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WO2003101490A1 - Composition de medicament contenant un antagoniste des canaux calciques - Google Patents

Composition de medicament contenant un antagoniste des canaux calciques Download PDF

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Publication number
WO2003101490A1
WO2003101490A1 PCT/JP2003/006847 JP0306847W WO03101490A1 WO 2003101490 A1 WO2003101490 A1 WO 2003101490A1 JP 0306847 W JP0306847 W JP 0306847W WO 03101490 A1 WO03101490 A1 WO 03101490A1
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group
oxazepine
atom
formula
dihydro
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Japanese (ja)
Inventor
Masaki Hashimoto
Kazuyoshi Takahashi
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Priority to AU2003241991A priority Critical patent/AU2003241991A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention has calcium channel antagonism, and has Alzheimer's disease, psychosis, premature dementia, manic depression, migraine, lactation disorder, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia BACKGROUND OF THE INVENTION
  • the present invention relates to a pharmaceutical composition useful for treating epilepsy or obesity
  • EP 0404359 A1 discloses that 5,11-dihydrodibenzo [b, e] [1,4] thiazepine derivatives are useful as calcium channel antagonists having selectivity for the gastrointestinal tract. ing. Also, Quinn, P. et al., Brit. J. Pharmacol., 1994, 112 (Suppl.) 5 Abst. 573P and Perris et al. (Wallis, M. et al.), Brit. J. Pharmacol., 1994, U2 (S Lord 1.), Abst.
  • 574P shows that one of the above derivatives is (S) -5- [C1- (4-methoxyphenyl) ethyl] pyrrolidine-12-ylmethyl] 15,11-dihydrodiben Zo [b, e] [1, 4] discloses that thiazepine maleate has a similar effect.
  • one of the drawbacks is that these compounds do not have sufficient activity and selectivity for the gastrointestinal tract, and have an anticholinergic effect that contributes to side effects such as blood loss and mydriasis. .
  • 9733885 A1 and 991 2925 A1 disclose 5- (2-pyridinylmethyl) -5,11-dihydrodibenzo [b, e] [1,4] as an agent for improving gastrointestinal motility dysfunction.
  • An oxazepine derivative has been disclosed.
  • International Patent No. 0040570 A1 discloses that 5-alkyl-1,5,11-dihydrodibenzo [b, e] [1,4] oxo is used as an agent for improving gastrointestinal motility dysfunction.
  • Sazepine derivatives are disclosed.
  • serotonin receptor subtypes include 5-HT1 (5- ⁇ 1 ⁇ ⁇ 5-HT1B, 5-HT1 D ⁇ 5-HT1Es 5-HT1F), 5-HT2 (5-HT2A ⁇ 5-HT2B, 5-HT2C ), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6, 5-HT7, and the like.
  • the stimulatory effects of various serotonin receptors include: appetite enhancement, anorexia, anxiety 'Anxiety, depressive', antidepressant, suppression of extrapyramidal symptoms, increased sexual behavior, suppression, aggressive behavior, hypothermia, arteriovenous contraction, Pulmonary artery contraction, vasoconstriction, atrial adrenaline release, smooth muscle contraction, platelet aggregation, gastric atrophy, penile erection, analgesia, nausea, vomiting, gastrointestinal tract constriction, neurotransmitter release (noradrenaline is suppressed), memory and cognitive function Improvement, steroid secretion, cardiac arrhythmia, cardiac contractility enhancement, intestinal motility hyperactivity, acetylcholine release, sleep cycle, pain, bronchial relaxation, memory impairment, dysrhythmia, aldosterone secretion, coronary vasodilation, vascular relaxation, hypotension, Colonic relaxation, tachycardia, etc.
  • the present invention treats Alzheimer's disease, mental illness, premature dementia, manic depression, migraine, lactation, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or obesity. To provide an excellent pharmaceutical composition for the same.
  • the present invention treats Alzheimer's disease, mental illness, premature dementia, manic depression, migraine, lactation, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or obesity.
  • a pharmaceutical composition containing a calcium channel antagonist having intestinal selectivity containing a calcium channel antagonist having intestinal selectivity.
  • the present invention also provides a serotonin release inhibitor containing a calcium channel antagonist having intestinal selectivity.
  • FIGS. 1 and 2 show the effect of the test compound on serotonin released from the isolated intestinal tract of mice.
  • calcium channel antagonist as the active ingredient of the present invention, a drug that acts on calcium channels present in skeletal muscle, cardiac muscle, vascular smooth muscle, brain, endocrine and kidney and inhibits influx of potassium is used. can do.
  • calcium channel antagonists having intestinal selectivity are preferred.
  • the calcium channel antagonist having intestinal selectivity refers to a compound having a calcium channel antagonistic activity whose antagonistic action on calcium channels present in the intestinal tract is stronger than that of calcium channels present in cardiac blood vessels. Further, it preferably has a serotonin release inhibitory action.
