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EP1641458A2 - Nouvelles associations pharmaceutiques de phthalazines (inhibiteurs vegf) et de benzamides (inhibiteurs hdfac) - Google Patents

Nouvelles associations pharmaceutiques de phthalazines (inhibiteurs vegf) et de benzamides (inhibiteurs hdfac)

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Publication number
EP1641458A2
EP1641458A2 EP03782372A EP03782372A EP1641458A2 EP 1641458 A2 EP1641458 A2 EP 1641458A2 EP 03782372 A EP03782372 A EP 03782372A EP 03782372 A EP03782372 A EP 03782372A EP 1641458 A2 EP1641458 A2 EP 1641458A2
Authority
EP
European Patent Office
Prior art keywords
group
compound
formula
phenyl
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03782372A
Other languages
German (de)
English (en)
Inventor
Detlef Schuppan
Christoph Herold
Marion Gansmayer
Matthias Ocker
Karl-Heinz Thierauch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to EP06090154A priority Critical patent/EP1738752A1/fr
Priority to EP03782372A priority patent/EP1641458A2/fr
Publication of EP1641458A2 publication Critical patent/EP1641458A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention concerns pharmaceutical combination and their use for the treatment of diseases resulting from persistent angiogenesis.
  • Persistent angiogenesis can be the source for different diseases, such as for example psoriasis, arthritis, such as rheumatoid arthritis, haemeangioma, angiofribroma, diseases of the eyes, such as diabetic retinopathie, neovascular glaucoma, diseases of the kidney, such as glomerulonephritis, diabetic nephropatic desease, malignant nephrosclerosis, thrombotic microangiopatic syndrome, disposes of transplants and glomerulopathy, fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases and artheriosclerosis, or can be change for the worse of these diseases.
  • diseases of the eyes such as diabetic retinopathie, neovascular glaucoma
  • diseases of the kidney such as glomerulonephritis, diabetic nephropatic desease, malignant nephrosclerosis, thrombotic microangiopatic syndrome,
  • a direct or indirect inhibition of the VEGF-receptor can be used for the treatment of the described diseases and other VEGF-induced pathological angiogenesis and vascular permeable conditions, such as tumor vasculature.
  • VEGF-induced pathological angiogenesis and vascular permeable conditions such as tumor vasculature.
  • the growth of a tumor can be inhibited by soluble receptors and antibodies against VEGF.
  • Persistent angiogenesis can be induced by VEGF via its receptor. For this, it is necessary that VEGF binds to the receptor and a tyrosine phosphorylation is achieved.
  • Compelling data implicate angiogenesis and tumor-associated neovascularization as a central step in the process of tumor growth, invasion, and metastasis.
  • Angiogenesis involves multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature, and the surrounding extracellular tissue matrix.
  • a tumor remains in a dormant state, where the cellular proliferation rate is balanced by the apoptotic rate, and it is unable to grow in size beyond a few millimeters if it has not acquired an angiogenic phenotype.
  • VEGF-A an endothelial cell specific mitogen, is considered to play a key role in angiogenic processes apparent in tumor growth. It has been shown to be secreted by hypoxic cells and cells of the reproductive apparatus under the regulation of oxygen partial pressure or hormones. VEGF has a variety of effects on vascular endothelium, including the ability to promote endothelial cell viability, mitogenesis, chemotaxis, and vascular permeability. It mediates its activity mainly via two tyrosine kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR), although other receptors, such as neuropilin-1 and -2, can also bind VEGF-A.
  • VEGFR-1 flt-1
  • VEGFR-2 flk-1/KDR
  • VEGF-A is also a potent inducer of vascular permeability (second name: vascular permeability factor, VPF) and may also play a key role in ascitic fluid formation and oedema associated with malignant disease.
  • VPF vascular permeability factor
  • VEGF-analogs Two VEGF-analogs, VEGF-C and VEGF-D have been described that bind to VEGFR-2 and VEGFR- 3.
