Patent Grant
10640495
The present invention relates to a compound that has a TrkA inhibitory activity and is useful in the treatment and/or prevention of TrkA mediated disorders, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same.
The tropomyosin receptor kinase (Trk) is a family of receptor tyrosine kinases and has a function as a receptor of neurotrophin (NT). Three major subtypes of Trk receptors are TrkA high-affinity receptor for nerve growth factor (NGF), TrkB high-affinity receptor for brain-derived neutrophic factor (BDNF) and NT-4/5, and TrkC high-affinity receptor for NT-3. All receptors involve in various physiological function in vivo. TrkA is mainly expressed in peripheral and central nerves, and involves in neuronal development and differentiation, and maintenance of neuronal functions. The gene mutation in TrkA is associated with painless anhidrosis in human (Patent Documents 1, 2 and Non-patent Documents 1 to 3). The activation of NGF-TrkA signal produces hypralgesia (Non-patent Documents 4 to 6). Clinical and non-clinical researches regarding anti-NGF antibodies and non-clinical researches regarding Trk inhibitors reveal the involvement of NGF-TrkA signal or NT-Trk signal in the pain of osteoarthritis, rheumatoid arthritis, bone fracture, interstitial cystitis, chronic pancreatitis and prostatitis in addition to nociceptive pain such as chronic low back pain, neuropathic pain such as diabetic peripheral neuropathic pain, acute pain sucha as postoperative pain and chronic pain such as pelvic pain and cancer pain (Patent Documents 1, 2 and Non-patent documents 7, 8).
Trk receptors are also expressed in several types of cancer cells such as neuroblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer and pancreatic cancer, and involve in the proliferation and migration of cancer cells. The fusion protein combined with TrkA kinase domain causes the proliferation of lung cancer cells. Trk inhibitor is shown to suppress the proliferation and metastasis of cancer cells in animal model. (Patent Document 1 and Non-patent Documents 9 to 12). Furthermore, Trk receptors are expressed in mast cells, eosinophils, immunocompetent cells such as T and B cells and keratinocytes, and NGF-trkA signal or NT-Trk signal involves in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, allergic diseases such as asthma and rhinitis, and skin diseases such as psoriasis, atopic dermatitis and pruritus (Patent Documents 1, 2). In addition, the inhibition of NGF-TrkA signal improves the overactive bladder (Patent Document 1). NT-Trk signal also involves in Sjogren's syndrome (Patent Document 1) and endometriosis (Patent Document 1). TrkA receptor plays a critical role in the infection process of the parasitic infection of Trypanosoma cruzi (Chagas disease) (Patent Document 1). Therefore, the compounds having an inhibitory activity for TrkA will be effective for various diseases including nociceptive pain, neuropathic pain, cancer, inflammatory diseases, allergic diseases and dermatological diseases.
The compounds that have an inhibitory activity for TrkA are disclosed in Patent Documents 1 to 16 and Non-patent Documents 6, 13 to 14. However, the compounds related to the present invention are not indicated and suggested in any of the documents.
The purpose of the present invention is to provide a compound that has a TrkA inhibitory activity or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present invention relates to a compound that has a TrkA inhibitory activity and is useful in the treatment and/or prevention of TrkA mediated disorders, or a pharmaceutically acceptable salt thereof.
The present invention relates to the following 1″) to 19″ and 101″) to 107″).
In addition, the present invention relates to the following items 1) to 17) and 101) to 107).
The present invention provides a compound useful in the treatment and/or prevention of TrkA mediated disorder, or a pharmaceutically acceptable salt thereof. The compound of the present invention shows an excellent TrkA kinase inhibitory activity as described in the following test examples. Thereby, a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, is available for therapeutic agent and/or prophylactic agent for pain associated with osteoarthritis, rheumatoid arthritis, fracture, interstitial cystitis, chronic pancreatitis and prostate inflammation; and nociceptive pain as typified by chronic low back pain, diabetic peripheral neuropathy pain, postoperative pain, pelvic pain and cancer pain; neuropathic pain, acute pain, chronic pain, cancer, inflammatory disease, allergic disease, dermatological disease and the like.
A compound of the present invention is the one having utility as a medicament. Herein, utility as a medicament includes the following points: the compound has good solubility; good metabolic stability; the induction of a drug-metabolizing enzyme is low; the inhibition of a drug-metabolizing enzyme which metabolizes another drug is low; the compound has high oral absorbency; the inhibition of hERG is low; the clearance is low; and/or the half-life is sufficiently long to express the efficacy; or the like.
Hereinafter, the present invention is described with reference to embodiments. It should be understood that, throughout the present specification, the expression of a singular form includes the concept of its plural form unless specified otherwise. Accordingly, it should be understood that an article in singular form (for example, in the English language, “a,” “an,” and “the”) includes the concept of its plural form unless specified otherwise. Furthermore, it should be understood that the terms used herein are used in a meaning normally used in the art unless specified otherwise. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field to which the present invention pertains. If there is a contradiction, the present specification (including definitions) precedes.
Terms used in this description are explained below. Each term, unless otherwise indicated, has the same meaning when it is used alone or together with other terms.
The term “halogen” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A fluorine atom and a chlorine atom are especially preferable.
The term “alkyl” includes a C1 to C15, preferably C1 to C10, more preferably C1 to C6 and further preferably C1 to C4 linear or branched hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.
A preferred embodiment of “alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. A more preferred embodiment is methyl, ethyl, n-propyl, isopropyl or tert-butyl.
The term “alkenyl” includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more double bond(s) at any position(s). Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.
A preferred embodiment of “alkenyl” is vinyl, allyl, propenyl, isopropenyl or butenyl.
The term “alkynyl” includes a C2 to C10, preferably a C2 to C8, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more triple bond(s) at any position(s). Furthermore, it may have double bond(s) at any position(s). Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.
A preferred embodiment of “alkynyl” is ethynyl, propynyl, butynyl or pentynyl.
The term “alkylene” includes a C1 to C15, preferably a C1 to C10, more preferably a C1 to C6 and further preferably a C1 to C4 liner or branched divalent hydrocarbon group. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene.
The term “aromatic carbocyclyl” means a cyclic aromatic hydrocarbon group which is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl.
A preferred embodiment of “aromatic carbocyclyl” is phenyl.
The term “aromatic carbocycle” means a cyclic aromatic hydrocarbon ring which is monocyclic or polycyclic having two or more rings. Examples include a benzene ring, a naphthalene ring, an anthracene ring, and a phenanthrene ring.
A preferred embodiment of “aromatic carbocycle” is a benzene ring and a naphthalene ring.
Examples of an aromatic carbocycle which may be formed by R14 and R15 together include the ring QA as follows:
The term “non-aromatic carbocyclyl” means a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group, which is monocyclic or polycyclic having two or more rings. The “non-aromatic carbocyclyl” which is polycyclic having two or more rings includes a fused ring group wherein a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”.
In addition, examples of the “non-aromatic carbocyclyl” also include a group having a bridge or a group to form a spiro ring as follows:
The non-aromatic carbocyclyl which is monocyclic is preferably C3 to C16, more preferably C3 to C12 and further preferably C4 to C8 carbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
Examples of non-aromatic carbocyclyl, which is polycyclic having two or more rings, include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.
The term “non-aromatic carbocycle” means a cyclic saturated hydrocarbon ring or a cyclic unsaturated non-aromatic hydrocarbon ring, which is monocyclic or polycyclic having two or more rings. The “non-aromatic carbocycle”, which is polycyclic having two or more rings, includes a fused ring wherein the non-aromatic carbocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocycle”.
In addition, examples of the “non-aromatic carbocycle” also include a ring having a bridge or a ring to form a spiro ring as follows:
The non-aromatic carbocycle which is monocyclic is preferably C3 to C16, more preferably C3 to C12 and further preferably C4 to C8 carbocyclyl. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclohexadiene.
Examples of a non-aromatic carbocycle, which is polycyclic having two or more rings, include indane, indene, acenaphthene, tetrahydronaphthalene, and fluorene.
Examples of a non-aromatic carbocycle which may be formed by R1A and R1B together include a ring as follows:
Examples of a non-aromatic carbocycle which may be formed by R14 and R15 together include a ring QB as follows:
The term “aromatic heterocyclyl” means an aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N. The “aromatic heterocyclyl”, which is polycyclic having two or more rings, includes a fused ring group wherein an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”.
The aromatic heterocyclyl, which is monocyclic, is preferably a 5- to 8-membered ring and more preferably a 5- to 6-membered ring. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl.
Examples of aromatic heterocyclyl, which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl.
Examples of aromatic heterocyclyl, which is bicyclic, include a group as follows:
Examples of aromatic heterocyclyl, which is polycyclic having three or more rings, include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.
The term “aromatic heterocycle” means an aromatic ring, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N.
The “aromatic heterocycle”, which is polycyclic having two or more rings, includes a fused ring wherein an aromatic heterocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocycle”.
The aromatic heterocycle, which is monocyclic, is preferably a 5- to 8-membered ring and more preferably a 5- or 6-membered ring. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, pyridone, triazole, triazine, tetrazole, furan, thiophen, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, and thiadiazole.
Examples of an aromatic heterocycle, which is bicyclic, include, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, and thiazolopyridine.
Examples of an aromatic heterocycle, which is polycyclic having three or more rings, include carbazole, acridine, xanthene, phenothiazine, phenoxathiine, phenoxazine, and dibenzofuran.
Examples of an aromatic heterocycle which may be formed by R14 and R15 together include the ring QC as follows:
The term “non-aromatic heterocyclyl” means a non-aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N. The “non-aromatic heterocyclyl”, which is polycyclic having two or more rings, includes an above-mentioned non-aromatic heterocyclyl fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”. The “non-aromatic heterocyclyl”, which is polycyclic having two or more rings, includes an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, fused with a ring of the above “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”.
In addition, examples of the “non-aromatic heterocyclyl” also include a group having a bridge or a group to form a spiro ring as follows:
The non-aromatic heterocyclyl, which is monocyclic, is preferably a 3- to 8-membered and more preferably a 5- to 6-membered ring. Examples include dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl, aziridinyl, dioxolynyl, oxepanyl, thiolanyl, thiinyl, and thiazinyl.
Examples of non-aromatic heterocyclyl, which is polycyclic having two or more rings, include indolinyl, isoindolinyl, chromanyl, and isochromanyl.
The term “non-aromatic heterocycle” means a cyclic non-aromatic ring, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected from O, S and N.
The “non-aromatic heterocycle”, which is polycyclic having two or more rings, includes an above-mentioned non-aromatic heterocycle fused with a ring of the above “aromatic carbocycle”, “non-aromatic carbocycle” and/or “aromatic heterocycle”.
In addition, the “non-aromatic heterocycle” also includes a ring having a bridge or a ring to form a spiro ring as follows:
The non-aromatic heterocycle which is non-bridged is preferably a 3 to 8-membered ring, more preferably a 4 to 8-membered ring, and further preferably a 5 or 6-membered ring.
The non-aromatic heterocycle which is bridged is preferably a 6 to 10-membered ring and more preferably a 8 or 9-membered ring. Herein, a number of members mean a number of all annular atoms of a bridged non-aromatic heterocycle.
The non-aromatic heterocycle which is monocyclic is preferably a 3 to 8-membered ring, and more preferably a 5 or 6-membered ring. Examples include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thiolane, thiine, and thiazine.
Examples of a non-aromatic heterocycle, which is polycyclic having two or more rings, include indoline, isoindoline, chromane, and isochromane.
Examples of a non-aromatic heterocycle which may be formed by R1A and R1B together include a ring as follows:
Examples of a non-aromatic heterocycle which may be formed by R14 and R15 together include the ring QD as follows:
The term “hydroxyalkyl” means a group wherein one or more hydrogen atom(s) attached to a carbon atom of the above “alkyl” is replaced with a hydroxyl group. Examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, and 1,2-dihydroxyethyl.
A preferred embodiment of “hydroxyalkyl” is hydroxymethyl.
The term “alkyloxy” means a group wherein the above “alkyl” is bonded to an oxygen atom. Examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, and hexyloxy.
A preferred embodiment of “alkyloxy” is methoxy, ethoxy, n-propyloxy, isopropyloxy, and tert-butyloxy.
The term “alkenyloxy” means a group wherein the above “alkenyl” is bonded to an oxygen atom. Examples include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, and 2-octenyloxy.
The term “alkynyloxy” means a group wherein the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, and 2-octynyloxy.
The term “haloalkyl” includes a group wherein one or more hydrogen atom(s) attached to a carbon atom of the above “alkyl” is replaced with the above “halogen”. Examples include monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl, and 1,1,1-trifluoropropan-2-yl.
A preferred embodiment of “haloalkyl” is trifluoromethyl and trichloromethyl.
The term “haloalkyloxy” means a group wherein the above “haloalkyl” is bonded to an oxygen atom. Examples include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, and trichloroethoxy.
A preferred embodiment of “haloalkyloxy” is trifluoromethoxy and trichloromethoxy.
The term “alkyloxyalkyl” means a group wherein the above “alkyloxy” is bonded to the above “alkyl”. Examples include methoxymethyl, methoxyethyl, and ethoxymethyl.
The term “alkyloxyalkyloxy” means a group wherein the above “alkyloxy” is bonded to the above “alkyloxy”. Examples include methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.
The term “alkylcarbonyl” means a group wherein the above “alkyl” is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl.
A preferred embodiment of “alkylcarbonyl” is methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.
The term “alkenylcarbonyl” means a group wherein the above “alkenyl” is bonded to a carbonyl group. Examples include ethylenylcarbonyl and propenylcarbonyl.
The term “alkynylcarbonyl” means a group wherein the above “alkynyl” is bonded to a carbonyl group. Examples include ethynylcarbonyl and propynylcarbonyl.
The term “alkylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “alkyl”. Examples include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino, and N-methyl-N-ethylamino.
A preferred embodiment of “alkylamino” is methylamino and ethylamino.
The term “alkylsulfonyl” means a group wherein the above “alkyl” is bonded to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, and sec-butylsulfonyl.
A preferred embodiment of “alkylulfonyl” is methylsulfonyl and ethylsulfonyl.
The term “alkenylsulfonyl” means a group wherein the above “alkenyl” is bonded to a sulfonyl group. Examples include ethylenylsulfonyl, and propenylsulfonyl.
The term “alkynylsulfonyl” means a group wherein the above “alkynyl” is bonded to a sulfonyl group. Examples include ethynylsulfonyl, and propynylsulfonyl.
The term “alkylcarbonylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “alkylcarbonyl”. Examples include methylcarbonylamino, dimethylcarbonylamino, ethylcarbonylamino, diethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, N,N-diisopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, and sec-butylcarbonylamino.
The term “alkylsulfonylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “alkylsulfonyl”. Examples include methylsulfonylamino, dimethylsulfonylamino, ethylsulfonylamino, diethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, N,N-diisopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, and sec-butylsulfonylamino.
A preferred embodiment of “alkylsulfonylamino” is methylsulfonylamino and ethylsulfonylamino.
The term “alkylimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkyl”. Examples include methylimino, ethylimino, n-propylimino, and isopropylimino.
The term “alkenylimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkenyl”. Examples include ethylenylimino, and propenylimino.
The term “alkynylimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkynyl”. Examples include ethynylimino, and propynylimino.
The term “alkylcarbonylimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkylcarbonyl”. Examples include methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, and isopropylcarbonylimino.
The term “alkenylcarbonylimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkenylcarbonyl”. Examples include ethylenylcarbonylimino, and propenylcarbonylimino.
The term “alkynylcarbonylimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkynylcarbonyl”. Examples include ethynylcarbonylimino and propynylcarbonylimino.
The term “alkyloxyimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkyloxy”. Examples include methyloxyimino, ethyloxyimino, n-propyloxyimino, and isopropyloxyimino.
The term “alkenyloxyimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkenyloxy”. Examples include ethylenyloxyimino, and propenyloxyimino.
The term “alkynyloxyimino” means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkynyloxy”. Examples include ethynyloxyimino, and propynyloxyimino.
The term “alkylcarbonyloxy” means a group wherein the above “alkylcarbonyl” is bonded to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, and sec-butylcarbonyloxy.
A preferred embodiment of “alkylcarbonyloxy” is methylcarbonyloxy and ethylcarbonyloxy.
The term “alkenylcarbonyloxy” means a group wherein the above “alkenylcarbonyl” is bonded to an oxygen atom. Examples include ethylenylcarbonyloxy and propenylcarbonyloxy.
The term “alkynylcarbonyloxy” means a group wherein the above “alkynylcarbonyl” is bonded to an oxygen atom. Examples include ethynylcarbonyloxy and propynylcarbonyloxy.
The term “alkyloxycarbonyl” means a group wherein the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl.
A preferred embodiment of “alkyloxycarbonyl” is methyloxycarbonyl, ethyloxycarbonyl and propyloxycarbonyl.
The term “alkenyloxycarbonyl” means a group wherein the above “alkenyloxy” is bonded to a carbonyl group. Examples include ethylenyloxycarbonyl and propenyloxycarbonyl.