  • Examples of the “calcium channel antagonist having intestinal selectivity” used in the present invention include compounds represented by the following (I) to (V) or pharmaceutically acceptable salts thereof.
  • rings G, J, and K each represent a benzene ring or a nitrogen-containing aromatic ring.
  • R 1 R 8 may be the same or different, and represent a halogen atom or a hydrogen atom
  • R 9 to R 13 may be the same or different
  • a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower group Represents an alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group and a lower acyl group thereof, a lower dialkylamino group, a cyclic alkylamino group, or R 9 and R 1 () , or R 1Q and R 11 Connected together 0 (CH 2 ) n
  • 0— represents a group (n is 1, 2 or 3).
  • A is any of CH 2 , CHOH, C ⁇ , or 0,
  • B is CH 2 , CHOH, or CO, or
  • D is CH 2 , CH 2 —CH 2 Or CH 2 — CH 2 — CH 2 — CH 2 , or BD represents CH 2 .
  • X and Z are joined to each other CH 2 - CH 2 or CH 2 - CH 2 - represents either CH 2
  • Y represents a hydrogen atom at that time.
  • Y and Z are joined to each other CH 2 - CH 2 - CH 2 or CH 2 - CH 2 - CH 2 - CH 2 - CH 2 , whichever is represents, X at that time represent a hydrogen atom.
  • any of R 9 to R 13 is a cyclic amino group represented by the formula [E]
  • any of R 1 to R 8 may be a halogen atom or a hydrogen atom
  • any of H 9 to R 13 also within the case is not cyclic amino group represented by the formula [E] is 1 ⁇ to 11 8 or 1 connected to 2 Tsugano the other a mouth Gen atoms denote the hydrogen atom.
  • n and m represent 1 or 2
  • W represents a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom which may be substituted with a lower alkyl group.
  • k, m and n are 1, 2 or 3, respectively;
  • P is 0, 1 or 2;
  • X is 0, S or a linking group; when X is 0 or S, n is 2 or 3; R 1 is H or —C 4 alkyl; and
  • R 4 are each independently H, C—C 4 alkyl, d—C 4 alkoxy, —OH, —NiCi—C 4 alkyl) 2 , halo, or —CF 3 .
  • X 1 and X 2 are each independently selected from ⁇ and —CH 2 —), or
  • 1 ⁇ to 15 may be the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a lower alkylamino group.
  • R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 together form a (CH 2 ) nO— group (n is 1, 2 or 3)
  • R 6 represents hydrogen or a lower alkyl group
  • Y represents a methylene, oxygen atom, zeo atom, or alkylamino group
  • A represents any of CH 2 , CHOH, CO or 0, and B represents CH 2 , represents either CHOH or CO, or
  • D represents either CH 2 , CH 2 —CH 2 or CH 2 —CH 2 —CH 2 , or ⁇ '— D represents CH 2.
  • the oxazepine derivative represented by the general formula [I] is disclosed in WO 02/096991 A1, which was published after the priority date of the present application. Are all included in this specification.
  • a 6-membered ring is desirable, and examples thereof include a pyridine ring, a pyrimidine ring, a virazine ring, and a pyridazine ring.
  • ⁇ 0, J there is no aromatic ring nitrogen atom on the oxazepine ring, and when any of 1 ⁇ to 18 is a halogen atom, the halogen atom is replaced with the aromatic ring nitrogen atom. Does not combine.
  • ring K the aromatic ring nitrogen atom does not bond to A and has no substituent on the nitrogen atom.
  • halogen atom of 1 to! ⁇ examples include a fluorine atom, a chlorine atom, a bromine atom and the like, and a fluorine atom or a chlorine atom is preferable.
  • Ri ⁇ R 8 any one of R ⁇ R 7 is a full Uz atom or a chlorine atom, and more preferably other is a hydrogen atom.
  • Examples of the halogen atom of R 9 to R 13 include a fluorine atom, a chlorine atom, a bromine atom, and the like.
  • Examples of the lower alkyl group include a methyl group, an ethyl group, a lower alkyl group having 1 to 5 carbon atoms such as a propyl group
  • Examples of the lower alkoxy group include a lower alkoxy group having 1 to 5 carbon atoms such as a methoxy group, an ethoxy group, and a propoxy group
  • examples of the lower alkylamino group include a carbon atom such as a monomethylamino group, a monoethylamino group, and a monopropylamino group.
  • Examples include lower alkylamino groups of the numbers 1 to 5. Amino groups and lower acyl forms of these lower alkylamino groups; Formylamino, acetylamino, propionylamino, formylmethylamino, formylethylamino, formylpropylamino, acetylmethylamino, acetylethylamino, acetylpropylamino, Examples thereof include fatty acid acyl groups having 1 to 3 carbon atoms, such as a pionylmethylamino group, a propionylethylamino group, and a propionylpropylamino group.
