WO2007055374A1 - Agent therapeutique pour l'osteoporose - Google Patents

Agent therapeutique pour l'osteoporose Download PDF

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Publication number
WO2007055374A1
WO2007055374A1 PCT/JP2006/322638 JP2006322638W WO2007055374A1 WO 2007055374 A1 WO2007055374 A1 WO 2007055374A1 JP 2006322638 W JP2006322638 W JP 2006322638W WO 2007055374 A1 WO2007055374 A1 WO 2007055374A1
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group
methyl
carboxamide
tetrahydronaphthalene
substituent
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PCT/JP2006/322638
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English (en)
Japanese (ja)
Inventor
Yoshiya Tanaka
Shingo Nakayamada
Hiroshi Sumichika
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Mitsubishi Tanabe Pharma Corporation
University Of Occupational And Environmental Health, Japan
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Publication of WO2007055374A1 publication Critical patent/WO2007055374A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to osteoporosis comprising a compound having a C5a receptor antagonistic action, preferably a specific amide derivative, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. It relates to preventive and therapeutic agents.
  • complement component C5a is a glycoprotein with a molecular weight of about 11,000 that is composed of 74 amino acids, and has a strong inflammation-inducing action.
  • C5a has a wide range of functions including smooth muscle contraction, increased vascular permeability, leukocyte migration, leukocyte degranulation, reactive oxygen species production, antibody production enhancement, cytoforce in, TNF (tumor necrosis factor), and leukotriene production induction.
  • Non-Patent Documents 1 to 4 Autoimmune diseases such as rheumatism and systemic lupus erythematosus, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, asthma and other allergic diseases, atherosclerosis, myocardial infarction, cerebral infarction , Psoriasis, Alzheimer's disease and ischemic reperfusion, a causative agent of diseases such as vital organ damage due to leukocyte activation (eg pneumonia, nephritis, hepatitis, knee inflammation) caused by trauma, burns, surgical invasion, etc. (Non-Patent Documents 1 to 4).
  • leukocyte activation eg pneumonia, nephritis, hepatitis, knee inflammation
  • compounds having a C5a receptor antagonistic action can be non-steroidal anti-inflammatory drugs.
  • Non-patent literature l Annu. Rev. Immunol., Pp. 12, 775-808 (1994)
  • Non-patent literature 2 Immunopharmacology, pp. 38-15, 1997 (1997)
  • Non-Patent Document 3 Curr. Pharm. Des., VIII, 737-755 (1999)
  • Non-Patent Document 4 IDrugs, II, 686-693 (1999)
  • An object of the present invention is to provide a prophylactic / therapeutic agent for osteoporosis based on a novel mechanism of action.
  • the present inventors have eagerly investigated the relationship between the complement system and osteoporosis for the purpose of finding a new drug discovery target for osteoporosis treatment.
  • C5a significantly promotes differentiation and maturation of osteoclasts, and that C5a can be one of the inducers or exacerbators of osteoporosis.
  • the compound showing C5a receptor antagonistic activity suppresses the osteoclast differentiation and maturation promoted by C5a.
  • a compound exhibiting a C5a receptor antagonistic action can be used as a prophylactic / therapeutic agent for osteoporosis by suppressing bone resorption by osteoclasts, thereby completing the present invention.
  • An osteoporosis preventive and Z or therapeutic agent comprising a compound having a C5a receptor antagonistic action as an active ingredient.
  • a compound having C5a receptor antagonistic activity is represented by the following general formula (1)
  • R 3 s are the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, A cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an aryl group which may have a substituent, It may have a substituent, a heteroaryl alkyl group, a substituent, an alkoxy group, an aryloxy group, an arylalkyloxy group, an optionally substituted acyloxy group, a halogen atom Hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio Group, alkylsulfol group, amino group, alkylamino group, dialkylamino group, cyclic amino group, rubamoyl group which
  • a, b, c, d, and e are all carbon atoms or one or two of a, b, c, d, and e are nitrogen atoms (however, the nitrogen atom is an oxygen atom) May combine to form an amineoxide), and the remainder represents a carbon atom,
  • R 4, R 5, R 6 are the same or different and each is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted Aruke - group, which may have a substituent
  • A may be a hydrogen atom, a cycloalkyl group that may have a substituent, an aryl group that may have a substituent, a substituent, a heteroaryl group, or a substituent.