The term “alkynyloxycarbonyl” means a group wherein the above “alkynyloxy” is bonded to a carbonyl group. Examples include ethynyloxycarbonyl and propynyloxycarbonyl.
The term “alkylsulfanyl” means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above “alkyl”. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, and isopropylsulfanyl.
The term “alkenylsulfanyl” means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above “alkenyl”. Examples include ethylenylsulfanyl, and propenylsulfanyl.
The term “alkynylsulfanyl” means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above “alkynyl”. Examples include ethynylsulfanyl, and propynylsulfanyl.
The term “alkylsulfinyl” means a group wherein the above “alkyl” is bonded to a sulfinyl group. Examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, and isopropylsulfinyl.
The term “alkenylsulfinyl” means a group wherein the above “alkenyl” is bonded to a sulfinyl group. Examples include ethylenylsulfinyl, and propenylsulfinyl
The term “alkynylsulfinyl” means a group wherein the above “alkynyl” is bonded to a sulfinyl group. Examples include ethynylsulfinyl and propynylsulfinyl.
The term “alkylcarbamoyl” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of a carbamoyl group is(are) replaced with the above “alkyl”. Examples include methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, and diethylcarbamoyl.
The term “alkylsulfamoyl” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of a sulfamoyl group is(are) replaced with the above “alkyl”. Examples include methylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, and diethylsulfamoyl.
The term “trialkylsilyl” means a group wherein three of the above “alkyl” are bonded to a silyl atom. Three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.
The alkyl part of “aromatic carbocyclylalkyl”, “non-aromatic carbocyclylalkyl”, “aromatic heterocyclylalkyl”, and “non-aromatic heterocyclylalkyl”,
The term “aromatic carbocyclylalkyl” means an alkyl substituted with one or more “aromatic carbocyclyl” described above. Examples include benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, and a group of the following formula:
A preferred embodiment of “aromatic carbocyclylalkyl” is benzyl, phenethyl or benzhydryl.
The term “non-aromatic carbocyclylalkyl” means an alkyl substituted with one or more “non-aromatic carbocyclyl” described above. The “non-aromatic carbocyclylalkyl” also includes “non-aromatic carbocyclylalkyl” wherein the alkyl part is substituted with the above “aromatic carbocyclyl”. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopenthylmethyl, cyclohexylmethyl, and a group of the following formula:
The term “aromatic heterocyclylalkyl” means an alkyl substituted with one or more “aromatic heterocyclyl” described above. The “aromatic heterocyclylalkyl” also includes “aromatic heterocyclylalkyl” wherein the alkyl part is substituted with the above “aromatic carbocyclyl” and/or “non-aromatic carbocyclyl”. Examples include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, and groups of the following formulae:
The term “non-aromatic heterocyclylalkyl” means an alkyl substituted with one or more “non-aromatic heterocyclyl” described above. The “non-aromatic heterocyclylalkyl” also includes “non-aromatic heterocyclylalkyl” wherein the alkyl part is substituted with the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”. Examples include tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, and groups of the following formulae:
The term “aromatic carbocyclylalkyloxy” means an alkyloxy substituted with one or more “aromatic carbocyclyl” described above. Examples include benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, and a group of the following formula:
The term “non-aromatic carbocyclylalkyloxy” means an alkyloxy substituted with one or more “non-aromatic carbocyclyl” described above. The “non-aromatic carbocyclylalkyloxy” also includes “non-aromatic carbocyclylalkyloxy” wherein the alkyl part is substituted with the above “aromatic carbocyclyl”. Examples include cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopenthylmethyloxy, cyclohexylmethyloxy, and a group of the following formula:
The term “aromatic heterocyclylalkyloxy” means an alkyloxy substituted with one or more “aromatic heterocyclyl” described above. The “aromatic heterocyclylalkyloxy” also includes “aromatic heterocyclylalkyloxy” wherein the alkyl part is substituted with the above “aromatic carbocyclyl” and/or “non-aromatic carbocyclyl”. Examples include pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, and groups of the following formulae:
The term “non-aromatic heterocyclylalkyloxy” means an alkyloxy substituted with one or more “non-aromatic heterocyclyl” described above. The “non-aromatic heterocyclylalkyloxy” also includes “non-aromatic heterocyclylalkyloxy” wherein the alkyl part is substituted with the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”. Examples include tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, and groups of the following formulae:
The term “aromatic carbocyclylalkyloxycarbonyl” means an alkyloxycarbonyl substituted with one or more “aromatic carbocyclyl” described above. Examples include benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, and a group of the following formula:
The term “non-aromatic carbocyclylalkyloxycarbonyl” means an alkyloxycarbonyl substituted with one or more “non-aromatic carbocyclyl” described above. The “non-aromatic carbocyclylalkyloxycarbonyl” also includes “non-aromatic carbocyclylalkyloxycarbonyl” wherein the alkyl part is substituted with the above “aromatic carbocyclyl”. Examples include cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopenthylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, and a group of the following formula:
The term “aromatic heterocyclylalkyloxycarbonyl” means an alkyloxycarbonyl substituted with one or more “aromatic heterocyclyl” described above. The “aromatic heterocyclylalkyloxycarbonyl” also include “aromatic heterocyclylalkyloxycarbonyl” wherein the alkyl part is substituted with the above “aromatic carbocyclyl” and/or “non-aromatic carbocyclyl”. Examples include pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyloxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, and groups of the following formulae:
The term “non-aromatic heterocyclylalkyloxycarbonyl” means an alkyloxycarbonyl substituted with one or more “non-aromatic heterocyclyl” described above. The “non-aromatic heterocyclylalkyloxycarbonyl” also includes “non-aromatic heterocyclylalkyloxycarbonyl” wherein the alkyl part is substituted with the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”. Examples include tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, and groups of the following formulae:
The term “aromatic carbocyclylalkyloxyalkyl” means an alkyloxyalkyl substituted with one or more “aromatic carbocyclyl” described above. Examples include benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, and a group of the following formula:
The term “non-aromatic carbocyclylalkyloxyalkyl” means an alkyloxyalkyl substituted with one or more “non-aromatic carbocyclyl” described above. The “non-aromatic carbocyclylalkyloxyalkyl” also includes “non-aromatic carbocyclylalkyloxyalkyl” wherein the alkyl part bonded to the non-aromatic carbocycle is substituted with the above “aromatic carbocyclyl”. Examples include cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopenthylmethyloxymethyl, cyclohexylmethyloxymethyl, and a group of the following formula:
The term “aromatic heterocyclylalkyloxyalkyl” means an alkyloxyalkyl substituted with one or more “aromatic heterocyclyl” described above. The “aromatic heterocyclylalkyloxyalkyl” also includes “aromatic heterocyclylalkyloxyalkyl” wherein the alkyl part bonded to the aromatic heterocycle is substituted with the above “aromatic carbocyclyl” and/or “non-aromatic carbocyclyl”. Examples include pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyloxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, and groups of the following formulae:
The term “non-aromatic heterocyclylalkyloxyalkyl” means an alkyloxyalkyl substituted with one or more “non-aromatic heterocyclyl” described above. The “non-aromatic heterocyclylalkyloxyalkyl” also includes “non-aromatic heterocyclylalkyloxyalkyl” wherein the alkyl part bonded to the non-aromatic heterocycle is substituted with the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”. Examples include tetrahydropyranylmethyloxymethyl, morpholinylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, and groups of the following formulae:
The term “aromatic carbocyclylalkylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “aromatic carbocyclylalkyl”. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, and dibenzylamino.
The term “non-aromatic carbocyclylalkylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “non-aromatic carbocyclylalkyl”. Examples include cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, and cyclohexylmethylamino.
The term “aromatic heterocyclylalkylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “aromatic heterocyclylalkyl”. Examples include pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolylmethylamino, and benzoxazolylmethylamino.
The term “non-aromatic heterocyclylalkylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “non-aromatic heterocyclylalkyl”. Examples include tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, and piperazinylmethylamino.
The aromatic carbocycle part of “aromatic carbocyclyloxy”, “aromatic carbocyclylcarbonyl”, “aromatic carbocyclyloxycarbonyl”, “aromatic carbocyclylsulfanyl”, and “aromatic carbocyclylsulfonyl” is also the same as above “aromatic carbocyclyl”.
The term “aromatic carbocyclyloxy” means a group wherein the “aromatic carbocycle” is bonded to an oxygen atom. Examples include phenyloxy and naphthyloxy.
The term “aromatic carbocyclylcarbonyl” means a group wherein the “aromatic carbocycle” is bonded to a carbonyl group. Examples include phenylcarbonyl and naphthylcarbonyl.
The term “aromatic carbocyclyloxycarbonyl” means a group wherein the above “aromatic carbocyclyloxy” is bonded to a carbonyl group. Examples include phenyloxycarbonyl and naphthyloxycarbonyl.
The term “aromatic carbocyclylsulfanyl” means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the “aromatic carbocycle”. Examples include phenylsulfanyl and naphthylsulfanyl.
The term “aromatic carbocyclylsulfonyl” means a group wherein the “aromatic carbocycle” is bonded to a sulfonyl group. Examples include phenylsulfonyl and naphthylsulfonyl.
The non-aromatic carbocycle part of “non-aromatic carbocyclyloxy”, “non-aromatic carbocyclylcarbonyl”, “non-aromatic carbocyclyloxycarbonyl”, “non-aromatic carbocyclylsulfanyl”, and “non-aromatic carbocyclylsulfonyl” is also the same as above “non-aromatic carbocyclyl”.
The term “non-aromatic carbocyclyloxy” means a group wherein the “non-aromatic carbocycle” is bonded to an oxygen atom. Examples include cyclopropyloxy, cyclohexyloxy, and cyclohexenyloxy.
The term “non-aromatic carbocyclylcarbonyl” means a group wherein the “non-aromatic carbocycle” is bonded to a carbonyl group. Examples include cyclopropylcarbonyl, cyclohexylcarbonyl, and cyclohexenylcarbonyl.
The term “non-aromatic carbocyclyloxycarbonyl” means a group wherein the above “non-aromatic carbocyclyloxy” is bonded to a carbonyl group. Examples include cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, and cyclohexenyloxycarbonyl.
The term “non-aromatic carbocyclylsulfanyl” means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the “non-aromatic carbocycle”. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, and cyclohexenylsulfanyl.
The term “non-aromatic carbocyclylsulfonyl” means a group wherein the “non-aromatic carbocycle” is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclohexenylsulfonyl.
The aromatic heterocycle part of “aromatic heterocyclyloxy”, “aromatic heterocyclylcarbonyl”, “aromatic heterocyclyloxycarbonyl”, “aromatic heterocyclylsulfanyl”, and “aromatic heterocyclylsulfonyl” is also the same as above “aromatic heterocyclyl”.
The term “aromatic heterocyclyloxy” means a group wherein the “aromatic heterocycle” is bonded to an oxygen atom. Examples include pyridyloxy and oxazolyloxy.
The term “aromatic heterocyclylcarbonyl” means a group wherein the “aromatic heterocycle” is bonded to a carbonyl group. Examples include pyridylcarbonyl and oxazolylcarbonyl.
The term “aromatic heterocyclyloxycarbonyl” means a group wherein the above “aromatic heterocyclyloxy” is bonded to a carbonyl group. Examples include pyridyloxycarbonyl and oxazolyloxycarbonyl.
The term “aromatic heterocyclylsulfanyl” means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the “aromatic heterocycle”. Examples include pyridylsulfanyl and oxazolylsulfanyl.
The term “aromatic heterocyclylsulfonyl” means a group wherein the “aromatic heterocycle” is bonded to a sulfonyl group. Examples include pyridylsulfonyl and oxazolylsulfonyl.
The non-aromatic heterocycle part of “non-aromatic heterocyclyloxy”, “non-aromatic heterocyclylcarbonyl”, “non-aromatic heterocyclyloxycarbonyl”, “non-aromatic heterocyclylsulfanyl”, and “non-aromatic heterocyclylsulfonyl” is also the same as above “non-aromatic heterocyclyl”.
The term “non-aromatic heterocyclyloxy” means a group wherein the “non-aromatic heterocycle” is bonded to an oxygen atom. Examples include piperidinyloxy and tetrahydrofuryloxy.
The term “non-aromatic heterocyclylcarbonyl” means a group wherein the “non-aromatic heterocycle” is bonded to a carbonyl group. Examples include piperidinylcarbonyl, and tetrahydrofurylcarbonyl.
The term “non-aromatic heterocyclyloxycarbonyl” means a group wherein the above “non-aromatic heterocyclyloxy” is bonded to a carbonyl group. Examples include piperidinyloxycarbonyl, and tetrahydrofuryloxycarbonyl.
The term “non-aromatic heterocyclylsulfanyl” means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the “non-aromatic heterocycle”. Examples include piperidinylsulfanyl and tetrahydrofurylsulfanyl.
The term “non-aromatic heterocyclylsulfonyl” means a group wherein the “non-aromatic heterocycle” is bonded to a sulfonyl group. Examples include piperidinylsulfonyl and tetrahydrofurylsulfonyl.
The term “acyl” includes “formyl”, “alkylcarbonyl”, “alkenylcarbonyl”, “alkynylcarbonyl”, “aromatic heterocyclylcarbonyl”, “non-aromatic heterocyclylcarbonyl”, “aromatic heterocyclylcarbonyl” and “non-aromatic heterocyclylcarbonyl”.
The substituents of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted or unsubstituted alkylcarbonyl”, “substituted or unsubstituted alkenylcarbonyl”, “substituted or unsubstituted alkynylcarbonyl”, “substituted or unsubstituted alkylamino”, “substituted or unsubstituted alkenylamino”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted or unsubstituted alkylcarbonylamino”, “substituted or unsubstituted alkenylcarbonylamino”, “substituted or unsubstituted alkylsulfonylamino”, “substituted or unsubstituted alkenylsulfonylamino”, “substituted or unsubstituted alkylimino”, “substituted or unsubstituted alkenylimino”, “substituted or unsubstituted alkynylimino”, “substituted or unsubstituted alkylcarbonylimino”, “substituted or unsubstituted alkenylcarbonylimino”, “substituted or unsubstituted alkynylcarbonylimino”, “substituted or unsubstituted alkyloxyimino”, “substituted or unsubstituted alkenyloxyimino”, “substituted or unsubstituted alkynyloxyimino”, “substituted or unsubstituted alkylcarbonyloxy”, “substituted or unsubstituted alkenylcarbonyloxy”, “substituted or unsubstituted alkynylcarbonyloxy”, “substituted or unsubstituted alkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”, “substituted or unsubstituted alkynyloxycarbonyl”, “substituted or unsubstituted alkylsulfanyl”, “substituted or unsubstituted alkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”, “substituted or unsubstituted sulfinyl”, “substituted or unsubstituted alkylsulfinyl”, “substituted or unsubstituted alkenylsulfinyl”, “substituted or unsubstituted alkynylsulfinyl”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted alkylcarbamoyl”, “substituted or unsubstituted alkenylcarbamoyl”, “substituted or unsubstituted alkynylcarbamoyl”, “substituted or unsubstituted sulfamoyl”, “substituted or unsubstituted alkylsulfamoyl”, “substituted or unsubstituted alkenylsulfamoyl” and “substituted or unsubstituted alkynylsulfamoyl” include the following substituents. A carbon atom at any positions may be bonded to one or more group(s) selected from the following substituents.
A substituent: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkylcarbonylamino, alkylsulfonylamino, alkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylsulfamoyl, alkenylsulfamoyl, alkynylsulfamoyl, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl, non-aromatic heterocyclyl, aromatic carbocyclyloxy, non-aromatic carbocyclyloxy, aromatic heterocyclyloxy, non-aromatic heterocyclyloxy, aromatic carbocyclylcarbonyl, non-aromatic carbocyclylcarbonyl, aromatic heterocyclylcarbonyl, non-aromatic heterocyclylcarbonyl, aromatic carbocyclyloxycarbonyl, non-aromatic carbocyclyloxycarbonyl, aromatic heterocyclyloxycarbonyl, non-aromatic heterocyclyloxycarbonyl, aromatic carbocyclylalkyloxy, non-aromatic carbocyclylalkyloxy, aromatic heterocyclylalkyloxy, non-aromatic heterocyclylalkyloxy, aromatic carbocyclylalkyloxycarbonyl, non-aromatic carbocyclylalkyloxycarbonyl, aromatic heterocyclylalkyloxycarbonyl, non-aromatic heterocyclylalkyloxycarbonyl, aromatic carbocyclylalkylamino, non-aromatic carbocyclylalkylamino, aromatic heterocyclylalkylamino, non-aromatic heterocyclylalkylamino, aromatic carbocyclylsulfanyl, non-aromatic carbocyclylsulfanyl, aromatic heterocyclylsulfanyl, non-aromatic heterocyclylsulfanyl, non-aromatic carbocyclylsulfonyl, aromatic carbocyclylsulfonyl, aromatic heterocyclylsulfonyl, and non-aromatic heterocyclylsulfonyl.