  • the latter receptor appears to be responsible for lymphangiogenesis and may play a role in lymphogenic metastasis.
  • a VEGF signal inhibitor will not directly inhibit tumor cell growth. It will influence tumor growth by inhibiting tumor vascularization. It needs a constant long term application to exert its efficacy. The desired compound should therefore not cause major adverse effects that compromise the patients quality of life.
  • VEGF signal inhibitors are intended for a continuous long lasting therapy. It is clear that VEGF signal inhibitors are much better tolerated than conventional cytotoxic antitumor agents if they are specific. VEGF signal inhibitors will interfere with important physiological processes (wound healing, menstrual cycle, pregnancy, fetal development) which may impose treatment interruptions and restrictions of indications. At present, none of these questions appears to compromise patient treatment. This is due to the fact that the majority of patients passed the reproductive age. Healing of small wounds might be regulated through other pathways like FGF signaling. From animal experiments and from treatments of patients it is known that potential effects on hematopoetic and other stem cells that express VEGFR did not materialize in changes of blood cell composition. VEGFR occurring in glomeruli of the kidney and in one cell layer near the chorioid plexus did not react with recognizable functional deficits on kinase blockade.
  • Ri and R 2 (i) are lower aikyl or
  • one or two of the ring members T-*, T , T 3 and T 4 can be nitrogen, and the others are in each case CH, and the binding is achieved via T-i and T 4
  • A, B, D and E are, independendently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;
  • G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, -CH 2 -O-, CH 2 -S- ; -CH 2 -NH-, oxa (-O-), thia (-S-), or imino (-NH-);
  • Q is lower alkyl
  • R is H or lower alkyl
  • X is imino, oxa, or thia
  • Y is unsubstituted or substituted aryl, pyridyl, or cycloalkyl
  • Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterfied carboxy, alkanoyl, carbamoyl, N-mono-or N, N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phnyl-Iower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present;
  • bonds characterized, if present, by a wavy line are either single or double bonds; or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom;
  • G is selected from the group comprising lower alkylene, -CH 2 -O-, -CH 2 -S-, oxa and thia; or a salt thereof, are of interest as compound A) of the inventive synergistic combination.
  • A, B, D and E are, independendently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;
  • G is lower alkylene, -CH 2 -O-, -CH 2 -S-, CH 2 -NH-, oxa, thia, or imino;
  • R is H or lower alkyl
  • X is imino, oxa, or thia
  • Y is unsubstituted or substituted aryl, pyridyl, or cycloalkyl
  • Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterfied carboxy, alkanoyl, carbamoyl, N-mono-or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present;
  • bonds characterized by a wavy line are either single or double bonds
  • G is selcted from the group comprising lower alkylene, -CH 2 -O-, -CH 2 -S-, oxa and thia; or a salt thereof.
  • r is 0 to 2
  • n is 0 or 1
  • m is 0 or 1
  • A, B, D and E are in each case CH,
  • G is lower alkylene, especially methylene, Q is methyl, which is bound to A, to D, or to A and D;
  • R is H or lower alkyl
  • Y is phenyl, which is unsubstituted or substituted by one or two substituents independently of one another from the group comprising amino; lower alkanoylamino; halogen; lower alkyl; halogen-lower alkyl; hydroxy; lower alkoxy; phenyl-lower alkoxy; and cyano, or is pyridyl;
  • Z is amino; N-lower alkylamino; hydroxy-lower alkylamino; phenyl-lower alkylamino; N, N-di-lower alkylamino; n-phenyl-lower alkyl-N-lower alkylamino; N, N-di-lower alkylphenylamino; lower alkanoylamino; or a substituent from the group comprising benzoylamino or phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or especially substituted by nitro or amino, or by halogen, amino, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl or carbamoly; or is halogen; and,
  • bonds characterized by a wavy line are in each case a double bond or in each case a single bond; or a salt thereof.