  • dialkylamino group examples include a lower alkylamino group having a total of 2 to 7 carbon atoms such as a dimethylamino group, a acetylamino group, and a methylethylamino group.
  • cyclic alkylamino group examples include an azetidino group, a pyrrolidino group, a piperidino group, and a homopiperidino group.
  • 4- to 7-membered amino group such as a piperazino group and a morpholino group, and a 10 (CH 2 ) ⁇ - group include a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group.
  • a fluorine atom and a chlorine atom are preferable as the halogen atom, and a lower alkyl group having 1 to 3 carbon atoms is preferable as the lower alkyl group.
  • a lower alkoxy group a lower alkoxy group having 1 to 3 carbon atoms is preferable.
  • the monoalkylamino group is preferably a lower alkylamino group having 1 to 3 carbon atoms
  • the dialkylamino group is preferably one having a total of 2 to 6 carbon atoms in the alkyl group.
  • the cyclic alkylamino group is preferably one having 4 to 6 ring members.
  • a formyl group such as a formyl group is preferred.
  • R 9 to R 13 are not simultaneously hydrogen atoms.
  • R 10 s R 11 are methoxy groups, or R lfl and R 11 together represent a methylenedioxy group, and R 9, R 12 and R 13 are water Elementary atom,
  • R 11 is a methoxy group
  • R 9 , R and R 12 , R 13 are a hydrogen atom
  • R 1 Q and R 11 are an amino group or a lower alkylamino group and a lower acyl group thereof, a lower dialkylamino group or a cyclic alkylamino group, and the other is a hydrogen atom,
  • one of R 1 to R 8 is a fluorine atom or a chlorine atom, and the other is a hydrogen atom
  • R ⁇ RR 6 and R 7 are a fluorine atom or a chlorine atom, the other is a hydrogen atom,
  • Examples of the cyclic amino group represented by the formula [E] include a azetidino group, a pyrrolidino group, a pyridino group and the like containing one nitrogen atom, a piperazino group, a morpholino group, a nitrogen atom, an oxygen atom, and the like.
  • Examples thereof include a cyclic amino group containing a heteroatom atom, and preferred are a pyrrolidino group and a morpholino group.
  • R 9 to R ′′ it is more preferable that one of R 1 () and R 11 is a cyclic amino group and the other is a hydrogen atom.
  • preferred compounds are, for example, compounds represented by the following formula [II].
  • the aromatic ring G, J, K, ⁇ 3 , A, B, D represent the same as the formula [I]
  • r is representative of 1 or 2.
  • Examples of the compound represented by [II] include 2-fluoro-5,11-dihydric 5- (1- (4-methoxyphenethyl) pyrrolidine-12-ylmethyl) dibenzo [b, e [1,4] oxazepine, 2-fluoro-5,11-dihydro-1- [1- (3-methoxyphenethyl) pyrrolidine-12-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2- Fluoro-5,11-dihydro-1-5- [1-1 (3,4-methylenedioxyphenethyl) pyrrolidine-1-2-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluoro-5,11 —Jihid Mouth 5- [1-1- (4-aminophenethyl) pyrrolidine-1-ylmethyl] dibenzo [b, e] [1,4] oxazepine, 2-fluor
  • the compound [II] that can be used in the present invention has one or more asymmetric carbon atoms, and may have optical isomers. These optical isomers, those Any mixtures or racemates are included in the compounds of the present invention. Among them, it is preferable that the configuration at the 2-position of the pyridine ring or the pyridine ring bonded to the dihydroxybenzoxazepine ring via methylene is R-form.
  • the aromatic rings G, J, K, R′-R 13 , A, B, and D represent the same as in the formula [I], and r represents 1 or 2.
  • the compound represented by the formula [III] include, for example, 2-fluoro-5,11-dihydro-1-5- [1- (4-methoxyphenethyl) pyrrolidine-13-yl] dibenzo [b, e] [1,4] oxazebine, 2-fluoro-5,11-dihydro-5- [1- (3-methoxyphenethyl) pyrrolidine-3-yl] dibenzo [b, e] [1 , 4] oxazepine, 2-fluoro-5,11-dihydro-1-5- [1-1- (3,4-methylenedioxyphenethyl) pyrrolidin-13-yl] dibenzo [b, e] [1,4 Oxazepine, 2-fluoro-5,11-dihydro-5- [1- (4-me
  • the compound [III] that can be used in the present invention has one or more asymmetric carbon atoms, and may have optical isomers. These optical isomers, arbitrary mixtures or racemates thereof are included in the compounds of the present invention. Among these, it is preferable that the configuration at the 2-position of the pyrrolidine ring or the piperidine ring bonded to the dihydrodibenzoxazepine ring is R-form.