The substituents on the ring of “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” part of “substituted or unsubstituted aromatic carbocyclyl”, “substituted or unsubstituted non-aromatic carbocyclyl”, “substituted or unsubstituted aromatic heterocyclyl” and “substituted or unsubstituted non-aromatic heterocyclyl”,
Additionally, “substituted or unsubstituted non-aromatic carbocyclyl” and “substituted or unsubstituted non-aromatic heterocyclyl” may be substituted with “oxo”. In this case, it means a group wherein two hydrogen atoms on the same carbon atom are substituted as below.
The non-aromatic carbocycle or non-aromatic heterocycle part of the above “substituted or unsubstituted non-aromatic carbocyclyloxy”, “substituted or unsubstituted non-aromatic heterocyclyloxy”, “substituted or unsubstituted non-aromatic carbocyclylcarbonyl”, “substituted or unsubstituted non-aromatic heterocyclylcarbonyl”, “substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl”, “substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl”, “substituted or unsubstituted non-aromatic carbocyclylsulfanyl”, “substituted or unsubstituted non-aromatic heterocyclylsulfanyl”, “substituted or unsubstituted non-aromatic carbocyclylsulfonyl”, and “substituted or unsubstituted non-aromatic heterocyclylsulfonyl” may be substituted with “oxo” as described above.
The substituent of “substituted or unsubstituted alkyl” in R1 includes, for example,
The substituent of “substituted or unsubstituted alkyl” in R1 includes, for example,
The substituent of “substituted or unsubstituted alkyl” in R1A includes, for example,
The substituent of “substituted or unsubstituted alkyl” in R1A includes, for example,
The substituent of “substituted or unsubstituted aromatic carbocyclyl” in B includes, for example,
The substituent of “substituted or unsubstituted aromatic carbocyclyl” in B includes, for example,
The substituent of “substituted or unsubstituted aromatic heterocyclyl” in B includes, for example,
The substituent of “substituted or unsubstituted aromatic heterocyclyl” in B includes, for example,
The substituent of “substituted or unsubstituted aromatic heterocycle” in the ring C includes, for example,
The substituent of “substituted or unsubstituted aromatic heterocycle” in the ring C includes, for example,
The substituent of “substituted or unsubstituted pyrazole” in the ring C includes, for example,
The substituent of “substituted or unsubstituted pyrazole” in the ring C includes, for example,
The substituent of “substituted or unsubstituted aromatic heterocycle” in the ring C includes, for example,
The substituent of “substituted or unsubstituted pyrazole” in the ring C includes, for example,
The substituent of “substituted or unsubstituted aromatic heterocyclyl” in R13 includes, for example, halogen.
The substituent of “substituted or unsubstituted aromatic carbocyclyl” in R13 includes, for example, halogen.
The substituent of “substituted or unsubstituted alkyl” in R13 includes, for example, dialkylamino; aromatic carbocyclyl; and hydroxy. It may be substituted with one or more group(s) selected from the above substituents.
The substituent of “substituted or unsubstituted alkyl” in R15 includes, for example, halogen and hydroxy.
The substituent of “substituted or unsubstituted aromatic heterocyclyl”, “substituted or unsubstituted aromatic carbocyclyl”, “substituted or unsubstituted non-aromatic heterocyclyl”, or “substituted or unsubstituted non-aromatic carbocyclyl” in R14 includes, for example,
The substituent of “substituted or unsubstituted alkyloxy” in R14 includes, for example, halogen; hydroxy; amino; alkylamino; and dialkylamino.
The substituent of “substituted or unsubstituted aromatic heterocyclyl”, “substituted or unsubstituted aromatic carbocyclyl”, “substituted or unsubstituted non-aromatic heterocyclyl”, or “substituted or unsubstituted non-aromatic carbocyclyl” in R14 includes, for example,
The substituent of “substituted or unsubstituted alkyloxy” in R14 includes, for example,
The substituent of “substituted or unsubstituted non-aromatic heterocyclyloxy” in R14 includes, for example, halogen, acyl, alkyl, alkyloxycarbonyl, alkyloxy, hydroxy, amino, alkylamino, and dialkylamino. It may be substituted with one or more group(s) selected from the above substituents.
The substituent of “substituted or unsubstituted aromatic heterocyclyloxy” in R14 includes, for example, halogen; alkyl; and haloalkyl. It may be substituted with one or more group(s) selected from the above substituents.
The substituent of “substituted or unsubstituted carbamoyl” in R14 includes, for example, unsubstituted alkyl; and substituted alkyl (the substituent: hydroxy, aromatic heterocyclyl).
The substituent of “substituted or unsubstituted alkyl” in R14 includes, for example, amino; alkylamino; dialkylamino; hydroxy; halogen; and alkylsilyloxy.
It may be substituted with one or more group(s) selected from the above substituents.
Embodiments of the present invention are exemplified below.
A compound represented by Formula (IA):
Embodiments of the group represented by Formula:
The group represented by Formula:
The group represented by Formula:
Formula:
Formula:
The compounds of Formula (I) or Formula (IA) are not limited to specific isomers but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers, or rotamers), racemates or mixtures thereof.
A radiolabeled compound of the compounds of Formula (I) or Formula (IA) can be prepared using well-known methods in this field of the invention. For example, a tritium-labeled compound of Formula (I) or Formula (IA) can be prepared by introducing a tritium to a certain compound of Formula (I) or Formula (IA) through a catalytic dehalogenation reaction using a tritium. This method comprises reacting an appropriately-halogenated precursor of the compound of Formula (I) or Formula (IA) with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absent of a base. The other appropriate method of preparing a tritium-labeled compound can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. A 14C-labeled compound can be prepared by using a raw material having 14C.
The pharmaceutically acceptable salts of the compounds of Formula (I) or Formula (IA) include, for example, salts with alkaline metal (e.g., lithium, sodium, or potassium), alkaline earth metal (e.g., calcium or barium), magnesium, transition metal (e.g., zinc or iron), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, or quinoline), amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, or hydroiodic acid) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid). Especially, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are included. These salts can be formed by the usual methods.
The compounds of Formula (I) or Formula (IA) of the present invention or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates), co-crystal and/or crystal polymorphs. The present invention encompasses those various solvates, co-crystal and crystal polymorphs. “Solvates” may be those wherein any numbers of solvent molecules (e.g., water molecules) are coordinated with the compounds of Formula (I) or Formula (IA). When the compounds of Formula (I) or Formula (IA) or pharmaceutically acceptable salts thereof are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds of Formula (I) or Formula (IA) or pharmaceutically acceptable salts thereof may produce crystal polymorphs. “Co-crystal” means that a compound of Formula (I) or Formula (IA) or a salt thereof and a counter-molecule exist in the same crystal lattice, and it can be formed with any number of counter-molecules.
The compounds of Formula (I) or Formula (IA) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs. The present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds of the present invention that have chemically or metabolically degradable groups, and compounds that are converted to the pharmaceutically active compounds of the present invention through solvolysis or under physiological conditions in vivo. Prodrugs include compounds that are converted to the compounds of Formula (I) or Formula (IA) through enzymatic oxidation, reduction, hydrolysis or the like under physiological conditions in vivo, compounds that are converted to the compounds of Formula (I) or Formula (IA) through hydrolysis by gastric acid etc., and the like. Methods for selecting and preparing suitable prodrug derivatives are described in, for example, “Design of Prodrugs, Elsevier, Amsrdam, 1985”. Prodrugs themselves may have some activity.
When the compounds of Formula (I) or Formula (IA) or pharmaceutically acceptable salts thereof have hydroxyl group(s), prodrugs include acyloxy derivatives and sulfonyloxy derivatives that are prepared by, for example, reacting compounds having hydroxyl group(s) with suitable acyl halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonyl anhydride and mixed anhydride, or with a condensing agent. For example, they include CH3COO—, C2H5COO—, tert-BuCOO—, C15H31COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH2CH2COO—, CH3CH(NH2)COO—, CH2N(CH3)2COO—, CH3SO3—, CH3CH2SO3—, CF3SO3—, CH2FSO3—, CF3CH2SO3—, p-CH3O-PhSO3—, PhSO3— and p-CH3PhSO3—.
General procedures for the synthesis of the compounds of the present invention are described below. Starting materials and reaction reagents used in such synthesis are commercially available or can be synthesized according to methods well known in the art using compounds commercially available. Further, extraction, purification and the like may be performed in accordance with the methods carried out in the art.
In the following all steps, when a substituent which impedes a reaction, e.g. hydroxy, mercapto, amino, formyl, carbonyl, carboxy, is possessed, the substituent is protected by the method described in Protective Groups in organic Synthesis, and Theodora W Greene (John Wiley & Sons, hereinafter referred to as literature A) in advance, and the protecting group may be removed at a desirable stage. In addition, in the all steps, an order of steps to be implemented may be appropriately changed, and each intermediate may be isolated, and used in a next step. All of reaction time, reaction temperature, solvents, reagents, protecting groups, etc. are mere exemplification and not limited as long as they do not cause an adverse effect on a reaction.
For example, the compounds represented by Formula (I) of the present invention can be prepared by the general synthetic methods described below.
(Method A)
(Step 1)
Compound (A-3) can be obtained by reacting Compound (A-1) with Compound (A-2) in the presence of phosphine and azodicarboxylic acid ester.
Compound (A-1) is commercially available or can be synthesized according to the known methods.
Compound (A-2) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (A-1).
As the phosphine, triphenylphosphine, tributylphosphine, trimethylphosphine and the like are exemplified, and it can be used at 1 to 3 mol equivalent(s) relative to Compound (A-1).
As the azodicarboxylic acid ester, diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like are exemplified, and it can be used at 1 to 3 mol equivalent(s) relative to Compound (A-1).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, THF, toluene and the like are exemplified, and it can be used alone or in combination.
(Step 2)
Compound (A-4) can be obtained by deprotection of the Boc group of Compound (A-3) which is obtained in the above step 1. For example, the method disclosed in the above literature A can be used.
(Step 3)
Compound (A-7) can be obtained by reacting Compound (A-4), Compound (A-5) and Compound (A-6) in the presence of a base.
Compound (A-5) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (A-4).
Compound (A-6) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 5 mol equivalent(s) relative to Compound (A-4).
As the base, triethylamine, diisopropylethylamine, N-methylmorpholine and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (A-4).
The reaction temperature is room temperature to the reflux temperature of the solvent, preferably 0 to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, xylene, toluene and the like are exemplified, and it can be used alone or in combination.
(Step 4)
Compound (A-8) can be obtained by deprotection of protecting group for carboxyl group of Compound (A-7) which is obtained in the above step 2. For example, the method disclosed in the above literature A can be used.
(Step 5)
The carboxyl group of Compound (A-8) which is obtained in the above step 4 can be converted to an amino group by Curtius rearrangement.
As the reagent used for Curtius rearrangement, DPPA and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (A-8).
The reaction temperature is room temperature to the reflux temperature of the solvent, preferably 50 to 100° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, 2-(trimethylsilyl)ethanol, t-BuOH, benzyl alcohol and the like can be used.
As the reaction solvent, toluene, benzene and the like can be also used. In this case, carbamate can be obtained by adding the above alcohol after preparation of isocyanate.
The above alcohol can be used at 1 to 5 mol equivalent(s) relative to Compound (A-8).
The obtained carbamate can be deprotected in accordance with the method described in the above literature A to give Compound (A-9).
(Step 6)
Compound (I-A) can be obtained by reacting Compound (A-9) with Compound (A-10) in the presence of a base.
Compound (A-10) can be synthesized in accordance with the method described in WO2012/158413. It can be used at 1 to 1.5 mol equivalent(s) relative to Compound (A-9).
As the base, pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (A-9).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, chloroform, THF, toluene, DMF, DMSO, dioxane and the like are exemplified, and it can be used alone or in combination.
(Method A′) Synthesis of Compound (A-9) from Compound (A-7)
(Step 1)
Compound (A-8-1) can be obtained by treating Compound (A-7) which is obtained in step 3 of the above Method A with a solution of ammonia in methanol.
The solution of ammonia in methanol can be used at 10 to 100 mol equivalents relative to Compound (A-7).
The reaction temperature is room temperature to the reflux temperature of the solvent, preferably room temperature to 40° C.
The reaction time is 0.1 to 120 hour(s), preferably 0.5 to 72 hour(s).
(Step 2)
Compound (A-8-2) can be obtained by reacting Compound (A-8-1) with allyl alcohol and iodobenzene diacetate.
The allyl alcohol can be used at 10 to 50 mol equivalents relative to Compound (A-8-1).
The iodobenzene diacetate can be used at 1 to 5 mol equivalent(s) relative to Compound (A-8-1).
The reaction temperature is 50° C. to the reflux temperature of the solvent, preferably 60 to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, 1,2-dichloroethane, toluene, xylene and the like are exemplified, and it can be used alone or in combination.
(Step 3)
Compound (A-9) can be obtained by reacting Compound (A-8-2) with amine in the presence of a palladium catalyst.
As the palladium catalyst, tetrakis(triphenylphosphine)palladium is exemplified, and it can be used at 0.01 to 0.1 mol equivalent relative to Compound (A-8-2).
As the amine, diethylamine, morpholine and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (A-8-2).
The reaction temperature is room temperature to the reflux temperature of the solvent, preferably 0 to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, xylene, toluene and the like are exemplified, and it can be used alone or in combination.
(Method B)
(Step 1)
Compound (B-1) can be synthesized by reacting Compound (A-9) with a sodium nitritein the presence of an acid.
Compound (A-9) can be synthesized in accordance with the above Method A.
Examples of the acid include hydrochloric acid and acetic acid, and it can be used at 1 to 5 mol equivalent relative to Compound (A-9).
Sodium nitrite can be used at 1 to 5 mol equivalent(s) relative to Compound (A-9).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 80° C.
The reaction time is 0.1 to 72 hour(s), preferably 0.5 to 60 hour(s).
Examples of the reaction solvent include dichloromethane, chloroform, THF, toluene, DMF, DMSO, NMP, and dioxane, and it can be used alone or in combination.
(Step 2)
Compound (B-2) can be obtained by reacting Compound (B-1) with paranitrobenzoic acid in the presence of phosphine and azodicarboxylic acid ester.
The paranitrobenzoic acid can be used at 1 to 5 mol equivalent(s) relative to Compound (B-1).
As the phosphine, triphenylphosphine, tributylphosphine, trimethylphosphine and the like are exemplified, and it can be used at 1 to 3 mol equivalent(s) relative to Compound (B-1).
As the azodicarboxylic acid ester, diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like are exemplified, and it can be used at 1 to 3 mol equivalent(s) relative to Compound (B-1).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, THF, toluene and the like are exemplified, and it can be used alone or in combination.
(Step 3)
Compound (B-3) can be obtained by deprotection of protecting group for carboxyl group of Compound (B-2) which is obtained in the above step 2. For example, the method disclosed in the above literature A can be used.
(Step 4)
Compound (I-B) can be obtained from Compound (B-3) which is obtained in the above step 3 in accordance with step 6 of the above Method A.
(Alternative Method)
Compound (I-B) in which carbamate is stereoinverted can be obtained from Compound (B-1) which is obtained in step 1 of the above Method B in accordance with step 6 of the above Method A.
(Method C)
(Step 1)
Compound (C-2) can be obtained by reacting Compound (A-9) with Compound (C-1) in the presence of a base.
Compound (A-9) can be synthesized in accordance with the above Method A.
Compound (C-1) is commercially available or can be synthesized according to the methods well known in the art and used at 1 to 1.5 mol equivalent(s) relative to Compound (A-9).
Examples of the base include pyridine, triethylamine, diisopropylethylamine, and N-methylmorpholine, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (A-9).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 100° C.
The reaction time is 0.1 to 72 hour(s), preferably 0.5 to 60 hour(s).
Examples of the reaction solvent include dichloromethane, chloroform, THF, toluene, DMF, DMSO, NMP, and dioxane, and it can be used alone or in combination.
(Step 2)
Compound (I-C) can be obtained from Compound (C-2) which is obtained in the above step 1 in accordance with step 6 of the above Method A.
(Method D)
Compound (I-D) can be obtained by reacting Compound (C-2) with Compound (D-1) in the presence of a condensing agent and a base.
Compound (C-2) can be synthesized in accordance with the above Method A and Method C.
Compound (D-1) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (C-2).
As the condensing agent, HATU, COMU, EDC and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (C-2).
As the base, pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (C-2).
The reaction temperature is −20° C. to the reflux temperature of the solvent, preferably −10 to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, chloroform, THF, toluene, DMF, DMSO, NMP, dioxane and the like are exemplified, and it can be used alone or in combination.
(Method E)
Compound (I-E) can be obtained in accordance with the above Method D.
Compound (E-1) is commercially available or can be synthesized according to the known methods.
Compound (E-2) is commercially available or can be synthesized according to the known methods.
(Method F)
(Step 1)
Compound (F-3) can be obtained by reacting Compound (F-1) with Compound (F-2) in the presence of a base. A catalyst can be also present.
Compound (F-1) is commercially available or can be synthesized according to the known methods.
Compound (F-2) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (F-1).