  • r is 0 to 2
  • n is O o
  • m is O oM
  • R ⁇ and R 2 are lower alkyl or (ii) together form a bridge in subformula
  • one of the ring members T-i, T 2 , T 3 and T 4 can be nitrogen, and the others are in each case CH, and the binding is achieved via T-i and T 4
  • A, B, D and E are in each case CH, or A, D and E are each CH and B is N;
  • G is lower alkylene, -CH 2 -NH-, -CH 2 -O-, hydroxymethylene, or benzolyoxymethylene,
  • Q is methyl, which is bound to A, to D, or to A and D;
  • R is H or lower alkyl
  • X is imino, oxa, or thia
  • Y is phenyl, which is unsubstituted or is substituted by one or two substituents independently of one another from the group comprising amino; lower alkanoylamino; halogen, lower alkyl; halogen-lower alkyl; hydroxy; lower alkoxy; phenyl-lower alkoxy; cyano; benzyloxy; lower alkenyl, C 8 -C ⁇ 2 alkoxy, lower alkoxycarbonyl, carbamoly lower alkylcarbamoly, lower alkanoyl, phenyloxy, halogen-lower alkyloxy, lower alkoxycarbonyl, lower alkylmercapto, halogen- lower alkylmercapto, hydroxy-lower alkyl, lower alkylsulfonyl, halogen-lower alkylsulfonyl, phenylsulfonyl, dihydroxybora, 2-methylpyrimidin-4-yl, oxazol-5-
  • Z is amino; N-lower alkylamino; hydroxy-lower alkylamino; phenyl-lower alkylamino; N, N-di-lower alkylamino; n-phenyl-lower alkyl-N-lower alkylamino, N, N-di-lower alkylphenylamino; lower alkanoylamino; or a substituent from the group comprising benzoylamino or phenyl-lower alkoxycaarbonylamino, wherein the phenyl radical in each case is unsubstituted or substituted by nitro or amino, or by halogen, amino, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl or carbamoly; or is halogen; and, if present (in formula IA), the bonds charaterized by
  • n 0 or 1
  • m 0;
  • A, B, D and E are in each case CH,
  • G is lower alkylene
  • R is H
  • Y is phenyl, which is unsubstituted or substituted by one or two substituents independently of one another from the group comprising amino; lower alkanoylamino; halogen; lower alkyl; halogen-lower alkyl; hydroxy; lower alkoxy; phenyl-lower alkoxy; and cyano; and
  • bonds chacracterized by a wavy line are double bonds; or a salt thereof.
  • A, B, D, and E are in each case CH,
  • G is methylene
  • R is H
  • Y is phenyl, 2-, 3- or 4-aminophenyl.
  • bonds characterized by the wavy line are double bonds; or a salt thereof.
  • G is a bivalent group -CH 2 -O-, -CH 2 -S-, or -CH 2 -NH-
  • the methylene group in each case is bound to the ring with ring members A, B, D, and E, whereas the heteroatom (O, S or NH) is bound to the phthalazine ring in formula I-A.
  • Lower alkylene G may be branched or preferably linear and is especially branched or preferably linear especially methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), trimethylene (-CH 2 - CH 2 - CH 2 -) or tetramethylene (-CH 2 - CH 2 -CH 2 -CH 2 -).
  • G is preferably methylene.
  • Acyl in lower alkylene substituted by acyloxy is preferably arylcarbonyloxy, wherein aryl is defined as below, especially benzoyloxy or lower alkanoyloxy, especially benzoyloxy; lower alkylene substituted by acyloxy is especially methylene substituted by benzoyloxy.
  • Lower alkylene sustituted by hydroxy is preferably hydroxymethylene (-CH(OH)-).
  • G as lower alkylene substituted by acyloxy or hydroxy is preferred, or G as otherwise defined hereinbefore and hereinafter is in each case especially preferred.
  • Lower alkyl is especially C ⁇ -C 4 alkyl, e.g. n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, or especially methyl or also ethyl.