  • a cyclic amino group may be a hydrogen atom, a cycloalkyl group that may have a substituent, an aryl group that may have a substituent, a substituent, a heteroaryl group, or a substituent.
  • W 2 is the same or different and represents an alkylene (C 1) (wherein n represents an integer of 1 to 3) which may have a bond or a substituent,
  • X represents an oxygen atom or a sulfur atom
  • Y is a bond, oxygen atom, CO, 1 N (R 7 ) (wherein R 7 represents a hydrogen atom or an optionally substituted alkyl group), —SO ⁇ (wherein m is 0 Represents an integer from 2 to 2), C m
  • Z represents a alkylene having a bond or a substituent.
  • R 3 s are the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, Cycloalkyl group, optionally substituted alkoxy group, optionally substituted acyloxy group, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkyl A sulfo group, an amino group, an alkylamino group, a dialkylamino group, a cyclic amino group, a strong rubamoyl group, an alkoxycarbo group, a carboxyl group, a tetrazolyl group, an oxadiazolyl group, a sulfamoyl group or a haloalkyl group, b, c, d, e are all carbon atoms or 1 or 2 of a
  • R 4 , R 5 and R 6 may be the same or different and each may have a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • A represents a hydrogen atom, a cycloalkyl group, an aryl group which may have a substituent, a substituent, a heteroaryl group or a cyclic amino group,
  • W 2 is the same or different and each represents an alkylene (C 1) (wherein n represents an integer of 1 to 3) which may have a bond or a substituent;
  • X represents an oxygen atom or a sulfur atom
  • Y is a bond, oxygen atom, —CO—, —N (R 7 ) (wherein R 7 has a hydrogen atom or a substituent) Represents an optionally substituted alkyl group. ), -SO-(wherein m represents an integer from 0 to 2), — C m
  • R 8 represents a hydrogen atom or an alkyl group which may have a substituent
  • R 9 represents a hydrogen atom or a substituent
  • Ri, R 2 and R 3 in the general formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group. Z or therapeutic agent.
  • Ri, R 2 and R 3 in the general formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 carbon atoms, or an alkoxy group having 2 to 4 carbon atoms.
  • Ri, R 2 and R 3 in the general formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 carbon atoms, or an alkoxy group having 2 to 4 carbon atoms.
  • Ri, R 2 and R 3 in the general formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 carbon atoms, or an alkoxy group having 2 to 4 carbon atoms.
  • R 4 , R 5 , R 6 in the general formula (1) are the same or different and each is a hydrogen atom, an alkyl group that may have a substituent, or an alkoxy that may have a substituent.
  • Group, which may have a substituent the above-mentioned acyloxy group, halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl group, haloalkyl group or haloalkyloxy group [2]
  • R 4 , R 5 , and R 6 in the general formula (1) are the same or different and each is a hydrogen atom, an alkyl group that may have a substituent, or an alkoxy that may have a substituent.
  • a in the general formula (1) may have a substituent, an aryl group or a substituent.
  • a in general formula (1) a phenyl group that may have a substituent, a pyridyl group that may have a substituent, a pyrazolyl group that may have a substituent, The prevention according to the above [2], which may have a thiazolyl group which may have a substituent, a oxazolyl group which may have a substituent or a substituent, and a Z or Therapeutic agent.
  • a in the general formula (1) may have a substituent, a phenyl group, or the following formulas (Aa) to (Ac)
  • R 1Q is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a cycloalkyl group.
  • the prophylactic and Z or therapeutic agent according to the above [2] which is a nitrogen heterocyclic group.
  • Ri, R 2 and R 3 in the general formula (1) are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group having 2 to 4 carbon atoms,
  • R 4 , R 5 and R 6 are the same or different and each represents a hydrogen atom, a methoxy group, a halogen atom or Is a hydroxyl group,
  • R 1Ua , 1 and R ′′ are the same or different and each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group or a substituent.
  • R 13 0 (CH) 0 (CH) O where j, k, R 13 are
  • R 1Gb is a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl which may have a substituent.