As the base, sodium hydride, potassium tert-butoxide and the like are exemplified, and it can be used at 1 to 1.5 mol equivalent(s) relative to Compound (F-1).
As the catalyst, sodium iodide, potassium iodide and the like are exemplified, and it can be used at 0.05 to 0.2 mol equivalents relative to Compound (F-1).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, DMF, THF and the like are exemplified, and it can be used alone or in combination.
(Step 2)
Compound (F-4) can be obtained by treating Compound (F-3) which is obtained in the above step 1 with an acid in a sealed tube.
As the acid, hydrochloric acid, sulfuric acid and the like are exemplified, and it can be used at 1 to 10 mol equivalent(s) relative to Compound (F-3).
The reaction temperature is 0° C. to 120° C., preferably room temperature to 100° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, methanol, ethanol and the like are exemplified, and it can be used alone or in combination.
(Step 3)
Compound (F-5) can be obtained by treating Compound (F-4) which is obtained in the above step 2 in the presence of a catalyst under hydrogen atmosphere.
As the catalyst, palladium-carbon, palladium hydroxide and the like are exemplified, and it can be used at 0.01 to 0.1 mol equivalent relative to Compound (F-4).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, methanol, ethyl acetate, tetrahydrofuran and the like are exemplified, and it can be used alone or in combination.
(Step 4)
Compound (F-6) can be obtained by deprotection of protecting group for carboxyl group of Compound (F-5) which is obtained in the above step 2. For example, the method disclosed in the above literature A can be used.
(Step 5)
Compound (I-F) can be synthesized in accordance with steps 5 and 6 of the above Method A, and Method B, Method C and Method D.
(Method G)
(Step 1)
Compound (G-3) can be obtained by reacting Compound (G-1) with Compound (G-2) in the presence of an acid.
Compound (G-1) is commercially available or can be synthesized according to the methods well known in the art.
Compound (G-2) is commercially available or can be synthesized according to the methods well known in the art. It can be used at 1 to 3 mol equivalent(s) relative to Compound (G-1).
As the acid, paratoluenesulfonic acid, hydrochloric acid and the like are exemplified, and it can be used at 0.01 to 0.2 mol equivalent relative to Compound (G-1).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
Examples of the reaction solvent include toluene and dichloroethane are exemplified, and it can be used alone or in combination.
(Step 2)
Compound (G-4) can be obtained by deprotection of protecting group for carboxyl group of Compound (G-3) which is obtained in the above step 1. For example, the method disclosed in the above literature A can be used.
(Step 3)
Compound (I-G) can be synthesized in accordance with steps 5 and 6 of the above Method A, and Method B, Method C and Method D.
(Method H)
(Step 1)
Compound (I-H) can be obtained in accordance with step 6 of the above Method A.
Compound (H-1) is commercially available or can be synthesized according to the known methods.
Compound (A-10) can be synthesized according to the known methods.
(Method M)
(Step 1)
Compound (M-3) can be obtained by reacting Compound (M-1) with Compound (M-2) in the presence of a base. A catalyst can be also present.
Compound (M-2) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (M-1).
As the base, diisopropyl ethylamine, triethylamine and the like are exemplified, and it can be used at 1 to 1.5 mol equivalent(s) relative to Compound (M-1).
As the catalyst, sodium iodide, potassium iodide and the like are exemplified, and it can be used at 0.05 to 0.2 mol equivalent relative to Compound (M-1).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 100° C.
The reaction time is 0.1 to 24 hour(s), preferably 8 to 24 hour(s).
As the reaction solvent, DMF, DMSO and the like are exemplified, and it can be used alone or in combination.
(Step 2)
Compound (M-6) can be obtained by reacting Compound (M-3) which is obtained in the above step 1 with Compound (M-4) and Compound (M-5) in the presence of a desiccant.
Compound (M-4) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (M-3).
Compound (M-5) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (M-3).
As the desiccant, molecular sieve 5 A, magnesium sulfate and the like are exemplified.
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 100° C.
The reaction time is 0.1 to 24 hour(s), preferably 8 to 24 hour(s).
As the reaction solvent, toluene, xylene and the like are exemplified, and it can be used alone or in combination.
(Step 3)
Compound (M-7) can be obtained by treating Compound (M-6) which is obtained in the above step 2 in the presence of a catalyst under hydrogen atmosphere.
As the catalyst, palladium-carbon, palladium hydroxide and the like are exemplified, and it can be used at 0.01 to 0.1 mol equivalent relative to Compound (M-6).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, methanol, ethyl acetate, tetrahydrofuran and the like are exemplified, and it can be used alone or in combination.
(Step 4)
Compound (M-9) can be obtained by deprotection of the Boc group of Compound (M-8). For example, the method disclosed in the above literature A can be used.
Compound (I-M) can be synthesized in accordance with the above Methods A, B, C, D and E by using Compound (M-7) as the starting material.
(Step 5)
Compound (I-M′) can be obtained by reacting Compound (I-M) with Compound (M-9) in the presence of a base. A catalyst can be also present.
Compound (M-9) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (I-M).
As the base, diisopropylethylamine, triethylamine and the like are exemplified, and it can be used at 1 to 1.5 mol equivalent(s) relative to Compound (I-M).
As the catalyst, sodium iodide, potassium iodide and the like are exemplified, and it can be used at 0.05 to 0.2 mol equivalent relative to Compound (I-M).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 8 to 24 hour(s).
As the reaction solvent, DMF, DMSO and the like are exemplified, and it can be used alone or in combination.
(Method J)
(Step 1)
Compound (J-3) can be obtained by reacting Compound (J-1) with Compound (J-2) in the presence of dimethylzinc. A catalyst can be also present.
Compound (J-1) is commercially available or can be synthesized according to the known methods.
Compound (J-2) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (J-1).
The dimethylzinc can be used at 1 to 5 mol equivalent(s) relative to Compound (J-1).
As the catalyst, Compound (J-9) is exemplified, and it can be used at 0.01 mol to 0.2 mol equivalent.
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably 0° C. to 50° C.
The reaction time is 0.1 to 100 hour(s), preferably 10 to 50 hours.
As the reaction solvent, xylene, toluene and the like are exemplified, and it can be used alone or in combination.
(Step 2)
Compound (J-5) can be obtained by reacting Compound (J-3) which is obtained in the above step 1 with Compound (J-4) in the presence of palladium acetate, tri-tert-butylphosphine, and acetic acid.
Compound (J-4) is commercially available or can be synthesized according to the known methods. Compound (J-4) means boronic acid of the above substituent B. It can be used at 1 to 5 mol equivalent(s) relative to Compound (J-3).
The palladium acetate can be used at 0.01 to 0.1 mol equivalent relative to Compound (J-3).
The tri-tert-butylphosphine can be used at 0.01 to 0.1 mol equivalent relative to Compound (J-3).
The acetic acid can be used at 0.05 to 0.2 mol equivalent relative to Compound (J-3).
The reaction temperature is room temperature to the reflux temperature of the solvent, preferably 0 to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, tetrahydrofuran, 1,4-dioxane and the like are exemplified, and it can be used alone or in combination.
(Step 3)
Compound (J-6) can be obtained by stirring Compound (J-5) which is obtained in the above step 2 in the presence of a catalyst under hydrogen atmosphere.
As the catalyst, palladium-carbon, palladium hydroxide and the like are exemplified, and it can be used at 0.01 to 0.2 mol equivalent relative to Compound (J-5).
The reaction temperature is room temperature to the reflux temperature of the solvent, preferably 0 to 60° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, ethyl acetate, tetrahydrofuran, methanol and the like are exemplified, and it can be used alone or in combination.
(Step 4)
Compound (J-7) can be obtained by reacting Compound (J-6) which is obtained in the above step 3 with a reducing agent.
As the reducing agent, diisobutyl aluminum hydride, lithium aluminum hydride, sodium borohydride and the like are exemplified, and it can be used at 1 to 3 mol equivalent(s) relative to Compound (J-6).
The reaction temperature is −78° C. to the reflux temperature of the solvent, preferably −78° C. to room temperature.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, tetrahydrofuran, methanol and the like are exemplified, and it can be used alone or in combination.
(Step 5)
Compound (I-J) can be obtained by reacting Compound (J-7) which is obtained in the above step 4 with Compound (J-8) in the presence of an acid.
Compound (J-8) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 5 mol equivalent(s) relative to Compound (J-7).
As the acid, paratoluenesulfonic acid and the like are exemplified, and it can be used at 0.01 mol to 2 mol equivalent(s) relative to Compound (J-7).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably 50° C. to the reflux temperature of the solvent.
The reaction time is 0.1 to 100 hour(s), preferably 10 to 50 hours.
As the reaction solvent, 1,4-dioxane, toluene and the like are exemplified, and it can be used alone or in combination.
(Method K)
(Step 1)
Compound (K-3) can be obtained by reacting Compound (K-1) with Compound (K-2) in the presence of a condensing agent and a base.
Compound (K-1) is commercially available or can be synthesized according to the known methods.
Compound (K-2) is commercially available or can be synthesized according to the known methods. It can be used at 1 to 3 mol equivalent(s) relative to Compound (K-1).
As the condensing agent, HATU, COMU, EDC and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (K-1).
As the base, pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (K-1).
The reaction temperature is −20° C. to the reflux temperature of the solvent, preferably −10 to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, chloroform, THF, toluene, DMF, DMSO, NMP, dioxane and the like are exemplified, and it can be used alone or in combination.
(Step 2)
Compound (K-4) can be obtained by reacting Compound (K-3) which is obtained in the above step 1 with a halogenating agent.
As the halogenating agent, thionyl chloride, N,N-diethylaminosulfur trifluoride and the like are exemplified, and it can be used at 1 mol to 3 mol equivalent(s) relative to Compound (K-3).
The reaction temperature is −78° C. to the reflux temperature of the solvent, preferably −78° C. to 50° C.
The reaction time is 0.1 to 100 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, chloroform and the like are exemplified, and it can be used alone or in combination.
(Step 3)
Compound (K-5) can be obtained by deprotection of protecting group for carboxyl group of Compound (K-4) which is obtained in the above step 2. For example, the method disclosed in the above literature A can be used.
(Step 4)
Compound (I-K) can be synthesized in accordance with steps 5 and 6 of the above Method A, and Method B, Method C and Method D.
(Method L)
(Steps 1 to 3)
Compound (L-7) can be obtained in accordance with steps 1, 2 and 3 of the above Method A.
(Step 4)
Compound (L-8) can be obtained in accordance with step 1 of Method A′.
(Step 5)
Compound (L-9) can be obtained by reacting Compound (L-8) with (9H-fluoren-9-yl)methanol and iodobenzene diacetate.
(9H-Fluoren-9-yl)methanol can be used at 1 to 10 mol equivalent(s) relative to Compound (L-8).
Iodobenzene diacetate can be used at 1 to 5 mol equivalent(s) relative to Compound (A-8-1).
The reaction temperature is 50° C. to the reflux temperature of the solvent, preferably 60 to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, 1,2-dichloroethane, toluene, xylene and the like are exemplified, and it can be used alone or in combination.
(Step 6)
Compound (I-L) can be obtained by reacting Compound (L-9) with Compound (L-10) in the presence of DMAP.
Compound (L-10) can be synthesized in accordance with the method described in WO2012158413. It can be used at 1 to 1.5 mol equivalent(s) relative to Compound (L-9).
DMAP can be used at 1 to 1.5 mol equivalent(s) relative to Compound (L-9).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, chloroform, THF, toluene, DMF, DMSO, dioxane and the like are exemplified, and it can be used alone or in combination.
(Method N)
(Step 1)
Compound (N-2) can be obtained by reacting Compound (N-1) which can be synthesized in accordance with the known methods with sulfonyl chloride in the presence of a base and a catalyst.
As the sulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like are exemplified, and it can be used at 1 to 1.5 mol equivalent(s) relative to Compound (N-1).
As the base, triethylamine, diisopropylethylamine, pyridine and the like are exemplified, and it can be used at 1 to 1.5 mol equivalent(s) relative to Compound (N-1).
As the catalyst, dibutyltin oxide and the like are exemplified, and it can be used at 0.01 to 0.1 mol equivalent relative to Compound (N-1).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, chloroform, 1,2-dichloroethane, toluene and the like are exemplified, and it can be used alone or in combination.
(Step 2)
Compound (N-3) can be obtained by treating Compound (N-2) with a base.
As the base, sodium hydride, potassium tert-butoxide, potassium carbonate and the like are exemplified, and it can be used at 1 to 1.5 mol equivalent(s) relative to Compound (N-2).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, THF, DMF, dioxane, methanol, tert-butanol and the like are exemplified, and it can be used alone or in combination.
(Step 3)
Compound (N-4) can be obtained by treating Compound (N-3) with vinyl magnesium bromide in the presence of a catalyst.
The vinyl magnesium bromide can be used at 1 to 1.5 mol equivalent(s) relative to Compound (N-3).
As the catalyst, copper iodide, copper cyanide and the like are exemplified, and it can be used at 0.01 to 0.2 mol equivalent relative to Compound (N-3).
The reaction temperature is −78° C. to the reflux temperature of the solvent, preferably −78° C. to room temperature.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, THF, diethyl ether and the like are exemplified, and it can be used alone or in combination.
(Step 4)
Compound (N-5) can be obtained by reacting Compound (N-4) with allylchlorodimethylsilane in the presence of a base.
The allylchlorodimethylsilane can be used at 1 to 1.5 mol equivalent(s) relative to Compound (N-4).
As the base, triethylamine, diisopropylethylamine, imidazole and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (N-4).
The reaction temperature is −20° C. to 50° C., preferably 0° C. to room temperature.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, 1,2-dichloroethane, DMF and the like are exemplified, and it can be used alone or in combination.
(Step 5)
Compound (N-6) can be obtained by reacting Compound (N-5) with a Grubbs catalyst.
As the Grubbs catalyst, first-generation Grubbs catalysts and second-generation Grubbs catalysts and the like are exemplified, and it can be used at 0.01 to 0.05 mol equivalent relative to Compound (N-5).
The reaction temperature is 0° C. to 50° C., preferably room temperature to 40° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, 1,2-dichloroethane, toluene and the like are exemplified, and it can be used alone or in combination.
(Step 6)
Compound (N-8) can be obtained by reacting Compound (N-6) with Compound (N-7) in the presence of a Lewis acid.
Compound (N-7) is commercially available or can be synthesized according to the known synthetic methods, and it can be used at 1 to 2 mol equivalent(s) relative to Compound (N-6).
As the Lewis acid, a boron trifluoride-diethyl ether complex, trimethylsilyl trifluoromethanesulfonate and the like are exemplified, and it can be used at 1 to 1.5 mol equivalent(s) relative to Compound (N-6).
The reaction temperature is −78° C. to 50° C., preferably −78° C. to room temperature.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, 1,2-dichloroethane and the like are exemplified, and it can be used alone or in combination.
(Step 7)
Compound (N-9) can be obtained by subjecting Compound (N-8) to ozone oxidation, followed by treatment with dimethyl sulfide.
Dimethyl sulfide can be used at 10 to 50 mol equivalents relative to Compound (N-8).
The reaction temperature is −100 to −50° C., preferably −78° C. to −60° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, methanol and the like are exemplified, and it can be used alone or in combination.
(Step 8)
Compound (N-10) can be obtained by reacting Compound (N-9) with sodium chlorite in the presence of 2-methyl-2-butene and sodium dihydrogen phosphate.
Sodium chlorite can be used at 1 to 5 mol equivalent(s) relative to Compound (N-9).
2-Methyl-2-butene can be used at 10 to 20 mol equivalents relative to Compound (N-9).
Sodium dihydrogen phosphate can be used at 3 to 10 mol equivalents relative to Compound (N-9).
The reaction temperature is 0° C. to the reflux temperature of the solvent, preferably room temperature to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, t-BuOH, water and the like are exemplified, and it can be used alone or in combination.
(Step 9)
Compound (N-11) can be obtained by reacting Compound (N-10) with diazoalkane.
As diazoalkane, diazomethane, trimethylsilyldiazomethane and the like are exemplified, and it can be used at 1 to 3 mol equivalent(s) relative to Compound (N-10).
The reaction temperature is −20° C. to 50° C., preferably 0° C. to room temperature.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 2 hour(s).
As the reaction solvent, dichloromethane, toluene, ether, methanol and the like are exemplified, and it can be used alone or in combination.
(Step 10)
Compound (N-12) can be obtained by treating Compound (N-11) with a base.
As the base, sodium methoxide, sodium ethoxide and the like are exemplified, and it can be used at 1 to 10 mol equivalent(s) relative to Compound (N-11).
The reaction temperature is −20° C. to 50° C., preferably 0° C. to room temperature.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 2 hour(s).
As the reaction solvent, methanol, ethanol and the like are exemplified, and it can be used alone or in combination.
(Step 11)
Compound (N-13) can be obtained by reacting Compound (N-12) with ammonia in the presence of a condensing agent and a base.
As ammonia, an ammonia-dioxane solution, ammonium chloride and the like are exemplified, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (N-12).
Examples of the condensing agent include HATU, COMU, and EDC, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (N-12).