  • aryl is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl, fiuorenyl or phenanthrenyl, the radicals defined above being unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from animo, mono-or disubstituted amino, hologen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono-or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfinyl, phenyl-lower alkylsulfinyl,
  • radicals or substituents as foundan alternative or in addition to" the previous group of radicals or substituents, these radicals or substituents and those of the previous group are to be regarded together as one group of substituents from which the respective radicals may be selected, or especially as separate groups.
  • the expression does not mean that one of the radicals following the expression may be added to a member of the previous group by binding. This applies, even if the expression Jr as an alternative or in addition to” is not mentioned again, for the radicals or substituents, as defined here, in the preferred compounds of formula I defined below.
  • Mono-or disubstituted amino is especially amino substituted by one or two radicals selected independently of one another from lower alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; phenyl-lower alkyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is unsubstituted or especially substituted by one or more, preferably one or two, sustituents selected from nitro or amino, or also from halogen, amino, N-lower alylamino, N,N-di-iower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstituted or especially substituted by one or more, preferably one or two, subsituent
  • Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
  • alkyl has up to a maximum of 12 carbon atoms and is especially lower alkyl, especially methyl, or also ethyl, n-propyl, isopropyl, or tert butyl.
  • Substituted alkyl is alkyl as last defined, especially lower alkyl, preferably methyl; where one or more, especially up to three, substituents may be present, primarily from the group selected from halogen, especially fluorine, and also from amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl- lower alkoxycarbonyl. Trifluoromethyl is especially preferred.
  • Etherified hydroxy is especially C 8 -C 20 alkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or n-pentyloxy, phenyl-lower alkoxy, such as benzyloxy, or also phenyloxy, or as an alternative or in addition to the previous group C 8 -C 20 alkyloxy, such as n-decyloxy, halogen-lower alkoxy, such as trifluoromethyloxy or 1 ,1 ,2, 2-tetrafluoroethoxy.
  • C 8 -C 20 alkyloxy such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or n-pentyloxy, phenyl-lower alkoxy, such as benzyloxy, or also phenyloxy, or as an alternative or in
  • Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or pheyl-lower alkoxycarbonyloxy, such as benzyloxcarbonyloxy.
  • Esterified carboxy is especially lower alkoxycarbonyl, such as tert- butoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
  • Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl.
  • N-mono- or N,N-disubstituted carbamoyl is especially substituted by one or two substituents, lower alkyl, phenyl-lower alkyl, or hydroxy-lower alkyl, at the terminal nitrogen atom.
  • Alkylphenylthio is especially lower alkylphenylthio.
  • Alkylphenylsulfinyl is especially lower alkylphenylsulfinyl.
  • Pyridyl Y is preferably 3- or 4-pyridyl.
  • Unsubstituted or substituted cycloalkyl is preferably C 3 -C 8 cycloalkyl, which is unsubstituted or substituted in the same way as aryl, especially as defined for phenyl. Cyclohexyl or also cyclopentyl or cyclopropyl are preferred.
  • Heterocyclyl is especially a five or six-membered heterocyclic system with 1 or 2 heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl; a radical slelected from 2- methylpyrimidin-4-yl, oxazol-5-yl, 2-methly-1,3-dioxolan-2-yl, 1 H-pyrazol-3-yl, and 1-methyl-pyrazol-3-yl is preferred.
  • Aryl in the form of phenyl which is substitued by lower alkylene dioxy bound to two adjacent C-atoms, such as methylenedioxy, is preferably 3,4- methylenedioxyphenyl.
  • bonds in formula I characterized by wavy lines are present either as single or as double bonds. Preferably both are at the same time either single or double bonds.
  • An N-oxide of a compound of formula I is preferably an N-oxide in which a phthalazine-ring nitrogen or a nitrogen in the ring with ring members A, B, D, and E carries an oxygen atom, or several of the said nitrogen atoms carry an oxygen atom.
  • Salts are especially the pharmaceutically acceptable salts of compounds of formula I (or an N-oxide thereof).