  • a nitrogen-containing heterocyclic group selected from the group of: X is an oxygen atom
  • N [(2 bromophenol) methyl] N— (4-isopropylphenol) 7-methoxy —1, 2, 3, 4-tetrahydronaphthalene mono 1-carboxamide, N— (4-Isopropylphenol) 1 7-methoxy 1 N— [(2, 3, 4 Trimethoxyphenyl)
  • prophylactic and Z or therapeutic agent according to any one of the above [2] to [16], which is selected from the group of
  • a compound having a C5a receptor antagonistic action preferably an amide derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is excellent It has an inhibitory effect on bone cell differentiation and maturation, and is useful as an agent for preventing and treating osteoporosis based on suppression of bone resorption.
  • Fig. 1 shows the effect of a test compound (Reference Example 2) on osteoclast differentiation and maturation. (Test Example 2).
  • “Substances that bind to the C5a receptor” are C5a and C5a degradation products (for example, C5a desArg lacking the arginine at the C-terminal of C5a), as well as other known or unknown C5a receptors. It is a substance with affinity.
  • a "C5a receptor antagonist” is a substance that inhibits the binding between a C5a receptor and a "substance that binds to a C5a receptor”.
  • C5a receptor antagonism means that a substance that binds to C5a receptor binds to cells expressing C5a receptor via C5a receptor, and some physiological changes (for example, intracellular Ca 2 This is an action that inhibits a reaction that causes an increase in + ).
  • the "compound having C5a receptor antagonism” may be any compound that has such an action! /, Not only a known compound but also a novel compound that has not been synthesized yet. Includes.
  • Preferable examples of "compound having C5a receptor antagonistic action” include TAN-2474 related compounds described in JP-A-10-182648, peptide derivatives described in WO94Z07815, and WO99Z00406 Cyclic peptide derivatives, WO02Z22556 and WO2006 / 082975 [Mids and derivatives described here, WO02 / 14265 [Claire derivatives described here, compounds as described in WO02 / 49993, WO2004 / 018460, WO2005 / 007087, etc.] It is done.
  • the exemplified compounds having C5a receptor antagonistic activity can be produced by the methods described in the respective literatures.
  • More preferable specific examples of the "compound having C5a receptor antagonistic action” include a compound represented by the general formula (1) described in WO02Z22556
  • R 3 s are the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, A cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an aryl group which may have a substituent, It may have a substituent, a heteroaryl alkyl group, a substituent, an alkoxy group, an aryloxy group, an arylalkyloxy group, an optionally substituted acyloxy group, a halogen atom , Hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkylsulfol group, amino group, alkylamino group, dialkylamino group, cyclic amino group, and rubamoyl which may have
  • a, b, c, d, and e are all carbon atoms or one or two of a, b, c, d, and e are nitrogen atoms (however, the nitrogen atom is an oxygen atom) May combine to form an amineoxide), and the remainder represents a carbon atom,
  • R 4 , R 5 , and R 6 are the same or different and each may have a hydrogen atom, an alkyl group that may have a substituent, an alkyl group that may have a substituent, or a substituent.
  • A may be a hydrogen atom, a cycloalkyl group that may have a substituent, an aryl group that may have a substituent, a substituent, a heteroaryl group, or a substituent.
  • ww 2 is the same or different and each represents an alkylene (C 1) (wherein n represents an integer of 1 to 3) which may have a bond or a substituent;
  • X represents an oxygen atom or a sulfur atom
  • Y is a bond, oxygen atom, CO—, —N (R 7 ) (wherein R 7 represents a hydrogen atom or an optionally substituted alkyl group), —SO— (where m is Represents an integer from 0 to 2), C m
  • R 8 represents a hydrogen atom or an alkyl group which may have a substituent
  • R 9 represents a hydrogen atom or a substituent
  • Z represents a alkylene having a bond or a substituent. Or an pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the alkyl group represents a linear or branched alkyl having 1 to 18, preferably 1 to 12 carbon atoms, such as methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, pentyl, 3-methylbutyl, neopentyl, 1-ethylpentyl, hexyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, dodecyl, hexadecyl And Octadecyl.
  • the alkenyl group is a linear or branched alkenyl having 2 to 18, preferably 2 to 12, more preferably 2 to 8 carbon atoms.
  • the alkyl groups include, for example, etul, 2 probule, 2 butur, 5 pentyl, 2-octyl, 2 dodecyl, etc.