Examples of the base include pyridine, triethylamine, diisopropylethylamine, and N-methylmorpholine, and it can be used at 1 to 5 mol equivalent(s) relative to Compound (N-12).
The reaction temperature is −20° C. to the reflux temperature of the solvent, preferably −10 to 50° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, dichloromethane, chloroform, THF, toluene, DMF, DMSO, NMP, dioxane and the like are exemplified, and it can be used alone or in combination.
(Step 12)
Compound (N-14) can be obtained by reacting Compound (N-13) with allyl alcohol in the presence of iodobenzene diacetate.
Iodobenzene diacetate can be used at 1 to 3 mol equivalent(s) relative to Compound (N-13).
The allyl alcohol can be used at 10 to 50 mol equivalents relative to Compound (N-13).
The reaction temperature is room temperature to the reflux temperature of the solvent, preferably 40° C. to 80° C.
The reaction time is 0.1 to 24 hour(s), preferably 0.5 to 12 hour(s).
As the reaction solvent, 1,2-dichloroethane, toluene and the like are exemplified, and it can be used alone or in combination.
(Step 13)
Compound (N-14) can be deprotected in accordance with the method described in the above literature A to give Compound (N-15).
(Step 14)
Compound (I-N) can be obtained in accordance with step 6 of the above Method A.
The Compounds of Formula (I) of the present invention prepared by the above general synthetic method can be purified by referring to the known methods (e.g., chromatography, and recrystallization).
The compound of the present invention has TrkA inhibitory activity and it can be available for therapeutic agent and/or prophylactic agent for pain associated with osteoarthritis, rheumatoid arthritis, fracture, interstitial cystitis, chronic pancreatitis and prostate inflammation; and nociceptive pain as typified by chronic low back pain, diabetic peripheral neuropathy pain, postoperative pain, pelvic pain and cancer pain; neuropathic pain, acute pain, chronic pain, cancer, inflammatory disease, allergic disease, dermatological disease and the like.
The compound of the present invention has not only TrkA inhibitory activity but also are useful as a medicine and has any or all of the following excellent characteristics:
A pharmaceutical composition of the present invention can be administered orally or parenterally. Methods for parenteral administration include dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, and inner ear or vaginal administration.
In the case of oral administration of pharmaceutical composition of the present invention, any forms, which are usually used, such as oral solid formulations (e.g., tablets, powders, granules, capsules, pills, or films), and oral liquid formulations (e.g., suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction, or tincture) may prepared according to the usual method and administered. The tablets can be sugar-coated tablets, film-coated tablets, enteric-coating tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets. Powders and granules can be dry syrups. Capsules can be soft capsules, micro capsules or sustained-release capsules.
In the case of parenteral administration of pharmaceutical composition of the present invention, any forms, which are usually used, such as injections, drips, and external preparations (e.g., ophthalmic drops, nasal drops, ear drops, aerosols, inhalations, lotion, infusion, liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm, external powder, or suppository) can be preferably administered. Injections can be emulsions whose type is O/W, W/O, O/W/O, W/O/W or the like.
The pharmaceutical composition may be manufactured by mixing an effective amount of the compound of the present invention with various pharmaceutical additives suitable for the formulation, such as excipients, binders, moistening agents, disintegrants, lubricants, and diluents. Furthermore, the pharmaceutical composition can be for pediatric patients, geriatric patients, serious cases or operations by appropriately changing the effective amount of the compound of the present invention, formulation and/or various pharmaceutical additives. The pediatric pharmaceutical compositions are preferably administered to patients under 12 or 15 years old. In addition, the pediatric pharmaceutical compositions can be administered to patients who are under 27 days old after the birth, 28 days to 23 months old after the birth, 2 to 11 years old, 12 to 16 years old, or 18 years old. The geriatric pharmaceutical compositions are preferably administered to patients who are 65 years old or over.
Although the dosage of a compound of the present invention should be determined in consideration of the patient's age and body weight, the type and degree of diseases, the administration route and the like, a usual oral dosage is 0.05 to 100 and preferably 0.1 to 10 mg/kg/day. For parenteral administration, although the dosage highly varies with administration routes, a usual dosage is 0.005 to 10 and preferably 0.01 to 1 mg/kg/day. The dosage may be administered in one to several divisions per day.
The compound of the present invention can be used in combination of therapeutic agents for pain, anti-inflammatory agents, anticancer agents, or the like (hereinafter referred to as a co-administered drug) to increase the activity of the compound or reduce the dose of the compound, or the like. In this case, the timing of administration for a compound of the present invention and the co-administered drug is not limited. They can be administered to the subjects to be treated, at a time or at different times. Furthermore, a compound of the present invention and the co-administered drug can be administered as two formulations independently comprising each active ingredient or a single formulation comprising the both active ingredients.
The dose for co-administered drugs may be appropriately selected in reference to the clinical dose. The compounding ratio of the compounds of the present invention and co-administered drugs may be appropriately selected depending on the subject to be treated, administration route, disease to be treated, symptoms, combination of the drugs and the like. For administration in humans, for example, 1 part by weight of the compounds of the present invention may be used in combination with 0.01 to 100 parts by weight of co-administered drugs.
For example, the therapeutic agent for pain includes cyclooxygenase inhibitor (e.g., ketoprofen, celecoxib), neuropathic disorder agent (e.g., pregabalin), antidepressant (e.g., duloxetine, amitriptyline), opioid receptor agonist (e.g., morphine, tramadol), regional anesthetic (e.g., lidocaine), ketamine, and acetaminophen.
For example, the anti-inflammatory agent includes steroid agent (e.g., prednisolone), and antihistamine agent (e.g., loratadine).
For example, the anticancer agent includes molecularly-targeted agent (e.g., lapatinib, rituximab), alkylating agent (e.g., cyclophosphamide), antimetabolite (e.g., methotrexate), alkaloid agent (e.g., paclitaxel), platinum agent (e.g., oxaliplatin), and hormonal agent (e.g., tamoxifen, leuprorelin).
The present invention will be described in more detail with reference to, but not limited to, the following Examples, Reference Examples and Test Examples.
In this description, meaning of each abbreviation is as follows:
Boc: tert-butoxycarbonyl
Boc2O: di-tert-butyl dicarbonate
CDCl3: deuterated chloroform
CD3OD: deuterated methanol
CF3: trifluoromethyl
COMU: (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate
DEAD: diethyl azodicarboxylate
DIEA: N,N-diisopropylethylamine
DMA: N,N-dimethylacetamide
DMAP: 4-dimethylaminopyridine
DMF: N,N-dimethylformamide
DMSO: dimethylsulfoxide
DPPA: diphenylphosphoryl azide
EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Fmoc: 9-fluorenylmethyloxycarbonyl
HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
Fmoc: 9-fluorenylmethyloxycarbonyl
HOBt: 1-hydroxybenzotriazole
Me: methyl
NO2: nitro
PdCl2(dppf): 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride
t-BuOH: tert-butanol
THF: tetrahydrofuran
TMS: trimethylsilyl
TFA: trifluoroacetic acid
NMR analysis of each example was performed by 400 MHz using DMSO-d6 or CDCl3. In the case of indicating NMR data, there are cases in which not all measured peaks are described.
(Method 1)
(Method 2)
(Method 3)
Hereinafter, MS(m/z) indicates the value observed in the mass spectrometry.
Step 1
Compound 1 (815 mg, 3.07 mmol) which can be synthesized in accordance with the known method (WO2014/078331) was dissolved in dichloromethane (10 mL) under nitrogen atmosphere, and phenyl chloroformate (0.424 ml, 3.38 mmol) and pyridine (0.298 ml, 3.69 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 1 hour.
Ethyl acetate was added to the mixture. The organic layer was washed with saturated ammonium chloride aqueous solution and subsequently brine and then dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to give Compound W (1184 mg, Yield 100%).
LC/MS (Method 1) RT=1.79, MS(m/z)=386.20.
Step 1 Synthesis of Compound 2
To a solution of Compound V (3 g, 9.34 mmol) which can be synthesized in accordance with the known method (WO2012/158413) in 1,4-dioxane (30 mL) were added boronic acid ester (2.89 g, 9.34 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (73 mg, 0.093 mmol), potassium phosphate (3.96 g, 18.7 mmol), and water (15 mL) under nitrogen atmosphere, and the reaction mixture was stirred at 90° C. for 12 hours. Brine was added to the mixture, followed by extraction with ethyl acetate twice. Then, the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 2 (3.17 g, Yield 96%).
1H-NMR (CDCl3) δ: 1.49 (s, 9H), 2.04 (s, 3H), 2.64 (brs, 2H), 3.58-3.62 (m, 4H), 4.09 (brs, 2H), 6.02 (brs, 1H), 7.32 (tt, J=7.6, 1.2 Hz, 1H), 7.64 (t, J=7.6 Hz, 2H), 7.56 (dd. J=8.4, 1.2 Hz, 2H).
Step 2 Synthesis of Compound Y
To a solution of Compound 2 (1.84 g, 5.19 mmol) in DMA (20 mL) were added pyridine (1.68 mL, 20.8 mmol) and phenyl chloroformate (0.684 mL, 5.45 mmol), and the reaction mixture was stirred at room temperature for 12 hours. Water was added to the mixture, followed by extraction with ethyl acetate twice. Then, the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound Y (1.47 g, Yield 60%).
1H-NMR (CDCl3) δ: 1.49 (s, 9H), 2.19 (brs, 3H), 2.68 (brs, 2H), 3.62 (t, J=5.2 Hz, 2H), 4.11 (brs, 2H), 6.09 (brs, 1H), 7.12-7.52 (m, 10H).
Synthesis of Compound I-7
Step 1 Synthesis of Compound 4
Commercially available optically active Compound 3 (1.078 g, 5.49 mmol) was dissolved in dichloroethane (10.78 mL), and 1,1,3-trimethoxypropane (1.017 mL, 7.14 mmol) and paratoluenesulfonic acid (0.052 g, 0.275 mmol) were added to the solution. The reaction mixture was refluxed for 1.5 hours. After the mixture was allowed to cool to room temperature, saturated sodium bicarbonate aqueous solution and chloroform were added to the mixture to separate an organic layer. The separated organic layer was washed with water and then dried over anhydrous sodium sulfate, and the solvent was distilled off to give a residue. The obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 4 (1.096 g, Yield 74.9%) as a colorless oil.
1H-NMR (CDCl3) δ: 2.04-2.26 (m, 2H), 3.37 (s, 3H), 3.63 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 4.36 (d, J=6.0 Hz, 1H), 5.04 (d, J=6.4 Hz, 1H), 5.40 (t, J=4.4 Hz, 1H), 7.32-7.45 (m, 5H)
Step 2 Synthesis of Compound 5
Compound 4 (1.09 g, 4.09 mmol) was dissolved in methanol (10.9 mL), and 2 mol/L sodium hydroxide aqueous solution (4.09 mL, 8.19 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 30 minutes. After the termination of the reaction was confirmed, 10% citric acid aqueous solution was added to the mixture, followed by extraction with chloroform three times. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to give crude Compound 5. The compound was used in the next reaction without further purification.
Step 3 Synthesis of Compound 6
The crude Compound 5 (4.409 mmol) which was obtained in the above step was dissolved in 1,4-dioxane (20.64 mL), and triethylamine (0.624 mL, 4.50 mmol) and DPPA (0.967 mL, 4.50 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 1 hour and 45 minutes. (9H-Fluoren-9-yl)methanol (1.204 g, 6.14 mmol) was added to the mixture, and the reaction mixture was stirred at 80° C. for 1 hour. After the mixture was allowed to cool to room temperature, the reaction was terminated by the addition of water. The product was extracted with ethyl acetate, washed with water, and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 6 (1.945 g, Yield 106.7% (including fluorenemethanol as an impurity)) as a colorless solid.
1H-NMR (CDCl3) δ: 2.10 (br s, 2H), 3.36 (s, 3H), 3.60 (br t, 2H), 4.04 (d, J=6.0 Hz, 1H), 4.21 (t, J=6.4 Hz, 1H), 4.44 (br s, 2H), 4.67 (br s, 1H), 5.37 (t, J=4.4 Hz, 1H), 5.45 (dd, J=5.6, 9.6 Hz, 1H), 5.59 (d, J=9.6 Hz, 1H), 7.26-7.78 (m, 13H)
Step 4 Synthesis of Compound (I-7)
Compound 6 (280 mg, 0.629 mmol) was dissolved in DMF (4.7 mL), and Compound X (235 mg, 0.629 mmol) which can be synthesized in accordance with the known method (WO2012/158413) was added to the solution, and further DMAP (1.153 g, 9.44 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then left standing overnight at room temperature. 10% Citric acid aqueous solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silicagel column chromatography (chloroform-methanol) to give Compound (I-7) (45 mg, Yield 14.2%) as a solid.
1H-NMR (CDCl3) δ: 2.01-2.12 (m, 2H), 2.17 (s, 3H), 3.33 (s, 3H), 3.56 (t, J=6.4 Hz, 2H), 3.97 (s, 3H), 4.54 (d, J=4.4 Hz, 1H), 5.27 (t, J=4.8 Hz, 1H), 5.48-5.51 (m, 2H), 6.34 (s, 1H), 7.23-7.53 (m, 10H), 7.78 (s, 1H), 7.89 (s, 1H).
Synthesis of Compound (I-28)
Step 1 Synthesis of Compound 8
A solution of Compound 7 (1.40 g, 6.14 mmol) which can be synthesized in accordance with the known method (JP201256944A) in tetrahydrofuran (14 mL) was cooled to 1° C. in an ice bath. 60% Sodium hydride (294 mg, 7.36 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 1° C. again, and sodium iodide (92 mg, 0.614 mmol) and 1-chloro-4-methoxybutan-2-one (1.17 g, 8.59 mmol) were added to the mixture. The reaction mixture was stirred at room temperature for 2.5 hours. Saturated ammonium chloride aqueous solution (50 mL) was added to the mixture, followed by extraction with ethyl acetate (100 mL) twice. The organic layer was washed with brine (30 mL) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel chromatography (hexane-ethyl acetate) to give Compound 8 (1.88 g, Yield 93%) as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.17 (3H, t, J=7.0 Hz), 2.65-2.83 (2H, m), 3.16 (1H, dd, J=18.4, 5.4 Hz), 3.28-3.38 (4H, m), 3.58-3.69 (2H, m), 4.13 (2H, q, J=7.2 Hz), 4.81 (1H, dd, J=8.4, 5.4 Hz), 7.22-7.33 (1H, m), 7.81-7.92 (2H, m).
Step 2 Synthesis of Compound 9
Compound 8 (1.83 g, 5.57 mmol) was dissolved in methanol (18 mL), and concentrated hydrochloric acid (2.79 mL, 33.4 mmol) was added to the solution. The reaction mixture was stirred at 100° C. for 2 hours under microwave irradiation in a sealed tube. The mixture was added to a sodium bicarbonate aqueous solution to be neutralized, followed by extraction with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silicagel chromatography (hexane-ethyl acetate) to give Compound 9 as a mixture with ethyl ester form (1.11 g, Yield 67%).
Step 3 Synthesis of Compound 10
The mixture of Compound 9 and its ethyl ester form (1.00 g, 3.38 mmol) which were obtained in step 2 was dissolved in ethyl acetate (10 mL), and 10% palladium-carbon (760 mg) was added to the solution. The reaction mixture was stirred for 21 hours under hydrogen atmosphere. The mixture was filtered through celite pad, and the solvent was concentrated under reduced pressure. The residue was purified by silicagel chromatography (hexane-ethyl acetate) to give a colorless oil (891 mg).
The obtained oil (888 mg) was dissolved in methanol (2.6 mL), and 28% sodium methoxide-methanol solution (2.94 mL, 14.8 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 67 hours. Water (1 mL) was added to the mixture, and the reaction mixture was further stirred for 1 hour and then neutralized by the addition of 2 mol/L hydrochloric acid aqueous solution (7.4 mL, 14.8 mmol). The solvent and water were distilled off under reduced pressure, and the obtained residue was purified by silicagel chromatography (chloroform-methanol) to give Compound 10 (racemate, 831 mg, Yield 84%) as a colorless oil.
1H-NMR (CDCl3) δ: 1.88-2.05 (3H, m), 2.42-2.48 (1H, m), 2.93 (1H, ddd, J=11.2, 5.9, 4.1 Hz), 3.36 (3H, s), 3.56 (2H, t, J=6.4 Hz), 4.20-4.27 (1H, m), 5.01 (1H, d, J=7.0 Hz), 7.08-7.17 (2H, m), 7.20-7.25 (1H, m).
Step 4 Synthesis of Compound 11
Compound 10 (750 mg, 2.62 mmol) was dissolved in DMF (7.5 mL), and DPPA (789 L, 3.67 mmol) and triethylamine (908 μL, 6.55 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 30 minutes, then stirred at 80° C. for 1 hour, and allowed to cool. 2-Trimethylsilylethanol (1.13 mL, 7.86 mmol) and triethylamine (1.45 mL, 10.5 mmol) were added thereto, and the reaction mixture was stirred at 80° C. for 7 hours. Sodium bicarbonate aqueous solution (70 mL) was added to the mixture, followed by extraction with ethyl acetate (100 mL) twice. The obtained organic layer was washed with brine (50 mL) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel chromatography (hexane-ethyl acetate) to give Compound 11 (racemate, 668 mg, Yield 64%) as a colorless oil.