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I (or an N-oxide thereof) with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydoxybuyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azalaic acid, malic acid, tartaric acid, citric acid, glucaric acid, glactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methlyglycine, acetylminoacetic acid, N-acetylasparagine or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1 -phospho
  • salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2- hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N, N'-dimethylpiperazine.
  • bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2- hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N, N'-dimethylpiperazine.
  • a compound of formula I may also form internal salts.
  • salts for isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
  • pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • a preferred salt of the compounds a) is a succinate or hydrochloride.
  • a succinate or hydrochloride is for example 1-(4-ChIoroanilino)-4-(4- pyridylmethyl)phthalazine hydrochloride or (4-Chlorophenyl)[4-(4-pyridylmethyl)- phthalazin-1-yl]-ammonium hydrogen succinate (ZK).
  • histone modification catalized by the histone acetyltansferase (HAT) and histone deacetylase (HDAC) enzymes, plays an important role in regulating gene expression by altering chromatin structure. Histone acetylation results in charge neutralization and separation of DNA from the histones. Thus, transcriptionally activated genes are typically associated with hyperacetylated loci. Because of the profound effect of histone modification on gene transcription, manipulation of the activities of histone- modifing HAT and HDAC enzymes has the potential for modifing the cell cycle and the neoplastic transfomation of cells. Some compounds with deacetylase inhibitory activity have been shown to be effective in suppressing tumor growth in animal models and in initial clinical trials, although the efficacy is limited, possibly due to their stability, low retention, or nonspecific toxicity in the body.
  • HDAC enzymes play a role in the regulation of hypoxia-induced angiogenesis. Hypoxia enhances HDAC function and HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.
  • a specific HDAC inhibitor upregulates p53 and von Hippel-Lindau expression and downregulates hypoxia-induced factor-1 alpha and vascular endothelial growth factor (VEGF). HDAC inhibitors are also shown to inhibit angiogenesis both in vitro and in vivo.
  • HDAC inhibitors are currently of major interest as potential anti-cancer therapeutics, largely because of their well-documented properties of inhibiting proliferation and induce apotosis of tumour cells. Furthermore, the finding that HDAC appears to be a critical regulator of angiogenesis in addition to tumour cell growth will cause further interest in the development of HDAC inhibitors as potential anticancer drugs.
  • benzamide derivatives which show differentiation-inducing effects, and which are useful a therapeutic or improving agent for malignant tumors, autoimmune diseases, dermatologic diseases and parasitism. In particular, they are highly effective as an anticancer drug, specifically to a hematologic malignancy and a solid carcinoma.
  • A is an optionally substituted phenyl group or an optionally substituted heterocyclic group wherein the substituent(s) for the phenyl group or the heterocyclic group is (are) 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a perflu ⁇ roalkyloxy group having 1 to 4 carbons, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbons, a phenyl group and a heterocyclic
  • e is an integer of 1 to 4; g and m are independently an integer of 0 to 4; R 4 is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons, or the acyl group represented by formula (3)
  • R 6 is an optionally substituted alkyl group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a phenyl group or a heterocyclic group
  • R 5 is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons
  • n is an integer of 0 to 4, provided that when X is a bond, n is not zero;
  • Q is a moiety having a structure selected from those illustrated in formula (4)
  • R 7 and R 8 are independently a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons
  • R and R 2 are independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group or an alkoxycarbonyl group having 1 to 4 carbons;
  • R 3 is a hydroxyl or amino group or a pharmaceutically acceptable salt thereof.
  • n is an integer of 1 to 4.
  • R7 and R8 are as defined above.
  • A is an optionally substituted hetero ring, especially an optionally substituted pyridyl group.
  • n 1 to 4
  • Q is selected from the structures illustrated in formula (5)
  • A is an optionally substituted hetero ring, especially optionally substituted pyridyl group; most preferred, wherein X is direct bond, most preferred wherein R 1 and R 2 are a hydrogen atom, most preferred, wherein R 3 is an amino group.