  • Straight chain or branched alkynyl having 2 to 18 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 5 carbon atoms.
  • cycloalkyl groups include, for example, Preferred are cycloalkyl having 3 to 7 carbon atoms, such as chloropropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • R 1C the alkoxy group, for example, methoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, Penchiruokishi, 3-methyl
  • alkoxy group for example, methoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, Penchiruokishi, 3-methyl
  • alkoxy having 1 to 18 carbon atoms such as butoxy, neopentyloxy, hexyloxy, heptyloxy, octyloxy, decyloxy, hexadecyloxy, octadecyloxy and the like.
  • examples of the acyloxy group include acetoxy, propio-oxy, butyryloxy, isobutyryloxy, 2-methylbutyryloxy, 2,2-dimethyl. C2-9 alkanoyloxy, cyclopentylcarboxyl, such as tilbutyryloxy, 3,3-dimethylbutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy, otatanoxy, nonanoyloxy, etc.
  • Examples thereof include arylalkylcarboxyls having 7 to 11 carbon atoms such as cycloalkylcarboxoxy having 4 to 8 carbon atoms such as ruoxy and cyclohexylcarboxoxy, benzoyloxy and naphthoyloxy, and the like.
  • the acyl group includes, for example, formyl, acetyl, propiol, butyryl, isobutyryl, valeryl, isovaleryl, hexanol, otatanyl and the like, preferably 1 to 8, preferably 2 to 8
  • a cycloalkyl group having 4 to 8 carbon atoms such as alkanoyl, cyclopropylcarbol, cyclopentylcarbol, cyclohexylcarbol, etc.
  • cycloalkyl part is the same as the above cycloalkyl
  • benzoyl examples include aromatics such as aromatic oils such as toluoyl and naphthoyl having 7 to 11 carbon atoms, nicotinol, tenoyl and furoyl.
  • the alkylthio group represents a linear or branched alkyl thio group having 1 to 18, preferably 1 to 12, carbon atoms, For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary petit Examples include ruthio, tertiary butylthio, pentylthio, 3-methylbutylthio, neopentylthio, 1-ethylpentylthio, hexylthio, 2-ethylbutylthio, heptylthio, octylthio, decylthio, hexadecylthio, octadecylthio and the like.
  • the alkylsulfol group means that the alkyl part has the same meaning as the above-mentioned “alkyl group” (linear or branched carbon number of 1 to 18, Preferably an alkylsulfol group of 1 to 12 alkyl), and examples thereof include a methylsulfol group, an ethylsulfol group, and a propylsulfonyl group.
  • the alkylamino group is an alkylamino group whose alkyl part is the same as the above “alkyl”, and includes, for example, a methylamino group, an ethylamino group, a propylamino group Group, isopropylamino group and the like.
  • a dialkylamino group has the same meaning as the above “alkyl group” for each alkyl part, and each alkyl may be the same Examples that may be different include a dimethylamino group, a jetylamino group, a dipropylamino group, a diisopropylamino group, an ethylmethylamino group, and a butylmethylamino group.
  • the cyclic amino group in R 6 to R 6 , R 1C) to R 12 , R 10 ⁇ A includes, as a ring constituent atom, an oxygen atom and a sulfur atom in addition to a carbon atom and a nitrogen atom. It is a 3- to 8-membered saturated cyclic amino group that may contain 2 or more. Examples include aziridyl, azetidyl, pyrrolidyl, piperidino, piperidyl, piperazino, piperazinyl, azepinyl, morpholinylated morpholinyl, thiomorpholinyl, imidazolidinyl, heptamethyleneimino, etc.
  • Sulfamoyl group means a sulfamoyl group which may be mono- or di-substituted by lower alkyl having 1 to 3 carbon atoms, such as sulfamoyl, methylsulfamoyl, ethylsulfamoyl, dimethyl And sulfamoyl.
  • the haloalkyl group is the same as the “alkyl group” in the alkyl part, and the “halogen atom” Represents alkyl substituted with one or more halogen atoms, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, chloromethyl, trichloromethyl, etc. Is mentioned.
  • R 4 ⁇ R 6, R U, R 12, R W R 1 () per cent to haloalkyl O alkoxy group in b Te, "Haroaruki Le” are as defined above haloalkyl.