1H-NMR (CDCl3) δ: 0.04 (9H, s), 0.98 (2H, t, J=8.1 Hz), 1.86-2.04 (4H, m), 3.37 (3H, s), 3.50-3.63 (2H, m), 4.06 (1H, br s), 4.11-4.22 (2H, m), 4.27-4.34 (1H, m), 4.75 (1H, br s), 4.88 (1H, br s), 7.07-7.21 (2H, m), 7.22-7.34 (2H, m).
Step 5 Synthesis of Compound (I-28)
To a solution of Compound 11 (40 mg, 0.10 mmol) in dichloromethane (0.4 mL) was added TFA (0.4 mL), and the reaction mixture was stirred at room temperature for 1 hour. The solvent and TFA were distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (1 mL) again, and DIEA (87 μL, 0.50 mmol) and Compound W (48 mg, 0.13 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 2 days. After concentration under reduced pressure, the obtained residue was purified by amino silicagel chromatography (hexane-ethyl acetate) to give Compound (I-28) (racemate, 42 mg, Yield 77%) as a pale yellow solid.
1H-NMR (CDCl3) δ: 1.74-1.81 (1H, m), 1.83-2.01 (3H, m), 2.24 (3H, s), 2.81 (3H, s), 3.35 (3H, s), 3.47-3.60 (2H, m), 4.11-4.22 (2H, m), 4.54 (1H, d, J=3.8 Hz), 4.85 (1H, d, J=7.5 Hz), 6.11 (1H, s), 7.01-7.12 (2H, m), 7.16 (1H, t, J=8.8 Hz), 7.41 (1H, t, J=7.3 Hz), 7.49 (2H, t, J=7.7 Hz), 7.56 (2H, d, J=7.9 Hz), 9.05 (2H, s).
Synthesis of Compound (I-31)
Step 1 Synthesis of Compound 13
Commercially available Compound 12 (6.7 g, 28.7 mmol), 2-methoxyethanol (2.267 mL, 28.7 mmol) and triphenylphosphine (9 g, 34.5 mmol) were dissolved in tetrahydrofuran (67 mL) under water-cooling bath, and 2.2 mol/L DEAD-toluene solution (15.67 mL, 34.5 mmol) was added dropwise to the solution over 30 minutes. Then, the reaction mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 13 (8.15 g, Yield 97.4%).
LC/MS (Method 2) RT=2.20, MS (m/z)=292
Step 2 Synthesis of Compound 14
To Compound 13 (1510 mg, 5.2 mmol) was added 4 mol/L hydrochloric acid-dioxane solution (20 mL), and the reaction mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, then the obtained residue was suspended in toluene (10 mL), and triethylamine (2.16 mL, 15.6 mmol), paraformaldehyde (468 mg, 15.6 mmol), and (E)-methyl 3-(3,4-difluorophenyl) acrylate (1030 mg, 5.2 mmol) were added to the suspension. Then, the reaction mixture was stirred overnight at 70° C.
The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 14 (racemate, 1293 mg, 82.6%).
LC/MS (Method 2) RT=1.90, MS (m/z)=302
Step 3 Synthesis of Compound 15
Compound 14 (1290 mg, 4.28 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and 2 mol/L sodium hydroxide aqueous solution (2.57 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 hour.
The mixture was neutralized by the addition of 2 mol/L hydrochloric acid (2.57 mL), and then the solvent was distilled off under reduced pressure. Further, water was removed by azeotropy with toluene to give Compound 15 (racemate). The compound was used in the next reaction without further purification.
LC/MS (Method 2) RT=1.66, MS (m/z)=288
Step 4 Synthesis of Compound 16
Compound 15 (100 mg, 0.348 mmol) was dissolved in DMF (2 mL), and triethylamine (0.097 mL, 0.696 mmol) and DPPA (0.090 mL, 0.418 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 0.5 hour.
Water was added to the mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 16 (racemate, 40 mg, Yield 32.1%).
LC/MS (Method 2) RT=1.99, MS (m/z)=359
Step 5 Synthesis of Compound Z
To Compound 16 (45 mg, 0.126 mmol) was added 4 mol/L hydrochloric acid-dioxane solution (1 mL), and the reaction mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure to give Compound Z (racemate). The compound was used in the next reaction without further purification.
LC/MS (Method 2) RT=1.01, MS (m/z)=259
Step 6 Synthesis of Compound 17
Compound Z (0.126 mmol) was dissolved in tetrahydrofuran (1 mL), and triethylamine (0.087 mL, 0.63 mmol) and Compound Y (71.8 mg, 0.151 mmol) which was synthesized in Reference Example 2 were added to the solution. The reaction mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 17 (racemate, 55 mg, Yield 68.3%).
LC/MS (Method 2) RT=2.63, MS (m/z)=639
Step 7 Synthesis of Compound 18
To Compound 17 (50 mg, 0.078 mmol) was added 4 mol/L hydrochloric acid-dioxane solution (1 mL), and the reaction mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, and then diisopropyl ether was added to the obtained residue for precipitating to give Compound 18 (racemate, 43 mg, Yield 95.5%) as a yellow solid.
LC/MS (Method 2) RT=1.56, MS (m/z)=539
Step 8 Synthesis of Compound (I-31)
Compound 18 (17 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (0.041 mL, 0.296 mmol) and acetyl chloride (5.27 μL, 0.074 mmol) were added to the solution. The reaction mixture was left standing overnight. Water was added to the residue, followed by extraction with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel column chromatography (chloroform-methanol) to give Compound (I-31) (racemate, 15 mg, Yield 87.4%).
LC/MS (Method 2) RT=1.95, MS(m/z)=581
1H-NMR (CDCl3) δ: 1.62 (m, 2H), 2.14 (s, 3H), 2.17 (m, 3H), 2.75 (m, 2H), 3.04 (m, 2H), 3.33 (s, 3H), 3.51 (m, 1H), 3.67 (m, 2H), 3.82 (m, 1H), 4.19 (m, 1H), 4.29 (m, 1H), 4.50 (m, 2H), 5.63 (brs, 1H), 6.12 (d, J=11.9 Hz, 1H), 6.34 (brs, 1H), 6.97-7.16 (m, 3H), 7.32 (m, 1H), 7.41 (m, 2H), 7.51 (m, 2H).
Synthesis of Compound (I-43)
Step 1 Synthesis of Compound 19
To a solution of Compound V (40 g, 121 mmol) which can be synthesized in accordance with the known method (WO2012/158413) in 1,4-dioxane (150 mL) were added Boc2O (85 mL, 364 mmol), triethylamine (50.5 mL, 364 mmol) and DMAP (0.3 g, 2.4 mmol), and the reaction mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 19 (33 g, Yield 78%).
1H-NMR (CDCl3) δ: 1.31 (s, 18H), 2.00 (s, 3H), 7.37-7.48 (m, 5H).
Step 2 Synthesis of Compound 20
To a solution of Compound 19 (31 g, 59 mmol) in 1,4-dioxane (230 mL) were added bis(pinacolato)diboron (18.1 g, 71.3 mmol), a dichloromethane adduct of PdCl2(dppf) (4.85 g, 5.94 mmol), and potassium acetate (17.5 g, 178 mmol) under nitrogen atmosphere, and the reaction mixture was stirred at 95° C. for 7 hours. The solvent was distilled off under reduced pressure until the amount of the solvent became one-third. Ethyl acetate (300 mL) was added to the residue. The organic layer was washed with water (100 mL) and brine (100 mL×2) and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 20 (26.5 g, Yield 90%).
1H-NMR (DMSO-d6) δ: 1.26-1.31 (m, 30H), 2.01 (s, 3H), 7.38 (d, J=7.6 Hz, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 2H).
Step 3 Synthesis of Compound 21
To a solution of Compound 20 (542 mg, 1.08 mmol) in 1,4-dioxane (25 mL) were added 6-bromo-2-methyl[1,2,4]triazolo[1,5-a]pyrimidine (231 mg, 1.08 mmol) which can be synthesized in accordance with the known method (J. Heterocyclic Chem. 2014, 51, E68), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (85 mg, 0.11 mmol), and cesium carbonate (707 mg, 2.17 mmol) under nitrogen atmosphere, and the reaction mixture was stirred at 90° C. for 7 hours. Brine was added to the mixture, followed by extraction with ethyl acetate twice. Then, the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 21 (446 mg, Yield 81%).
1H-NMR (CDCl3) δ: 1.35 (s, 18H), 2.22 (s, 3H), 2.67 (s, 3H), 7.39-7.52 (m, 5H), 9.08 (d, J=2.4 Hz, 1H), 9.27 (d, J=2.4 Hz, 1H).
Step 4 Synthesis of Compound 22
To a solution of Compound 21 (445 mg, 0.88 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and the reaction mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and saturated sodium hydrogen carbonate aqueous solution was added to the residue, followed by extraction with chloroform twice. Then, the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure to give Compound 22 (269 mg, Yield 100%).
1H-NMR (CDCl3) δ: 2.17 (s, 3H), 2.59 (s, 3H), 7.44 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 2H), 7.63 (d, J=7.6 Hz, 2H), 9.15 (d, J=2.4 Hz, 1H), 9.26 (d, J=2.4 Hz, 1H).
Step 4 Synthesis of Compound (I-43)
To a solution of Compound 22 (28.6 mg, 0.094 mmol) in DMA (2 mL) were added pyridine (0.030 mL, 0.375 mmol) and phenyl chloroformate (0.013 mL, 0.103 mmol), and the reaction mixture was stirred at room temperature for 12 hours. Compound Z (27.5 mg, 0.094 mmol) which was synthesized in step 5 of Example 3 and triethylamine (0.065 mL, 0.468 mmol) were added to the mixture, and the reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, followed by extraction with ethyl acetate twice. Then, the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silicagel column chromatography (ethyl acetate-methanol) to give Compound (I-43) (racemate, 29.0 mg, Yield 56%).
1H-NMR (CDCl3) δ: 2.29 (s, 3H), 2.68 (s, 3H), 2.884-3.13 (m, 4H), 3.35 (s, 3H), 3.94-3.52 (m, 1H), 3.68 (brs, 1H), 4.54-4.59 (m, 2H), 7.00-7.14 (m, 3H), 7.41 (t, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.58 (d, J=7.6 Hz, 2H), 9.09 (d, J=2.4 Hz, 1H), 9.25 (d, J=2.4 Hz, 1H).
Synthesis of Compound (I-36)
Step 1 Synthesis of Compound 23
To a solution of Compound V (1.34 g, 4.17 mmol) which can be synthesized in accordance with the known method (WO2012/158413) in 1,4-dioxane (15 mL) were added (4-(tert-butoxycarbonyl)phenyl)boronic acid (1.11 g, 5.00 mmol), potassium phosphate (1.77 g, 8.34 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.033 g, 0.042 mmol), and water (7.5 mL), and the reaction mixture was stirred at 90° C. for 6 hours. Brine was added to the mixture, followed by extraction with ethyl acetate twice. Then, the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 23 (1.21 g, Yield 83%).
1H-NMR (CDCl3) δ: 1.61 (s, 9H), 2.14 (s, 3H), 3.67 (s, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H).
Step 2 Synthesis of Compound 24
To a solution of Compound 23 (268 mg, 0.766 mmol) in ethyl acetate (3 mL) were added 2 mol/L sodium hydroxide aqueous solution (1.92 mL, 3.83 mmol) and phenyl chloroformate (0.288 mL, 2.30 mmol), and the reaction mixture was stirred at room temperature for 12 hours. Water was added to the mixture, followed by extraction with ethyl acetate twice. Then, the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 24 (320 mg, Yield 89%).
1H-NMR (CDCl3) δ: 1.62 (s, 9H), 2.29 (brs, 3H), 7.14-7.37 (brm, 5H), 7.43 (t, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 2H), 7.60 (d, J=6.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H).
Step 3 Synthesis of Compound 25
Compound Z (113 mg, 0.383 mmol) which was synthesized in step 5 of Example 3, Compound 24 (180 mg, 0.383 mmol) and N,N-diisopropylethylamine (334 μL, 1.91 mmol) were dissolved in tetrahydrofuran (1.9 mL), and the solution was stirred overnight at room temperature. Sodium hydrogen carbonate aqueous solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 25 (racemate, 117 mg, Yield 48%).
LC/MS (Method 1) RT=2.57, MS (m/z)=634.25
Step 4 Synthesis of Compound 26
To Compound 25 (107 mg, 0.169 mmol) was added 4 mol/L hydrogen chloride-dioxane solution (2.00 ml, 8.00 mmol), and the reaction mixture was stirred at room temperature for 2 hours. Next, the mixture was stirred at 40° C. for 2 hours. After the mixture was allowed to cool, the solvent was distilled off under reduced pressure. The residue was solidified by the addition of diethyl ether to give Compound 26 (racemate, 113 mg, Yield 115%).
LC/MS (Method 1) RT=1.87, MS (m/z)=578.20
Step 5 Synthesis of Compound (I-36)
Compound 26 (59.9 mg, 0.104 mmol) was dissolved in DMF (1 ml). N,N-Diisopropylethylamine (65 μL, 0.373 mmol), 1-ethylpiperidin-4-amine (18 μL, 0.124 mmol) and COMU (53.3 mg, 0.124 mmol) were added to the solution, and the reaction mixture was stirred overnight at room temperature. Sodium hydrogen carbonate aqueous solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, successively and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel column chromatography (ethyl acetate-methanol) to give Compound (I-36) (racemate, 49.8 mg, Yield 70%).
LC/MS (Method 1) RT=1.34, MS (m/z)=688.30
1H-NMR (CDCl3) δ: 0.84 (m, 1H), 1.11 (t, J=7.2 Hz, 3H), 1.64 (m, 1H), 2.05-2.20 (m, 4H), 2.24 (s, 3H), 2.45 (q, J=7.3 Hz, 2H), 2.85-3.15 (m, 5H), 3.33 (s, 3H), 3.51 (m, 1H), 3.65 (m, 1H), 4.05 (m, 1H), 4.54 (br s, 2H), 5.56 (br, 1H), 6.02 (d, J=7.9 Hz, 1H), 6.15 (br, 1H), 6.98-7.20 (m, 3H), 7.37 (t, J=7.4 Hz, 1H), 7.46 (t, J=7.8 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.85 (dd, J=15.1, 8.6 Hz, 4H).
Synthesis of Compound (I-10)
Step 1 Synthesis of Compound 28
1-Bromo-2-methoxyethane (2 g, 14.4 mmol) was dissolved in DMSO (10 mL), and NaI (216 mg, 1.44 mmol), diisopropylethylamine (2.51 ml, 14.4 mmol) and commercially available tert-butyl carbazate (1.9 g, 1.44 mmol) were added to the solution. The reaction mixture was heated at 90° C. for 20 hours. After the mixture was allowed to cool, water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 28 (340 mg, 1.79 mmol, Yield 12%).
1H-NMR (CDCl3) δ: 1.46 (s, 11H), 3.04 (t, J=5.1 Hz, 2H), 3.37 (s, 3H), 3.49 (t, J=5.1 Hz, 2H), 6.23 (s, 1H).
Step 2 Synthesis of Compound 29
To Compound 28 (100 mg, 0.53 mmol) were added toluene (3 mL), formaldehyde (0.080 mL, 1.05 mmol), (E)-1,2-difluoro-4-(2-nitrovinyl)benzene (146 mg, 0.79 mmol) and molecular sieve 5 A (100 mg), and the reaction mixture was stirred overnight at 90° C. Saturated ammonium chloride aqueous solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 29 (racemate, 28 mg, 0.072 mmol, Yield 13.8%).
1H-NMR (DMSO-d6) 1H-NMR (CDCl3) δ: 1.40 (s, 7H), 1.49 (s, 2H), 2.97 (dq, J=12.6, 3.9 Hz, 1H), 3.09-3.18 (m, 1H), 3.35 (s, 3H), 3.56-3.65 (m, 2H), 3.79 (dd, J=7.3, 4.5 Hz, 1H), 5.20 (q, J=7.1 Hz, 1H), 5.63 (d, J=6.1 Hz, 1H), 7.05-7.10 (m, 1H), 7.14-7.24 (m, 2H).
LC/MS (Method 1) RT=2.20, MS (m/z)=332.05
Step 3 Synthesis of Compound 30
To Compound 29 (28 mg, 0.072 mmol) were added methanol (3 mL), tetrahydrofuran (1 ml), and palladium-carbon (16 mg), and the reaction mixture was stirred at room temperature under hydrogen atmosphere. The mixture was filtered through celite pad, and then the solvent was distilled off under reduced pressure to give Compound 30 (racemate, 26 mg, 0.072 mmol, Yield 100%, crude product).