  • n is 1 to 4; wherein Q is selected from the structures illustrated in formula (5); A is an optionally substituted hetero ring, especially optionally substituted pyridyl group; most preferred, wherein X is the structure represented by formula (6): -(CH 2 )e- (6) wherein e is an integer of 1 to 4; most preferred wherein n is 1 and R 1 and R 2 are a hydrogen atom; most preferred, wherein R 3 is an amino group.
  • e, g and R4 are as defined above; most preferred wherein n is 1 and R 1 (CH 2 )g — O— (CH 2 )e , (CH 2 )g — S— (CH 2 )e ,
  • R4 (CH 2 )g — — (CH,)e and R 2 are a hydrogen atom; most preferred, wherein R 3 is an amino group.
  • g, m and R5 are as defined above; most preferred wherein n is 1 and R 1 and R 2 are a hydrogen atom; most preferred, wherein R 3 is an amino group.
  • Selected compounds of general formula II are for example the following compounds:
  • the inventive combination may also comprise a compound of general Formula lia)
  • interesting compounds are those compounds of formula lia), wherein A is an optionally substituted heterocycle; R 3 is an amino group; and Y is a moiety having -CO- which is linear, cyclic or their combination and links A and B.
  • n maybe zero or an integer of 1 to 4.
  • Q in the above formula (II) may be any structure illustrated in formula (5);
  • R7 and R8 are as defined above.
  • X in the above formula (II) may be a moiety having the structure represented by formula (6); -(CH 2 )e- (6) wherein e is as defined above.
  • X in the above formula (II) may be also a moiety having any structure illustrated in formula (7);
  • X in the above formula (II) may be also a moiety having any structure illustrated in formula (8); O ⁇ O (CH 2 )g I CI — (CH 2 )m , (CH 2 )g f N I CI (CH 2 )m '
  • the compounds represented by formula (lia) may be one wherein A is an optionally substituted heterocycle; B is an optionally substituted phenyl; and R 3 is an amino group. These compounds may be also one wherein Y has --CO- and is linear, cyclic or their combination.
  • 1 to 4 carbons means a carbon number per a single substituent; for example, for dialkyl substitution it means 2 to 8 carbons.
  • a heterocycle in the compound represented by formula (II) or (lia) is a monocyclic heterocycle having 5 or 6 members containing 1 to 4 nitrogen, oxygen or sulfur atoms or a bicyclic-fused heterocycle.
  • the monocyclic heterocycle includes pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine, tetrahydrofuran, morpholine, thiomorpholine and the like.
  • the bicyclic fused heterocycle includes quinoline; isoquinoline; naphthyridine; fused pyridines such as furopyridine, thienopyridine, pyrrolopyridine, oxazolopyridine, imidazolopyridine and thiazolopyridine; benzofuran; benzothiophene; benzimidazole and the like.
  • a halogen may be fluorine, chlorine, bromine or iodine.
  • An alkyl having 1 to 4 carbons includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl and tert-butyl.
  • An alkoxy having 1 to 4 carbons includes methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • An aminoalkyl having 1 to 4 carbons includes aminomethyl, 1-aminoethyl, 2- aminopropyl and the like.
  • An alkylamino having 1 to 4 carbons includes N-methylamino, N,N- dimethylamino, N,N-diethylamino, N-methyl-N-ethylamino, N,N- d ⁇ sopropylamino and the like.
  • An acyl having 1 to 4 carbons includes acetyl, propanoyl, butanoyl and like.
  • An acylamino having 1 to 4 carbons includes acetylamino, propanoylamino, butanoylamino and the like.
  • An alkylthio having 1 to 4 carbons includes methylthio, ethylthio, propylthio and the like.
  • a perfluoroalkyl having 1 to 4 carbons includes trifluoromethyl, pentafluoroethyl and the like.
  • a perfluoroalkyloxy having 1 to 4 carbons includes trifluoromethoxy, pentafluoroethoxy and the like.
  • An alkoxycarbonyl having 1 to 4 carbons includes methoxycarbonyl and ethoxycarbonyl.