  • Examples of the compound represented by the formula [IV] include 2-fluoro-5,11-dihydro-5- ⁇ 2- [N- (4-methoxyphenethyl) -1-N-methyl] aminoethyl ⁇ dibenzo [ b, e] [1, 4] oxazebine, 2-fluoro-5,11-dihydro-5- ⁇ 2- [N- (3-methoxyphenethyl) -N-methyl] aminoethyl ⁇ dibenzo [b, e [1, 4] oxazepine, 2-fluoro-5,11-dihydro-5- ⁇ 2- [N- (3,4-methylenedioxyphenethyl) -1-N-methyl] aminoethyl ⁇ dibenzo [b , e] [1,4] oxazepine, 2-fluoro 1,5-dihydro-5- ⁇ 2- [N- (4-aminophenethyl) -1-N-methyl] aminoethyl ⁇ dibenzo
  • R 9 to R 13 is a cyclic amino group represented by the formula [E], the other is a hydrogen atom, and all of Ri R 8 are a hydrogen atom A derivative of the formula [I],
  • one of R 9 to R 13 is a linear amino group represented by the formula [E], the other is a hydrogen atom, and one of R 1 to R 8 One or two is a fluorine atom or a chlorine atom, Other represents derivatives of the formula [I] is a hydrogen atom, a (iii) none of R 9 to R 13 is other than cyclic Amino groups Table by formula [E] group, R 1 ⁇ : 1 of R 8 A derivative of the formula [I] in which one or two are a fluorine atom or a chlorine atom and the other is a hydrogen atom is preferred.
  • Examples of the pharmacologically acceptable salt of the compound [I] that can be used in the present invention include mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate and phosphate, and acetic acid. Organic salts such as salts, lactate, fumarate, maleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate can be mentioned.
  • the compound represented by the formula [II] is, for example, according to the method disclosed in International Patent No. 9733885A1 It can be produced by the following method (reaction formula 1). Note that the entire contents of this patent document are included in this specification.
  • aromatic rings G, J, K, R 1 to: 13 , A, B, and D are the same as those in the formula (I), r represents 1 or 2, W is a chlorine atom, a bromine atom, Represents a halogen atom such as an iodine atom. ]
  • compound [II] usable in the present invention By reacting compound [V] with a compound represented by the above general formula [VI] in a solvent in the presence of a base, compound [II] usable in the present invention can be produced.
  • the reaction solvent in the above reaction include amides such as dimethylsulfoxide, N, N-dimethylformamide, ethers such as tetrahydrofuran, dimethyl ether, dioxane, 1,2-dimethoxyethane, etc., acetonitrile, toluene and xylene. , Benzene and the like can be suitably used.
  • Examples of the base include sodium carbonate, potassium carbonate, sodium hydrogen hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide, and potassium pentoxide.
  • the reaction temperature is usually 0 ° C to 150 ° C, preferably Is carried out at room temperature to 10 oc.
  • the reaction time depends on the reaction temperature and the type of solvent, but usually:! ⁇ 50 hours.
  • the amount of the compound [VI] and the base to be used is 0.5 to 5 molar equivalents, preferably 0.8 to 2 molar equivalents, based on the amount of the compound [V] used, respectively.
  • the compound [V] used as a starting material for the reaction can be produced by a known method [J. Med. Chem., ⁇ , 609 (1964)].
  • the halide represented by the general formula [VI] can be reduced by using proline and homoproline as raw materials in accordance with the method disclosed in EP 0 440 359 A1. N-alkylation of the resulting alcohol, followed by halogenation of the hydroxyl group with methanesulfonyl chloride, tosyl chloride, etc., enables the production with ring expansion. Note that the entire contents of this patent document are included in this specification. 'Further, the compound [II] which can be used in the present invention can also be produced by the following method (reaction formula 2) according to the method disclosed in International Patent No. 9912925A1. . Note that the entire contents of this patent document are included in this specification.
  • the compound [V] is reacted in the presence of a base by dropwise addition of Nt-butoxycarbonyl-12-piperidylmethyl tosylate represented by the above general formula [VII], and the compound of the general formula [VIII] is reacted.
  • the compound is then prepared and then deprotected to give a compound of the general formula [IX], and the compound of the general formula [X] is reacted in the presence of a base to give a compound [II] which can be used in the present invention.
  • the reaction solvent and base from [V] to [VIII] and from [IX] to [II] the same solvents and bases as those in the above Reaction Formula 1 can be used.
  • the compound represented by the formula [III] can be prepared, for example, according to the method disclosed in International Patent Application No. (Reaction formula 3). The contents of this patent document are all included in this specification.
  • aromatic rings K, R 9 to R 13 , A, B, D, V and r represent the same as those in Reaction Scheme 2.