  • Examples of the haloalkyloxy group include trifluoromethyloxy and 2,2,2-trifluoroethyloxy.
  • the aryl group includes, for example, aryl having 6 to 14 carbon atoms such as phenol, 1 naphthyl, 2 naphthyl, 1-anthryl, and 2 anthryl.
  • the aryl group may have one or more substituents, and the substitution position is not particularly limited.
  • the substituent may be condensed with an aryl which may form a ring, or may be partially reduced.
  • heteroaryl is a 5- to 14-membered ring group containing one or more heteroatoms such as nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms as ring-constituting atoms. They may be monocyclic or polycyclic or partially reduced.
  • examples include zolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, phenazinyl, tetrazolyl, oxadiazolyl, imidazole, 1,3 dioxadanyl, 4 oxachromal, and the like.
  • These heteroaryl groups may have one or two or more substituents, but the substitution position is not particularly limited, and any ring may be substituted in the case of polycyclic.
  • R 2 and R 3 and the adjacent carbon atoms may be condensed with aryl (herein, "aryl” is as defined above). It may be partially reduced.
  • the ring contains one or more hetero atoms such as nitrogen atom, oxygen atom, sulfur atom, etc., and may be a heteroaryl (herein, “heteroaryl” has the same meaning as above).
  • heteroaryl has the same meaning as above.
  • a ring in which a part of heteroaryl is reduced is also included.
  • the alkoxy moiety is the above-mentioned “a”. Synonymous with “lucoxy group”.
  • Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbon group, and a tertiary butoxycarbonyl group.
  • An acylamino group is one in which the acyl group has the same meaning as the above-mentioned “acyl”. Furthermore, alkylsulfonylamino-substituted arylamino is also included in the acylamino, and “alkyl” and “aryl” here are as defined above. Examples of the acylamino group include acetamide, benzamide and the like.
  • the alkylene group represents an alkylene having 1 to 10 carbon atoms, preferably 1 to 2 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, otatamethylene, nonamethylene, decamethylene. Etc.
  • allyl alkyl has the same meaning as the above-mentioned “aryl group”, and the alkyl part is a linear or branched carbon number of 1 to 12, preferably 1 to 3. Is an aryl alkyl.
  • arylalkyl include benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthenoremethinole, 2- (1naphthinore) ethinore, 2-naphthinoremethinole, 2- (2-naphthinore) ethyl.
  • the substitution position that may have one or more substituents is not particularly limited.
  • the heteroaryl alkyl group has the same heteroaryl moiety as the above-mentioned “heteroaryl group”, and the alkyl moiety has a linear or branched carbon number of 1 to 12, preferably 1. It is a heteroaryl alkyl which is an alkyl of ⁇ 3.
  • heteroarylalkyl examples include 2 pyridylmethyl, 3 pyridylmethyl, 4 pyridylmethyl, 2 cenylmethyl, 3 cenylmethyl, 2 furylmethyl, 3 furylmethyl, 2 pyrrolylmethyl, 3 pyrrolylmethyl, 3- virazolylmethyl, 4-virazolylmethyl, 5 —Vyrazolylmethyl, 2 imidazolylmethyl, 4 imidazolylmethyl, 5 imidazolylmethyl, 2 oxazolylmethyl, 4 oxazolylmethyl, 5—oxazolylmethyl, 3-isoxazolylmethyl, 4 isoxazolylmethyl, 5-isoxazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 5-thiazolylmethyl, 3-isothiazolylmethyl, 4-isothiazolylmethyl, 5-isothiazolylmethyl, 2- (2-pi Lysyl) ethyl, 2- (3 pyridyl) e
  • a substituted rubamoyl group is a lower alkyl having 1 to 3 carbon atoms and may be a mono- or di-substituted rubamoyl group, for example, Examples include carbamoyl, methylcarbamoyl, ethylcarbamoyl, and dimethylcarbamoyl.
  • an aryloxy group is an aryloxy group in which the aryl moiety is synonymous with the “aryl group”.
  • Examples of the aryloxy group include phenoxy and the like.
  • An arylalkyloxy group is an arylalkyl group in which the aryl alkyl group is synonymous with the aforementioned “aryl alkyl”. It is a xy group. Examples of arylalkyloxy groups include benzyloxy and the like.
