido [4, 3-d ] pyrimidin-4-yl, pyrido [3, 2-d ] pyrimidin-4-yl or pteridin-4-yl;
m is 0 or m is 1, R1Is methyl or methylthio;
R2is methyl;
R3is hydrogen;
q is 0;
R4is 2-morpholinopyridin-4-yl; and
R5is hydrogen.
8. A bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
it is selected from:
4- [ 2-methyl-5- (2-morpholinopyridine-4-formamido) anilino ] thieno [3, 2-d ] pyrimidine,
4- [ 2-methyl-5- (2-morpholinopyridine-4-formamido) anilino ] pyrido [4, 3-d ] pyrimidine,
4- [ 2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino ] pteridine and
6- [ 2-methyl-5- (2-morpholinopyridine-4-carboxamido) anilino ] purine.
9. A process for preparing a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which process comprises:
a) reacting an aniline of formula (II):
with an acyl compound of formula (III):
g, R therein1、R2、R3、R4、R5Ring X, m and q are as defined in claim 1, L is a displaceable group;
b) reacting an activated bicyclic heteroaryl ring of formula (IV):
g, R therein1Ring X and m are as defined in claim 1, L is a displaceable group, with an aniline of formula (V):
wherein R is2、R3、R4、R5And q is as defined in claim 1;
or c) for the preparation of compounds of the formula (I), in which R is1Or R4The substituent on is C1-6Alkoxy or substituted C1-6Alkoxy radical, C1-6Alkyl S-, N-C1-6Alkylamino, N- (C)1-6Alkyl radical)2Amino or substituted C1-6Alkylamino, wherein R may be generally substituted in the presence of a suitable base1Or R4Alkylation of compounds of formula (I) wherein the substituents are suitably hydroxy, mercapto or amino;
then, if necessary:
i) converting a compound of formula (I) into another compound of formula (I);
ii) removing any protecting groups; and
iii) forming a pharmaceutically acceptable salt.
10. A pharmaceutical composition which comprises a bicyclic compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier.
11. Use of a bicyclic compound of formula (I) or a pharmaceutically acceptable salt thereof or the compound 7-amino-4- (3-acetamidoanilino) pyrido [4, 3-d ] pyrimidine according to claim 1 for the manufacture of a medicament for the treatment of a disease or medical condition mediated by cytokines.
HK05110610.4A 1999-03-23 2005-11-23 Pyridine and pyrimidine derivatives and their use as inhibitors of cytokine mediated disease HK1078849B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9906566.6 1999-03-23
GBGB9906566.6A GB9906566D0 (en) 1999-03-23 1999-03-23 Chemical compounds

Publications (2)

Publication Number Publication Date
HK1078849A1 HK1078849A1 (en) 2006-03-24
HK1078849B true HK1078849B (en) 2007-11-09

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