  • compound [III] usable in the present invention By reacting compound [V] with a compound represented by the above general formula [XI] in a solvent in the presence of a base, compound [III] usable in the present invention can be produced.
  • the reaction solvent in the above reaction include amides such as dimethyl sulfoxide, N, N-dimethylformamide, ethers such as tetrahydrofuran, dimethyl ether, dioxane, 1,2-dimethoxyethane, etc., acetonitrile, toluene, xylene , Benzene and the like can be suitably used.
  • Examples of the base include sodium hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide, potassium t-butoxide and the like.
  • the reaction temperature is usually in the range of 0 ° C to 150 ° C, preferably room temperature to 100 ° C.
  • the reaction time varies depending on the reaction temperature or the type of the solvent, but is usually 1 to 50 hours.
  • the amount of the compound [XI] and the base used is based on the amount of the compound [V] used. And 0.5 to 10 molar equivalents, preferably 0.8 to 5 molar equivalents.
  • the compound represented by the above general formula [XI] reacts N-alkylated 3-hydroxypyrrolidine and 3-hydroxypiperidine, and then acts on oxyphosphorus chloride, thionyl chloride, tosyl chloride, methanesulfonyl chloride, and the like. Can be obtained.
  • the compound represented by the formula (IV) is, for example, according to the method disclosed in International Patent Application No. It can be produced by the following method (Reaction Scheme 4).
  • aromatic rings G, J, K, 3 , A, B, D and V are the same as described above, and R 14 represents a lower alkyl group.
  • the compound [V] is converted to a compound represented by the above general formula [XII], and reacted with the compound of the general formula [XIII] in the presence of a base.
  • the reaction solvent in this reaction include amides such as dimethyl sulfoxide and N, N-dimethylformamide, ethers such as tetrahydrofuran, getyl ether, dioxane, 1,2-dimethoxyethane, acetonitrile, toluene, Xylene, benzene, etc. can be suitably used.
  • Examples of the base include sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide, and potassium t-ptoxide.
  • the reaction temperature is usually in the range of 0 ° C. to 150 ° C., preferably in the range of room temperature to 100 ° C.
  • the reaction time varies depending on the reaction temperature or the type of the solvent, but is usually 1 to 50 hours.
  • the amount of the base to be used is 1 mol or more, preferably 1 to 5 mol, per mol of the compound [XII], and the ratio of the compound [XII] to [XIII] is 0.5 to 2 mol, preferably. Or 0.7 to 1.5 times.
  • the compound [V] is converted to a compound represented by the general formula [XIV], and then condensed with the compound [X] in the presence of a base to produce a compound [IV] that can be used in the present invention.
  • a base to produce a compound [IV] that can be used in the present invention.
  • the amount of the base to be used is equimolar or more, preferably 1 to 5 moles, relative to compound (XIV), and the ratio of the compounds (XIV) to (X) is 0.5 to 2 moles, preferably It is 0.7 to 1.5 times.
  • Compound [XII] is obtained by alkylating compound [V] with a monohaloacetic acid ester and reducing it to an alcohol, and further converting the hydroxyl group to a leaving group, or using a 2-haloethanol having a protected hydroxyl group. It can be easily produced by combining known methods such as alkylating the conjugated product [V] and converting the hydroxyl group to a leaving group after deprotection.
  • Compound (XIII) is disclosed in International Patent Application No. Various reactions such as alkylation reaction of primary amine with corresponding halide, reductive alkylation reaction of primary amine with corresponding aldehyde, reduction of amine after acylation with corresponding carboxylic acid, etc. It can be easily manufactured by a known method.
  • the compound [XIV] can be prepared by various known methods such as alkylation of the compound [V] with a haloacetate ester followed by amidation and reduction as disclosed in International Patent Publication No. It can be easily manufactured by the method described above.
  • the compound represented by the formula [II] or the formula [IV] is described in International Patent Publication No.
  • the compound can be produced via a compound represented by the following formulas [XVI] and [XV] by a method similar to the method described in (1). That is, when the compound represented by the formula (II) is represented by the formula (11-1), and the compound represented by the formula (IV) is represented by the formula (IV-1), these are represented by the formula (XVI) according to the reaction formula 5.
  • the compound represented by the formula is converted into an intramolecular aryl to obtain the compound represented by the formula [XV], and then reduced to obtain the corresponding intermediate.
  • examples of the reaction solvent in the present reduction reaction include ethers such as getyl ether, dioxane, tetrahydrofuran, and 1,2-dimethoxyethane.
  • the solvent may contain 0 to 50% of benzene, toluene, xylene and the like.