  • substituents in “may have a substituent!” include an alkyl group, an alkyl group, an alkyl group, and the same definition as described above.
  • R 13 has the same meaning as above. ), R 13 0 (CH) 0 (CH) 0 (CH) (where j, k, 1, R 13 are the previous
  • Examples of the amide derivative represented by the general formula (1), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include:
  • R 3 s are the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, an alkyl group which may have a substituent, Cycloalkyl group, optionally substituted alkoxy group, optionally substituted acyloxy group, halogen atom, hydroxyl group, nitro group, cyano group, acyl group, mercapto group, alkylthio group, alkyl Represents a sulfol group, an amino group, an alkylamino group, a dialkylamino group, a cyclic amino group, a strong rubamoyl group, an alkoxycarbo group, a carboxyl group, a tetrazolyl group, an oxadiazolyl group, a sulfamoyl group or a haloalkyl group
  • a, b, c, d, e are all carbon atoms or 1 or 2 of a, b, c, d, e are nitrogen atoms, and the rest are carbon atoms,
  • R 4 , R 5 and R 6 may be the same or different and each may have a hydrogen atom, an alkyl group which may have a substituent, an alkyl group which may have a substituent, or a substituent.
  • A represents a hydrogen atom, a cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group or a cyclic amino group which may have a substituent,
  • W 2 is the same or different and each represents an alkylene (C 1) (wherein n represents an integer of 1 to 3) which may have a bond or a substituent;
  • X represents an oxygen atom or a sulfur atom
  • Y is a bond, oxygen atom, —CO—, —N (R 7 ) (wherein R 7 represents a hydrogen atom or an optionally substituted alkyl group), —SO — (formula M represents an integer of 0 to 2), C m ON (R 8 )-(wherein R 8 represents a hydrogen atom or an alkyl group which may have a substituent.) Or — N (R 9 ) CO— (wherein R 9 is a hydrogen atom or a substituent An alkyl group which may have a group).
  • R 2 and R 3 are the same or different and are preferably a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group, more preferably a hydrogen atom, an alkyl group having 2 to 4 carbon atoms. Or an alkoxy group having 2 to 4 carbon atoms, more preferably a hydrogen atom, an alkyl group having 2 to 4 carbon atoms, or a methoxy group.
  • R 1 is preferably an alkyl group having 2 to 4 carbon atoms or an alkoxy group having 2 to 4 carbon atoms.
  • R 2 and R 3 are preferably a hydrogen atom.
  • R 4, R 5, R 6 in the general formula (1) is a hydrogen atom, an optionally substituted alkyl group, an alkoxy group which may have a substituent
  • alkyl groups which may have substituents
  • alkoxy groups which may have substituents
  • acyloxy groups which may have substituents
  • halogen atoms hydroxyl groups, amino groups, alkylamino groups, dialkyls
  • an aryl group which may have a substituent or a heteroaryl group which may have a substituent is preferable, and a substituent may be more preferable.
  • Phenyl, optionally substituted pyridyl, optionally substituted pyrazolyl, optionally substituted! /, Thiazolyl, optionally substituted, oxazolyl It may be a group or a substituent, and is a chenyl group, and more preferably a substituent, a phenyl group or the following formulas (Aa) to (Ac):
  • R 1Q represents a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a cycloalkyl group.
  • R 10 ⁇ 1 and R 12 are the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
  • R 1Gb may have a hydrogen atom, a substituent, an alkyl group, or a substituent! A cycloalkyl group, an aryl group that may have a substituent, or a substituent.
  • a nitrogen-containing heterocyclic group selected from the group consisting of
  • b, c, d, and e in the general formula (1) all are preferably carbon atoms, or b (or d) is a nitrogen atom, and the rest are carbon atoms.
  • R 2 and R 3 are the same or different and each is a hydrogen atom, an alkyl group having 2 to 4 carbon atoms or an alkoxy group having 2 to 4 carbon atoms,
  • R 4 , R 5 and R 6 are the same or different and each represents a hydrogen atom, a methoxy group, a halogen atom or a hydroxyl group,
  • R 10 ⁇ 1 and R 12 are the same or different and each represents a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
  • R 1 () b has a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent.