LC/MS (Method 1) RT=1.23, MS (m/z)=358.20
Step 4 Synthesis of Compound 31
To a solution of Compound 30 (26 mg, 0.072 mmol) in dichloromethane (1 mL) were added Compound X (25 mg, 0.070 mmol) which can be synthesized in accordance with the known method (WO2012/158413) and triethylamine (0.019 mL, 0.140 mmol) under nitrogen atmosphere, and the reaction mixture was stirred at room temperature. Saturated ammonium chloride aqueous solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by amino silicagel column chromatography (chloroform-methanol) to give Compound 31 (racemate, 4.4 mg, 6.9 μmol, Yield 11%) as a crude product.
LC/MS (Method 1) RT=1.95, MS (m/z)=637.30
Step 5 Synthesis of Compound (I-10)
To a solution of Compound 31 (4.4 mg, 6.9 μmol) in dichloromethane (1 mL) was added TFA (0.2 mL, 2.6 mmol) under nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1 hour. After the mixture was concentrated, dichloromethane (1 mL) was added to the mixture. The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by amino silicagel column chromatography (chloroform-methanol), and the obtained crude product was further purified by reverse-phase chromatography (HP20SS, acetonitrile-water) to give Compound (I-10) (racemate, 2.6 mg, 4.9 μmol, Yield 70%).
1H-NMR (CD3OD) δ: 2.06 (s, 3H), 3.15-3.23 (m, 1H), 3.26-3.34 (m, 4H), 3.35-3.41 (m, 1H), 3.38 (s, 1H), 3.60-3.68 (m, 1H), 3.68-3.75 (m, 1H), 3.94 (s, 3H), 5.45 (t, J=6.3 Hz, 1H), 7.18-7.27 (m, 1H), 7.33-7.48 (m, 6H), 7.52-7.61 (m, 1H), 7.83 (s, 1H), 7.95 (s, 1H).
LC/MS (Method 1) RT=1.28, MS (m/z)=537.25
Synthesis of Compound (I-235)
Step 1 Synthesis of Compound 33
To Compound 32 (12.15 g, 101 mmol) which can be synthesized in accordance with the method described in Synthetic Communications 1992, 22, 83-95 was added dichloromethane (97 mL), and triethylamine (14.7 mL, 106 mmol), dibutyltin oxide (503 mg, 2.02 mmol), and p-toluenesulfonyl chloride (20.24 g, 106 mmol) were subsequently added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then water was added to the mixture, followed by extraction with chloroform. The organic layer was washed with brine, then dried over anhydrous sodium sulfate, and filtered, and the organic solvent was distilled off under reduced pressure. The obtained crude product (38.88 g) was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 33 (25.0 g, Yield 90%) as a colorless oil.
Compound 33 LC/MS (Method 1) RT=1.47, MS (m/z)=275.15
1H-NMR (CDCl3) δ: 1.69-1.78 (2H, m), 2.45 (3H, s), 3.32 (3H, s), 3.48-3.55 (1H, m), 3.55-3.62 (1H, m), 3.92-4.07 (3H, m), 7.35 (2H, d, J=8.0 Hz), 7.80 (2H, d, J=8.3 Hz).
Step 2 Synthesis of Compound 34
Compound 33 (25.0 g, 91.0 mmol) was dissolved in THF (100 mL). After the solution was cooled in an ice bath, sodium hydride (60% in oil, 3.86 g, 97.0 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 14 hours. Further, sodium hydride (971 mg, 24.3 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride aqueous solution was added to the mixture, followed by extraction with diethyl ether twice. The organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and then the organic solvent was distilled off under reduced pressure to give Compound 34 (49.4 g, 12.5% purity, 66% yield).
Step 3 Synthesis of Compound 35
Compound 34 (49.4 g, 12.5% purity, 60.5 mmol) was dissolved in THF (50 mL), and copper(I) cyanide (542 mg, 6.05 mmol) was added to the solution. Then, the reaction mixture was cooled to −78° C. in a dry ice-acetone bath. Vinyl magnesium bromide solution (1 mol/L THF solution, 79 mL, 79 mmol) was added dropwise thereto, and then the reaction mixture was allowed to warm up gradually to room temperature. The mixture was left standing overnight at room temperature, and saturated ammonium chloride aqueous solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product (18.0 g) was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 35 (12.1 g, <65% purity) as a yellow liquid.
1H-NMR (CDCl3) δ: 1.69-1.97 (2H, m), 2.25 (2H, t, J=6.5 Hz), 2.80-2.91 (1H, m), 3.32-3.50 (4H, m), 3.52-3.75 (1H, m), 3.82-3.94 (1H, m), 5.07-5.22 (2H, m), 5.78-5.97 (1H, m).
Step 4 Synthesis of Compound 36
Compound 35 (12.1 g, <65% purity, 60.3 mmol) was dissolved in dichloromethane (60 mL), and the mixture was cooled in an ice bath. Allylchlorodimethylsilane (8.53 g, 63.3 mmol) and triethylamine (17.6 mL, 127 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 90 minutes. Then, saturated sodium bicarbonate aqueous solution was added to the mixture, followed by extraction with dichloromethane. The solvent in the organic layer was distilled off under reduced pressure, and the obtained crude product (25.4 g) was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 36 (17.6 g, 42% purity, Yield 54%) as a colorless liquid.
1H-NMR (CDCl3) δ: 0.13 (6H, s), 1.59-1.69 (4H, m), 1.71-1.80 (1H, m), 2.23 (2H, t, J=6.5 Hz), 3.32 (3H, s), 3.35-3.50 (2H, m), 3.86-3.93 (1H, m), 4.83-4.95 (2H, m), 5.04 (1H, s), 5.07 (1H, d, J=4.4 Hz), 5.74-5.87 (2H, m).
Step 5 and Step 6 Synthesis of Compound 38
Compound 36 (17.6 g, 42% purity, 32.4 mmol) was dissolved in dichloromethane (882 mL), and a second-generation Grubbs catalyst (413 mg, 0.487 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 1 week. After conversion to Compound 37 was confirmed by NMR, the volume of the organic solvent was concentrated into approximately one-tenth. The residue was cooled in a dry ice-acetone bath. A boron trifluoride-diethyl ether complex (4.11 mL, 32.4 mmol) was added thereto, and the reaction mixture was stirred at −78° C. for 5 minutes. Then, 2-fluoro-4-pyridinecarboxaldehyde (10.1 g, 40% purity, 32.4 mmol) was added to the mixture, and the reaction mixture was stirred at −78° C. for 30 minutes. The mixture was allowed to warm up gradually to room temperature and stirred for 21 hours. Brine was added to the mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue (20.7 g) was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 38 (3.68 g, Yield 45%) as a yellow oil.
1H-NMR (CDCl3) δ: 1.49-1.58 (1H, m), 1.95-2.10 (2H, m), 2.25-2.31 (1H, m), 3.20-3.28 (1H, m), 3.38 (3H, s), 3.58 (2H, t, J=6.4 Hz), 4.13-4.22 (1H, m), 4.84 (1H, dd, J=10.0, 1.7 Hz), 4.96 (1H, dd, J=17.1, 1.6 Hz), 5.02 (1H, d, J=8.2 Hz), 5.12 (1H, dt, J=18.3, 8.5 Hz), 6.84 (1H, s), 7.00 (1H, d, J=5.1 Hz), 8.12 (1H, d, J=5.1 Hz).
Compound 38 LC/MS (Method 1) RT=1.82, MS (m/z)=252.25
Step 7 and Step 8 Synthesis of Compound 40
Compound 38 (3.68 g, 14.6 mmol) was dissolved in dichloromethane (74 mL), and the solution was treated with ozone at −78° C. for 4 hours. Then, dimethyl sulfide (10.8 mL, 146 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 21 hours. The mixture was concentrated under reduced pressure to give a crude product of Compound 39 (5.75 g) as a brown oil.
To the obtained crude product were added t-BuOH (45 mL) and water (22 mL), and 2-methyl-2-butene (15.5 mL, 146 mmol), sodium dihydrogen phosphate (8.79 g, 73.2 mmol) and sodium chlorite (3.97 g, 43.9 mmol) were added successively thereto. The reaction mixture was stirred at room temperature for 1 hour. Then, citric acid monohydrate was added to the mixture, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silicagel column chromatography (chloroform-methanol) to give Compound 40 (2.19 g, Yield 56% over two steps) as a yellow oil.
Compound 40 LC/MS (Method 1) RT=1.13, MS (m/z)=270.15
Step 9 Synthesis of Compound 41
To Compound 40 (2.19 g, 8.13 mmol) were added dichloromethane (10 mL) and methanol (22 mL), and the reaction mixture was cooled in an ice bath. Trimethylsilyldiazomethane-hexane solution (11.1 mL, 22.2 mmol) was added dropwise thereto, and the reaction mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the mixture until the yellow mixture became colorless. Then, the reaction mixture was concentrated under reduced pressure, and the obtained residue (2.53 g) was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 41 (1.05 g, Yield 46%) as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.98-2.19 (3H, m), 2.30 (1H, ddd, J=13.6, 7.5, 5.3 Hz), 3.27 (3H, s), 3.37 (3H, s), 3.50 (1H, q, J=8.2 Hz), 3.55-3.62 (2H, m), 4.12-4.22 (1H, m), 5.10 (1H, d, J=8.5 Hz), 6.91 (1H, s), 7.10 (1H, d, J=5.1 Hz), 8.14 (1H, d, J=5.3 Hz).
Compound 41 LC/MS (Method 1) RT=1.47, MS (m/z)=284.20
Step 10 Synthesis of Compound 42
Compound 41 (1.05 g, 3.71 mmol) was dissolved in methanol (10.5 mL), and sodium methoxide (28% methanol solution, 3.58 g, 18.5 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. Water (1.0 mL) was added to the mixture, and the reaction mixture was stirred at room temperature for 30 minutes. Then, 2 mol/L hydrochloric acid aqueous solution (9 mL) was added to the mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 42 (982 mg, 3.65 mmol) as a yellow oil.
Compound 42 LC/MS (Method 1) RT=1.24, MS (m/z)=270.20
Step 11 Synthesis of Compound 43
Compound 42 (982 mg, 3.65 mmol) was dissolved in DMF (20 mL), and HATU (2.77 g, 7.29 mmol) and DIEA (2.55 mL, 14.6 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 1 minute. Ammonia-dioxane solution (0.5 mol/L, 21.9 mL, 10.9 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with 3% citric acid aqueous solution and brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a crude product (1.90 g). The crude product was purified by amino silicagel column chromatography (hexane-10% methanol/ethyl acetate) to give Compound 43 (542 mg, Yield 55%) as a white solid.
1H-NMR (CDCl3) δ: 1.86-2.07 (3H, m), 2.42-2.48 (1H, m), 2.65 (1H, dt, J=13.0, 4.9 Hz), 3.36 (3H, s), 3.56 (2H, dt, J=16.2, 4.5 Hz), 4.35 (1H, dt, J=13.9, 6.4 Hz), 5.10 (1H, d, J=7.8 Hz), 5.42 (2H, br s), 6.99 (1H, s), 7.18 (1H, d, J=5.1 Hz), 8.17 (1H, d, J=5.1 Hz).
Compound 43 LC/MS (Method 1) RT=0.99, MS (m/z)=269.20
Step 12 Synthesis of Compound 44
Compound 43 (540 mg, 2.01 mmol) was dissolved in 1,2-dichloroethane (11 mL), and allyl alcohol (2.74 mL, 40.3 mmol) and iodobenzene diacetate (1.30 g, 4.03 mmol) were added to the solution. The reaction mixture was stirred at 80° C. for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the mixture, followed by extraction with ethyl acetate twice. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue (1.89 g) was purified by silicagel column chromatography (hexane-ethyl acetate) to give Compound 44 (542 mg, Yield 83%) as a clear colorless oil.
1H-NMR (CDCl3) δ: 1.80-2.08 (4H, m), 3.37 (3H, s), 3.54-3.60 (2H, m), 4.11 (1H, t, J=7.0 Hz), 4.36 (1H, dt, J=15.9, 6.3 Hz), 4.60 (2H, d, J=5.6 Hz), 4.88 (1H, s), 5.00-5.12 (1H, m), 5.25 (1H, d, J=10.4 Hz), 5.33 (1H, d, J=17.2 Hz), 5.83-6.01 (1H, m), 7.05 (1H, s), 7.29-7.37 (1H, m), 8.17 (1H, d, J=5.1 Hz).
Compound 44 LC/MS (Method 1) RT=1.59, MS (m/z)=325.20
Step 13 Synthesis of Compound 45
Compound 44 (542 mg, 1.67 mmol) was dissolved in THF (5.42 mL), and diethylamine (0.524 mL, 5.01 mmol) and tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.167 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. 2 mol/L hydrochloric acid aqueous solution (5 mL) was added to the residue. The reaction mixture was washed with ether, and 2 mol/L sodium hydroxide aqueous solution (5 mL) and saturated sodium bicarbonate aqueous solution were added to the aqueous layer, followed by extraction with 10% methanol-chloroform five times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give Compound 45 (362 mg, Yield 90%) as a pale yellow oil.
Compound 45 LC/MS (Method 1) RT=0.62, MS (m/z)=241.20
Step 14 Synthesis of Compound (I-235)
Compound (I-235) (32 mg, Yield 98%) was obtained as a colorless foam in the same manner as described in the step 4 of Example 6 by using Compound 45 (15 mg, 0.062 mmol) as the starting material.
1H-NMR (CDCl3) δ: 1.71-1.99 (4H, m), 2.20 (3H, s), 3.35 (3H, s), 3.53 (2H, dt, J=16.4, 5.1 Hz), 3.99 (3H, s), 4.16 (2H, tt, J=12.7, 4.5 Hz), 4.58 (1H, d, J=3.3 Hz), 4.87 (1H, d, J=7.3 Hz), 6.15 (1H, s), 6.92 (1H, s), 7.16 (1H, d, J=5.1 Hz), 7.37 (1H, t, J=7.4 Hz), 7.47 (2H, t, J=7.8 Hz), 7.56 (2H, d, J=7.7 Hz), 7.79 (1H, s), 7.90 (1H, s), 8.11 (1H, d, J=5.3 Hz).
Compound (I-235) LC/MS (Method 1) RT=1.53, MS (m/z)=520.30
The following Compounds were obtained in accordance with the general synthetic methods and Examples. The chemical structures and the physical properties(LC/MS data) of Compounds are described below.
In the following tables, Compound with “HCl” in the chemical structure means that Compound forms “HCl” salt. Compound with plural “HCl” in the chemical structure means that Compound forms plural “HCl salt”.
In addition, “wedged bond” and “hashed wedged bond” in the chemical structure means configuration. Specifically Compound with “racemate” in item of “configuration” means racemic compound whose relative configuration was determined. Compound with “trans” in item of “configuration” means compound whose relative configuration between the group of —Z-L-ZA-(ring C) and the group of —Y—B was trans, and other configuration were not determined. Compound with “diastereo mixture” in item of “configuration” means compound whose relative configuration between the group of —Z-L-ZA-(ring C) and the group of —Y—B was trans, and other absolute configuration were as described in the chemical structure. Compound whose item of “configuration” is blank means Compound in which absolute configurations at the carbon atom binding to the group of —Z-L-ZA-(ring C) and the carbon atom binding to the group of —Y—B were as described in the chemical structure. Compound with “single isomer” is a single isomer compound.
Moreover, the bond which binds to the asymmetric carbon is indicated as solid line when their configurations were not determined.
To produce the stable cells expressing four types of NT receptors (TrkA, TrkB, TrkC and p75) highly and simultaneously, each human NT receptor gene was transfected by a retrovirus vector into human erythroleukemic cell line TF-1 cells (ATCC Number:CRL-2003). The inhibition assay against NGF, BDNF and NT-3 were done in TF-1 cells expressing TrkA+p75, TrkB+p75 and TrkC+p75, respectively. Two hundred nL per well of each compound (final concentration: 20 μmol/L-0.05 nmol/L) dissolved in DMSO was applied in a white 384 well flat-bottom plate. The cells were suspended in RPMI-1640 medium containing 10% fetal bovine serum and seeded in each well at 400 cells for the TF1 cells expressing TrkA and p75 or TrkC and p75, and 800 cells for the TF cells expressing TrkB and p75. Forty μL of human NGF (final concentration: 4 ng/mL), human BDNF (final concentration: 8 ng/mL) or human NT-3 (final concentration: 8 ng/mL) was added in each well and the plate was incubated for 3 days. Then, twenty μL of CellTiter-Glo reagent for CellTiter-Glo Luminescent Cell Viability Assay (manufactured by Promega) was added in each well and chemiluminescence was measured by a microplate reader to evaluate the growth of TF-1 cells. Luminescence value in the well incubated with or without each growth factor is 0% or 100% inhibition, respectively. The inhibitory activity of each compound was calculated by the following formula.
Inhibition (%)=(1−(luminescence value with compound−luminescence value of 100% inhibitory activity)/(luminescence value of 0% inhibitory activity−luminescence value of 100% inhibitory activity))×100
The 50% inhibitory concentration (IC50) was determined by the logistic regression using the inhibition data in 10 points of 3-fold dilution series at a compound concentration range of 20 μmol/L to 1 nmol/L or 10 points of 3-fold dilution series at a range of 1 μmol/L to 0.05 nmol/L.