  • Examples of the reducing agent include diborane, borane ammonia complex, borane-tert-butylamine complex, borane-N, N-getylaniline complex , Borane N, N-diisoprovirethylamine complex, borane dimethylamine complex, borane 4- (dimethylamino) pyridine complex, borane diphenylphosphine complex, borane 4-ethyl morpholine complex, borane 1-2, 6-lutidine complex, borane 4-methyl morpholine complex, borane dimethyl sulfide complex, porane morpholine complex, borane-1,4-oxathiane complex, borane 1-4-phenylmorpholine complex, borane pyridine complex, borane tetrahydrofuran complex, borane triptyl Borane compounds such as phosphine complexes, borantrietylamine complexes, boranetrimethylamine complexe
  • a reducing agent may be prepared in a reaction vessel by adding an acid or the like to these metal hydrides.
  • the acids used herein include, for example, Bronsted acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesnoleic acid, paratoluenesulfonic acid, camphorsulfonic acid, acetic acid, and trifluoroacetic acid; boron trifluoride; Examples thereof include Lewis acids such as boron chloride and aluminum trichloride and complexes thereof.
  • reducing agents for example, a method using diborane, borane tetrahydrofuran complex or the like, or adding a methanesulfonic acid, boron trifluoride and a complex thereof to sodium borohydride to prepare a reducing agent in a reaction vessel.
  • the production method can be suitably used.
  • the reaction temperature depends on the boiling point of the solvent, but is usually 5 ° C to 100 ° C, preferably 30 ° C! It is carried out in the range of up to 60 ° C.
  • the reaction time varies depending on the type of the reducing agent, the reaction temperature or the type of the solvent, but is usually 4 to 70 hours.
  • the amount of the reducing agent used depends on the type of the reducing agent, but the amount of hydride that can be generated is 4 times or more, preferably 7 times or more.
  • the compound [11-1] or compound [IV-1] obtained by the reaction can be purified by silica gel column chromatography or crystallization.
  • compound [11-1] or compound [ IV-1] may be obtained by crystallization in the form of a salt with an appropriate acid.
  • the salt with an appropriate acid include mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate, phosphate, and nitrate, and acetate, lactate, fumarate, and maleate.
  • Organic acid salts such as acid, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate.
  • Compound [XV] used as a raw material for the reduction reaction can be produced by subjecting compound [XVI] to intramolecular arylation with a metal catalyst in the presence of a base.
  • the reaction solvent in this reaction includes, for example, benzene and its substituted product, pyridine and its substituted product, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone And amides.
  • these reaction solvents for example, toluene, pyridine, picoline, N-methylpyrrolidone and the like can be suitably used.
  • Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate, metal alkoxides such as sodium methoxide, sodium t-butoxide and potassium t-butoxide, trimethylamine, Examples include amines such as triethylamine, diisopropylethylamine, and N-methylmorpholine.
  • carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate
  • metal alkoxides such as sodium methoxide, sodium t-butoxide and potassium t-butoxide
  • trimethylamine examples include amines such as triethylamine, diisopropylethylamine, and N-methylmorpholine.
  • sodium carbonate, potassium carbonate, cesium carbonate and the like can be suitably used.
  • the metal catalyst examples include copper, copper catalysts such as copper chloride (I), copper bromide (I), copper iodide (I), palladium, palladium chloride, palladium acetate, and tetrakis (triphenylphosphine).
  • Palladium catalysts such as palladium or complexes thereof, or platinum catalysts such as platinum and platinum chloride and complexes thereof.
  • copper, copper (I) bromide and the like can be suitably used.
  • These metal catalysts may also be prepared in a reaction vessel. The reaction temperature depends on the boiling point of the solvent,
  • the reaction time varies depending on the type of the base or metal catalyst, the reaction temperature or the type of the solvent. But usually 8 to 200 hours.
  • the amount of the base to be used varies depending on the kind thereof, but is usually 1 to 10 mol, preferably 1 to 4 mol.
  • the amount of the metal catalyst to be used varies depending on the kind thereof, but is usually 0.001 times to 1 times, preferably 0.005 times to 0.2 times the mole.
  • the compound [XV] obtained by the reaction can be extracted from the reaction solution, purified by silica gel column chromatography or crystallization, and used in the next reaction, or can be used as it is in the next reaction.
  • the present compound [XV] may be obtained in the form of a salt with an appropriate acid.
  • the salt with an appropriate acid includes, for example, mineral salts (inorganic salts) such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, fumarate, Organic acid salts such as oleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate can be mentioned.
  • the compound [XVI] used as a starting material for the intramolecular arylation reaction can be produced by the following method (reaction formula 6).
  • compound [XVI] can be produced by condensing compound [XVII] and compound [XVIII].
  • the condensation reaction refers to, for example, an amidation reaction using N, N, -dicyclohexylcarbodiimide or N-dimethylaminopropyl-N, -ethylcarbodiimide or a salt thereof, or the compound [XVIII] being acid anhydride.
  • the method can be selected from known methods such as an acid anhydride method of condensing after that, and a method via an acid chloride or acid bromide of compound [XVIII].