  • a nitrogen-containing heterocyclic group selected from the group consisting of
  • X is an oxygen atom
  • W 1 — Y— W 2 is one (CH 2 ) — or one (CH 2) —.
  • X in the general formula (1) is preferably an oxygen atom.
  • Wi—Y—W 2 in general formula (1) one (CH 2) or one (CH 2) — is preferred.
  • Z in the general formula (1) is preferably CH—.
  • N [(2,6 Dimethoxypyridine 1-yl) methyl] -5 Hydroxy 1 N— (4-Isopropylpyrrole) 1 1,2,3,4-Tetrahydronaphthalene 1-carboxamide ,
  • N [((1 ethylvirazole 4-yl) methyl] 5 hydroxy-1 N— (6 —isopropylpyridine 1-3-yl) 1, 2, 3, 4-tetrahydronaphthalene 1-carboxamide has its optical activity.
  • (1S)-(-)-N-[(1-Ethylvirazol-4-yl) methyl] -5 hydroxy-1-N- (6-isopropylpyridine-1 3 as described in Example 3 of WO2006Z082975 —Yl) 1, 2, 3, 4-tetrahydronaphthalene 1-carboxamide is preferred.
  • Examples of the pharmaceutically acceptable salt of the compound of the general formula (1) include a salt with an inorganic acid, a salt with an organic acid, a salt with a metal, and a salt with an organic base.
  • a solvate for example, hydrate of a compound of the general formula (1) or a salt thereof, is metabolized in vivo and converted to the compound of the general formula (1). It also includes prodrugs or active metabolites of compounds of general formula (1).
  • optically pure antipodes, diastereomers, or mixtures of these forms are also included.
  • a part of the compound of the general formula (1) of the present invention may be prepared by using an acid (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, Methanesulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, benzoic acid, citrate, malic acid, mandelic acid, p-toluenesulfonic acid, acetic acid, succinic acid, malonic acid, lactic acid, salicylic acid, gallic acid, picric acid , Carbonic acid, ascorbic acid, trifluoroacetic acid, tartaric acid, etc.), alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), metals such as aluminum and organic bases (piperidine, Perazine, morpholine, diethanolamine, ethylenediamine, etc.) to form a salt.
  • an acid hydroochloric acid, sulfuric acid, hydrobromic acid
  • the obtained crystal of the compound of the general formula (1) when it is not a solvate or the like, it can be converted into a solvate by treating the compound with water, a hydrous solvent or another solvent.
  • Compound having C5a receptor antagonistic activity of the present invention (preferably an amide derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof, and the like ) Inhibits bone resorption by inhibiting osteoclast differentiation It is useful as an agent for preventing and treating osteoporosis.
  • the compound having a C5a receptor antagonistic activity of the present invention is used for the above-described prevention 'treatment, it is usually administered systemically or locally in an oral or parenteral form.
  • the dose to patients depends on age, weight, sex, general health condition, therapeutic effect, diet, administration time, administration method, excretion rate, combination of drugs, and the degree of disease being treated. In general, take 1 to several times a day, orally, in the range of 0.1 mg to 500 mg per adult per person, or 0. Olmg to 200 mg per adult, per day. It is desirable to administer parenterally several times (preferably intravenously) once.
  • the dose may vary depending on various conditions. Therefore, when V or an amount smaller than the above dose is sufficient, administration beyond the above range may be necessary.
  • the compound having a C5a receptor antagonistic action can be used orally or parenterally (for example, inhalation, rectal injection, or topical administration), and can be used as a pharmaceutical composition or formulation (for example, powder, granule) , Tablets, pills, capsules, syrups, elixirs, suspensions, solutions, etc.), and they contain at least one compound having C5a receptor antagonism alone or as a medicament. It can be used by mixing with an acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent and / or solubilizing agent).
  • an acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent and / or solubilizing agent.
  • the pharmaceutical composition can be formulated according to a conventional method.
  • parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion method, and the like.
  • injectable compositions such as sterile injectable suspensions or oily suspensions can be prepared by methods known in the art using suitable dispersing agents, wetting agents or suspending agents. .
  • Examples of the solid composition for oral administration include tablets, pills, capsules, powders, granules and the like.
  • one or more active compounds can be mixed with at least one additive.