  • An optionally substituted alkyl having 1 to 4 carbons includes methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl and these having 1 to 4 substituents selected from the group consisting of a halogen, hydroxyl, amino, nitro, cyano, phenyl and a heterocycle.
  • the structure of Y which has -CO-, -CS-, — SO- or -SO z - and links A and B and which is linear, cyclic or their combination means either (a) one consisting of carbon and/or hetero atoms linking A and B, whose linear or branched moiety has -CO-, -CS— , -SO- or - S0 2 --; (b) one linking A and B, whose cyclic moiety has -CO-, -CS-, -SO- or -SO. 2 -; and (c) one linking A and B wherein a combination of cyclic and linear moieties form a structural unit having -CO-, -CS-, -SO- or -SO 2 -.
  • a basic cyclic structure includes cyclic moieties having 4 to 7 members containing carbons and/or hetero atoms or their fused cycles.
  • it may be cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxetane, oxolane, oxane, oxepane, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, indoline, isoindoline, thiolane, thiazolidine and oxazolidine rings, which may contain unsaturated bonds, hydrogen bond acceptors and/or substituents.
  • the ring centroid used in definition of the spatial configuration may be defined as an average of X, Y and Z axes of the ring-forming atoms.
  • the centroid of either the overall fused ring or of a partial ring may be used as that for defining the space.
  • Porsion of formation of a configuration means that a conformer filling the spatial configuration is within 15 kcal/mol, preferably 8 kcal/mol from the energetically most stable structure.
  • a pharmaceutically acceptable salt of the compound of this invention includes salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and with an organic acid such as acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluroacetic acid, p-toluenesulfonic acid and methanesulfonic acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid
  • organic acid such as acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluroacetic acid, p-toluenesulfonic acid and methanesulfonic acid.
  • Such a salt includes N-(2-aminophenyl)-4-[N-(pyridin-3- yl)methoxycarbonylaminomethyl]benzamide hydrochloride, N-(2-aminophenyi)- 4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamideh ydrobromide, N-(2- aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide sulfate, N-(2-aminophenyl)-4-[N-(pyridin-3- yl)methoxycarbonylaminomethyl]benzamide phosphate, N-(2-aminophenyl)-4- [N-(pyrid ⁇ n-3-yl)methoxycarbonylaminomethyl]benzamide acetate, N-(2- aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide
  • the compound represented by formula (II) or (lia) may be obtained as an individual stereoisomer or a mixture of stereoisomers including a racemic modification.
  • This invention encompasses the above-specified different forms, which may be also used as an active ingredient.
  • the prepared acid chloride solution was added dropwise to a solution of 22.88 g of the compound from the process (1-2) (110 mmol) in 100 ml of dichloromethane and 200 ml of pyridine, maintaining the inner temperature within 7 to 9 °C. by ice-cooling.
  • Example 2 As described in Example 1, the compounds of Examples 2 to 44 were prepared, each of whose melting point (mp), 1 H NMR data and/or IR data are described below.
  • Example 2 As described in Example 1, the compounds of Examples 2 to 44 were prepared, each of whose melting point (mp), 1 H NMR data and/or IR data are described below.
  • Example 2
  • IR(KBr)cr ⁇ 1 3297, 1630, 1527, 1505, 1457, 1256, 1177, 1024,843, 749
  • IR(KBr)cm-1 3302, 1636, 1602, 1523, 1489, 1457, 1313, 751
  • IR(KBr)cm-1 3325(br.), 1630, 1551, 1520, 1507, 1324, 1265, 1154, 740
  • IR(KBr)cm-1 3288, 3058, 1675, 1633, 1523, 1457, 1314, 912, 755
  • IR(KBr)cm-1 3282, 1690, 1645, 1527, 1421, 1314, 1217, 1028, 994, 911, 753, 701
  • IR(KBr)cm-1 3406, 1662, 1529, 1507, 1420, 1313, 1209, 1139, 1170, 1139, 924, 741
  • IR(neat)cm-1 3276, 1645, 1614, 1536, 1509, 1435, 1415, 1385, 1333, 1280, 1247, 1091, 737
  • IR(KBr)cm-1 3272, 3067, 1661, 1647, 1598, 1536, 1455, 1334, 1288, 1194, 1024, 742
  • Example 48 the compounds of Examples 49 to 87 were prepared, each of whose melting point (mp), 1 H NMR data and/or IR data are shown below.