Seven point five μL per well of human TrkA (PV3144, Lifetechnologies, final concentration: 1 nmol/L) suspended in the assay buffer (100 mmol/L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 10 mmol/L magnecium chloride, 0.003 vol % Brij-35, 0.004 vol % Tween20 and 1 mmol/L dithiothreitol (DTT)) was applied in a 384 well plate and the plate was pre-incubated for 15 min at room temperature with 0.4 μL of each compound (final concentration: 200 μmol/L-1 pmol/L) dissolved in DMSO. Then, fluorescent substrate (FL-peptide 27, 760424, PerkinElmer, final concentration: 1.5 μmol/L) and ATP (final concentration 500 μmol/L) dissolved in the assay buffer was added in each well. After the incubation of 120 min at 37° C., fifteen μL of termination buffer (100 mmol/L HEPES, 40 mmol/L ethylenediaminetetraacetic acid (EDTA), 10 mmol/L magnecium chloride, 0.003 vol % Brij-35, 0.004 vol % Tween20, 1 mmol/L DTT and 0.16 vol % Coating Reagent 3) was added in each well to stop the enzyme reaction. Fluorescent intensities (FI) of phosphorylated and non-phosphorylated fluorescent substrates were measured by LabChip EZReader II (Caliper LifeSciences, Inc.), and conversion ratio (CR) was calculated by the following formula-1. The CR in the well applied with DMSO alone was used as a negative control and the CR in the well without applying TrkA was used as a positive control. The inhibitory effect of each compound on TrkA phosphorylation was calculated by the following formula-2.
CR (%)=(FI of phosphorylated substrate/(FI of phosphorylated substrate+FI of non-phosphorylated substrate))×100 (Formula-1)
Phosphorylation inhibition (%)=(1−(CR with compound treatment−CR of positive control)/(CR of negative control−CR of positive control))×100 (Formula-2)
IC50 values (nmol/L) were determined by the logistic regression using the inhibition data in 10 points of 3-fold dilution series at a compound concentration range of 20 nmol/L to 1 pmol/L, or 10 points of 3-fold dilution series at the range of 2 μmol/L to 0.1 nmol/L, or 10 points of 3-fold dilution series at the range of 200 μmol/L to 10 nmol/L, or 15 points of 3-fold dilution series at the range of 200 μmol/L to 0.04 nmol/L.
(Result)
The evaluation results of the compounds in the present invention are indicated as follows. IC50 values of 0 to 100 nM, 100 to 1000 nM and over 1000 nM were shown as “A”, “B” and “C”, respectively.
IC50 values of the compounds in the present invention are as follows.
Compound I-1: 5200 nM,
Compound I-3: 120 nM,
Compound I-7: 6.1 nM,
Compound I-10: 170 nM,
Compound I-22: 0.81 nM,
Compound I-25: 2.9 nM,
Compound I-28: 2.5 nM,
Compound I-31: 0.78 nM,
Compound I-36: 1.4 nM,
Compound I-39: 0.48 nM,
Compound I-40: 1.6 nM,
Compound I-47: 4.0 nM,
Compound I-57: 2.2 nM,
Compound I-65: 0.92 nM,
Compound I-66: 1.6 nM,
Compound I-73: 1.2 nM,
Compound I-79: 1.5 nM,
Compound I-82: 22.0 nM,
Compound I-96: 15.0 nM,
Compound I-108: 1.0 nM,
Compound I-119: 4.0 nM,
Compound I-122: 2.7 nM,
Compound I-135: 0.52 nM,
Compound I-136: 30.0 nM,
Compound I-145: 0.87 nM,
Compound I-146: 330 nM,
Compound I-159: 2.1 nM,
Compound I-165: 5.3 nM,
Compound I-166: 4.8 nM,
Compound I-190: 2.1 nM,
Compound I-193: 4.0 nM,
Compound I-211: 1.5 nM,
Compound I-217: 4.6 nM,
Compound I-232: 4.2 nM,
Compound I-233: 1.5 nM,
Compound I-236: 1.4 nM,
Compound I-237: 8.1 nM,
Compound I-239: 3.8 nM,
Compound I-241: 3.2 nM,
Compound I-244: 17.0 nM,
Compound I-245: 3.0 nM,
Compound I-253: 1.3 nM,
Compound I-258: 0.48 nM,
Compound I-268: 0.55 nM,
Compound I-273: 4.7 nM,
Compound I-275: 3.0 nM,
Compound I-278: 3.7 nM,
Compound I-279: 2.0 nM,
Compound I-285: 2.7 nM,
Compound I-291: 2.0 nM,
Compound I-298: 0.6 nM,
Compound I-299: 2.1 nM,
Compound I-302: 8.2 nM,
Compound I-303: 1.5 nM,
Compound I-309: 2.0 nM,
Compound I-313: 3.6 nM,
Compound I-315: 0.76 nM,
Compound I-319: 1.2 nM,
Compound I-322: 2.4 nM,
Compound I-325: 2.5 nM,
Compound I-329: 1.7 nM,
Compound I-332: 1.2 nM,
Compound I-344: 0.97 nM,
Compound I-356: 1.5 nM,
Compound I-392: 6.8 nM,
Compound I-406: 2.2 nM,
Compound I-413: 2.5 nM,
Compound I-431: 3.1 nM,
Compound I-436: 4.0 nM,
Compound I-458: 0.52 nM,
Compound I-508: 1.1 nM,
Compound I-0509: 1.3 nM,
Compound I-526: 22 nM,
Compound I-536: 4.0 nM,
Compound I-552: 1.7 nM,
Compound I-555: 0.93 nM,
Compound I-620: 6.8 nM,
Compound I-627: 4.8 nM,
Compound I-638: 1.4 nM,
Compound I-639: 0.52 nM,
Compound I-645: 68 nM,
Compound I-655: 5 nM,
Compound I-660: 70 nM,
Compound I-674: 5.8 nM.
For the purpose of assessing risk of an electrocardiogram QT interval prolongation of the compound of the present invention, effects of the compound of the present invention on delayed rectifier K+ current (IKr), which plays an important role in the ventricular repolarization process, was studied using CHO cells expressing human ether-a-go-go related gene (hERG) channel.
After a cell was retained at a membrane potential of −80 mV by whole cell patch clamp method using an automated patch clamp system (QPatch; Sophion Bioscience A/S) and gave a leak potential of −50 mV, IKr induced by depolarization pulse stimulation at +20 mV for 2 seconds, and further, repolarization pulse stimulation at −50 mV for 2 seconds, was recorded. A vehicle, which is the 0.1-0.3% dimethyle sulfoxide solution in extracellular solution (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl2: 2 mmol/L, MgCl2: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH7.4), or the compound of the present invention had been dissolved at an objective concentration in the extracellular solution is applied to the cell at room temperature for 7 minutes or more. From the recording IKr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using analysis software (QPatch assay software; Sophion Bioscience A/S). Further, the % inhibition of tail peak current for the compound of the present invention relative to the tail peak current after application of the vehicle is calculated to assess influence of the compound of the present invention on IKr.
(Result) % inhibition was shown at 5 mol/L of test compound.
Compound I-4: 14.1%
Compound I-6: 8.9%
Compound I-7: 4.2%
Compound I-12: 17.6%
Using commercially available pooled human liver microsomes, an inhibitory degree of each metabolite production amount by the compound of the present invention is assessed as marker reactions of human main five CYP isoforms (CYP1A2, 2C9, 2C19, 2D6, and 3A4), 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation.
The reaction conditions are as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenitoin (CYP2C19), 5 mol/L dextromethorphan (CYP2D6), 1 μmol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human liver microsomes 0.2 mg protein/mL; concentrations of the compound of the present invention, 1.0, 5.0, 10, 20 μmol/L (four points).
Each five kinds of substrates, human liver microsomes, or compound of the present invention in 50 mmol/L Hepes buffer are added to a 96-well plate at the composition as described above, and NADPH, as a cofactor is added to initiate metabolism reactions. After the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution is added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant is quantified by a fluorescent multilabel counter or LC/MS/MS and hydroxytolbutamide (CYP2C9 metabolite), 4′ hydroxymephenytoin (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol metabolite (CYP3A4 metabolite) are quantified by LC/MS/MS.
The sample adding only DMSO as a solvent to a reaction system instead of a solution dissolving a compound of the present invention is adopted as a control (100%). Remaining activity (%) is calculated and IC50 is calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.
CYP3A4 (MDZ) MBI test is a test of investigating mechanism based inhibition potential on CYP3A4 by the enhancement of inhibitory degree of a metabolic reaction caused by the compound of the present invention. CYP3A4 inhibition is evaluated using pooled human liver microsomes by 1-hydroxylation reaction of midazolam (MDZ) as a marker reaction.
The reaction conditions are as follows: substrate, 10 μmol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate reaction time, 2 minutes; reaction temperature, 37° C.; protein content of pooled human liver microsomes, at pre-reaction time 0.5 mg/mL, at reaction time 0.05 pmg/mL (at 10-fold dilution); concentrations of the compound of the present invention, 1, 5, 10, 20 μmol/L (four points).
Pooled human liver microsomes and a solution of the compound of the present invention in K-Pi buffer (pH 7.4) as a pre-reaction solution are added to a 96-well plate at the composition of the pre-reaction. A part of pre-reaction solution is transferred to another 96-well plate, and 1/10 diluted by K-Pi buffer containing a substrate. NADPH as a co-factor is added to initiate a reaction as a marker reaction (preincubation 0 min). After a predetermined time of a reaction, methanol/acetonitrile=1/1 (v/v) solution is added to stop the reaction. In addition, NADPH is added to a remaining pre-reaction solution to initiate a pre-reaction (preincubation 30 min). After a predetermined time of a pre-reaction, a part is transferred to another 96-well plate, and 1/10 diluted by K-Pi buffer containing a substrate to initiate a reaction as a marker reaction. After a predetermined time of a reaction, methanol/acetonitrile=1/1 (v/v) solution is added to stop the reaction. After centrifuged at 3000 rpm for 15 minutes, 1-hydroxymidazolam in the supernatant is quantified by LC/MS/MS.
The sample adding DMSO as a solvent to a reaction system instead of a solution dissolving the compound of the present invention is adopted as a control (100%). Remaining activity (%) is calculated at each concentration of the compound of the present invention compared to a control, and IC value is calculated by reverse-presumption by a logistic model using a concentration and an inhibition rate. Shifted IC value is calculated as “IC of preincubation at 0 min/IC of preincubation at 30 min”. When a shifted IC is 1.5 or more, this is defined as positive. When a shifted IC is 1.0 or less, this is defined as negative.
Materials and Methods for Experiments to Evaluate Oral Absorption
Oral administration 1 mg/kg or 2 μmol/kg (n=2)
Intravenous administration 0.5 mg/kg or 1 μmol/kg (n=2)
Materials and Methods for Experiments
(Result)
Compound I-12: 13.6 mL/min/kg
Compound I-19: 15.6 mL/min/kg
Compound I-040: 2.82 mL/min/kg
Compound I-057: 7.93 mL/min/kg
Compound I-090: 6.35 mL/min/kg
Compound I-275: 3.73 mL/min/kg
Mutagenicity of Compounds of the Present Invention is Evaluated.
A 20 μL of freezing-stored Salmonella typhimurium (TA98 strain, TA100 strain) is inoculated on 10 mL of a liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and this is incubated at 37° C. for 10 hours under shaking. The 7.70 mL of TA98 culture medium is centrifuged (2000×g, 10 minutes) and TA98 is suspended in 7.70 mL Micro F buffer (K2HPO4: 3.5 g/L, KH2PO4: 1 g/L, (NH4)2SO4: 1 g/L, trisodium citrate dehydrate: 0.25 g/L, MgSO4.7H2O: 0.1 g/L) after removing the culture medium. The TA98 suspension is mixed with 120 mL Exposure medium (Micro F buffer containing Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL). The 3.42 mL of TA100 culture medium strain is mixed with 130 mL Exposure medium. Each 12 μL of DMSO solution of the compound of the present invention (several stage dilution from maximum dose 50 mg/mL at 2 to 3 fold ratio), DMSO as a negative control, and 50 μg/mL of 4-nitroquinoline 1-oxide DMSO solution for the TA98 strain and 0.25 μg/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain in the assay without metabolic activation, 40 μg/mL of 2-aminoanthracene DMSO solution for the TA98 strain and 20 μg/mL of 2-aminoanthracene DMSO solution for the TA100 strain in the assay with metabolic activation as a positive control, and 588 μL of the test bacterial suspension (498 μL and 90 μL of S9 mixture in the case of metabolic activation assay) are mixed, and this is incubated at 37° C. for 90 minutes under shaking. A 460 μL of the mixture is mixed with 2300 μL of Indicator medium (Micro F buffer containing 8 μg/mL biotin, 0.2 μg/mL histidine, 8 mg/mL glucose, 37.5 μg/mL bromocresol purple), each 50 μL is dispensed to microplate 48 wells/dose, and this is incubated at 37° C. for 3 days. Since the wells containing the bacteria which gained growth ability by point mutation in amino acid (histidine) synthesizing enzyme gene turns from purple to yellow due to a pH change, the number of yellow wells in 48 wells is counted per dose, and is compared with the negative control group. (−) and (+) means negative and positive in mutagenicity respectively.
Using commercially available pooled human hepatic microsomes, a compound of the present invention is reacted for a constant time, and a remaining rate is calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver is assessed.
A reaction is performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant is quantified by LC/MS/MS or Solid Phase Extraction (SPE)/MS, and a remaining amount of the compound of the present invention after the reaction is calculated, letting a compound amount at 0 minute reaction time to be 100%.
Appropriate quantity of the compound of the present invention is put in a suitable container and 200 μL of pH 4 citrate buffer (100 mmol/L citric acid monohydrate aqueous solution and 100 mmol/L trisodium citrate dihydrate aqueous solution are mixed in appropriate quantity to adjust pH to 4) or JP-2 fluid (1 volume of water is added to 1 volume of the solution in which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate are dissolved in water to reach 1000 mL) is independently added to each container. When total amount is dissolved after adding the test reagent, the compound of the present invention is added appropriately. After sealing and shaking at 25° C. or 37° C. for 1 hour, solution is filtrated and 100 μL of methanol is added to 100 μL of each filtrate to dilute two-fold. The dilution rate is changed as necessary. After checking that there is no bubble and precipitate, the container is sealed and shaken. The compound of the present invention is measured using HPLC by absolute calibration curve method.
The solubility of the compound of the present invention is determined under 1% DMSO addition conditions. A 10 mmol/L solution of the compound is prepared with DMSO, and 2 μL of the solution of the compound of the present invention is added, respectively, to 198 μL of JP-2 fluid (see below). The mixture is shaked for 1 hour at a room temperature, and the mixture is filtered. The filtrate is ten or hundred-fold diluted with methanol/water=1/1(v/v) or acetonitrile/methanol/water=1/1/2(V/V/V) and the compound concentration in the filtrate is measured with LC/MS or Solid Phase Extraction (SPE)/MS by the absolute calibration method.
The following Formulation Examples are only exemplified and not intended to limit the scope of the invention.
The compounds of the present invention, lactose and calcium stearate are mixed. The mixture is crushed, granulated and dried to give a suitable size of granules. Next, calcium stearate is added to the granules, and the mixture is compressed and molded to give tablets.
The compounds of the present invention, lactose and calcium stearate are mixed uniformly to obtain powder medicines in the form of powders or fine granules. The powder medicines are filled into capsule containers to give capsules.
The compounds of the present invention, lactose and calcium stearate are mixed uniformly and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to give suitable sizes of granules.
The compounds of the present invention and crystalline cellulose are mixed, granulated and tablets are made to give orally disintegrating tablets.
The compounds of the present invention and lactose are mixed, crushed, granulated and sieved to give suitable sizes of dry syrups.
The compounds of the present invention and phosphate buffer are mixed to give injection.
The compounds of the present invention and phosphate buffer are mixed to give injection.
The compound of the present invention and lactose are mixed and crushed finely to give inhalations.
The compounds of the present invention and petrolatum are mixed to give ointments.
The compounds of the present invention and base such as adhesive plaster are mixed to give patches.
The compound of the present invention has TrkA inhibitory activity and it can be useful for a TrkA mediated disorder such as pain associated with osteoarthritis, rheumatoid arthritis, fracture, interstitial cystitis, chronic pancreatitis and prostate inflammation; and nociceptive pain as typified by chronic low back pain, diabetic peripheral neuropathy pain, postoperative pain, pelvic pain and cancer pain; neuropathic pain, acute pain, chronic pain, cancer, inflammatory disease, allergic disease, dermatological disease and the like.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2015-135844 | Jul 2015 | JP | national |
| 2016-004010 | Jan 2016 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2016/069968 | 7/6/2016 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2017/006953 | 1/12/2017 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20180201607 A1 | Jul 2018 | US |