  • the above composition may contain further additives, such as a lubricant, a preservative, an antioxidant, a disintegrant, a stabilizer, a solubilizer, a binder, a thickener, It may contain a sweetening agent, a flavoring agent, a perfume agent and the like.
  • Tablets or pills may be gastric as necessary! / ⁇ may be coated with a film of an enteric substance or may be coated with two or more layers.
  • capsules of substances that can be absorbed may be included.
  • Liquid compositions for oral administration include pharmaceutically acceptable solutions, emulsions, syrups, elixirs, etc., and may contain commonly used inert diluents. Good. In addition to the inert diluent, the composition may contain adjuvants such as wetting and suspending agents, sweeteners, flavors, fragrances and preservatives. Other compositions for oral administration include sprays containing one or more active substances and formulated by methods known per se.
  • compositions for parenteral administration may contain sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous solution and suspension include distilled water for injection and physiological saline.
  • the composition may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation.
  • the injectable composition can also be used by producing a sterile solid composition and dissolving, for example, a lyophilized product in sterilized water or a sterile solvent for injection before use.
  • parenteral compositions include external solutions, ointments, coatings, suppositories and the like that contain one or more active substances and are formulated in a conventional manner.
  • Suppositories for rectal administration are drugs and appropriate nonirritating excipients such as solid at room temperature but liquid properties at the temperature of the intestinal tract, and dissolution within the rectum. It can be manufactured by mixing with substances that release drugs.
  • 50 mg of the compound of the present invention is sufficiently kneaded in a kneader with 98 mg of lactose, 45 mg of corn starch and 3 mg of hydroxypropylcellulose. Pass the kneaded material through a 200 mesh screen, dry at 50 ° C, and pass through a 24 mesh screen. Mix with 3 mg of talc and lmg of magnesium stearate to obtain tablets with a weight of 200 mg using a 9 mm diameter punch. These tablets can be sugar-coated or film-coated as necessary.
  • Test Example 1 1 C5a receptor binding test
  • vine albumin (BSA, Sigma), suspended in 0.02% NaN (pH 7.2)], then at ⁇ 80 ° C
  • the C5a binding inhibition rate (% inhibition) of the test compound is calculated using the total count value when no test compound is added, the count value when non-labeled C5a is added, and the count value when the test compound is added. The test was performed using the following formula.
  • Test Example 1 2 C5a receptor binding test
  • Test Example 2 Effects on osteoclast differentiation and maturation
  • Test Example 3 Toxicity test
  • test compounds were administered to male and female SD rats (3 animals in Z group) and gynecological monkeys (1 animal in Z group). Evaluate toxicity in the given dose.
  • male and female SD rats (6 animals in Z group) and male and female cynomolgus monkeys (2 animals in Z group) were administered repeatedly for 2 weeks to determine general condition, body weight, food intake, The toxicity of the test compound after repeated administration is evaluated using hematological tests, blood biochemical tests, organ weights, and autopsy (including histopathology) as indices.
  • Test Example 4 Evaluation of bioavailability in rats
  • test compound is administered intravenously and orally to SD female rats (5 per group), and then blood is collected over time, and the plasma drug concentration is measured using a high-performance liquid chromatograph.
  • bioavailability (BA) by the following formula.
  • a U C for oral administration Dose for intravenous administration
  • a U C Area under the plasma concentration hour curve

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Abstract

L'invention concerne un agent prophylactique et/ou thérapeutique pour l'ostéoporose. Cet agent comprend, en tant qu'ingrédient actif, un composé présentant une activité antagoniste sur le récepteur C5a, de préférence un dérivé amide représenté par la formule (1), un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou un solvate du dérivé amide ou du sel. Dans la formule (1), les symboles individuels sont tels que définis dans la description.
PCT/JP2006/322638 2005-11-14 2006-11-14 Agent therapeutique pour l'osteoporose WO2007055374A1 (fr)

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US9221832B2 (en) 2011-07-22 2015-12-29 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
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US9376380B2 (en) * 2011-12-15 2016-06-28 University of Pittsburgh—of the Commonwealth System of Higher Education Cannabinoid receptor 2 (CB2) inverse agonists and therapeutic potential for multiple myeloma and osteoporosis bone diseases
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US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
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