  • the compound [XVI] obtained in the reaction can be extracted from the reaction solution, purified by silica gel column chromatography, or purified by crystallization, etc., and used in the next reaction, but can also be used as it is in the next reaction.
  • the present compound [XVI] may be obtained in the form of a salt with an appropriate acid.
  • the salt with an appropriate acid include, for example, mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate, phosphate, and nitrate, acetate, lactate, fumarate, and maleate.
  • Organic acid salts such as phosphate, malate, tartrate, citrate, oxalate, aspartate, and mesylate sulfonate.
  • Compound [XVIII] can be produced by the following method (reaction formula 7).
  • aromatic rings K, R 9 to R 13 , Lj and L 2 are the same as above, and Y and Z are bonded to each other to form CH 2 —CH 2 —CH 2 or CH 2 —CH 2 — CH 2 — represents CH 2 , or When Y and Z do not bond to each other, Y represents a hydrogen atom, and Z represents a lower alkyl group. ]
  • compound [XVIII] can be produced by condensing compound [XIX] and compound [XX].
  • condensation reaction with, for example, New, New '- to not hexyl carbodiimide dicyclohexyl ⁇ - dimethyl ⁇ amino propyl one New 5 - E chill carbonitrile di imide and amine de reactions and the like salts thereof, compound [XIX Is converted to an acid anhydride and then condensed, or a known method such as a method via an acid chloride or an acid bromide of compound [XIX].
  • the compound [XVIII] obtained by the reaction can be used in the next reaction by extracting the reaction solution, purifying it by silica gel column chromatography or crystallization, etc., but can also be used in the next reaction as it is.
  • Compound (XVI II) may also be produced by protecting the carboxylic acid moiety of compound (XX) with an appropriate protecting group, followed by deprotection after the same condensation reaction as described above with compound (XIX). .
  • Suitable protecting groups here include, for example, methyl, ethyl, ⁇ -propyl, is ⁇ -propyl, n-butyl, iso_butyl, tert-butyl, or an ester thereof or a substituted product thereof, trimethylsilyl, triethylsilyl, tert And silyl esters with monobutyldimethylsilyl and the like.
  • the compound represented by the formula [III] can also be produced by the following method (reaction formula 8).
  • compound [III] can also be produced by subjecting compound [XXI] to intramolecular arylation with a metal catalyst in the presence of a base.
  • the reaction solvent in this reaction include amides such as benzene and its substituted products, pyridine and its substituted products, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, and the like. And the like.
  • Examples of the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, and cesium carbonate; metal alkoxides such as sodium methoxide, sodium t-butoxide, and potassium t-butoxide; trimethylamine, triethylamine; Examples include amines such as diisopropylpyrethylamine and N-methylmorpholine.
  • Examples of the metal catalyst include copper catalysts such as copper, salted copper (I), salted copper (I), copper iodide (I), palladium, palladium chloride, palladium acetate, and tetrakis (triphenylphosphine).
  • Palladium catalysts such as palladium or complexes thereof, and platinum catalysts such as platinum and shiridani platinum and complexes thereof. These metal catalysts may also be prepared in a reaction vessel.
  • the reaction temperature depends on the boiling point of the solvent, but is usually in the range of room temperature to 200 ° C, preferably 80 ° C to: 160 ° C.
  • the reaction time varies depending on the type of the base or the metal catalyst, the reaction temperature or the type of the solvent, but is usually 5 to 150 hours.
  • the amount of the base to be used varies depending on its kind, but it is usually 1 to 20 mol, preferably 1.5 to 8 mol.
  • the amount of the metal catalyst to be used varies depending on the type thereof, but is usually from 0.1 to 1 mol, preferably from 0.005 to 0.3 mol.
  • the compound [III] obtained by the reaction can be purified from the reaction solution by extraction, silica gel column chromatography, high performance liquid chromatography or crystallization.
  • the compound [III] that can be used in the present invention may be obtained by crystallization in the form of a salt with an appropriate acid.
  • the salt with an appropriate acid include, for example, mineral salts (inorganic salts) such as hydrochloride, hydrogen bromide, sulfate, phosphate, and nitrate, and acetate, lactate, and fumarate.
  • organic acid salts such as maleate, malate, tartrate, citrate, oxalate, aspartate, and methanesulfonate.
  • Compound [XXI] used as a raw material for the intramolecular arylation reaction can be produced by alkylating an amino group of compound [XVII] with a conjugate [XI].
  • the alkylation reaction includes, for example, an alkylation reaction in the presence of a base.
  • the compound [XVII] and compound [XI] can be produced by reacting compound [XVII] and compound [XI] in an appropriate solvent in the presence of a base.