  • IR(KBr)cm-1 3330, 1690, 1633, 1594, 1524, 1277, 760
  • IR(KBr)cm-1 3394, 3290, 1711 , 1645, 1624, 1535, 1504, 1321 , 1251, 1138, 1049, 763
  • IR(KBr)cm-1 3443, 3362, 3313, 1732, 1706, 1636, 1527, 1493, 1458, 1305, 1217, 748
  • IR(KBr)cm-1 3293, 1688, 1651, 1534, 1506, 1259, 1121, 1043, 748
  • IR(KBr)cm-1 3330, 1694, 1633, 1524, 1457, 1298, 1269, 1045, 760
  • IR(KBr)cm-1 3333, 3259, 1694, 1645, 1529, 1267, 720
  • IR(KBr)cm-1 3204, 3035, 1631 , 1523, 1456, 1289, 1191 , 920, 753
  • IR(KBr)cm-1 3344, 3241, 1645, 1560, 1527, 1505, 1283, 751, 708
  • Example 89 the compounds of Examples 90 to 95 were prepared, each of whose melting point (mp), 1 H NMR data and/or IR data are shown below.
  • reaction mixture was stirred at room temperature for 10 min. and at 40°C for additional 30 min. After cooling, the mixture was evaporated and the excess oxalyl chloride was removed by evaporation with toluene. To the residue was added 10 ml of dichloromethane. Under ice-cooling, to the mixture was added dropwise a solution of 0.83 g of the compound from Example 1, the process (1-2) (4.0 mmol) in 8 ml of dichloromethane and 8 ml of pyridine, and the solution was warmed to room temperature with stirring for 7 hours and left overnight.
  • Example 101 As described in Example 100, the compounds of Examples 101 to 128 were prepared, each of whose melting point (mp), 1 H NMR data and/or IR data are shown below.
  • Example 101
  • IR(KBr)cm-1 3300, 2759, 1670, 1638, 1514, 1250
  • IR(KBr)cm-1 3260, 1664, 1605, 1521, 1327, 1119
  • IR(KBr)cm-1 3298, 1693, 1637, 1602, 1544, 1454, 1262, 848, 762
  • IR(KBr)cm-1 3317, 1691, 1652, 1601, 1522, 1312, 982, 847, 764, 701
  • IR(KBr)cm-1 3394, 3269, 1683, 1630, 1593, 1521 , 1460, 1131, 750, 716
  • IR(KBr)cm-1 3395, 3283, 1683, 1639, 1604, 1506, 1459, 1307, 1124
  • IR(KBr)cm-1 3333, 3272, 1666, 1583, 1561, 1458, 1314, 1247, 1143, 807, 746, 713
  • IR(KBr)cm-1 3403, 3341, 3250, 1694, 1630, 1610, 1506, 1314, 1259, 1118, 764
  • Example 133 As described in Example 132, the compound of Example 133 was prepared, whose melting point (mp), 1 H NMR data and IR data are shown below.

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Abstract

L'invention concerne des associations pharmaceutiques comprenant au moins un composé de formule générale I-A ou I-AA et au moins un composé de formule générale II) ou Iia), ou des associations pharmaceutiques comprenant au moins un composé de formule générale I-A ou I-AA et au moins un composé de formule générale II) ou Iia) et une anti-hormone, ainsi que leur utilisation pour traiter différentes maladies dues à une angiogenèse persistante.
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EP1738752A1 (fr) 2007-01-03
AU2003292888A8 (en) 2004-07-22

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