  • the base include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium methoxide, sodium t-toxide, and potassium t-toxide. Any metal alkoxides, amines such as trimethylamine, triethylamine, disopropylethylamine, N-methylmorpholine and the like can be mentioned.
  • the compound [XXI] obtained by the reaction can be extracted from the reaction solution, purified by silica gel column chromatography, etc. and used for the next reaction, but can also be used for the next reaction as it is.
  • the compound that can be used in the present invention is used as a pharmaceutical preparation or a pharmaceutical composition
  • pharmaceutically acceptable excipients, carriers, diluents, and other formulation auxiliaries are appropriately mixed, and tablets and capsules are prepared in a conventional manner. It can be administered orally or parenterally in the form of granules, fine granules, powders, pills, syrups, suspensions, emulsions, ointments, suppositories or injections.
  • a pharmaceutical preparation or a pharmaceutical composition containing the compound of the present invention as an active ingredient and a pharmaceutically acceptable carrier and / or diluent is preferable.
  • examples of the carrier and the diluent include glucose, sucrose, lactose, talc, silica, cellulose, methylcellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerin, ethanol, water and oils and fats.
  • the dose and frequency of administration of the compound that can be used in the present invention can be appropriately selected according to the type of the disease, the age and weight of the patient, and the like.
  • the pharmaceutical composition of the present invention may be used to treat Alzheimer's disease, psychosis, premature dementia, manic depression, migraine, lactation disorder, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy.
  • about 0.1 to 100 mg per day may be administered to an adult in one to several divided doses.
  • a compound represented by the following formula, a stereoisomer thereof, a pharmacologically acceptable salt thereof, and a calcium channel antagonist which is a hydrate or solvate thereof are further particularly preferred.
  • the organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in 25 ml of dichloromethane, and 712 mg (5.5 mmo 1) of diisopropylethylamine and 63 Omg (5.5 mmo 1) of methanesulfonyl chloride were added while stirring under ice cooling. The mixture was stirred for 1 hour under ice-cooling and further for 2 hours at room temperature.
  • the reaction solution was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure.
  • 3-Pyrrolidinophenetyl alcohol is dissolved in dichloromethane (20 ml), and triethylamine (3.7 ml ⁇ 26.7 mmo 1) and methanesulfone are dissolved at 0 ° C. Nyl chloride (1.9 ml, 24.5 mmol) was added and stirred overnight.
  • the reaction solution was partitioned between a 5% aqueous sodium hydrogen carbonate solution and dichloromethane. After drying the organic layer, the solvent was distilled off under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography, and eluted with hexane and ethyl acetate (7: 3). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give 3-pyrrolidininophenethyl mesylate as a white solid (5.13 g, 87%).
  • the desired product was extracted from the ethyl acetate layer with 1M hydrochloric acid, the aqueous layer was neutralized, and then extracted again with ethyl acetate. After drying the organic layer and distilling off the solvent under reduced pressure, the (S) -3-hydroxy-1- (4-pyrrolidinofe (Netyl) Pyrrolidine was obtained as a pale yellow solid (6.30 g, 52%).
  • the obtained residue is purified by silica gel column chromatography. The mixture was applied to a filter and eluted with methylene chloride and methanol (10: 1). The appropriate fractions were collected and the solvent was distilled off under reduced pressure to give the title compound as a brown solid (0.67 g, 74%) o
  • reaction solution was successively washed with water (10 ml), water (5 ml), a 5% aqueous solution of citric acid (5 ml), and a 5% aqueous solution of sodium bicarbonate (5 ml). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a pale red solid (3.06 g, 96%
  • the following mixture was mixed in a conventional manner, and the mixture was tableted to give tablets containing 50 mg of the active drug per tablet.
  • the following mixture was granulated according to a conventional method to obtain granules.
  • Alzheimer's disease dementia, manic depression, migraine, lactation disorder, dementia, autism, hypertension, glaucoma, pain, thromboembolism, arrhythmia, epilepsy or Obesity can be treated.

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Abstract

L'invention porte sur une composition de médicament comprenant un antagoniste des canaux calciques présentant une sélectivité du tractus intestinal, cette composition étant utilisée pour traiter la maladie d'Alzheimer, les maladies mentales, l'aliénation mentale des adolescents, la manie-dépression, la migraine, les troubles dus à la lactation, la démence, l'autisme, l'épilepsie ou l'obésité. L'invention porte également sur un inhibiteur de la libération de la sérotonine qui comprend un antagoniste des canaux calciques présentant une sélectivité du tractus intestinal.
PCT/JP2003/006847 2002-05-31 2003-05-30 Composition de medicament contenant un antagoniste des canaux calciques Ceased WO2003101490A1 (fr)

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WO2019191502A1 (fr) * 2018-03-29 2019-10-03 Elex Biotech, Inc. Composés pour le traitement d'arythmies cardiaques et de l'insuffisance cardiaque

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